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• Research article
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• Published: 16 November 2020

Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews

• Pawel Posadzki 1 , 2 ,
• Dawid Pieper   ORCID: orcid.org/0000-0002-0715-5182 3 ,
• Ram Bajpai 4 ,
• Hubert Makaruk 5 ,
• Nadja Könsgen 3 ,
• Annika Lena Neuhaus 3 &
• Monika Semwal 6  

BMC Public Health volume  20 , Article number:  1724 ( 2020 ) Cite this article

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Sedentary lifestyle is a major risk factor for noncommunicable diseases such as cardiovascular diseases, cancer and diabetes. It has been estimated that approximately 3.2 million deaths each year are attributable to insufficient levels of physical activity. We evaluated the available evidence from Cochrane systematic reviews (CSRs) on the effectiveness of exercise/physical activity for various health outcomes.

Overview and meta-analysis. The Cochrane Library was searched from 01.01.2000 to issue 1, 2019. No language restrictions were imposed. Only CSRs of randomised controlled trials (RCTs) were included. Both healthy individuals, those at risk of a disease, and medically compromised patients of any age and gender were eligible. We evaluated any type of exercise or physical activity interventions; against any types of controls; and measuring any type of health-related outcome measures. The AMSTAR-2 tool for assessing the methodological quality of the included studies was utilised.

Hundred and fifty CSRs met the inclusion criteria. There were 54 different conditions. Majority of CSRs were of high methodological quality. Hundred and thirty CSRs employed meta-analytic techniques and 20 did not. Limitations for studies were the most common reasons for downgrading the quality of the evidence. Based on 10 CSRs and 187 RCTs with 27,671 participants, there was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% confidence intervals (CI) 0.78 to 0.96]; I 2  = 26.6%, [prediction interval (PI) 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]. Data from 15 CSRs and 408 RCTs with 32,984 participants showed a small improvement in quality of life (QOL) standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]. Subgroup analyses by the type of condition showed that the magnitude of effect size was the largest among patients with mental health conditions.

There is a plethora of CSRs evaluating the effectiveness of physical activity/exercise. The evidence suggests that physical activity/exercise reduces mortality rates and improves QOL with minimal or no safety concerns.

Trial registration

Registered in PROSPERO ( CRD42019120295 ) on 10th January 2019.

Peer Review reports

The World Health Organization (WHO) defines physical activity “as any bodily movement produced by skeletal muscles that requires energy expenditure” [ 1 ]. Therefore, physical activity is not only limited to sports but also includes walking, running, swimming, gymnastics, dance, ball games, and martial arts, for example. In the last years, several organizations have published or updated their guidelines on physical activity. For example, the Physical Activity Guidelines for Americans, 2nd edition, provides information and guidance on the types and amounts of physical activity that provide substantial health benefits [ 2 ]. The evidence about the health benefits of regular physical activity is well established and so are the risks of sedentary behaviour [ 2 ]. Exercise is dose dependent, meaning that people who achieve cumulative levels several times higher than the current recommended minimum level have a significant reduction in the risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events [ 3 ]. Benefits of physical activity have been reported for numerous outcomes such as mortality [ 4 , 5 ], cognitive and physical decline [ 5 , 6 , 7 ], glycaemic control [ 8 , 9 ], pain and disability [ 10 , 11 ], muscle and bone strength [ 12 ], depressive symptoms [ 13 ], and functional mobility and well-being [ 14 , 15 ]. Overall benefits of exercise apply to all bodily systems including immunological [ 16 ], musculoskeletal [ 17 ], respiratory [ 18 ], and hormonal [ 19 ]. Specifically for the cardiovascular system, exercise increases fatty acid oxidation, cardiac output, vascular smooth muscle relaxation, endothelial nitric oxide synthase expression and nitric oxide availability, improves plasma lipid profiles [ 15 ] while at the same time reducing resting heart rate and blood pressure, aortic valve calcification, and vascular resistance [ 20 ].

However, the degree of all the above-highlighted benefits vary considerably depending on individual fitness levels, types of populations, age groups and the intensity of different physical activities/exercises [ 21 ]. The majority of guidelines in different countries recommend a goal of 150 min/week of moderate-intensity aerobic physical activity (or equivalent of 75 min of vigorous-intensity) [ 22 ] with differences for cardiovascular disease [ 23 ] or obesity prevention [ 24 ] or age groups [ 25 ].

There is a plethora of systematic reviews published by the Cochrane Library critically evaluating the effectiveness of physical activity/exercise for various health outcomes. Cochrane systematic reviews (CSRs) are known to be a source of high-quality evidence. Thus, it is not only timely but relevant to evaluate the current knowledge, and determine the quality of the evidence-base, and the magnitude of the effect sizes given the negative lifestyle changes and rising physical inactivity-related burden of diseases. This overview will identify the breadth and scope to which CSRs have appraised the evidence for exercise on health outcomes; and this will help in directing future guidelines and identifying current gaps in the literature.

The objectives of this research were to a. answer the following research questions: in children, adolescents and adults (both healthy and medically compromised) what are the effects (and adverse effects) of exercise/physical activity in improving various health outcomes (e.g., pain, function, quality of life) reported in CSRs; b. estimate the magnitude of the effects by pooling the results quantitatively; c. evaluate the strength and quality of the existing evidence; and d. create recommendations for future researchers, patients, and clinicians.

Our overview was registered with PROSPERO (CRD42019120295) on 10th January 2019. The Cochrane Handbook for Systematic Reviews of interventions and Preferred Reporting Items for Overviews of Reviews were adhered to while writing and reporting this overview [ 26 , 27 ].

Search strategy and selection criteria

We followed the practical guidance for conducting overviews of reviews of health care interventions [ 28 ] and searched the Cochrane Database of Systematic Reviews (CDSR), 2019, Issue 1, on the Cochrane Library for relevant papers using the search strategy: (health) and (exercise or activity or physical). The decision to seek CSRs only was based on three main aspects. First, high quality (CSRs are considered to be the ‘gold methodological standard’) [ 29 , 30 , 31 ]. Second, data saturation (enough high-quality evidence to reach meaningful conclusions based on CSRs only). Third, including non-CSRs would have heavily increased the issue of overlapping reviews (also affecting data robustness and credibility of conclusions). One reviewer carried out the searches. The study screening and selection process were performed independently by two reviewers. We imported all identified references into reference manager software EndNote (X8). Any disagreements were resolved by discussion between the authors with third overview author acting as an arbiter, if necessary.

We included CSRs of randomised controlled trials (RCTs) involving both healthy individuals and medically compromised patients of any age and gender. Only CSRs assessing exercise or physical activity as a stand-alone intervention were included. This included interventions that could initially be taught by a professional or involve ongoing supervision (the WHO definition). Complex interventions e.g., assessing both exercise/physical activity and behavioural changes were excluded if the health effects of the interventions could not have been attributed to exercise distinctly.

Any types of controls were admissible. Reviews evaluating any type of health-related outcome measures were deemed eligible. However, we excluded protocols or/and CSRs that have been withdrawn from the Cochrane Library as well as reviews with no included studies.

Data analysis

Three authors (HM, ALN, NK) independently extracted relevant information from all the included studies using a custom-made data collection form. The methodological quality of SRs included was independently evaluated by same reviewers using the AMSTAR-2 tool [ 32 ]. Any disagreements on data extraction or CSR quality were resolved by discussion. The entire dataset was validated by three authors (PP, MS, DP) and any discrepant opinions were settled through discussions.

The results of CSRs are presented in a narrative fashion using descriptive tables. Where feasible, we presented outcome measures across CSRs. Data from the subset of homogeneous outcomes were pooled quantitatively using the approach previously described by Bellou et al. and Posadzki et al. [ 33 , 34 ]. For mortality and quality of life (QOL) outcomes, the number of participants and RCTs involved in the meta-analysis, summary effect sizes [with 95% confidence intervals (CI)] using random-effects model were calculated. For binary outcomes, we considered relative risks (RRs) as surrogate measures of the corresponding odds ratio (OR) or risk ratio/hazard ratio (HR). To stabilise the variance and normalise the distributions, we transformed RRs into their natural logarithms before pooling the data (a variation was allowed, however, it did not change interpretation of results) [ 35 ]. The standard error (SE) of the natural logarithm of RR was derived from the corresponding CIs, which was either provided in the study or calculated with standard formulas [ 36 ]. Binary outcomes reported as risk difference (RD) were also meta-analysed if two more estimates were available. For continuous outcomes, we only meta-analysed estimates that were available as standardised mean difference (SMD), and estimates reported with mean differences (MD) for QOL were presented separately in a supplementary Table  9 . To estimate the overall effect size, each study was weighted by the reciprocal of its variance. Random-effects meta-analysis, using DerSimonian and Laird method [ 37 ] was applied to individual CSR estimates to obtain a pooled summary estimate for RR or SMD. The 95% prediction interval (PI) was also calculated (where ≥3 studies were available), which further accounts for between-study heterogeneity and estimates the uncertainty around the effect that would be anticipated in a new study evaluating that same association. I -squared statistic was used to measure between study heterogeneity; and its various thresholds (small, substantial and considerable) were interpreted considering the size and direction of effects and the p -value from Cochran’s Q test ( p  < 0.1 considered as significance) [ 38 ]. Wherever possible, we calculated the median effect size (with interquartile range [IQR]) of each CSR to interpret the direction and magnitude of the effect size. Sub-group analyses are planned for type and intensity of the intervention; age group; gender; type and/or severity of the condition, risk of bias in RCTs, and the overall quality of the evidence (Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria). To assess overlap we calculated the corrected covered area (CCA) [ 39 ]. All statistical analyses were conducted on Stata statistical software version 15.2 (StataCorp LLC, College Station, Texas, USA).

The searches generated 280 potentially relevant CRSs. After removing of duplicates and screening, a total of 150 CSRs met our eligibility criteria [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ] (Fig.  1 ). Reviews were published between September 2002 and December 2018. A total of 130 CSRs employed meta-analytic techniques and 20 did not. The total number of RCTs in the CSRs amounted to 2888; with 485,110 participants (mean = 3234, SD = 13,272). The age ranged from 3 to 87 and gender distribution was inestimable. The main characteristics of included reviews are summarised in supplementary Table  1 . Supplementary Table  2 summarises the effects of physical activity/exercise on health outcomes. Conclusions from CSRs are listed in supplementary Table  3 . Adverse effects are listed in supplementary Table  4 . Supplementary Table  5 presents summary of withdrawals/non-adherence. The methodological quality of CSRs is presented in supplementary Table  6 . Supplementary Table  7 summarises studies assessed at low risk of bias (by the authors of CSRs). GRADE-ings of the review’s main comparison are listed in supplementary Table  8 .

Study selection process

There were 54 separate populations/conditions, considerable range of interventions and comparators, co-interventions, and outcome measures. For detailed description of interventions, please refer to the supplementary tables . Most commonly measured outcomes were - function 112 (75%), QOL 83 (55%), AEs 70 (47%), pain 41 (27%), mortality 28 (19%), strength 30 (20%), costs 47 (31%), disability 14 (9%), and mental health in 35 (23%) CSRs.

There was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% CI 0.78 to 0.96]; I 2  = 26.6%, [PI 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]; 10 CSRs, 187 RCTs, 27,671 participants) following exercise when compared with various controls (Table 1 ). This reduction was smaller in ‘other groups’ of patients when compared to cardiovascular diseases (CVD) patients - RR 0.97 [95% CI 0.65, 1.45] versus 0.85 [0.76, 0.96] respectively. The effects of exercise were not intensity or frequency dependent. Sessions more than 3 times per week exerted a smaller reduction in mortality as compared with sessions of less than 3 times per week RR 0.87 [95% CI 0.78, 0.98] versus 0.63 [0.39, 1.00]. Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low ROB exerted smaller reductions in mortality when compared to RCTs at an unclear or high ROB, RR 0.90 [95% CI 0.78, 1.02] versus 0.72 [0.42, 1.22] versus 0.86 [0.69, 1.06] respectively. CSRs with moderate quality of evidence (GRADE), showed slightly smaller reductions in mortality when compared with CSRs that relied on very low to low quality evidence RR 0.88 [95% CI 0.79, 0.98] versus 0.70 [0.47, 1.04].

Exercise also showed an improvement in QOL, standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]; 15 CSRs, 408 RCTs, 32,984 participants) when compared with various controls (Table 2 ). These improvements were greater observed for health related QOL when compared to overall QOL SMD 0.30 [95% CI 0.21, 0.39] vs 0.06 [− 0.08, 0.20] respectively. Again, the effects of exercise were duration and frequency dependent. For instance, sessions of more than 90 mins exerted a greater improvement in QOL as compared with sessions up to 90 min SMD 0.24 [95% CI 0.11, 0.37] versus 0.22 [− 0.30, 0.74]. Subgroup analyses by the type of condition showed that the magnitude of effect was the largest among patients with mental health conditions, followed by CVD and cancer. Physical activity exerted negative effects on QOL in patients with respiratory conditions (2 CSRs, 20 RCTs with 601 patients; SMD -0.97 [95% CI -1.43, 0.57]; I 2  = 87.8%; MES = -0.46 [IQR-0.97, 0.05]). Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low or unclear ROB exerted greater improvements in QOL when compared to RCTs at a high ROB SMD 0.21 [95% CI 0.10, 0.31] versus 0.17 [0.03, 0.31]. Analogically, CSRs with moderate to high quality of evidence showed slightly greater improvements in QOL when compared with CSRs that relied on very low to low quality evidence SMD 0.19 [95% CI 0.05, 0.33] versus 0.15 [− 0.02, 0.32]. Please also see supplementary Table  9 more studies reporting QOL outcomes as mean difference (not quantitatively synthesised herein).

Adverse events (AEs) were reported in 100 (66.6%) CSRs; and not reported in 50 (33.3%). The number of AEs ranged from 0 to 84 in the CSRs. The number was inestimable in 83 (55.3%) CSRs. Ten (6.6%) reported no occurrence of AEs. Mild AEs were reported in 28 (18.6%) CSRs, moderate in 9 (6%) and serious/severe in 20 (13.3%). There were 10 deaths and in majority of instances, the causality was not attributed to exercise. For this outcome, we were unable to pool the data as effect sizes were too heterogeneous (Table 3 ).

In 38 CSRs, the total number of trials reporting withdrawals/non-adherence was inestimable. There were different ways of reporting it such as adherence or attrition (high in 23.3% of CSRs) as well as various effect estimates including %, range, total numbers, MD, RD, RR, OR, mean and SD. The overall pooled estimates are reported in Table 3 .

Of all 16 domains of the AMSTAR-2 tool, 1876 (78.1%) scored ‘yes’, 76 (3.1%) ‘partial yes’; 375 (15.6%) ‘no’, and ‘not applicable’ in 25 (1%) CSRs. Ninety-six CSRs (64%) were scored as ‘no’ on reporting sources of funding for the studies followed by 88 (58.6%) failing to explain the selection of study designs for inclusion. One CSR (0.6%) each were judged as ‘no’ for reporting any potential sources of conflict of interest, including any funding for conducting the review as well for performing study selection in duplicate.

In 102 (68%) CSRs, there was predominantly a high risk of bias in RCTs. In 9 (6%) studies, this was reported as a range, e.g., low or unclear or low to high. Two CSRs used different terminology i.e., moderate methodological quality; and the risk of bias was inestimable in one CSR. Sixteen (10.6%) CSRs did not identify any studies (RCTs) at low risk of random sequence generation, 28 (18.6%) allocation concealment, 28 (18.6%) performance bias, 84 (54%) detection bias, 35 (23.3%) attrition bias, 18 (12%) reporting bias, and 29 (19.3%) other bias.

In 114 (76%) CSRs, limitation of studies was the main reason for downgrading the quality of the evidence followed by imprecision in 98 (65.3%) and inconsistency in 68 (45.3%). Publication bias was the least frequent reason for downgrading in 26 (17.3%) CSRs. Ninety-one (60.7%) CSRs reached equivocal conclusions, 49 (32.7%) reviews reached positive conclusions and 10 (6.7%) reached negative conclusions (as judged by the authors of CSRs).

In this systematic review of CSRs, we found a large body of evidence on the beneficial effects of physical activity/exercise on health outcomes in a wide range of heterogeneous populations. Our data shows a 13% reduction in mortality rates among 27,671 participants, and a small improvement in QOL and health-related QOL following various modes of physical activity/exercises. This means that both healthy individuals and medically compromised patients can significantly improve function, physical and mental health; or reduce pain and disability by exercising more [ 190 ]. In line with previous findings [ 191 , 192 , 193 , 194 ], where a dose-specific reduction in mortality has been found, our data shows a greater reduction in mortality in studies with longer follow-up (> 12 months) as compared to those with shorter follow-up (< 12 months). Interestingly, we found a consistent pattern in the findings, the higher the quality of evidence and the lower the risk of bias in primary studies, the smaller reductions in mortality. This pattern is observational in nature and cannot be over-generalised; however this might mean less certainty in the estimates measured. Furthermore, we found that the magnitude of the effect size was the largest among patients with mental health conditions. A possible mechanism of action may involve elevated levels of brain-derived neurotrophic factor or beta-endorphins [ 195 ].

We found the issue of poor reporting or underreporting of adherence/withdrawals in over a quarter of CSRs (25.3%). This is crucial both for improving the accuracy of the estimates at the RCT level as well as maintaining high levels of physical activity and associated health benefits at the population level.

Even the most promising interventions are not entirely risk-free; and some minor AEs such as post-exercise pain and soreness or discomfort related to physical activity/exercise have been reported. These were typically transient; resolved within a few days; and comparable between exercise and various control groups. However worryingly, the issue of poor reporting or underreporting of AEs has been observed in one third of the CSRs. Transparent reporting of AEs is crucial for identifying patients at risk and mitigating any potential negative or unintended consequences of the interventions.

High risk of bias of the RCTs evaluated was evident in more than two thirds of the CSRs. For example, more than half of reviews identified high risk of detection bias as a major source of bias suggesting that lack of blinding is still an issue in trials of behavioural interventions. Other shortcomings included insufficiently described randomisation and allocation concealment methods and often poor outcome reporting. This highlights the methodological challenges in RCTs of exercise and the need to counterbalance those with the underlying aim of strengthening internal and external validity of these trials.

Overall, high risk of bias in the primary trials was the main reason for downgrading the quality of the evidence using the GRADE criteria. Imprecision was frequently an issue, meaning the effective sample size was often small; studies were underpowered to detect the between-group differences. Pooling too heterogeneous results often resulted in inconsistent findings and inability to draw any meaningful conclusions. Indirectness and publication bias were lesser common reasons for downgrading. However, with regards to the latter, the generally accepted minimum number of 10 studies needed for quantitatively estimate the funnel plot asymmetry was not present in 69 (46%) CSRs.

Strengths of this research are the inclusion of large number of ‘gold standard’ systematic reviews, robust screening, data extractions and critical methodological appraisal. Nevertheless, some weaknesses need to be highlighted when interpreting findings of this overview. For instance, some of these CSRs analysed the same primary studies (RCTs) but, arrived at slightly different conclusions. Using, the Pieper et al. [ 39 ] formula, the amount of overlap ranged from 0.01% for AEs to 0.2% for adherence, which indicates slight overlap. All CSRs are vulnerable to publication bias [ 196 ] - hence the conclusions generated by them may be false-positive. Also, exercise was sometimes part of a complex intervention; and the effects of physical activity could not be distinguished from co-interventions. Often there were confounding effects of diet, educational, behavioural or lifestyle interventions; selection, and measurement bias were inevitably inherited in this overview too. Also, including CSRs only might lead to selection bias; and excluding reviews published before 2000 might limit the overall completeness and applicability of the evidence. A future update should consider these limitations, and in particular also including non-CSRs.

Conclusions

Trialists must improve the quality of primary studies. At the same time, strict compliance with the reporting standards should be enforced. Authors of CSRs should better explain eligibility criteria and report sources of funding for the primary studies. There are still insufficient physical activity trends worldwide amongst all age groups; and scalable interventions aimed at increasing physical activity levels should be prioritized [ 197 ]. Hence, policymakers and practitioners need to design and implement comprehensive and coordinated strategies aimed at targeting physical activity programs/interventions, health promotion and disease prevention campaigns at local, regional, national, and international levels [ 198 ].

Availability of data and materials

Data sharing is not applicable to this article as no raw data were analysed during the current study. All information in this article is based on published systematic reviews.

Abbreviations

Adverse events

Cardiovascular diseases

Cochrane Database of Systematic Reviews

Cochrane systematic reviews

Confidence interval

Grading of Recommendations Assessment, Development and Evaluation

Hazard ratio

Interquartile range

Mean difference

Prediction interval

Quality of life

Randomised controlled trials

Relative risk

Risk difference

Risk of bias

Standard error

Standardised mean difference

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PP wrote the protocol, ran the searches, validated, analysed and synthesised data, wrote and revised the drafts. HM, NK and ALN screened and extracted data. MS and DP validated and analysed the data. RB ran statistical analyses. All authors contributed to writing and reviewing the manuscript. PP is the guarantor. The authors read and approved the final manuscript.

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Supplementary Table 1. Main characteristics of included Cochrane systematic reviews evaluating the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 2. Additional information from Cochrane systematic reviews of the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 3. Conclusions from Cochrane systematic reviews “quote”. Supplementary Table 4 . AEs reported in Cochrane systematic reviews. Supplementary Table 5. Summary of withdrawals/non-adherence. Supplementary Table 6. Methodological quality assessment of the included Cochrane reviews with AMSTAR-2. Supplementary Table 7. Number of studies assessed as low risk of bias per domain. Supplementary Table 8. GRADE for the review’s main comparison. Supplementary Table 9. Studies reporting quality of life outcomes as mean difference.

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Posadzki, P., Pieper, D., Bajpai, R. et al. Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews. BMC Public Health 20 , 1724 (2020). https://doi.org/10.1186/s12889-020-09855-3

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• Review Article
• Published: 24 May 2023

Exercise metabolism and adaptation in skeletal muscle

• Jonathon A. B. Smith   ORCID: orcid.org/0000-0003-2452-1655 1 ,
• Kevin A. Murach   ORCID: orcid.org/0000-0003-2783-7137 2 ,
• Kenneth A. Dyar   ORCID: orcid.org/0000-0002-9010-8757 3 , 4 &
• Juleen R. Zierath   ORCID: orcid.org/0000-0001-6891-7497 1 , 5 , 6  

Nature Reviews Molecular Cell Biology volume  24 ,  pages 607–632 ( 2023 ) Cite this article

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Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.

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Change history

21 july 2023.

In the version of this article originally published, in the Glossary definition for ‘Adrenoceptor’, ‘Transmembrane G-protein-coupled adrenergic receptors’ now reads as ‘Adrenergic transmembrane G-protein-coupled receptors’. In the figure legends for Figs. 1a and 2c , citations to the section ‘Acute exercise metabolism in skeletal muscle’ mistakenly named the section as ‘Acute exercise muscle metabolism’. Under the ‘Oxygen-dependent exercise metabolism’ subsection, in the third sentence of the first paragraph, H 2 O 2 was incorrectly defined as ‘superoxide’ rather than ‘hydrogen peroxide’. In the same subsection, in the paragraph beginning ‘Muscle lipid metabolism…’, the ‘post-exercise plasma metabolome’ was initially stated to be the ‘post-exercise serum metabolome’ in the second sentence. Furthermore, some proteins in the article were missing mentions of their standard names and/or definitions from UniProt, which have now been added: ‘SLC25A12’ has been added for ‘AGE’, ‘mitochondrial 2-oxoglutarate/malate carrier, M2OM’ for ‘MOE’, and ‘AATM’ for ‘mAspAT’. In addition, a typographical error in the sentence beginning ‘This occurs through a muscle…’ in Box 4 caused ‘PPARα/PPARδ’ to read as ‘PPAα/δ’. Similarly, in the last paragraph of the ‘The post-exercise transcriptome’ subsection, ‘45S pre-rRNA’ was incorrectly written as ‘pre-45S rRNA’ in the second sentence. Lastly, the supplementary file has been exchanged with an updated version showing corrected positioning of myosin headgroups in their relaxed conformations in Supplementary Fig. 2 . The updates are made in the HTML and PDF versions of the article.

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Acknowledgements

The authors apologize to all colleagues whose work could not be included owing to space constraints. The authors thank M. Karlén for preparation of the artwork in the supplementary figures. K.A.M. was supported by the National Institutes of Health (NIH R00 AG063994). K.A.D. was supported by Deutsches Zentrum für Diabetesforschung (2020/21). J.R.Z. was supported by the Swedish Research Council (Vetenskapsrådet) (2015-00165), the Swedish Research Council for Sport Science (P2022-0013, P2023-0093) and the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900).

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Jonathon A. B. Smith & Juleen R. Zierath

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Kevin A. Murach

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Adrenergic transmembrane G-protein-coupled receptors (GPCRs) that mediate the actions of the endogenous catecholamines adrenaline and noradrenaline. There are nine subtypes of adrenoceptors: α 1A , α 1B , α 1D , α 2A , α 2B , α 2C , β 1 , β 2 and β 3 . The α 2A and α 2C adrenoceptors regulate presynaptic neurotransmitter release from central adrenergic and peripheral sympathetic nerves.

A performance-enhancing effect.

Typically refers to an increase in the cross-sectional area (or radial growth) of muscle fibres, resulting in gains of skeletal muscle mass in response to mechanical loading activities, such as resistance exercise.

A lipid-derived, water-soluble, organic compound produced in the liver that can be used as an alternative energy source by extra-hepatic tissues — predominantly the brain, but also heart and skeletal muscle.

( \(\mathop{{\rm{V}}}\limits^{.}\) O 2max ). The maximum volume of oxygen (ml kg −1  min −1 ) that can be inspired and utilized during exhaustive exercise, such that the value ( \(\mathop{{\rm{V}}}\limits^{.}\) O 2 ) plateaus despite increasing workloads. \(\mathop{{\rm{V}}}\limits^{.}\) O 2max is a measure of aerobic or cardiorespiratory fitness and is commonly used to standardize exercise intensity for clinical trials (for example, x % of \(\mathop{{\rm{V}}}\limits^{.}\) O 2max ).

A specific form of lysosome-dependent catabolism (autophagy), through which damaged mitochondria are selectively removed. Mitophagy of the mitochondrial reticulum has an essential role in maintaining cellular energy homeostasis.

Structures embedded in most mammalian skeletal muscles that continuously relay proprioceptive information regarding muscle length and movement to the central nervous system. Muscle spindles consist of intrafusal muscle fibres enclosed within a capsule layer and are distinct from the extrafusal muscle fibres discussed in this Review.

(NEFAs). A metabolic substrate utilized by muscle at rest and in an intensity-dependent manner during exercise.

The force produced by muscle (through a moment arm) evoked by a single electrical stimulation from, for example, applied electrodes.

A rapid energy-producing pathway comprising the ATP regenerating adenylate kinase (ADP + ADP  ⇌  ATP + AMP) and creatine kinase (CrP + ADP  ⇌  ATP + Cr) reactions. Of these reactions, creatine kinase has a greater capacity for ATP resynthesis in muscle due to the availability of creatine phosphate stores.

Able to sense intrinsic information regarding bodily position and locomotion. The primary proprioceptive sensory organ of the body is the muscle spindle.

The proton electrochemical gradient in mitochondria consisting of an electrical charge gradient (also known as the ‘membrane potential’) and a pH gradient. The proton-motive force is generated by the proton-pumping action of respiratory complexes across the inner mitochondrial membrane and couples substrate oxidation to ATP generation.

(T-tubules). Invaginations in the sarcolemmal membrane that insert between myofibrils. T-tubules tightly associate with two terminal cisternae (calcium-releasing regions) of the sarcoplasmic reticulum, forming the ‘triads’, which are essential for excitation–contraction coupling.

The conscious or ‘voluntary’ production of muscle force (in other words, not triggered by exogenous electrical stimulation).

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Smith, J.A.B., Murach, K.A., Dyar, K.A. et al. Exercise metabolism and adaptation in skeletal muscle. Nat Rev Mol Cell Biol 24 , 607–632 (2023). https://doi.org/10.1038/s41580-023-00606-x

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Why Exercise Is More Important Than Weight Loss for a Longer Life

People typically lower their risks of heart disease and premature death far more by gaining fitness than by dropping weight.

By Gretchen Reynolds

For better health and a longer life span, exercise is more important than weight loss, especially if you are overweight or obese, according to an interesting new review of the relationships between fitness, weight, heart health and longevity. The study, which analyzed the results of hundreds of previous studies of weight loss and workouts in men and women, found that obese people typically lower their risks of heart disease and premature death far more by gaining fitness than by dropping weight or dieting.

The review adds to mounting evidence that most of us can be healthy at any weight, if we are also active enough.

I have written frequently in this column about the science of exercise and weight loss, much of which is, frankly, dispiriting, if your goal is to be thinner. This past research overwhelmingly shows that people who start to exercise rarely lose much, if any, weight, unless they also cut back substantially on food intake. Exercise simply burns too few calories, in general, to aid in weight reduction. We also tend to compensate for some portion of the meager caloric outlay from exercise by eating more afterward or moving less or unconsciously dialing back on our bodies’ metabolic operations to reduce overall daily energy expenditure, as I wrote about in last week’s column .

Glenn Gaesser, a professor of exercise physiology at Arizona State University in Phoenix, is well versed in the inadequacies of workouts for fat loss. For decades, he has been studying the effects of physical activity on people’s body compositions and metabolisms, as well as their endurance, with a particular focus on people who are obese. Much of his past research has underscored the futility of workouts for weight loss. In a 2015 experiment he oversaw , for instance, 81 sedentary, overweight women began a new routine of walking three times a week for 30 minutes. After 12 weeks, a few of them had shed some body fat, but 55 of them had gained weight.

In other studies from Dr. Gaesser’s lab , though, overweight and obese people with significant health problems, including high blood pressure, poor cholesterol profiles or insulin resistance, a marker for Type 2 diabetes, showed considerable improvements in those conditions after they started exercising, whether they dropped any weight or not. Seeing these results, Dr. Gaesser began to wonder if fitness might enable overweight people to enjoy sound metabolic health, whatever their body mass numbers, and potentially live just as long as thinner people — or even longer, if the slender people happened to be out of shape.

So, for the new study, which was published this month in iScience, he and his colleague Siddhartha Angadi, a professor of education and kinesiology at the University of Virginia in Charlottesville, began scouring research databases for past studies related to dieting, exercise, fitness, metabolic health and longevity. They were especially interested in meta-analyses, which pool and analyze data from multiple past studies, allowing researchers to look at results from far more people than in most individual studies of weight loss or exercise, which tend to be small-scale.

They wound up with more than 200 relevant meta-analyses and individual studies. Then they set out to see what all of this research, involving tens of thousands of men and women, most of them obese, indicated about the relative benefits of losing weight or getting fit for improving metabolisms and longevity. In effect, they asked whether someone who is heavy gets more health bang from losing weight or getting up and moving.

The contest, they found, was not close. “Compared head-to-head, the magnitude of benefit was far greater from improving fitness than from losing weight,” Dr. Gaesser said.

As a whole, the studies they cite show that sedentary, obese men and women who begin to exercise and improve their fitness can lower their risk of premature death by as much as 30 percent or more, even if their weight does not budge. This improvement generally puts them at lower risk of early death than people who are considered to be of normal weight but out of shape, Dr. Gaesser said.

On the other hand, if heavy people lose weight by dieting (not illness), their statistical risk of dying young typically drops by about 16 percent, but not in all studies. Some of the research cited in the new review finds that weight loss among obese people does not decrease mortality risks at all.

The new review was not designed to determine precisely how exercise or weight loss affect longevity in people with obesity, though. But in many of the studies they looked at, Dr. Gaesser said, people who shed pounds by dieting regained them, then tried again, a yo-yo approach to weight loss that often contributes to metabolic problems like diabetes and high cholesterol and lower life expectancy.

On the other hand, exercise combats those same conditions, he said. It may also, unexpectedly, remake people’s fat stores. “People with obesity usually lose some visceral fat when they exercise,” he said, even if their overall weight loss is negligible. Visceral fat, which collects deep inside our bodies, raises risks for Type 2 diabetes, heart disease and other conditions.

A few of the studies they cite find that exercise likewise alters molecular signaling inside other fat cells in ways that may improve insulin resistance, no matter how much weight someone carries. “It looks like exercise makes fat more fit,” Dr. Gaesser said.

The primary takeaway of the new review, he concluded, is that you do not need to lose weight to be healthy. “You will be better off, in terms of mortality risk, by increasing your physical activity and fitness than by intentionally losing weight,” he said.

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Health benefits of physical activity: a systematic review of current systematic reviews

Affiliation.

• 1 Physical Activity Promotion and Chronic Disease Prevention Unit, University of British Columbia, Vancouver, British Columbia, Canada.
• PMID: 28708630
• DOI: 10.1097/HCO.0000000000000437

Purpose of review: The health benefits of physical activity and exercise are clear; virtually everyone can benefit from becoming more physically active. Most international guidelines recommend a goal of 150 min/week of moderate-to-vigorous intensity physical activity. Many agencies have translated these recommendations to indicate that this volume of activity is the minimum required for health benefits. However, recent evidence has challenged this threshold-centered messaging as it may not be evidence-based and may create an unnecessary barrier to those who might benefit greatly from simply becoming more active. This systematic review evaluates recent systematic reviews that have examined the relationship between physical activity and health status.

Recent findings: Systematic reviews and/or meta-analyses (based largely on epidemiological studies consisting of large cohorts) have demonstrated a dose-response relationship between physical activity and premature mortality and the primary and secondary prevention of several chronic medical conditions. The relationships between physical activity and health outcomes are generally curvilinear such that marked health benefits are observed with relatively minor volumes of physical activity.

Summary: These findings challenge current threshold-based messaging related to physical activity and health. They emphasize that clinically relevant health benefits can be accrued by simply becoming more physically active. VIDEO ABSTRACT: http://links.lww.com/HCO/A42.

Publication types

• Systematic Review
• Chronic Disease / prevention & control*
• Health Status*
• Physical Fitness*

• Open access
• Published: 20 April 2021

The effects of exercise and low-calorie diets compared with low-calorie diets alone on health: a protocol for systematic reviews and meta-analyses of controlled clinical trials

• Sara Beigrezaei 1 , 2 ,
• Zeinab Yazdanpanah 1 , 2 ,
• Sepideh Soltani 3 ,
• Seyede Hamide Rajaie 1 , 2 ,
• Sahar Mohseni-Takalloo 1 , 2 , 4 ,
• Tayebeh Zohrabi 1 , 2 ,
• Mojtaba Kaviani 5 ,
• Scott C. Forbes 6 ,
• Julien S. Baker 7 &
• Amin Salehi-Abargouei   ORCID: orcid.org/0000-0002-7580-6717 1 , 2  

Systematic Reviews volume  10 , Article number:  120 ( 2021 ) Cite this article

5876 Accesses

6 Citations

Metrics details

Exercise and weight loss diets are two independent non-pharmaceutical strategies used to improve several aspects of body composition and health. We plan to systematically review controlled clinical trials investigating weight loss diets alone compared to weight loss diets in conjunction with exercise on energy intake, body weight, body composition, cardiometabolic risk factors, sex hormones, and mental health.

Methods and analysis

PubMed/MEDLINE, EMBASE, ISI (Web of Science), Scopus, and Google Scholar will be searched to retrieve potential controlled clinical trials investigating the effects of exercise in conjunction with weight loss diets compared with weight loss diets alone on energy intake, body weight and composition (fat mass, fat-free mass), anthropometrics (waist circumference), cardiometabolic markers, sex hormones [testosterone, estradiol, and sex hormone binding globulin (SHBG)], liver and kidney enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), uric acid, blood urea nitrogen (BUN), glomerular filtration rate (GFR), quality of life, and depression in adults. The weighted mean difference (WMD) and its corresponding 95% confidence intervals (CIs) will be derived using random effects model. Several subgroup analyses based on follow-up duration, the health status of the participants, the diet used for weight loss, the exercise protocol, participants’ sex, and other possible variables will be conducted to explore possible sources of heterogeneity. Publication bias will be explored by inspecting funnel plots and by conducting asymmetry tests. Overall quality of the evidence will be assessed by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool.

We envisage that this systematic review and meta-analysis will provide valuable information regarding the effectiveness of adding exercise to weight loss diets. No primary data is going to be collected; therefore, ethical approval is not required. The resulting manuscripts will be disseminated in peer-reviewed journals and at international and national conferences.

Systematic review registration

The study protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO, Registration ID: CRD42020173434 ).

Peer Review reports

The worldwide prevalence of obesity and associated metabolic abnormalities has resulted in a huge strain on health care systems [ 1 , 2 ]. The increase in prevalence of obesity in recent decades is multifactorial; however, sedentary lifestyle and poor quality diets are proposed to be the two major contributing factors [ 2 , 3 ]. Furthermore, obesity is associated with a reduced quality of life and higher risk factors for several diseases, such as metabolic syndrome, diabetes, cardiovascular disease (CVD), and cancers [ 4 , 5 ].

Lifestyle modifications including changes in diet and physical activity are regarded as the main non-pharmacological and non-surgical strategies to treat obesity [ 6 ]. Modified dietary macro-nutrient intake leading to a hypocaloric diet is effective for weight loss over the short term and may be important for weight loss maintenance compared to exercise alone. Low-calorie diets not only reduce body weight but also improve cardiometabolic health, quality of life, and mental health [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; however, it is proposed that weight loss diets might adversely affect bone health in adults [ 15 ]. It is also plausible that exercise may alter energy balance and influence body weight and health over time. Despite the well-known benefits of exercise, the increase in energy expenditure and the potential to decrease hunger and energy intake exercise alone does not seem to be effective at modifying weight status [ 16 , 17 , 18 ]. Beyond weight loss, exercise, may modulate metabolism and lead to an increase in muscle mass [ 18 , 19 , 20 , 21 ]. Furthermore, exercise (particularly weight-bearing exercise) may be effective at enhancing bone health [ 15 ].

In theory, exercise in conjunction with weight loss diets may be ideal to improve weight loss as well as appetite (i.e., energy intake), body composition, cardiovascular health and mental health [ 22 , 23 , 24 ]. However, controlled clinical trials have led to inconsistent results [ 25 , 26 , 27 , 28 , 29 ], with some studies demonstrating no additive effects of exercise [ 25 , 26 ], while others found a greater effect with exercise for improving multiple cardiometabolic risk factors in obese adults [ 27 , 28 ]. A number of clinical trials have revealed that subjects show a significant weight loss and reduction in energy intake during an exercise intervention, while others have shown less reduction in body weight due to an increase in energy intake [ 30 , 31 , 32 ]. These conflicting results were also observed on other health outcomes such as bone health, appetite, and mood [ 33 , 34 , 35 , 36 , 37 ].

A number of systematic reviews and meta-analyses have compared the effects of diet, exercise or both in specific health conditions [ 38 , 39 ]. Hemmingsen et al. [ 38 ] reported no differences between the effects of diet alone or exercise alone compared to a standard treatment on the risk of type 2 diabetes mellitus and related complications. In addition, another systematic review evaluated the effects of diet or exercise or both on excessive weight gain during pregnancy and showed that diet or exercise alone and diet plus exercise during pregnancy appears to reduce the risk of excessive gestational weight gain [ 39 ]. Aside from the aforementioned reviews, we are not aware of any systematic review attempting to summarize the current evidence on other outcomes such as bone health, sex hormones, liver and kidney enzymes, quality of life, and depression.

In this study, we will describe the protocols used to systematically compare the effects of a low-calorie diet with a low-calorie diet plus exercise on energy intake, body weight and composition, anthropometric measures, cardiometabolic markers, bone health markers, sex hormones, liver and kidney enzymes, quality of life, and depression in adults.

The present protocol is being reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [ 40 ] (see checklist in Additional file 1 ). The study protocol is also registered in the International Prospective Register of Systematic Reviews (PROSPERO, Registration ID: CRD42020173434).

Information sources and search strategy

The relevant articles will be identified in the following databases up to August 2020: PubMed/MEDLINE, EMBASE, ISI (Web of Science), Scopus, and Google Scholar using Medical Subject Heading (MeSH) and non-MeSH keywords. We will not apply any language or other restrictions. In addition, we will check the reference lists of all relevant studies to identify additional relevant articles. Unpublished studies will be identified by searching the websites indexing the preprints such as Research Square ( https://www.researchsquare.com/ ) and the registered clinical trials approved by the World Health Organization (WHO). All abstracts of interest will be evaluated for further information by contacting the authors. The draft searches for the main databases are available in Additional file 2 .

Study selection

Two investigators will independently perform the study selection. All articles from electronic searches will be imported into the EndNote software (version: desktop, X7; Thompson Reuters, New York, USA) and duplicate studies will be deleted. Titles, abstracts, and full-text articles will be screened and cross-checked according to the eligibility criteria for study inclusion independently by 6 reviewers (Z.Y, S.S, S.B, SH.R, S.MT, and T.Z). Any disagreements will be resolved by discussion and consensus. The PRISMA flow chart will be presented to describe the process of the study selection.

Articles selected for full-text review must meet the following criteria:

Participants must be a minimum 18 years of age and older and have a body mass index (BMI) ≥ 25 kg/m 2 (pregnant and lactating women will be excluded);

Interventions must contain one arm in which participants receive an exercise intervention (i.e., aerobic or resistance) with a weight loss (i.e., hypocaloric) diet and one arm where participants only receive a weight loss diet (exactly according to the diet considered for the intervention group);

Interventions must be randomized or non-randomized controlled clinical trials with either a parallel, cross-over, or factorial design with at least 2 weeks of follow-up.

Data extraction and management

The following data will be extracted using a predefined data extraction form by two independent investigators from the eligible studies and any discrepancy will be resolved by a third author:

Study and participant’s characteristics

The participants’ age, number of males and females, number of participants in the intervention and control group/period, the geographical location of the study, and the health condition of participants.

Intervention details

The study design (parallel/cross-over/factorial), number of study arms, the intervention duration, funding source(s), amount of calorie restriction, type of diets and exercise programs, intensity, frequency, compliance, and delivery of each exercise used for the intervention group.

Outcome measures

Data on baseline, post-intervention, or change from baseline mean ± standard deviation (SD) for energy intake, body weight, anthropometrics and body composition measures, blood glucose control markers (serum/plasma fasting glucose, insulin, insulin resistance markers including HOMA-IR and hemoglobin A1C), lipid profile [serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apoproteins], systolic and diastolic blood pressure, sexual hormones (testosterone and estradiol), SHBG, serum/plasma inflammation (hs-CRP, IL-6, and TNF-a), bone health markers, liver and kidney enzymes, depression, and quality of life, will be extracted for the intervention and control groups/periods. P values for within-group and between-group comparison will also be collected to calculate the change values.

Assessment of risk of bias in individual studies

The eligible randomized trials will be assessed using the Cochrane collaboration’s risk of bias assessment tool considering seven domains: (i) random sequence generation (selection bias), (ii) allocation concealment (selection bias), (iii) blinding of participants and personnel (performance bias), (iv) blinding of outcome assessment (detection bias), (v) incomplete outcome data (attrition bias), (vi) selective reporting (reporting bias), and (vii) the dietary compliance as another possible source of bias in dietary interventions. Each study will be judged as low risk of bias, high risk of bias, or unclear risk of bias according to the mentioned domains [ 41 ]. The overall quality of studies will be classified as low risk (low risk for all domains), unclear risk (unclear for at least one domain), and high risk (high risk for at least one domain). As well, the non-randomized trials will be evaluated using risk of bias in non-randomized studies of interventions (ROBINS-I) tool [ 42 ]. According this tool, bias will be examined based on 7 domains (i.e., confounding factors, selection of participants, interventions classification, deviations from intended interventions, missing data, outcomes measurement, and selective reporting), and then reporting an overall risk of bias (i.e., low, moderate, serious, critical, or no information).

Data analysis

The data for study characteristics, participants, outcomes, and findings will be used to build evidence tables for eligible studies to provide an overall description of included studies. The mean change values from baseline for the intervention (weight loss diet + exercise) and control group/period (weight loss diet alone) and their standard deviations (SDs) will be used to calculate the raw mean difference and standard error (SE) between the intervention and control. The hedges’ g (bias corrected standardized mean difference) statistic and corresponding SD will be calculated for outcome variables reported in different scales. The mean difference will be used as the effect size for meta-analysis. If the change values were not reported, we will calculate SD for the change values by selecting 0.5 as the reference correlation coefficient between baseline and end point values ( r = 0.5) and to make sure that the meta-analysis was not sensitive to the selected correlation coefficient, all analyses will be repeated using 0.2 and 0.8 as the correlation coefficient. The weighted mean difference (WMD) and its corresponding 95% confidence intervals (CIs) will be derived using the random effects model which takes the between-study heterogeneity into account [ 43 ]. All statistical analyses will be performed using STATA, version 11.2 (Stata Corp, College Station, TX) and a two-sided P value less than 0.05 will be considered as statistically significant. If data cannot be meta-analyzed, we will summarize the articles and conclude on high-quality studies.

Between study heterogeneity and subgroup analysis

The heterogeneity will be checked using Cochran’s Q test and I 2 statistic ( I 2 is an estimate for between study variation to total meta-analysis variation ratio ranging from 0 to 100%) [ 44 ]. We will report Cochran Q test with a P value of < 0.05 considered statistically significant (heterogeneity). I 2 with values of 0–25% and 75–100% will be taken to indicate low and considerable heterogeneity, respectively. To examine the potential sources of between-study heterogeneity, several subgroup analyses based on follow-up duration, the health status of the participants, the diet used for weight loss, the exercise, participants’ sex, and other possible variables will be conducted.

Sensitivity analysis

The sensitivity analysis will be done by sequentially removing individual studies included in the meta-analyses to assess the robustness of the meta-analyses [ 45 ].

Publication bias

In case there are fewer than 10 studies in a meta-analysis, we will construct a funnel plot to investigate the potential for publication bias for the primary outcome by visual inspection for asymmetry. If our meta-analysis involves 10 or more studies, publication bias will be evaluated by inspecting Begg’s funnel plots and Egger’s and Begg’s asymmetry tests [ 46 ]. Duval and Tweedie’s trim and fill analysis will be conducted if the publication bias becomes evident [ 47 ].

Dealing with missing data

If data are missing, we will attempt to contact the authors through e-mails to obtain missing data or additional information twice, 1 week apart. The impact of missing data will also be evaluated in the sensitivity analysis. Additionally, we will describe the possible influences of missing data in the “Discussion” section of the resulting publications.

Confidence in cumulative evidence

Overall quality of the evidence will be assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool [ 48 ] with GRADEprofiler (GRADEpro) V.3.6 software, identifying the quality of evidence for each outcome as the extent to which one can be confident that an estimate of effect is near to the quantity of certain interest [ 46 ]. There are four levels used to rate the quality of evidence across trials in the GRADE system: very low, low, moderate, and high. Randomized clinical trials are categorized as high quality but can be downgraded due to limitation in study design, indirectness of evidence, imprecision of results, unexplained heterogeneity or inconsistency of results, or high probability of publication bias [ 48 ].

For decades, epidemiological and clinical studies have been elucidating the link between lifestyle modifications and health outcomes through different mechanisms [ 49 ]. Previous reviews have assessed the impacts of diet or exercise alone on energy intake and different health indicators, while there is no comprehensive investigation summarizing the evidence evaluating the effects of weight loss diets combined with exercise interventions on energy intake, anthropometric and body composition, blood glucose control, cardio-metabolic markers, and mental health. Nevertheless, this systematic review and meta-analysis might face several potential limitations. High heterogeneity between included studies might arise from differences in study characteristics not anticipated by authors or not explained at study level. The limited number of studies particularly RCTs with risk of bias on some outcome variables might lead to inconclusive results.

In this manuscript, we present the study protocol for a systematic review and meta-analysis to compare the effects of a low-calorie diet plus exercise with a low-calorie diet on risk factors associated with chronic diseases. Finally, this systematic review and meta-analyses will provide more information regarding the effectiveness of adding exercise to a weight loss diet.

Availability of data and materials

The studies included in the review will be available upon request.

Abbreviations

Alanine aminotransferase

Aspartate aminotransferase

Body mass index

Uric acid, blood urea nitrogen

Confidence interval

Cardiovascular disease

Glomerular filtration rate

Gamma-glutamyl transferase

High-density lipoprotein cholesterol

Highly sensitive C-reactive protein

Interleukin 6

Low-density lipoprotein cholesterol

Medical Subject Headings

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols

International Prospective Register of Systematic Reviews

Standard deviation

Standard error

Sex hormone-binding globulin

Tumor necrosis factor alpha

World Health Organization

Weighted mean difference

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Acknowledgements

We would like to thank the research council of Nutrition and Food Security Research Center for their scientific support.

The present systematic review was supported by the Research Council of the Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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Sara Beigrezaei, Zeinab Yazdanpanah, Seyede Hamide Rajaie, Sahar Mohseni-Takalloo, Tayebeh Zohrabi & Amin Salehi-Abargouei

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Sepideh Soltani

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Sahar Mohseni-Takalloo

Faculty of Pure & Applied Science, School of Nutrition and Dietetics, Acadia University, Wolfville, NS, Canada

Mojtaba Kaviani

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ASA conceived the study and will be the guarantor of the review. ASA, ZY, and SS contributed in defining the search strategy. SB wrote the first draft of the manuscript. ZY, SS, SHR, SMT, TZ, MK, and SF facilitated with preparation of the manuscript and its finalization. All authors read and approved the final version of the manuscript.

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PRISMA-P 2015 Checklist.

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Search strategies used to find related publications in PubMed, Scopus and ISI web of science.

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Beigrezaei, S., Yazdanpanah, Z., Soltani, S. et al. The effects of exercise and low-calorie diets compared with low-calorie diets alone on health: a protocol for systematic reviews and meta-analyses of controlled clinical trials. Syst Rev 10 , 120 (2021). https://doi.org/10.1186/s13643-021-01669-7

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Mind body exercise improves cognitive function more than aerobic- and resistance exercise in healthy adults aged 55 years and older – an umbrella review

• Peter Blomstrand   ORCID: orcid.org/0000-0002-3907-1637 1 , 2 , 3 ,
• Dario Tesan 2 ,
• Elisabeth Mueller Nylander 4 &
• Nerrolyn Ramstrand 5  

European Review of Aging and Physical Activity volume  20 , Article number:  15 ( 2023 ) Cite this article

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Exercise is often cited as a major factor contributing to improved cognitive functioning. As a result, the relationship between exercise and cognition has received much attention in scholarly literature. Systematic reviews and meta-analyses present varying and sometimes conflicting results about the extent to which exercise can influence cognition. The aim of this umbrella review was to summarize the effects of physical exercise on cognitive functions (global cognition, executive function, memory, attention, or processing speed) in healthy adults ≥ 55 years of age.

Methods  An umbrella review of systematic reviews with meta-analyses investigating the effect of exercise on cognition was performed. Databases (CINAHL, Cochrane Library, MEDLINE, PsycInfo, Scopus, and Web of Science) were searched from inception until June 2023 for reviews of randomized or non-randomised controlled trials. Full-text articles meeting the inclusion criteria were reviewed and methodological quality assessed. Overlap within included reviews was assessed using the corrected covered area method (CCA). A random effects model was used to calculate overall pooled effect size with sub-analyses for specific cognitive domains, exercise type and timing of exercise.

Results  Database searches identified 9227 reviews. A total of 20 met the inclusion criteria. They were based on 332 original primary studies. Overall quality of the reviews was considered moderate with most meeting 8 or more of the 16 AMSTAR 2 categories. Overall pooled effects indicated that exercise in general has a small positive effect on cognition (d = 0.22; SE = 0.04; p  < 0.01). Mind–body exercise had the greatest effect with a pooled effect size of (d = 0.48; SE = 0.06; p  < 0.001). Exercise had a moderate positive effect on global cognition (d = 0.43; SE = 0,11; p  < 0,001) and a small positive effect on executive function, memory, attention, and processing speed. Chronic exercise was more effective than acute exercise. Variation across studies due to heterogeneity was considered very high.

Conclusions Mind–body exercise has moderate positive effects on the cognitive function of people aged 55 or older. To promote healthy aging, mind–body exercise should be used over a prolonged period to complement other types of exercise. Results of this review should be used to inform the development of guidelines to promote healthy aging.

Trial registration  PROSPERO (CDR 42022312955).

An active lifestyle has long been promoted as a means of slowing down the aging process and helping people retain their independence. Physical exercise in particular has been identified as beneficial for older adults and has been suggested to have positive effects on both physical and cognitive health outcomes [ 1 ]. While there is high-level evidence supporting exercise as an effective intervention for maintaining physical function in older adults [ 2 ], recent research has provided reason to question previous claims of a positive association between physical exercise and cognitive functioning [ 3 ].

Cognitive functioning can be analysed from a general perspective (global cognition) or sub-divided into specific domains, each representing different abilities. These include executive functions, memory, attention, and processing speed [ 4 ]. Each of these domains has been associated with a measurable decline with age [ 5 ] which begins before the age of 60 in healthy adults [ 6 ]. Murman [ 5 ] suggests that the greatest impact of age-related change in cognition results from deterioration in a person’s ability of perform cognitive tasks requiring rapid processing of information and then a decision. These types of tasks require effective use of working memory, processing speed, and executive functions.

Slowing or even reversing age related cognitive decline has been a popular topic of many scholarly publications and physical exercise is one intervention that has received much attention as a potential mediating factor. Studies to date have attempted to identify the most effective type of exercise to promote maintenance of cognitive functions [ 7 , 8 , 9 ], determine the optimal intensity, duration and frequency of exercise for promoting cognitive function [ 8 , 10 , 11 , 12 ] and to identify which specific cognitive domains may benefit most from an exercise intervention [ 13 ]. Specific types of physical exercise that have been investigated can be loosely categorised into three groups; aerobic exercise (e.g. walking, running, dancing, swimming or bicycling), resistance exercise (e.g. weight training, training by use of body weight or elastic bands) and mind body exercise (e.g. yoga, tai chi or qi gong) [ 7 , 8 , 9 ]. The link between exercise and cognition has also been studied as an acute intervention, involving a single bout of training, and as a chronic intervention, consisting of multiple bouts of training performed over a period of weeks or months [ 14 ].

A recent meta-analysis comparing the effects of resistance and aerobic exercise on global cognition, memory and executive function concluded that both types of exercise were beneficial for older adults with and without cognitive decline [ 15 ]. Another recent systematic review by Huang et al. showed that resistance exercise had the highest probability for slowing down cognitive decline [ 16 ]. Zhang et al. reported that mind–body exercise has significant benefits for global cognition, executive functions, learning and memory [ 17 ]. In contrast to these findings, a recent umbrella review including 23 meta-analyses and including people between the ages of 6 and 80 showed only small exercise related benefits on cognition and demonstrated that these effects became negligible after correcting for publication bias [ 3 ].

Many physiological processes are stimulated by exercise and support the premise that increased physical activity contributes to maintenance or even improvements in cognitive health. These processes are generally related to an exercise induced increase in neural activity or increased levels of exerkines. For example, high intensity aerobic exercise has been associated with increased activity in the frontal and parietal cortices as well as the supplementary motor area [ 18 ], all key areas for executive functions and motor planning. Aerobic exercise but not resistance exercise has also been linked to an increase in resting concentrations of brain-derived neutrophic factor (BDNF) in peripheral blood [ 19 ], and hippocampus [ 20 ], a regions which plays a major role in learning and memory. BDNF expression has also been found to be affected by the duration and intensity of exercise [ 19 , 21 ].

Recent data has also linked potential beneficial effects of exercise to crosstalk which takes place between the brain and the liver, muscle, adipose tissue and gut [ 22 ]. In these studies, exercise-related signalling molecules and exerkines have been identified to regulate the positive effects of exercise on cognitive function. An example of this is Cathepsin B which increases in plasma and muscles during exercise and which is strongly associated with memory functions [ 23 ]. Similarly, Glycosylposphatidylinositol-Specific Phospholipase D1 (GLDP1) from the liver is increased after exercise. GLDP1 is correlated with neurogenesis, increased expression of BDNF and improved hippocampal dependent learning and memory in aged mice [ 24 ]. Exercise also increases circulating interleukin-6 (IL-6) which reduces the pathological amyloid precursor protein in prefrontal cortex and hippocampus. This protein plays a central role in the pathophysiology Alzheimer´s disease [ 25 ].

While pathophysiological evidence seems to support exercise induced benefits on cognition, inconsistencies in data syntheses which have studied cognitive outcomes after exercise suggest that further investigation is warranted. Umbrella reviews are a relatively new concept which may help to shed light on uncertainties that exist regarding the relationship between exercise and cognition. This research method allows researchers to synthesise results from previous reviews under a single “umbrella” and to draw conclusions about the overall strength and quality of studies which may have inconsistent of conflicting conclusions [ 26 ]. Umbrella reviews represent one of the highest levels of evidence [ 27 ].

The aim of this study was to conduct an umbrella review to evaluate the impact of physical exercise on cognitive functions in healthy adults who are 55 years of age or older. More specifically we aimed to determine the type of exercise that is most effective for improving cognitive functions (aerobic exercise, resistance exercise or mind body exercise), which cognitive domains are likely to be most affected (global cognition, executive functions, memory, attention, or processing speed) and if exercise duration (acute versus chronic) has a significant effect on cognitive outcomes.

Protocol and registration

The protocol for this umbrella review was pre-registered in PROSPERO and is available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=42022312955 . This review complies with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA [ 28 ]).

Literature search strategy

In March 2022 and June 2023, the following databases were searched for systematic reviews with meta-analyses of randomized controlled trials (RCTs) or non-randomized controlled trials (NRCTs): CINAHL (EBSCOhost), Cochrane Library (Wiley), MEDLINE (EBSCOhost), PsycInfo (ProQuest), Scopus, and Web of Science. The search strategies were based on the concepts of age (older adults), exercise, and cognition. Searches were further limited by study type but not by language or publication date. The full search strategy for each database is reported in Supplementary data, S 1 . A manual search of the reference lists of included reviews was performed in addition to the digital search to ensure that no relevant articles were missed.

The literature selection criteria

Studies were included in this umbrella review if they were systematic reviews with meta-analyses which assessed the effect of acute or chronic exercise interventions on cognitive functions. The definition of systematic review used in the study was: “A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review” [ 29 ]. Participants were required to be ≥ 55 years and healthy, with no specific disorders such as cancer, heart failure, mental illness, neurological disease, cognitive impairment, or dementia. The age cut-off of 55 years deviates from the original Prospero registration and was made for pragmatic reasons as few reviews were found to include participants from 65 years of age. Reviews that comprised of both healthy and unhealthy participants were included only if results from the healthy participants were reported independently and meta data for this specific group could be extracted. Reviews were required to investigate a physical exercise intervention compared to a control group performing no activity or another type of activity. Physical exercise interventions included in this umbrella review were required to be categorised as either: aerobic exercise, resistance exercise, mind body exercise or a combination of these. These categorisations were selected as they represent the broad classifications commonly used by health promoting organisations and have previously been used to classify exercise types in systematic reviews [ 30 , 31 ]. For the purposes of the review, aerobic exercise was defined as any exercise intervention aiming to improve cardiovascular fitness. This included activities such as walking, running, dancing, bicycling, swimming, or exergaming [ 7 ]. Resistance exercise was defined as interventions which aimed to improve muscle strength and included weight training, bodyweight training or use of resistance bands [ 8 ]. Mind–body exercise was classified as exercise which combines movement sequences, breathing control, and attention regulation [ 32 ]. Examples of mind–body exercise are Tai Chi, Pilates and Yoga.

In addition to an exercise intervention, meta-analyses included in the umbrella review were required to investigate at least one cognitive outcome that could be classified into one or more of the following categories: global cognition, executive functioning, memory, attention, or processing speed. Only peer reviewed, English language publications were included. No supplemental primary studies were added.

Study selection and data extraction

Publications identified by the search were exported to EndNote where duplicate publications were removed using methods described by Bramer et al. [ 33 ]. In contrast to other de-duplication methods, this method does not rely on digital object identifies (DOI’s) and PubMedIDs (PMIDs) which are not present in every database, rather combines other fields (e.g. author, year, title) with page numbers to identify duplicate publications. Following the deduplication process remaining publications were exported to Rayyan online software where titles and abstracts were initially reviewed [ 34 ]. Publications were excluded if they were not systematic reviews with meta-analyses, if they included participants under 55 years of age in the analysis or if they included patients with cognitive impairment, dementia, or severe medical disorders and did not present separate analyses for healthy people. The reviewers (PB, NR, DT) worked in pairs to review titles and abstract. Each pair initially reviewed the studies independently before results were compared to the second reviewer. Any disagreement was resolved through discussion with the third reviewer. Finally, the reviewers read the full text of remaining articles. Manuscripts were excluded during the full text review if they had; A. the wrong study design (e.g. not a systematic review or meta-analysis); B. wrong or no intervention; C. wrong outcome (e.g. no cognitive test reported); D. wrong participants (e.g. participants with mild cognitive impairment or dementia, or aged < 55 years); or E. were not published in English. During this process reviewers read the full text of each article independently before comparing their decision to include or exclude the review with at least one other author. Conflicts were discussed among all three authors until consensus was reached.

Data extracted from the remaining articles included citation (author/year), study design, population characteristics, description of the exercise intervention, cognitive outcome measures used, and results of the study (effect size, confidence intervals). At least two authors independently extracted all the data and then met to compare their results. Discrepancies were resolved through discussion among all three authors.

Study quality assessment

The validated AMSTAR tool for systematic reviews was used to assess the risk of bias and the quality of reviews [ 35 , 36 ]. Risk of bias was initially rated independently by all three authors. Ratings were then compared between the authors and any conflicts were resolved through discussion within the group. To assess the potential impact of overlap, where the same primary studies were included in two or more reviews, we used the corrected cover area (CCA) method. This is a validated measure which uses a citation matrix to calculate overlapping publications included in reviews. A CCA score of 0–5 indicates slight overlap, 6–10 moderate, 11–15 high and > 15very high [ 37 ]. The authors agreed that reviews would be removed from the analysis if the overlap was found to be high or very high.

Statistical analysis

Data analysis was performed with IBM SPSS Statistics v. 28.0.1.0. Pooled effect sizes were calculated from effect size data reported in each review (Cohen’s d) together with standard error data calculated from 95% confidence intervals [ 38 ]. Four studies included in this umbrella review reported effect size as Hedge’s g [ 10 , 39 , 40 , 41 ]. The main difference between Cohen´s d and Hedge´s g is that Hedge´s g is multiplied by a correction factor for small samples. Given that the sample sizes in studies reporting Hedge´s g were relatively large, and considering that Hedge´s g would provide a more conservative estimate, this data was not converted to Cohen´s d [ 42 ]. No re-analysis of raw data from reviews included in this study was performed.

When available, data was extracted to allow for a sub-analysis of a/ global cognition and specific cognitive domains; b/ different types of exercise and c/ acute versus chronic exercise. Specific domains were included in sub-analyses when they were identified in at least two reviews. Cognition was analysed as global cognition or one of the following specific domains; executive function, memory, attention and processing speed.

Data related to the specific type of exercise performed was classified as being aerobic, resistance or mind–body exercise. Classifications were based on the definitions presented above and agreed upon by all three authors. Classifications of acute versus chronic exercise were determine in the same manner.

Data was pooled into one overall effect size for each analysis. A random effects model was used to adjust the weights according to the extent of variation, or heterogeneity. Effect sizes were interpreted as small d = 0.2; medium d = 0.5 and large d = 0.8 [ 38 ].

Publication bias and small study effects biases were evaluated using funnel plots and Egger’s test. Small-study effects bias was considered an issue for p values < 0.01 in the regression asymmetry test [ 43 ]. Heterogeneity was estimated using I 2 and interpreted as very large (> 75%); large (50–74); moderate (25–49); and low (< 25%) [ 44 ]. In both instances p  < 0.05 was considered significant. To explore if results related to the overall effect size were sensitive to exclusion of specific studies, we calculated effect size while systematically excluding one study at a time.

Database searches identified 9227 reviews. No additional reviews were identified by manually searching reference lists. 3149 reviews were removed as they were identified to be duplicate publications, and 5881 reviews were removed following the authors’ review of titles and abstracts. Full text copies of four reviews were not able to be retrieved. Full text versions 193 articles were read by the authors, of which 173 were excluded due to; wrong study design ( n  = 77); wrong intervention ( n  = 37); wrong outcome ( n  = 11); wrong participants ( n  = 47); wrong language ( n  = 1). This left a total of 20 meta-analyses that were identified as assessing the effects of exercise on cognition in healthy individuals aged 55 years and older. Figure  1 presents the PRISMA flowchart and reasons for exclusion. A list of all articles excluded during the full-text review is included as Supplementary data, S 2  (Fig.  1 ).

PRISMA flow diagram. Legends Flow chart illustrating the literature search

Characteristics of included studies

Study characteristics are presented as Table 1 . The average number of studies included in each meta-analysis ranged from two (45) to 50 (41) with an average of 13 studies. Overlap in the included reviews is presented in supplementary data, S 3 . The CCA was calculated to be 1.84% representing only slight overlap [ 37 ].

The total number of participants included in meta-analyses ranged from 68 (45) to 3523 (40). Fifteen meta-analyses included only RCTs, three included both RTCs and NRTCs [ 9 , 14 , 51 ], and one included systematic reviews of studies with an experimental design [ 48 , 55 ]. Most reviews included studies with passive control groups although Clifford et al. [ 45 ] and Jiang et al. [ 47 ] did include both passive and active control groups. It was not possible to determine the characteristics of control groups in two reviews [ 40 , 49 ] (Table 1 ).

Age span of participants included in the reviews varied from 55 to 94 years. Most studies ( n  = 11) investigated the effects of aerobic exercise on cognition [ 7 , 13 , 14 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 54 ]. Three studies investigated the effects of mind body exercise on cognition [ 9 , 32 , 39 ], two analysed the effects of resistance exercise [ 8 , 49 ] and five investigated the effects of mixed exercise interventions [ 10 , 39 , 40 , 41 , 53 ] (Table 1 ). Only two studies investigated cognition after a single bout of exercise (Acute) [ 14 , 48 ] while all others investigated cognition after prolong exercise (Chronic). The duration of chronic exercise ranged from one month [ 10 ] to two-years [ 41 ]. The most common intervention for control groups was no training, other control interventions included balance training, flexibility training, health education and even social activities.

Outcomes were typically reported for one or more cognitive domains. Six studies reported results for global cognition [ 8 , 13 , 40 , 49 , 51 , 52 ], while others reported outcomes for more specific cognitive domains. Memory and executive function were the most frequently reported domains (15 studies and 11 studies respectively). Processing speed and attention were reported in five and three studies respectively. Ma et al. [ 13 ] reported analyses for global cognition and memory but it was unclear if memory data was reported as mean differences or standardised mean differences so only data for global cognition was analysed.

Several meta-analyses chose to report specific domain broken down into sub-categories. An example of this was Angevaren et al. [ 7 ] who presented separate analyses for verbal memory, visual memory, working memory and memory functions. Cognitive domains along with cognitive tests used to measure cognition are presented in Supplementary file S 4 . The most frequently used tests for executive functioning were the Trail making test B and Task switching test. Memory was most frequently evaluated using the Wechsler Memory Scale and Rey’s Auditory test. Many studies used several different tests of memory and over 40 different memory tests were reported across the studies included in this umbrella review.

Methodological quality assessment

The AMSTAR 2 rating of overall confidence in reviews is presented in Fig.  2 . In the AMSTAR 2 rating overall quality was considered high in six studies, moderate in 12 studies and low in two studies. The review by Hindin et al. was considered to have critical flaws, having scored satisfactorily on only one of the sixteen AMSTAR 2 criteria. This study was removed from further analysis [ 40 ]. Five studies contained an explicit statement that the review methods were established prior to the review. Recently published studies presented a fully comprehensive literature search strategy to a greater extent than older studies. No studies reported on sources of funding for articles included in their review. Most authors used appropriate methods for study selection and methods used for meta-analyses were generally performed well (Fig.  2 ).

Amstar rating. The validated AMSTAR tool for systematic reviews was used to assess the risk of bias and the quality of reviews. RCT, Randomized controlled trials; NRSI, Not randomized studies of interventions

Results from pooling of effect sizes

Effect size data used in our analysis are presented in Fig.  3 . Pooled results of all studies assessing the effect of exercise on cognition resulted in a small, positive effect in favour of exercise (d = 0.22; SE = 0.04; p  < 0.01). Sub-analyses for each cognitive domain are presented in Fig.  3 (Global Cognition, Executive functioning, Memory, Attention and Processing speed), for type of exercise in Fig.  4 (aerobic, resistance and mind–body) and for duration of intervention (Acute vs Chronic) in Fig.  5 .

Effect size for each cognitive domain. Forest Plot showing the effect of exercise on cognitive domains (a = control group received no intervention, b = control group received any other intervention, c = exercise immediately before memory test, d = exercise during memory test, e = general memory, f = short-term memory, g = working memory, h = long-term memory, i = Digital span backwards, j = digit symbol test, k = trail making test a, l = trail making test b, m = letter fluency test, n  = stroop test)

Effect size for each type of exercise. Forest Plot showing the effect of exercise on cognitive function. Sub-analyses are presented for different types of exercise (a = control group received no intervention, b = control group received any other intervention, c = exercise immediately before memory test, d = exercise during memory test, e = general memory, f = short-term memory, g = working memory, h = long-term memory, i = Digital span backwards, j = digit symbol test, k = trail making test a, l = trail making test b, m = letter fluency test, n  = stroop test)

Effect size for each acute versus chronic exercise. Forest Plot showing the effect of acute and chronic exercise on cognitive function. Sub-analyses are presented for different types of exercise (a = control group received no intervention, b = control group received any other intervention, c = exercise immediately before memory test, d = exercise during memory test, e = general memory, f = short-term memory, g = working memory, h = long-term memory, i = Digital span backwards, j = digit symbol test, k = trail making test a, l = trail making test b, m = letter fluency test, n = stroop test)

In several studies included in this review, authors presented results separately for categories within a specific cognitive domain or separated their analysis based on study design (see Table 2 ). For example, Angevaren et al. presented effect sizes which were categorised into four types of memory (verbal memory, visual memory, working memory and memory function) as well as separating their analysis into 1/controls with no interventions and 2/controls with any other type of intervention [ 7 ]. Given that there is no overlap in the data included in each of these analyses we have chosen to include all relevant results (Table 2 ).

Sub-analyses for global cognition and specific cognitive domains

Global cognition was investigated in 5 studies and pooled data resulted in a moderate positive effect of exercise on cognition (d = 0.43; SE = 0,11; p  < 0,001) [ 8 , 13 , 40 , 49 , 52 ].

Data presenting the effect of exercise on executive function was able to be extracted from 8 systematic reviews. Pooled data indicated a small, significant effect in favour of exercise (d = 0.26; SE = 0.07; p  < 0.001).

Memory was the most frequently investigated cognitive domain and was reported in a total of 15 reviews, ten reporting effect size data relevant for this analysis. When studies reported separate results which were categorised by a specific type of memory (e.g. long-term and short-term memory) we included all results. Exercise was found to have a small, significant effect on pooled memory data (d = 0.20; SE = 0.05; p  < 0.001).

Only two reviews were found to investigate the effect of exercise on attention. Angevaren et al. presented pooled data for auditory attention and visual attention as separate analyses [ 7 ]. Exercise was found to have a positive, but small effect on attention (d = 0.20; SE = 0.11; p  = 0.01).

Four reviews investigated the effect of exercise on processing speed with three of these reporting relevant effect size data. Exercise was found to have a positive but small, effect on processing speed (d = 0.21; SE = 0.05; p  < 0.001).

Sub analyses for types of exercise

Mind–body exercise had the greatest effect on cognition with a pooled effect size of d = 0.48 (SE = 0.06; p  < 0.001) (Fig.  4 ). Five systematic reviews with meta-analyses included all together 31 original primary studies (overlaps excluded) that evaluated the effect of mind body exercise on cognitive function [ 9 , 10 , 32 , 39 , 53 ]. Eleven reviews investigated the effects of aerobic exercise on cognitive function with several studies evaluating the effects of aerobic exercise on multiple cognitive domains [ 7 , 14 , 48 ]. Aerobic exercise had a small effect on cognition (d = 0.17; SE = 0.04; p  < 0.001), as did resistance exercise (d = 0.24; SE = 0,24; p  < 0.32). The effect of mixed exercise on cognition was also small (d = 0.18; SE = 0.05; p  < 0.001). Note that all cognitive domains were in this sub-analysis.

In order to investigate if the type of exercise had an effect of different cognitive domains we performed a separate analysis which stratified domains and exercise types. Results of this analysis can be found in Supplementary file S 6 . Mind–body exercise was not represented in every cognitive domain however was found to have the greatest effect size on executive function (d = 0.5; SE = 0.10; p  < 0.001) and processing speed (d = 0,39; SE = 0.13; p  < 0.01). Only aerobic and resistance exercise were investigated for their effects on global cognition and both resulted in moderate effect sizes (Aerobic d = 0.51; SE = 0.2; p  = 0.01), Resistance d = 0.68; SE = 0.23; p  < 0.01).

Sub analysis for acute versus chronic exercise

Nineteen reviews investigated the effects of chronic exercise on cognition while two studied the effects of acute exercise [ 14 , 48 ]. Roig et al. [ 14 ] included analyses for both chronic and acute exercise. Chronic exercise had a small positive effect on cognition (d = 0,24;SE = 0,04; p  < 0.001) while acute exercise has a small negative effect (d = -0.20; SE = 0.54; p  = 0.71) (see Fig.  5 ).

Analysis of heterogeneity and publication bias

Variation across studies due to heterogeneity was very high (I 2  = 85%). A funnel plot showing effect estimates from all studies and 95% confidence limits around the summary treatment effect is presented as Fig.  6 . Egger’s test including all data revealed a significant deviation from zero (β 0  = 0.23; CI = 0.107–0.350; t = 3.783; p  < 0.001) confirming that small study effects may have influenced the results. This was further analysed by evaluating sub-groups (see Supplementary data S 5 ). Results suggest that the heterogeneity is mainly due to the subgroups for memory and executive functions as well as the subgroups for aerobic and mixed exercise.

Funnel plot. Funnel plot including studies assessing the impact of exercise on cognitive functions. The plot shows the effect estimates from all studies and 95% confidence limits around the summary treatment effect

Sensitivity analysis

Supplementary Table S 7 presents results of a sensitivity analysis showing the overall effect size for all reviews and the effect size calculated while systematically excluding A/ one review at a time and B/ reviews that included acute exercise interventions. Individual reviews which had the greatest influence on effect size were Ye et al. and Gasquoin et al. [ 32 , 41 ]. The overall effect size varied from a minimum of 0.19 with Ye al al removed to a maximum of 0.25 with Gasquoine et al. removed. Removing any one study did not vary how the overall effect size would be interpreted, ie. a weak positive effect size [ 44 ]. Removing reviews including acute exercise interventions ( n  = 2) had little effect on the overall effect size which raised from d = 0.22 to d = 0.24.

To the best of our knowledge, this is the first umbrella review investigating the effects of exercise on cognitive functions in healthy adults (≥ 55 years of age). Our analyses indicate that aerobic and resistance exercise have a rather small effect on cognitive functioning while mind–body exercise has a moderate positive effect which would be more likely to result in a noticeable change in cognitive functions in adults over the age of 55. Chronic exercise was found to have a greater effect than acute exercise suggesting that regular training over a longer period is more beneficial for promoting cognitive functioning than a single bout of acute exercise.

Of the exercise modalities studied in this review, mind body exercise showed the greatest potential for slowing age-related cognitive decline. In contrast to aerobic and resistance exercise, which focus on cardiovascular fitness and strength, mind–body exercise combines movement sequences together with breathing control and attention regulation. This combination of physical and neurological resources may provide an explanation for the observed differences in the exercise modalities investigated. The potential relationship between physical activity and changes in neurological activity is supported by results from a recent systematic review which demonstrated that mind–body exercise induces changes in neural activity and functional connectivity in the brain [ 47 ], including the pre-frontal cortex which has an important role for cognitive functions [ 56 , 57 ].

It is important to reflect on results related to exercise modality from a holistic perspective and with consideration of previous work demonstrating that aerobic and resistance exercise play an important role in maintaining physical function and in protecting against falls in older adults [ 58 , 59 ]. Considering this previous work, combined with result of the present study, we suggest that a regular exercise routine including all three modalities (aerobic, resistance and mind–body) is most beneficial for promoting healthy aging.

Effect sizes across specific cognitive domains, executive functioning, memory, attention, and processing speed, ranged between 0.20 and 0.26 suggesting a relatively small effect when types of exercise are pooled. Whether these effects translate into clinically meaningful outcomes for older adults remains unclear. A sub-analysis for each domain, stratified by exercise type does indicate that different types of exercise may affect cognitive domains to different extents. For example, mind–body exercise had the greatest effect on executive function and processing speed, but no reviews reported the effects of mind–body exercise on attention or global cognition. These results are support by Ye et al. who reported mind–body exercise having a large effect on memory functions but only small to moderate effects on executive function [ 32 ]. Ren et al. call for additional research to clarify the effects of exercise types on different cognitive domains [ 60 ].

Effects of exercise on global cognition were higher than more specific cognitive domains (d = 0.43). Tests for global cognition aim to assess an individual’s general mental status and typically comprise of items representing a wide variety of different cognitive domains. For example, the Mini-Mental State Examination, included in many reviews, comprises of items that test memory, attention, speech perception and visuo-spatial skills [ 61 ]. Based on our study results it is not possible to determine why exercise has a greater effect on global cognition, although it is possible that the generalised global cognition tests included items covering cognitive domains that were not addressed in this review.

Exercise intensity and duration

Exercise intensity was poorly reported in many of the reviews and may have affected results of this study. Exercise intensity has been suggested as an important factor in promoting healthy aging however, there appears to be significant discrepancy in the literature regarding the optimal intensity for promoting cognitive function [ 62 , 63 , 64 ].

Results of this umbrella review indicated that prolonged (chronic) exercise has a greater effect on cognitive function than a single (acute) bout of exercise. It should be noted however that only two reviews included data for acute exercise and these had contrasting results. Roig et al. concluded that acute aerobic exercise had a large, positive effect on memory functions by priming molecular processes involved in encoding and consolidation, while long-term exercise had negligible effects [ 14 ]. Loprinzi et al. found that acute aerobic exercise before memory encoding and during early consolidation had a negative effect on episodic memory [ 48 ]. Empirical studies involving younger adults have demonstrated an intensity-dependent effect of acute exercise on cognitive functions [ 65 , 66 ]. El-Sayes et al. [ 67 ] propose a model of neuroplasticity which is induced by acute exercise and facilitates cognitive and motor function. They report that concentrations of BDNF and vascular endothelian growth factor (VEGF) increase after a bout of acute exercise and that this, together with increases in neurotransmitter and metabolite concentrations induces neuroplasticy within the brain to facilitate cognitive functions. It is important to recognise that this model based on studies involving adults in their early to late 20 s and further research is necessary to determine its validity with an older population.

Timing of the application of cognitive tests post exercise may be an important factor that influences results of empirical studies. In a recent systematic review, again involving young adults, a single, acute exercise workout immediately before a learning activity improved learning and memory functions and the effects remained for 30 to 120 min [ 68 ]. Unfortunately, most studies in our review did not report the time elapsing between physical activity and cognitive testing. This, along with clear details of exercise dosage (frequency, duration and intensity) are recommended as standard reporting parameters when studying exercise interventions.

An additional factor that must be taken into consideration when interpreting results of this umbrella review is the activity level of control groups. Some reviews only included studies with control group participants who did not undertake training [ 14 ], while others also included controls who undertook another form of exercise which would likely result in smaller effect sizes when comparing the means of intervention and control groups [ 7 , 9 , 51 ].

Many studies of exercise in older adults include both healthy individuals and those with mild cognitive decline. In this umbrella review we made a conscious decision to only include healthy individuals as previous work has identified differences in the effects of exercise on cognition between the two groups [ 10 ]. We also set the minimum age limit to 55 years. It has been found that cognitive outcomes are moderated by age with significant benefits for young-old (55–65 years) compared to older adults [ 10 ]. This decision was a rather pragmatic one based upon classifications used in previous studies and we recognised that results may have varied if we had limited our review to adults within a higher age range. Six of the selected studies in our meta-analysis included adults from the age of 55 and older [ 7 , 9 , 10 , 46 , 50 , 51 ].

Limitations

As is the case with all review studies, umbrella reviews are limited by the number, quality and comprehensiveness of data which is possible to extract from primary sources [ 69 ]. Inconsistency in use and classification of outcome measures representing specific cognitive domains as well as specific exercise interventions may limit the specificity of results in this review. Including sample populations from 55 years of age may also be considered a limitation of this study although age-related cognitive decline had been demonstrated to begin well before the age of 60 [ 6 ].

We are confident that a thorough search of the literature was performed in this umbrella review however with so many studies identified in the initial search it is possible that some relevant meta-analyses were overlooked. Our umbrella review also recorded high levels of heterogeneity suggesting high levels of variability in the data. This may be due to differences in target populations, measurement instruments or analytical methods. There were also a large number and variety of outcome measures that were included in reviews and inconsistencies in the cognitive domain classifications allocated to some measures. The variety of outcome measures together with overlap in the classification of outcomes is also likely to have contributed to high levels of heterogeneity. To manage heterogeneity we used a random-effects model for calculating effect size.

Conclusions

This umbrella review has been a search for answers regarding the effects of exercise on cognitive functioning in healthy people aged 55 years and older. Results indicate that aerobic and resistance exercise have a rather small, and likely negligible effect, on cognitive functions in adults aged 55 years or older. A noteworthy finding is that mind body exercise had a moderate effect on cognition. Choice of cognitive outcomes along with timing and dosage of exercise may be key factors that influence the cognitive functions and require further investigation. Based upon results of this study we recommend that mind–body exercise be incorporated in the regular exercise routine of people aged 55 years and older. To promote healthy aging, mind–body exercise should serve as a complement to other types of exercise such as endurance training, resistance and balance activities all of which have been shown to improve body functions. It is anticipated that results of this review will be beneficial in supporting future studies, standardisation of study designs and the development of guidelines including mind body exercises for interventions which support healthy aging.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Brain-derived neutrophic factor

Confidence interval

Corrected covered area method

Digital Object Identifies

Glycosylphosphatidylinositol-Specific Phospholipase S1

Interleukin-6

Meta-analyses

Mild cognitive impairment

Missing data

Non-randomized controlled trials

Randomized Controlled Trials

Standardized mean difference

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Peter Blomstrand: Design, literature selection, data extraction, writing manuscript and illustrations. Dario Tesan: Literature selection, data extraction, writing manuscript and illustrations. Elisabeth Mueller Nylander: Design, literature search, writing manuscript and illustrations. Nerrolyn Ramstrand: Design, literature selection, data extraction, statistical analysis, writing manuscript and illustrations. All authors have read and approved the final manuscript.

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Supplementary Information

Additional file 1: supplementary s1..

Search strategies.

Additional file 2:

Supplement S2. Characteristics of excluded studies.

Additional file 3:

Supplement S3. Included studies overlap.

Additional file 4:

Supplement 4. Cognitive domains and tests.

Additional file 5:

Supplement S5. Funnel plots for subgroups.

Additional file 6: Supplement S6.

Type of exercise stratified by cognitive domain.

Additional file 7: Supplement S7.

A) Sensitivity analysis showing effect size when each study is individually removed from the analysis.

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Blomstrand, P., Tesan, D., Nylander, E.M. et al. Mind body exercise improves cognitive function more than aerobic- and resistance exercise in healthy adults aged 55 years and older – an umbrella review. Eur Rev Aging Phys Act 20 , 15 (2023). https://doi.org/10.1186/s11556-023-00325-4

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Exercise Training and Heart Failure: A Review of the Literature

Jacqueline H Morris

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Exercise and cardiac rehabilitation have been underused therapy options for patients with congestive heart failure despite being recommended in international guidelines and being covered by Medicare in the US. This article reviews the evidence behind this treatment strategy and details current trials that will contribute to the evidence base.

Exercise training , cardiac rehabilitation , congestive heart failure , transplantation , quality of life ,

Disclosure: The authors have no conflicts of interest to declare

Received: 21 August 2018

Accepted: 29 November 2018

Published online: 11 February 2019

Citation: Cardiac Failure Review 2019;5(1):57–61.

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DOI: https://doi.org/10.15420/cfr.2018.31.1

Correspondence Details: Leway Chen, University of Rochester Medical Center, 601 Elmwood Ave, Box 679-T, Rochester, NY 14642-8679, USA. E: [email protected]

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Congestive heart failure (CHF) is a progressive cardiovascular disease with significant morbidity and mortality that affects an increasing amount of people worldwide. There are approximately 6.5 million people in the US, more than 14 million people in Europe, and 26 million people worldwide who are living with heart failure, and the prevalence continues to grow. 1–3 In the US alone, there were 960,000 new cases of CHF diagnosed in 2017, and this is expected to continue to increase year on year in the ageing population. It has been estimated that by 2030, the prevalence in the US will exceed 8 million people. 4

Along with the high disease prevalence, there is also a significant cost burden related to CHF. The annual worldwide cost of heart failure has been estimated to be US$108 billion, which is about 1–2% of the global healthcare budget. 5 The US is responsible for about 28% of the global expenditure, while Europe accounts for about 7%. 5,6 In an evaluation of US costs published in 2014, the direct and indirect costs of heart failure were calculated from publicly available resources to be about US$60.2 billion and US$115.4 billion, respectively, significantly higher than previous estimates. 7 Given the significant disease prevalence and cost burden, it is essential that healthcare providers investigate multiple therapies to improve clinical outcomes for people with CHF.

Despite there being many evidence-based therapies that are endorsed by guidelines and have shown to reduce mortality rates and hospitalisations and improve quality of life (QoL) and symptoms, many patients with CHF remain dyspnoeic and fatigued with recurrent hospitalisations, a diminished exercise tolerance and a poor QoL. 8 Many studies have shown numerous benefits of cardiac rehabilitation (CR) and exercise training in patients with heart failure, including a reduction in morbidity and mortality. 9–11 Guidelines from the American College of Cardiology/American Heart Association, European Society of Cardiology and Canadian Cardiovascular Society have included evidence-based recommendations for the use of exercise in the management of CHF ( Table 1 ). 12–14 Additionally, given the data supporting the use of exercise in heart failure as well as the revised guidelines, the US Centers for Medicare & Medicaid Services (CMS) extended coverage for CR for patients with heart failure with a reduced ejection fraction (HFrEF) in 2014. 15 Despite inclusion in guidelines and CMS coverage and numerous studies showing clinical benefit from exercise therapy and its safety, it has been underused by people with CHF. It is essential that healthcare providers understand the available literature regarding the safety and clinical benefits related to exercise in this population, as well as the barriers to participation and adherence to CR. It is important that patients are referred to CR programmes and they are encouraged to participate.

Guideline Recommendations for Exercise for People with Heart Failure

Safety of exercise has been consistently demonstrated in patients with numerous types of clinical HF ( Table 2 ). The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, which was the largest trial of exercise training in patients with HF with a reduced ejection fraction (HFrEF), investigated the efficacy and safety of exercise for these patients. This was a multicentre, randomised controlled trial that included 2,331 medically stable patients with HF with left ventricular ejection fraction (LVEF) ≤35% and New York Heart Association (NYHA) Class II–VI symptoms despite optimal medical therapy for 6 weeks. Exercise training was demonstrated to be well tolerated and safe for these patients. 10 A meta-analysis of 33 trials (including HF-ACTION), involving 4,740 patients with HFrEF with an LVEF <40% and NYHA Class II or III, demonstrated no significant adverse effects of exercise in patients with HF. 16 In an evaluation of outcomes for HF with preserved ejection fraction (HFpEF), a meta-analysis that included 276 patients with well-compensated heart failure in six randomised controlled trials demonstrated no major adverse effects of exercise training. 17 A study of rehabilitation with 27 patients and another including 278 patients both demonstrated that exercise was safe for patients with acute decompensated HF (ADHF). 18,19 The Rehabilitation ventricular assist device (Rehab-VAD) trial and the 2017 Cochrane review of exercise-based cardiac rehabilitation in heart transplant recipients demonstrated the safety of exercising with a LV assist device (LVAD) and orthotropic heart transplant (OHT), respectively. 20,21

There has been investigation into the pathophysiology of exercise intolerance in patients with HF and the beneficial effects of exercise training. Mechanisms that may lead to decreased exercise capacity in this patient population include cardiac dysfunction, abnormalities in peripheral flow, endothelial dysfunction, skeletal muscle dysfunction, ventilatory deficits and abnormalities of autonomic nervous system function. 22 Exercise capacity is best quantified by peak oxygen consumption (peak VO 2 ) and many studies have demonstrated improvements in peak VO 2 with exercise training. 9,11,22–24 Additionally, exercise with moderate aerobic training has led to favourable effects on central haemodynamic function, sympathetic tone, peripheral vascular and skeletal muscle function, ventilatory efficiency with decreased dyspnoea and improved QoL. 22,25,26

Clinical Outcomes and CMS Coverage in Congestive Heart Failure

Heart Failure with Reduced Ejection Fraction

The majority of studies investigating the effects of exercise on HF have been related to chronic HFrEF and have demonstrated beneficial clinical outcomes ( Table 2 ). Exercise Training Meta-Analysis of Trials in Patients with Chronic Heart Failure (ExTraMATCH) was a 2004 meta-analysis of nine prospective randomised controlled trials comparing exercise training and usual care in patients with CHF related to LV dysfunction. Significant reductions in mortality and hospitalisations were demonstrated. 27 Subsequent systematic reviews have also demonstrated a decrease in hospitalisations, but failed to show significant reductions in mortality. 8,28

An updated Cochrane review in 2017, which examined 33 randomised controlled trials including 4,740 participants, predominantly with HFrEF and NYHA Class II and III, demonstrated a reduction in all-cause hospital admissions and HF-specific admissions in up to 12 months of follow-up. Additionally, there was an improved health-related QoL in the exercise training programme group compared with the control. 16 There is also evidence to support cost–effectiveness of exercise-based rehabilitation based on two trials included in the review that was attributed to a reduction in hospital bed days. 16 The HF-ACTION trial was included in this Cochrane review; it demonstrated safety and an improved QoL among CHF patients randomised to the exercise therapy group. 10 Although there was a non-significant reduction in the risk of all-cause mortality and all-cause hospitalisation in this group of patients with chronic HFrEF, there was a risk reduction in the primary endpoint of death or hospitalisation of any cause when adjusted for highly prognostic predictors, including duration of the cardiopulmonary exercise test, LVEF, Beck Depression Inventory II score and a history of atrial fibrillation or flutter. Further sub-study analysis demonstrated that the volume of exercise was a logarithmic predictor of the primary outcome of all-cause mortality or hospitalisation and that there was significant benefit demonstrated from moderate exercise. 29

Heart Failure with Preserved Ejection Fraction

Multiple studies have demonstrated safety and effectiveness of exercise for people with HFrEF to improve symptoms, aerobic capacity/endurance and QoL, although people with HFpEF have been under-represented in the studies. Given that HFpEF leads to about 50% of hospital admission for HF and that there is a lack of demonstrated benefit from pharmacotherapies in this patient population, investigation of other potential beneficial interventions for people with HFpEF is essential. 16,17 In addition to demonstrating the safety of exercise with no major adverse effects reported in the 276 patients with well-compensated HFpEF in a meta-analysis that included six randomised controlled trials, it was suggested that exercise training improved cardiorespiratory fitness by an increase in peak VO 2 and QoL. 17 These improvements were noted to be unrelated to a significant change in the diastolic LV function.

The Exercise Training in Diastolic Heart Failure (Ex-DHF) pilot study was a randomised study involving 64 patients that compared supervised exercise or usual care and it demonstrated improvements in exercise capacity and health-related QoL. 30 There have been no studies evaluating the effect of exercise on hospitalisations or mortality in the HFpEF population, and HFpEF was excluded from CMS coverage for CR in the most recent decision memo in 2014. 15 The Ex-DHF trial, which is currently enrolling participants, is the first multicentre trial to evaluate the long-term effects of exercise on a composite outcome of all-cause mortality, hospitalisations, NYHA functional class, global self-rated heath, maximal exercise capacity, and diastolic function in HFpEF patients. 31

Acute Decompensated Heart Failure

There is extremely limited data on the safety and clinical outcomes related to exercise therapy in people with ADHF, which is a leading cause of hospitalisation and is associated with significant morbidity, mortality, and healthcare costs, especially in older patients. These patients have been excluded from previous exercise training trials and the updated CMS memo for CR coverage from 2014. 15

The Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) pilot study provided feasibility of an ongoing multicentre, randomised, attention-controlled trial funded by the National Institute of Health to evaluate the use of rehabilitation to improve physical function and reduce rehospitalisations for patients ≥60 years beginning in the hospital during an admission for ADHF (including HFrEF and HFpEF) and continuing for 12 weeks after discharge. 18 This pilot study included 27 patients with admissions for ADHF that were randomised into a novel rehabilitation intervention group, focusing on improved balance, strength, mobility and endurance, an attention control group or usual care, and demonstrated feasibility, safety and a trend toward improved physical function and decreased hospitalisations in the intervention group. Given that this is a pilot study with a small sample size of the larger and randomised controlled trial (REHAB-HF) that is currently enrolling participants, the authors recommend caution in instituting immediate rehabilitation in older patients with ADHF.

The Exercise Joins Education: Combined Therapy to Improve Outcomes in Newly-discharged Heart Failure (EJECTION-HF) trial was a multicentre randomised controlled trial in Australia that included 278 recently discharged CHF patients who were randomised to 24 weeks of supervised centre-based exercise therapy commencing within 6 weeks of discharge or standard care. 19 Average time to initiation of CR in these patients was 43 days and there were no adverse events associated with the therapy, suggesting that exercise therapy in patients recently hospitalised with acute HF is safe and feasible. Adherence in the home exercise group was 75% at 3 months and 68% at 6 months, while the centre-based exercise group had poor adherence with only 43% of patients participating in ≥50% of the sessions. There was no difference in the primary outcome of all-cause death or readmissions, although there was a significant reduction in all-cause mortality in the exercise group (based on a small number of events), which should be interpreted with caution. The results of the REHAB-HF trial will provide additional insight into the benefit of early rehabilitation for patients with ADHF.

Left Ventricular Assist Devices

Patients that have been implanted with LVADs are reported to have improved survival, functional capacity and health status, although many continue to report exercise intolerance and heart failure symptoms. The Rehab-VAD trial is the largest prospective randomised trial of the beneficial effects of exercise on LVAD patients. It included 26 patients randomised to CR or usual care after implantation of an LVAD. It demonstrated that exercise was safe in the CR group with only one event (syncope) in more than 300 sessions, and showed an improved total treadmill time, muscle strength and improved health status (evaluated by the Kansas City Cardiomyopathy Questionnaire) with continuous flow LVADs compared with usual care. 20 There was no difference in the peak VO 2 , which has been a marker of exercise capacity in people with CHF, although additional studies have suggested an improvement in VO 2 with exercise therapy after VAD implantation. 32 A recent study of 1,164 Medicare beneficiaries receiving LVADs demonstrated low participation in CR (30%). Of those who participated in CR, there was a decreased risk of hospitalisation and mortality at 1 year after multivariate adjustment with a 23% and 47% reduction, respectively, compared with those who did not participate in CR. 33 This was not the primary outcome of this study and there were likely additional confounding variables, although it suggests potential clinical benefits and identifies a need for further studies to evaluate the value of exercise in people with LVADs ( Figure 1A ).

Patients Exercising

Cardiac Transplantation

Although there have been significant improvements in OHTs over the past 40 years, long-term survival remains limited. Exercise capacity and health-related QoL in transplant recipients have been noted to be inferior compared with age-matched healthy people. 34 In the past, transplant patients were advised not to exercise due to concerns of chronotropic incompetence in the denervated heart, although further studies have shown evidence of sympathetic reinnervation, which is associated with improved exercise capacity and may be improved by physical training. 35 An updated Cochrane review in 2017 included ten randomised controlled trials with 300 patients who had OHTs demonstrated the safety of exercise therapy in transplant patients with only one reported adverse event. Nine studies compared exercising to control and one study compared high-intensity to moderate-intensity training. 21 CR participation was associated with an improvement in peak VO 2 and exercise capacity, although there was no significant improvement in health-related QoL in a 12-week period. There was no data to report hospitalisations or mortality benefit in these studies. Additional studies have demonstrated improvement of peak heart rate, ventilatory capacity, autonomic function and QoL with exercise training. 36 In an evaluation of CR and readmission rates for 595 Medicare beneficiaries that received heart transplants in the US in 2013, 55% of patients were enrolled in CR. Participation in CR was associated with a 29% lower readmission risk at 1 year. 36 Younger patients (aged 35–49 years) were significantly less likely to enrol in CR, and those that enrolled were likely to attend fewer sessions that patients older then 65 years. There have been no published studies investigating the effects on mortality of OHT patients who have participated in exercise training or CR. Given the significant benefits of CR and the CMS coverage of CR in orthotopic heart transplant patients that was approved in 2006, there should be a significant effort to improve uptake of CR in this patient population ( Figure 1B ). 37

Indications for CMS Cardiac Rehabilitation Coverage

CMS Coverage

In 2006, CMS published a decision that there was adequate evidence to approve coverage of CR for patients with an acute MI, coronary artery bypass graft, stable angina, heart valve repair or replacement, percutaneous transluminal coronary angioplasty or coronary stenting, and heart or heart and lung transplant ( Table 3 ). 37 At that time, there was insufficient evidence to approve CR coverage for CHF patients. After numerous studies were published demonstrating benefit of exercise training for patients with HFrEF, the largest of which being HF-ACTION, CMS expanded coverage for stable, chronic HF defined as patient with an LVEF ≤35% with NYHA II–IV symptoms despite optimal medical therapy for at least 6 weeks without recent or planned hospitalisation or procedure. 15 Specific CR coverage is not available for patients with HFpEF, ADHF or LVAD, although many LVAD patients are eligible for CR under the HFrEF indication, or by medical criteria for disability with LVEF ≤30% with symptoms affecting daily living. 33 Although HFpEF patients represent a significant number of CHF patients and hospital admissions, and ADHF is a significant cause of morbidity, mortality and is a component of healthcare expenditures, there is currently no CMS coverage for CR for these patients. Additional studies, including the Ex-DHF trial for HFpEF and REHAB-HF trial for ADHF, are necessary to demonstrate safety and clinical benefit to encourage CMS coverage for CR. 18,30,31

Uptake and Adherence

Despite numerous benefits and CMS coverage for many patients, there has been significant underuse of CR for people with CHF. An earlier study demonstrated that only 10.4% (12.2% HFrEF, 8.8% HFpEF) of 105,619 eligible patients with HF (48% with HFrEF, 52% with HFpEF) received a CR referral after hospitalisation for CHF. 38 In the HF-ACTION trial with HFrEF patients, despite numerous methods to reinforce adherence, about 30% of those enrolled in the exercise arm exercised at or above the target goal. 10 A retrospective study using the CMS and the Veterans Health Administration (VA) national data between 2007 and 2011 evaluated CHF patient enrolment in one or more sessions of CR. Of the 66,710 veterans and 243,208 Medicare beneficiaries hospitalised for HF, 2.3% and 2.6% respectively, attended one or more sessions of outpatient CR. 39 The investigators noted that they were unable to determine the prevalence of HFrEF that would be eligible for CR in these populations by using the ICD-9 codes. Much of the US data was collected before CMS coverage expansion of HFrEF in 2014. For LVAD and OHT recipients with Medicare coverage, uptake of CR was 30% (of 1,164 LVAD patients) and 55% (of 595 OHT patients). 33,36 In a 2010 European survey, it was reported that <20% of HF patients were participating in CR. 40

There are many potential barriers involving either the healthcare system or patient adherence that influence the use of CR. The healthcare provider should understand that current guidelines, consensus statements and high-impact studies demonstrate the value of exercise training, in addition to confirming available CR sites with educated CR teams. Additionally, many patient factors, including socioeconomic factors, work conflicts, inadequate transportation, lack of reimbursement, significant symptoms, as well as patient attitude, beliefs and motivations, affect enrolment and adherence to CR. 43 In many cases, there are multiple barriers that need to be addressed to significantly improve CR use in people with CHF.

CHF is an increasingly prevalent disease with significant morbidity and mortality despite optimal drug and device therapies. Exercise training and cardiac rehabilitation have demonstrated numerous benefits for people with CHF, including improved exercise capacity and QoL, in addition to improved clinical outcomes. Exercise has also been established as safe and feasible with HF and, in some studies, exercise therapy has demonstrated improved cost-efficiency in HF management. The majority of current studies and subsequent guidelines have been established based on the benefits of exercise in HFrEF patients, although further studies are necessary to evaluate clinical outcomes with exercise in different HF populations to drive expansion of the guidelines to include HFpEF, VAD and OHT patients. Despite numerous benefits in multiple HF groups, there is significant underuse of CR due to many barriers that need to be overcome. Healthcare providers should strongly consider referring their patients with CHF to CR and encouraging participation in and adherence to exercise training programmes.

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Power up! —

Getting a charge: an exercise bike that turns your pedaling into power, lifespan's ampera offers a solid workout, but it has a lot of quirks..

John Timmer - Mar 28, 2024 9:39 pm UTC

I enjoy getting my exercise but hate doing it indoors. I'd much rather get some fresh air and watch the world drift past me as I cycle or hike somewhere than watch a screen while sweating away on something stationary.

To get a bit more of what I like, I've invested in a variety of gear that has extended my cycling season deeper into the winter. But even with that, there are various conditions—near-freezing temperatures, heavy rains, Canada catching fire—that have kept me off the roads. So, a backup exercise plan has always been on my to-do list.

The company LifeSpan offers exercise equipment that fits well into a home office and gave me the chance to try its Ampera model . It's a stationary bike that tucks nicely under a standing desk and has a distinct twist: You can pedal to power the laptop you're working on. Overall, the hardware is well-designed, but some glitches, software issues, and design decisions keep it from living up to its potential.

Solid hardware

Many aspects of the Ampera are pretty well-designed. Its hefty weight keeps it stable even when someone my size (~90 kg/200 lbs) is pedaling away on it. If it starts tilting, there's a metal ring around the base that should keep it from falling over, although I've been fortunate enough not to test this. Despite its size, it's still easy to move around since it tilts forward onto some wheels and rolls around easily.

That tilting is best managed by using a handle that attaches to the underside of the seat. That's more of a mixed bag, as it limits how far back on the seat you can sit. It should be possible to install it upside-down so the handle tilts under the seat if this is a problem, though. The height of the seat is easily adjustable. It telescopes out of the base on a metal pole; pull up on a lever under the seat, and it will slide up or down to wherever you find comfortable.

Even with my relatively long legs, I had no problem finding a comfortable setting. However, to keep working while pedaling, I needed to set a standing desk at its maximum height. This is not something that you can expect to use while sitting at a more traditional desk.

As for the seat itself, it's wide and cushy, so quite unlike a typical bike saddle. There are a few things about this that I'm not convinced by. To start with, the padding will eventually wear down if it's heavily used, and the use of a non-cycling attachment—it bolts onto a flat metal plate—means it's going to be harder to replace. The fabric might also be a problem if, as I do, you tend to sweat a lot while exercising. (More expensive stationary bikes, like Pelotons, can fit standard bicycle seats.)

The pedals are fine. The texture of the polymer mostly kept my feet where I wanted them. The occasional slip was likely because I'm unused to thinking about how to keep my feet in place—the product of using clipless pedals on both my road and mountain bikes.

The two other notable features of the hardware are a ring of colored LEDs around the cranks, a USB-C port at the front of the base, and a Qi wireless charging pad in the center of the pedestal. There aren't any controls on the hardware; everything is controlled via software.

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Exercise can help treat depression, but what works best depends on age and gender: study

Health Exercise can help treat depression, but what works best depends on age and gender: study

Treating depression can be complicated and financially draining.

Seeing a psychologist can leave a big hole in your wallet, and anti-depressants can have such  debilitating withdrawal symptoms  that some people have to take them indefinitely.

But what if there was one more treatment option you could consider?

There is; it's exercise. And a new study suggests it can actually be more beneficial than antidepressant medication alone.

But the type you do, and how you do it, matters.

Australian researchers recently completed a major review of 200 randomised trials  on exercising to treat depression. It meant analysing over 14,000 people with clinical depression, which is characterised by at least two weeks of feeling low.

After concluding exercise was an effective treatment, they went further and compared specific types of exercise.

So let's unpack what they found.

And just quickly, before we do that, it's important to note anti-depressants and cognitive behavioural therapy are effective for some people and anyone changing their treatment plan should talk to their doctor.

Which activities are most beneficial?

Walking or jogging , yoga and strength training are about as effective as cognitive behavioural therapy and more effective than anti-depressant medication alone.

But we can narrow it down further.

The review found yoga and qigong (a Chinese system of physical exercises and breathing control) are likely to be more effective for men , and strength training is best for women .

Yoga is somewhat more effective for older adults and strength training can lead to greater improvements among younger patients.

Dance is also great at lowering depressive symptoms.

"I think that's because it has that social interaction, vigorous exercise, uplifting music and so it seems a really promising avenue for research," says Michael Noetel, lead researcher and senior psychology lecturer at the University of Queensland.

However, most studies on dance are on young women so Dr Noetel says there needs to be more varied research before it's recommended more widely.

Interestingly, the review found stretching to be the least helpful type of exercise for treating depression.

How often do I need to exercise?

The Australian guidelines suggest supervised group exercise for 30 to 40 minutes three times a week for a minimum of nine weeks.

But this new review found it didn't matter how many minutes or sessions of exercise people did per week (as long as they did some).

The effect of exercise was also the same whether you had mild or severe depression.

However, the intensity of the activity does matter; so the more vigorous, the better.

The benefits are also greater if you participate in exercise with other people as opposed to going at it alone.

What if I don't like any of these exercises?

There's no point trying to pursue yoga or weight training if you really hate it.

In fact, pushing yourself to do something you get no sense of satisfaction from can actually have a negative effect, says Rhiannon White, senior lecturer at the University of Western Sydney, who was not involved in the review. 

She's been studying the link between physical activity and mental health for 10 years and says it can be unhelpful to be overly prescriptive about what exercise people with depression should do.

"If we say 'this is the best type' and someone doesn't feel competent doing it or can't access that activity due to cost then exercise doesn't feel like an option to them," Dr White says.

"It's good to know what types are more beneficial but then we need to guide people to find the one that gives them the biggest sense of accomplishment ... that might not be resistance training, it might be a walk to the park with their dog or a friend."

Context matters, she says, and e ven the time of day you exercise can alter the mental health benefits you receive.

So why is exercise good for depression?

Experts believe there are a few reasons.

When someone is depressed they can get stuck in a cycle of isolation — they withdraw socially and then find it hard to re-integrate — but exercising with others can break that cycle.

Depression can also make you feel hopeless, making it difficult to get out of bed and do the things that are important to you. This can create a loop of guilt, but exercise can break this by providing a sense of accomplishment, Dr Noetel says.

That's why resistance training can be so effective as it's based on the number of repetitions and it's easy to set small goals and see progress.

There's also a lot to be said for novel experiences. If you are learning something new, there's a greater sense of satisfaction when you master it.

Dr Noetel suggests this could be the reason why yoga is more effective for men.

"If I think of my dad, he would not have done a downward dog in his whole lifetime ... so it's about learning something new, it's the cognitive aspect."

On top of that, when we exercise we get a surge of neurotransmitters like dopamine (ever had runners high?) which could be why more vigorous exercise has stronger effects.

How can I get started?

Those experiencing depression might meet the criteria for a chronic disease management (CDM) plan, which could get them  up to five subsidised sessions under Medicare  with an exercise physiologist.

Accredited exercise physiologists often design programs for people with anxiety, depression and post-traumatic stress disorder.

"They could support you as you start exercising and although five appointments isn't a lot, it's a start and starting is often the biggest hurdle," Dr Noetel says.

CDM plans can be arranged by a GP but Dr Noetel says not many doctors use them to refer people to exercise physiologists, perhaps because the field is relatively new.

Dr White says unfortunately many GPs don't go further than giving their patient a nudge to get moving, which isn't much help. 

Both experts say it's important exercise isn't considered an "add-on" treatment and research shows patients do a lot better when they are given a structured exercise program, rather than just encouragement.

How can I stay motivated?

Depression is often characterised by days where leaving the house is an impossibility, so getting to a gym or a group class won't be realistic.

Dr White says this is why it might be more helpful to have a support person, like a family member or friend, who can be on standby to come around and accompany you on a walk around the block on bad days.

She says online exercise videos might be preferable when symptoms are worse, as they can be done at home.

"It might not be the best exercise you'll ever do but it's the small steps that build a bit of confidence."

She suggests keeping in mind three factors that determine whether we feel motivated to exercise:

• who we're exercising with and whether we feel supported by them
• a sense of competence
• value and enjoyment from the activity

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Fitness influencers swear by the 'carnivore diet'—it's 'basically a terrible idea,' doctor says

Beef, butter, bacon and eggs — that's what some influencers swear by for the " carnivore diet ." The diet beefs up on meat and minimizes or cuts out fruit and vegetables entirely.

On TikTok, people can be seen eating bowls of steak and 12 scrambled eggs all in one day — and some even snack on a stick of butter , biting off a piece the way one would a carrot.

The diet, similar in style to the Atkins and keto diets, goes by many names: carnivore diet, lion diet, high-fat diet and animal-based diet. Devout followers of the lifestyle boast that their skin is clearer than it's ever been, their gut is healthier and they're in the best shape of their lives.

"One of the best things that's happened since I quit the vegan diet and went carnivore is that my body odor just disappeared," TikToker @steakandbuttergal said in one of her videos . "I don't use any soap, I don't use any deodorant and I smell amazing."

Here's what experts have to say about the safety and sustainability of the carnivore diet.

The carnivore diet 'sounds like basically a terrible idea'

Weight loss is one of the huge benefits that people who follow the carnivore diet claim they've experienced since adding more animal-based products to their diet. This is likely because the eating pattern also cuts down on carbs, says Dr. Walter Willett , a professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health.

"It's possible that some people who have been eating a lot of refined starch and sugar may get better in the short run," with the carnivore diet, Willett says. "But this sounds like a diet that is going to be very unhealthy in the long run."

With a diet of just beef, butter, bacon and eggs, people won't get enough fiber, carotenoids and polyphenols which are rich in fruits and vegetables.

Getting fiber in your diet is vital for gut health and can lower your chances of developing depression and breast cancer . Carotenoids have cancer-fighting properties , and polyphenols have properties that can protect against the development of health conditions like diabetes, heart disease and cancer.

The foods that are prominent in carnivore diets also contain high amounts of saturated fat and cholesterol, Willett adds.

In a 2012 study published in the Archives of Internal Medicine, Harvard researchers found that of more than 100,000 men and women, "People in the study who ate the most red meat tended to die younger, and to die more often from cardiovascular disease and cancer," according to Harvard Health Publishing .

Despite the multitude of studies that connect red meat consumption and heart disease , some people just don't agree that consuming red meat often is bad for your heart.

"This is the the mainstream messaging that we hear about red meat. It's essentially been blamed for all kinds of human health catastrophes, from cardiovascular disease to colon cancer," says Dr. Georgia Ede , a Harvard-trained, board-certified psychiatrist who specializes in nutritional psychiatry.

"They're based almost entirely on a type of research method called nutrition epidemiology, which is just untested theories, essentially, guesswork, about how red meat might be affecting us, that have never been tested in clinical trials and been found to be supported," Ede says. "Then the rest of the very little additional evidence that does come from experimental studies, that comes from very strange animal studies."

To better understand how food intake may lead to disease, researchers have study participants write down or complete surveys about what they've eaten, which are all self-reported.

Some believe that this is a flawed way of coming to conclusions about how foods impact health, but experts have yet to land on a better alternative.

'If you're eating that kind of meal, you're helping bring down another tree'

But even if people are really weary about the way in which nutritional studies are conducted, what can't be denied are the effects of meat production on the climate.

To this, Ede says: "Industrialized food production, whether it's plants or animals, is really very harmful for the planet."

And while this is true, there is a clear difference between how much the production of plant foods is impacting the environment versus animal-based products. The emissions of global greenhouse gases, like methane, from the production of animal-based foods are double that of the production of plant-based foods.

"In addition to the direct health effects that are going to be quite adverse," Willett says. "There's also the issue of justice that basically the Global North, Europe [and] the United States, cause most of the problems with climate change that we have today, and this sort of perpetuates that."

"You can think [that] if you're eating that kind of meal, you're helping bring down another tree on the other side," he adds. "Sounds like basically a terrible idea."

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• v.13(10); 2021 May 31

Effects of exercise on cellular and tissue aging

Priscila viana carapeto.

1 Beta Cell Aging Lab, Joslin Diabetes Center, Harvard Medical School, Boston MA 02115, USA

Cristina Aguayo-Mazzucato

The natural aging process is carried out by a progressive loss of homeostasis leading to a functional decline in cells and tissues. The accumulation of these changes stem from a multifactorial process on which both external (environmental and social) and internal (genetic and biological) risk factors contribute to the development of adult chronic diseases, including type 2 diabetes mellitus (T2D). Strategies that can slow cellular aging include changes in diet, lifestyle and drugs that modulate intracellular signaling. Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation. Herein, we review the effects of exercise to attenuate aging from a clinical to a cellular level, listing its effects upon various tissues and systems as well as its capacity to reverse many of the hallmarks of aging. Additionally, we suggest AMPK as a central regulator of the cellular effects of exercise due to its integrative effects in different tissues. These concepts are especially relevant in the setting of T2D, where cellular aging is accelerated and exercise can counteract these effects through the reviewed antiaging mechanisms.

INTRODUCTION

The natural aging process is carried out by a progressive loss of homeostasis entailing a variety of physiological changes in the function of cells and tissues. To systematically dissect the biological aging process, Lopez-Otin et al. characterized nine major hallmarks of aging that are divided as primary (genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis), antagonistic (deregulated nutrient-sensing, mitochondrial dysfunction and cellular senescence), and integrative hallmarks (stem cell exhaustion and altered intercellular communication). Due to their functional characteristics, primary hallmarks are considered causes of damage, antagonistic hallmarks are responses to damage while the integrative hallmarks reflect the end results of the first two categories [ 1 ]. The interconnectivity between the different hallmarks provides a systematic approach to evaluate interventions that target aging at a cellular level.

Exercise is a lifestyle intervention with known antiaging effects capable of counteracting several of the hallmarks of aging including senescence and age-associated inflammation [ 2 – 4 ]. We propose that 5’ adenosine monophosphate-activated protein kinase (AMPK) can orchestrate many of the antiaging effects of exercise through its regulation of diverse cellular pathways in the setting of energetic stress [ 5 ]. Activating AMPK is sufficient to extend lifespan in many organisms. It is naturally activated in response to muscle contraction and nutrient depletion, both of which are components of exercise [ 6 ]. Whereas most of the studies supporting AMPK as an antiaging strategy are based in animal models, the use of metformin (an AMPK activator) in clinical trials (TAME) as an antiaging drug is based on its capacity to delay heart disease, cancer, cognitive decline and death in people with diabetes [ 7 ]. These results suggest that the antiaging effects of AMPK are also relevant in humans, but the molecular mechanisms underlying these effects remain to be determined.

Type 2 diabetes (T2D), a condition that integrates these concepts, is considered a disease of aging, affecting 30 million people in the United States, most of whom are over the age of 50 [ 8 ]. Mortality risk is 50% higher in people with T2D with doubled medical costs and lost work and wages per year. Additionally, longevity and healthspan are impaired by its associated health complications including blindness, kidney failure, heart disease, stroke and amputations.

From a pathophysiological point of view, accelerated cellular aging plays a role in T2D. Studies have shown that people with T2D have shorter telomeres and mitochondrial DNA depletion [ 9 ] and at a cellular level the following tissues display markers of the hallmarks of aging: endothelium [ 10 , 11 ], collagen [ 12 ], pancreatic β-cells [ 13 ] and muscle [ 14 , 15 ]. Many of these can worsen metabolic control and contribute to the development of cardiovascular complications.

Exercise is known to be an effective lifestyle intervention for T2D since it improves metabolic control. However, to consider the effects of exercise from a cellular aging point of view is a conceptual change in how physical activity is envisioned as a therapeutic tool for diabetes.

Herein, the antiaging effects of exercise are reviewed from a tissue and cellular level, its effects upon the individual hallmarks of aging and how AMPK can integrate many of these effects. Finally, these concepts are applied to the setting of T2D to provide a novel view of how this disease can be approached from a cellular aging perspective.

Definitions and search criteria

This review follows the guidelines of exercise and physical activity for older adults from the American College of Sports Medicine [ 16 ] where exercise is defined as planned, structured and repetitive movement to improve or maintain one or more components of physical fitness. Sedentary living is defined as a way of living or lifestyle that requires minimal physical activity and encourages inactivity through limited choices, disincentives and/or structural or financial barriers.

The aim of the present review paper is to survey the literature related to exercise and its association with longevity and aging. The rationale for conducting this review is that aging is often accompanied by declining cellular homeostasis which is crucial to the development of chronic diseases, but lifestyle interventions can slow down its effects. The literature was surveyed on MEDLINE through freely accessible PubMed as a search engine for the terms: “exercise”, “longevity” and “aging”; the most relevant studies were included as they related to the 9 hallmarks of aging. Additional searches were performed to elucidate the potential role of AMPK activation upon the hallmark of aging. Studies from animal models, human, meta-analysis and bibliographic reviews were consulted and cited accordingly.

Exercise as an antiaging strategy

The aging process affects longevity and health span which are influenced by both genetic and environmental factors [ 17 ]. To systematize its study, Holloszy defined primary and secondary aging. Primary aging refers to the inevitable deterioration of cellular structure and function, independent of disease and environment such as hearing and visual loss. However, secondary aging refers to physiological changes influenced by disease and environmental factors, they are not inevitable and can be accelerated by sedentary lifestyle or delayed by exercise [ 18 ]. Examples of secondary aging include insulin resistance, lessened skeletal mass and function, decline of components of the immune system and of cognitive function [ 19 ].

The complex relationship between factors that are accelerated by a sedentary lifestyle and those that are solely due to age, has been successfully addressed in various reviews [ 19 , 20 ]. These studies highlight the importance of studying aging in physically active individuals, ideally in longitudinal studies across the life course of an individual such that the confounding effect of sedentary behavior in the loss of functionality during aging is avoided. As an example, a landmark 21-year longitudinal study at Stanford that followed runners and compared them with a sedentary group, found that those who exercise had a significantly lower risk of dying (15%) during that time frame than the sedentary group (34%) while also having reduced disabilities [ 21 ]. It is unclear whether the beneficial effects of exercise in this study were due to a delay in secondary aging or to countering of the effects of sedentarism.

Regardless of this limitation, numerous studies have shown that maintaining a minimum quantity and quality of exercise improves cardiorespiratory fitness and muscle function, flexibility and balance [ 22 ]. Current guidelines recommend a minimum of 150 min/week of moderate intensity aerobic activity for maximum longevity benefits, with higher duration and intensity increasing cardiovascular and metabolic effects. It has been estimated that performing three to five times the recommended physical activity (450-750 min/week) reaches the maximal healthspan benefit that can be achieved with endurance exercise. Strength training should be added to minimize loss of muscle mass that is characteristic of aging and disease [ 23 ].

The beneficial effects of exercise upon longevity and health span are also evident in individuals that have a genetically determined longevity, such as centenarians. In this unique population, the decline in lung function and sarcopenia can be counteracted by exercise programs which increase their physical capacity and health span [ 24 ].

When compared with other interventions directed at slowing aging, such as caloric restriction, some studies have shown that in mice, exercise lacks the adverse outcomes that were observed with time restricted feeding (lean mass and cardiovascular maladaptation) [ 25 ] and should therefore be a first line choice as an antiaging strategy. Additionally, it is currently unclear whether caloric restriction has a positive effect in humans. Current research is exploring intermittent fasting as an alternative with beneficial antiaging effects at a cellular level in animals and humans [ 26 , 27 ].

The effects of exercise upon different organs and systems and its contribution to longevity and health span have been summarized in Figure 1 and Table 1 .

Effects of exercise upon the aging process of different organs and systems. Created in BioRender.

Cardiopulmonary

Cardiovascular (CV) disease is a major cause of mortality worldwide and sedentary lifestyle highly contributes to CV disease burden. Cardiorespiratory fitness, as measured by maximal oxygen uptake (VO 2 max), is a strong and independent predictor of all-cause mortality [ 28 ] and improvement of CV health can be achieved through frequent physical activity and exercise. Even a generally active daily life, without regular exercise, is positively associated with CV health and longevity in older adults [ 29 ].

However, appropriate volume and intensity are essential to maximally benefit from exercise interventions as excessive exercise is counteractive [ 30 ]. Several publications reviewed in [ 31 ] have studied marathon runners as examples of strenuous and endurance exercise. There is general consensus that vigorous exercise, acutely and transiently, increases the risk of sudden cardiac death but only in individuals with underlying cardiac disease. Additionally, several studies have measured cardiac enzymes in runners after completing a marathon and have shown that a subset of them display elevation of cardiac enzyme creatine kinase, troponins and natriuretic peptides, suggesting myocardial injury. Elevation of these markers correlated with younger age, presence of cardiovascular risk factors, running inexperience, increased exercise duration and intensity as well as dehydration. Additionally, it has been shown that prolonged exercise (>2000 min/week) correlates with a higher prevalence of atherosclerotic plaques. However, the composition of these plaques was more benign with fewer mixed plaques and more plaques with only calcification, which might explain the increased longevity of endurance athletes even in the presence of atherosclerotic plaques [ 32 ]. Overall, exercise is beneficial to cardiovascular health, and proper training techniques that allow for the proper cardiac adaptations to long-term exercise, also named athlete’s heart , can counteract the transient increased CV risk linked to prolonged and strenuous exercise.

The effect of exercise amongst the population with established CV events is also beneficial. After a myocardial infarction, exercise has been shown to prevent future complications, improve the quality of life and longevity of patients [ 33 ]. Amongst older adults with heart failure and preserved ejection fraction, exercise training is the most effective intervention to improve functional outcomes. In a mouse model of this disease, RNASeq of explanted hearts showed that exercise reversed age-related pathways such as those that correlated with cell cycle [ 34 ].

One of the mechanisms by which exercise mediates CV benefits is by enhancing the function of endothelial progenitor cells, which play a role repairing endothelial injuries. With age, progenitor cells have been shown to dysfunction; exercise increases expression of CXCR4 and phosphorylation of JAK-2 thus improving progenitor cell functional capacity [ 35 ]. Additionally, exercise decreases age-associated vascular endothelial oxidative stress, improves vascular endothelial function [ 36 ] and increases hematopoietic stem cells, markers of neovascularization and vascular repair [ 37 ].

Muscle/bone/skin

Loss of muscle mass is characteristic of aging and it starts to decline after 25-30 years of age such that by 80 years 40% of muscle mass has been lost [ 38 , 39 ]. This is thought to contribute to a wide array of age associated pathologies such as frailty, weakness, loss of function, metabolic syndrome, cancer, Alzheimer’s and Parkinson’s disease [ 39 – 41 ], and is believed to be secondary to the loss of myokines (muscle-derived growth factors and cytokines) that modulate systemic physiology.

Progressive skeletal muscle wasting is known as sarcopenia and is characterized by a decrease in muscle cross-sectional area due to reduction fiber number and its atrophy [ 42 ]. A number of mechanisms underlying this process have been proposed, being correlated with the primary and antagonistic hallmarks of aging, including loss of mitochondrial density and instability of its DNA (mtDNA) [ 43 ]. Another aspect suspected to play a role is failure of adaptive responses to contractile activity, such as the ability to clear reactive oxygen species. A study using mice lacking the Cu, Zn superoxide dismutase showed an accelerated, age-related loss of muscle mass and function which correlated to chronic exposure to increased oxidant activity [ 44 ].

Regular physical activity is the only efficient intervention to prevent and treat this age-associated degeneration. Aerobic endurance training improves peak oxygen consumption by 10-15% while resistance training increases muscle strength and mass. On a mechanistic level, exercise reduces sarcopenia by decreasing inflammation and increasing anabolism and protein synthesis [ 45 ]. Additionally, activation of peroxisome proliferator-activated receptor gamma (PGC-1α) improves muscle endurance, mitochondrial remodeling and enhanced balance and motor coordination in animal models [ 46 ].

Bone is another tissue profoundly affected by secondary aging. Loss of bone mass and strength characterize the aging process predisposing to the onset of osteoporosis and fractures. Exercise interventions are a long-term strategy to maximize bone mass and delay the onset of osteoporosis. These interventions need to include weight-bearing activities to generate bone formation and delay telomere shortening and modification of DNA methylation [ 47 ].

Skin, a component of the integumentary system, is also affected by secondary aging which deteriorates its structure compromising its function as a barrier, healing and making it prone to disease. Endurance exercise attenuates age-associated changes to skin in humans and mice partly through IL15, which acts as a regulator of mitochondrial function in aging skin. Upregulation of IL15 is thought to occur through activation of muscle AMPK, a central regulator of metabolism, therefore the elimination of muscle AMPK causes a deterioration of skin structure [ 48 ].

Peripheral and central nervous systems

Chronological aging is associated with a decline in cognitive, memory and executive functions as well as a decline in peripheral nervous system such as neuromuscular junctions. Some of these changes are thought to be due to primary aging and are therefore not amenable to interventions; however, a subset of age-related changes is thought to be due to secondary aging and therefore is influenced by sedentary lifestyle and exercise.

High levels of exercise have been associated with better executive function and memory in cross-sectional and longitudinal analyses [ 49 ]. In fact, regular physical activity is one of the few interventions capable of preventing Alzheimer’s disease and other age-associated neurodegenerative disorders [ 50 ]. This benefit relates to exercise’s ability to increase the endurance of cells and tissues to oxidative stress, and to increase vascularization, energy metabolism and neurotrophin synthesis, all of which play a role in neurogenesis, memory and brain plasticity. Additional mechanisms of exercise action on the central nervous system are increased neurotrophins, growth factors and synaptic markers coupled with a reduction in inflammation [ 51 – 55 ].

Retinal ganglion cells (RGCs) which become vulnerable to injury with advancing age with resultant impaired vision, are also restored by exercise in mice. This is due to sustained levels of brain-derived neurotrophic factor (BDNF) levels in the retina underscoring the role of this critical factor in maintaining retinal health during aging of animal models [ 56 ].

Within the peripheral nervous system, neuromuscular junctions modify their structure with age. These changes are characterized by axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites and fragmentation of the postsynaptic specialization. However, one month of voluntary exercise in 22-mo-old mice reversed age-related synaptic changes with no change on motor neuron number or muscle fiber turnover [ 57 ].

Additionally, the psychological effects of exercise are profound and include relaxation and alleviation of anxiety and depression. These effects are strong enough that exercise can turn into an addiction [ 58 ]. Given its effectiveness and safety, it should be considered a first line of choice to treat many psychological ailments among the elderly, including insomnia.

Metabolism and glucose control

Secondary aging is associated with the development of insulin resistance, increased adiposity, and accumulation of ectopic lipid deposits in tissues and organs; all of which contribute to metabolic dysfunction [ 59 ] increasing the risk of T2D.

Several metabolic alterations accumulate over time along with a reduction in physical fitness, suggesting the existence of a "metabolic clock" that influences aging. The main features of the "westernized" lifestyle (hypercaloric nutrition and sedentary behavior) accelerate the metabolic decline of secondary aging factors, such as insulin resistance, while the promotion of metabolic fitness leads to health span extension [ 60 ].

The beneficial effects of exercise upon glucose metabolism are well known and have been thoroughly studied [ 61 ], converting increase physical activity in one of the pillars of the treatment of T2D. The human body reacts to an acute bout of exercise by decreasing insulin secretion and increasing circulating glucagon, leading to improved insulin sensitivity and decreased glycosylated hemoglobin [ 62 ]. However, exercise as an antiaging strategy in the context of T2D is novel and could add to its known beneficial metabolic effects.

In summary, exercise has shown to have beneficial antiaging effects of many human organs and tissues either by reversing some of the aging phenotypes or by delaying their appearance ( Figure 1 and Table 1 ).

Signaling pathways through which exercise mediates anti-aging effects

The consequences of exercise on the aging of specific organs and tissues can be studied at a cellular perspective and structured based on the changes it has upon the hallmarks of aging.

Primary hallmarks

Genomic instability.

Age is characterized by the accumulation of lesions in the DNA and defects in the nuclear architecture leading to genomic instability. These are the result of exogenous (physical, chemical and biological agents) and endogenous factors (DNA replication errors, spontaneous hydrolytic reactions and reactive oxygen species) [ 63 ] that result in mutations, translocations, chromosomal gain and losses, telomere shortening and gene disruption.

Exercise minimizes these lesions, partly through: reduction of the age-associated 8-hydroxy-2'-deoxyguanosine (8-OHdG) [ 64 ], increased activity of DNA repair, resistance to oxidative stress in proteins, and nuclear factor kappa B (NF-kB) and PGC-1α signaling [ 64 – 66 ].

Telomere attrition

Telomeres protect the integrity of chromosomal DNA during cellular division but are particularly susceptible to age-related deterioration [ 67 ]. Studies have demonstrated a direct correlation between telomere length and life expectancy, stress, DNA damage and onset of age-related diseases. Various genetic and environmental factors, such as diet, physical activity, obesity and stress, are known to influence health and longevity as well as telomere dynamics.

Exercise is able to increase telomere length through changes in telomerase activity, inflammation, oxidative stress and skeletal muscle satellite cell content. Long-term exercise can activate telomerase reverse transcriptase (TERT) in leukocytes and also upregulate protective and DNA repair regulator proteins (such as telomeric repeat-binding factor 2 and Ku protein). This has important physiological consequences since a positive correlation has been shown between muscle regeneration processes and telomere length in older adults [ 68 ].

Epigenetic alterations

Exercise is capable of inducing widespread epigenetic changes. General loss of histones, imbalanced histone modifications, transcriptional deregulations, changes in heterochromatin, breakdown of nuclear lamina, as well as DNA and histone methylation, are characteristics of aging [ 69 ].

Physical activity increases DNA methylation, causes histone modifications and induces miRNA in muscle, brain and the cardiovascular system. Acute aerobic exercise decreases methylation of PGC-1α, mitochondrial transcription factor (TFAM), MEF2A, citrate synthase (CS) and pyruvate hydrogenase kinase isozyme (PDK4) [ 70 ]. In addition, aerobic-induced SIRT-1 downregulates p53, PGC-1α and NF-kB via its deacetylase activity [ 71 , 72 ]. Chronic moderate aerobic exercise reduces inflammation through a decrease of pro-inflammatory cytokines (IL-1b and IL18) that is mediated by methylation of pro-inflammatory apoptosis-associated speck-like protein caspase (ASC) gene [ 73 ].

Loss of proteostasis

Some age-related diseases are linked to impaired protein homeostasis – known as proteostasis. Cell autophagy is one of the mechanisms for degradation and recycling of damaged macromolecules and organelles, and its alteration can lead to disease. Although human data are still scarce, muscle autophagy markers are up-regulated after exercise training in older women [ 74 ] and could underlie the promotion of health span and longevity.

The target of rapamycin complex 1 (TORC1) - a central kinase involved in protein translation- is a negative regulator of autophagy and so may be an effector of exercise. TORC-1 is downregulated by exercise through modulation of IGF-1, Akt/mTOR, and Akt/FoxO3a signaling. This cascade has been shown to prevent loss of muscle mass and strength [ 75 , 76 ]. Additionally, the protective effect of chronic exercise on diabetes-induced muscle atrophy is partly due to decreased muscle autophagy [ 77 ].

Antagonistic hallmarks

Deregulated nutrient-sensing.

Deregulation of nutrient sensing pathways have been extensively involved in age-related phenotypes, and their downregulation is one of the most effective strategies to extend lifespan and health span. As humans age, the loss of muscle mass occurs due to acute changes in net protein balance, particularly in the myofibrillar protein fraction [ 78 , 79 ], and exercise regulates the nutrient sensing pathways.

Insulin like growth factor (IGF-1) acts as a key link between mechanical contraction and protein synthesis since it is acutely stimulated and promotes ribosomal biogenesis and translation to form new myofibril proteins. During exercise the mechanical loading and contraction cause the local release of IGF1 which activates IGF and leads to to muscle protein synthesis [ 80 ].

Another exercise-regulated nutrient sensing pathway is AMPK, which is activated in response to decreased intracellular ATP and changes in the NAD+/NADH ratio. Its function is to preserve ATP by inhibiting both biosynthetic and anabolic pathways while simultaneously stimulating catabolic pathways to re-establish cellular energy stores. The increased concentration of Ca 2+ during muscle contraction can also directly activate AMPK and is implicated in the regulation of numerous intracellular proteins that mediate cellular transduction, including kinase C, calcineurin, and CaMKs [ 81 – 83 ]. Both AMPK and CaMKII lead to PGC-1α activation, a member of a family of transcriptional coactivators that regulate mitochondrial biogenesis [ 84 ] ( Figure 2 ).

AMPK as an effector node on the effects of exercise upon the different hallmarks of aging. AMP, adenosine monophosphate; AMPK, AMP- activated protein kinase; ATP, adenosine triphosphate; AGEs, advanced glycation end-products; FoxO3, Forkhead Box O3; LKB1, Liver kinase B1; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; NAD+, Nicotinamide adenine dinucleotide; NADH, Reduced Nicotinamide adenine dinucleotide; NFkB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NRF2, Nuclear factor erythroid 2-Related Factor 2; p53, Tumor suppressor protein 53; PGC-1, peroxisome proliferator-activated receptor gamma; SIRT1, Silent information regulator. Created in BioRender.

Oxidative stress is yet another mechanism through which exercise can regulate nutrient sensing by producing sestrins and activating the MAPK cascade [ 85 ], a family of intracellular signaling that include the extracellular signal regulated kinase 1 and 2 (ERK1/2), the c-Jun NH2- terminal kinase (JNK) and p38 [ 86 ]. Activation of this pathway leads to the inhibition mTOR complex 1 (mTORC1) [ 87 ] and activation of PGC-1α [ 88 ].

Mitochondrial dysfunction

The accumulation of mitochondrial damage due to ROS generated from the electron transport chain is the base of the mitochondrial theory of aging first proposed by Harman [ 89 ]. It postulates that the oxidative damage to mtDNA affects cellular replication and transcription, altering the functionality of mitochondrial proteins.

It has been known for a long time that exercise increases mitochondrial content in skeletal muscle [ 90 ]. Additionally, it can attenuate mitochondrial dysfunction through recovery of oxidative capacity and the activity of electron transport chain protein complexes [ 90 , 91 ]. In agreement with this, endurance athletes showed absence of age-related decline in mitochondrial oxidative capacity and elevated expression of mitochondrial proteins, mtDNA and mitochondrial transcription factors [ 92 ]. In mtDNA mutator mice, which exhibit an accelerated aging phenotype, a 5-month aerobic exercise program promoted systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly. These changes restored mitochondrial morphology and blunted pathological levels of apoptosis in multiple tissues [ 93 ].

Regular exercise has a profound beneficial effect on human mitochondrial function and biogenesis, partly mediated by PGC-1α upregulation. Phosphorylation of PGC-1α drives the production of fibronectin type III domain-containing protein 5 (FNDC5), followed by its cleavage to generate irisin [ 94 – 96 ], which can be secreted, activated and transported to multiple tissues to exert its beneficial effects.

Cellular senescence

Cellular senescence is characterized by lack of cellular proliferation in response to stressors and secretion of an array of proteins specific to each cell type. This array of proteins known as senescence-associated secretory phenotype (SASP) is part of the aging hallmark of altered intercellular communication.

Cellular senescence is linked to other mechanisms of aging. ROS accumulation in mitochondria leads to single-strand DNA breaks that accumulate in telomere regions and result in telomere shortening and premature cellular senescence. Senescence has been linked to numerous age-related chronic diseases and risk factors, such as T2D [ 13 , 97 , 98 ]. Exercise enhances telomere length and reduces the expression of apoptosis regulators (such as cell cycle checkpoint kinase 2, p16 INK4a , and P53) shedding light on the beneficial impact of exercise on senescence [ 68 ].

Expression of p16 INK4a , a marker and effector of senescence, in cellular fractions of human whole blood exponentially increased with chronological age and associated significantly with sedentary life style [ 99 ]. In addition, p16 INK4a expression correlated with plasma interleukin-6 (IL-6) concentration, a marker of human frailty. Exercise induces increased IL-6 derived from muscle which has anti-inflammatory properties, whereas paradoxically, IL-6 resulting from TNF or NFkB activation relates to aging phenotypes [ 100 ]. In a senescence rat model, exercise suppresses senescence markers and down-regulates inflammatory mediators by reducing gamma glutamyltranspeptidase activity and levels of p53, p21, and IL-6 [ 101 ].

In some settings, exercise-induced senescence is beneficial, such as the appearance of fibro-adipogenic progenitors in response to muscle damage, and leads to regenerative inflammation [ 102 ].

Integrative hallmarks

Stem cell exhaustion.

A decline in the regenerative potential of tissues is expected with age. Specifically, a decline in satellite cells results in impaired repair of muscle fibers while decreased hematopoietic stem cells leads to immunosenescence [ 103 – 105 ]. Exercise is one of the most potent stimuli for the migration of stem cell subsets from their home tissue to impaired ones for later regeneration. It increases the number and differentiation of satellite cells type II fibers [ 106 ]. In addition, exercise activates pluripotent cell progenitors in several tissues, including mesenchymal and neural stem cells leading to improved brain regenerative capacity and cognitive ability [ 107 ].

Altered intercellular communication

Pro-inflammatory tissue, damage accumulation, cumulative dysfunction of the immune system and elevated levels of pro-inflammatory cytokines secretion underlie the development of inflammaging, a pro-inflammatory phenotype associated with progressive aging that affects intercellular communication [ 108 ]. This is characterized by the activation of the NOD-like receptor protein 3 (NLRP3) and elevation of IL-1b, tumor necrosis factor-a (TNF-α) and interferons [ 108 , 109 ]. Exercise downregulates this inflammatory response through AUF1 [ 110 ], a decay factor implicated in maintenance of telomere length by TERT modulation [ 111 ].

Moreover, exercise further suppresses inflammation via IL-6 released from muscle [ 112 ]. Recent studies support the notion that IL-6 can activate pathways that have insulin-sensitizing effects [ 113 , 114 ] by activating AMPK in skeletal muscle, leading to increased glucose uptake and translocation of the glucose transporter GLUT4 from intracellular compartments to the plasma membrane [ 115 ]. Chronic moderate exercise increases methylation levels of the pro-inflammatory apoptosis-associated speck-like protein caspase (ASC) gene that controls secretion of IL-1β and IL-18 in leukocytes [ 73 ]. Exercise also controls age-related increases of pro-inflammatory cytokines thereby preventing accumulation of misfolded proteins [ 1 , 116 ].

In summary, exercise attenuates all hallmarks of aging through different molecular pathways and effectors that seem independent and disconnected. We hypothesize there must be molecular regulatory nodes able to coordinate these responses and that AMPK can play such a role.

AMPK as a central regulator

We propose that activation of AMPK plays a significant integrative role impacting the primary, secondary and integrative hallmarks of aging in response to exercise. In muscle, AMPK is a long known exercise effector that is activated by increased AMP/ATP and NAD + /NADH ratio [ 117 ]. Mammalian AMPK is a heterotrimeric complex with α, β, and γ subunits. Mechanistically, AMP interacts with AMPK’s γ subunit, facilitating activation of the α subunit by upstream regulatory kinases such as LKB1. In parallel, the increase in NAD + /NADH causes activation of silent information regulator 1 (SIRT1) deacetylase activating LKB1.

Thus cellular energy balance effectively controls cellular responses via an integrated signaling network mediated by AMPK [ 118 ], which phosphorylates its downstream targets and is able to attenuate the hallmarks of aging [ 119 , 120 ] ( Figure 2 ). Below is a list of the main effectors of AMPK and their actions upon the hallmarks of aging.

PGC-1α

PGC-1α is a critical regulator of gene transcription that controls energy homeostasis and is involved in mitochondrial biology [ 121 ]. In mouse skeletal muscle cells, PGC-1α mediates the conversion of IIb fibers into mitochondria-rich type IIa and I fibers [ 122 ]. Although PGC-1α mediated conversion has not been directly shown across species, type IIa fibers in humans have the highest concentration of PGC-1a [ 123 , 124 ], which could support a parallel mechanism. In addition, PGC-1α activation by AMPK has shown to act as a regulator of human telomere transcription via telomeric repeat-containing RNA (TERRA), important for telomere integrity [ 125 ].

Some of the effects of PGC-1α are mediated through its inhibition of NFκB. Ablation of PGC-1α led to activation of NFκB and upregulated pro-inflammatory cytokines [ 126 ] while increased expression of PGC-1α inhibited NFκB signaling in aortic smooth muscle and endothelial cells [ 127 ]. These observations suggest that AMPK controls NFκB activation and that deficiency of AMPK signaling during aging disturbs energy metabolism and enhances inflammation ( Figure 2 ).

Nuclear factor erythroid 2-related factor 2 (Nrf2)

Nrf2 is a basic leucine zipper protein involved in regulation of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. Studies using AICAR (an AMP analog and AMPK activator) showed stimulated expression of Nrf2 and upregulation of glutathione peroxidase 7 (Gpx7), leading to suppression of cellular senescence and SASP [ 128 ]. In addition, activation of Gpx7 via Nrf2 delayed cellular attrition related to stem cell aging [ 128 , 129 ] ( Figure 2 ).

Crosstalk between AMPK activated signaling pathways is demonstrated by inhibition of Nrf2 by the p65 component of NFκB complex through kelch-like ECH-associated protein 1 (Keap1). This crosstalk can have an additive effect upon decreased cellular senescence and stem cell maintenance ( Figure 2 ).

Activation of the FoxO3a axis by AMPK increased stress resistance in long-lived animals [ 118 ]. By mediating epigenetic and transcriptional changes, FoxO3, a member of the FOXO subfamily of forkhead transcription factors, is able to mediate the effects of therapeutic interventions on age-related diseases and promote healthy aging [ 120 ]. Target genes of the AMPK-FoxO3 pathway include uncoupling protein UCP2 and GAD45a, which are involved in defense against oxidative stress and DNA damage leading to longevity [ 130 ] ( Figure 2 ).

Tumor protein P53 regulates the cell cycle and functions as a tumor suppressor. The effects of exercise-activated AMPK upon P53 are complex, with both activating and inhibiting effects. AMPK activation has been shown to induce phosphorylation of P53 and lead to cell cycle arrest. This promotes cellular survival in response to glucose deprivation (as might occur during exercise), however these cells can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated P53-dependent cellular senescence, underscoring the importance of the timing and pulsatility of AMPK activation [ 131 ]. Interestingly, acute exercise has also been shown to decrease nuclear P53 directly or through upregulation of Nrf2 leading to inactivation of P53-P21 Cip1 and P16 INK4a -RB signaling pathways [ 118 , 132 ]. Due to these varied effects in vitro , it has been difficult to elucidate the in vivo functional role of P53 during aging. It is likely that the response partly depends on its cellular localization as well as the duration and intensity of the stimulus.

FoxO and P53

When activated simultaneously by AMPK, P53 and FoxO can induce the expression of sestrins, a family of highly conserved stress-response proteins with oxidoreductase activity that can protect cells from oxidative stress. Loss of sestrins has been linked to age related pathologies such as mitochondrial dysfunction, muscle degeneration and lipid accumulation. These effects are attributed to increased TOR activity and the associated decrease in autophagic uptake ( Figure 2 ). These pathologies were prevented by the activation of AMPK by AICAR and the inhibition of TOR by rapamycin [ 133 ]. Thus, sestrins are suggested as part of a negative feedback loop through mTOR signaling that operates via the activation of AMPK [ 118 ].

Serine/threonine protein kinase mTOR was identified in mammalian cells as a target of the antiproliferative molecule rapamycin [ 134 ]. It participates in the formation of two protein complexes called mTORC1 and mTORC2, known be sensitive and insensitive to rapamycin, respectively [ 135 ]. Phosphorylation and activation of AMPK leads to inhibition of mTORC1 through v-ATP-ase-AXIN/LKB1, which leads to increased lifespan in C. elegans [ 136 ].

Whereas autophagy declines during aging, AMPK activation can restore it by inducing the dissociation of mTORC1 from the ULK1 complex, directly binding and phosphorylating ULK1, an autophagy-initiating kinase, with the result of stimulating autophagy. [ 137 ]. Furthermore, the direct inhibition of mTORC1 by AMPK can have effects similar to nutrient depletion [ 120 ] ( Figure 2 ).

Autophagy and protein synthesis inhibition mediated by downregulation of mTOR have direct effects on proteostasis. In a mouse model of Parkinson’s disease, AMPK activation reversed behavioral impairments, reduced α-synuclein accumulation and enhanced LC3-II-mediated autophagy in dopaminergic neurons [ 138 , 139 ]. AMPK-activation has also been shown to rescue misfolding and trafficking of rhodopsin, highlighting the AMPK role against impairment in proteostasis [ 140 ] ( Figure 2 ).

Advanced glycation end products (AGEs)

AMPK-activation can also exert antiaging effects through inhibiting the effects of AGEs [ 141 ]. AGEs, major inflammatory mediators in macrophages, affect the progression of age-related atherosclerosis and diabetes and inhibit AMPK activity through allosteric competitive binding to its AMP-binding site in the γ subunit [ 142 ]. However, AMPK activation inhibits AGEs-induced inflammatory response in murine macrophages [ 143 ]. These findings show bidirectional modulation between these two pathways that can be shifted through environmental factors to enhance protective mechanisms against genotoxic stress.

In summary, AMPK activation through exercise can impact all the hallmarks of aging through different signaling pathways as summarized in Figure 2 and can act as a signaling node capable of orchestrating many of the effects of exercise on the health span of different tissues and organs.

Effects of exercise on cellular aging in T2D

T2D is a complex disorder that combines a genetic hereditary component and environmental risk factors, such as nutrition and lifestyle. Amongst the risk factors, age stands out with most patients being over 60 years old. There is evidence of accelerated cellular aging with hyperglycemia and in both Type 1 (T1D) and Type 2 (T2D) diabetes mellitus [ 11 , 144 ].

Hyperglycemia increases the hallmarks of aging, such as senescence of endothelial cells in atherosclerotic lesions and telomere shortening [ 10 ]. The exposure of endothelial progenitor cells to high glucose concentrations increased cellular senescence in aortas of a streptozotocin-induced diabetes model [ 11 ], strengthening the association among hyperglycemia, diabetes and senescence [ 10 ]. Additionally, increased mitochondrial DNA depletion and increased aging of collagen have also been reported in patients with T2D [ 9 , 12 ].

Pancreatic β-cells, which play a crucial role in the development of T2D, have also been shown to undergo cellular senescence in the setting of insulin resistance [ 145 ], T2D and high body mass index (BMI). Senolysis (the specific removal of senescence cells either pharmacologically or through transgenic models) improved insulin secretion, blood glucose levels and the gene identity of the remaining β-cell population [ 13 ]. Muscle is another tissue impacted by accelerated aging during diabetes as evidenced by accelerated loss of strength and mitochondrial dysfunction in T1D [ 14 , 15 ]. Skin biopsies obtained from subjects of different ages demonstrated that the onset of cellular senescence occurred earlier in people with juvenile diabetes and in subjects genetically predisposed to diabetes [ 144 ]. Additionally, premature senescence has been observed in endothelial colony-forming cells in the cord blood of infants from mothers with diabetes [ 146 ]. These data suggest T2D as a disease where cellular aging is accelerated, and therefore is a pathology in need of strategies that can broadly impact aging at the molecular level.

Exercise and physical activity are already cornerstones in the metabolic management of T2D [ 147 ]. Randomized trials have shown that lifestyle interventions including 150 minute of physical activity per week, combined with diet-induced weight loss, reduced the risk of T2D by 58% in an at-risk population [ 148 , 149 ]. Increasing physical activity in adults with T2D resulted in complete remission of the disease in 11.5% of subjects within the first year of intervention and an additional 7% had partial or complete remission of type 2 diabetes after 4 years [ 150 ].

The benefits are mainly related to exercise improving blood glucose levels through both a reduction of peripheral insulin resistance [ 151 – 153 ] and its capacity to induce insulin-independent glucose uptake [ 154 ]. Depending on whether the exercise is acute or chronic, the activated pathways in muscle are different ( Figure 3 ). Acute exercise is able to promote translocation of GLUT4 to the plasma membrane through at least two signaling pathways, one involves AMPK and the second an increase of intracellular Ca 2+ . Muscle cell contraction is ATP-dependent and an acute exercise bout increases AMP levels, activating the AMPK signaling pathway and leading the fusion of GLUT-4 containing vesicles with the plasma membrane [ 155 , 156 ] ( Figure 3 ).

Exercise activated pathways in muscle capable of contributing to improved metabolic control in T2D. AMP, adenosine monophosphate; AMPK, AMP- activated protein kinase; ATP, adenosine triphosphate; Ca2+, divalent cation calcium; CaMKs, calcium/calmodulin dependent protein kinases; GLUT4, glucose transporter type 4; LKB1, liver kinase B1; PGC-1, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species. Created in BioRender.

Muscle contraction increases ROS generation due to high oxygen consumption that takes place during mitochondrial activity, in fact, superoxide generation in skeletal muscle increases about 50-100-fold during exercise [ 157 , 158 ]. ROS have been reported to inhibit plasma membrane Ca 2+ ATPase activity indirectly by formation of reactive aldehydes. Hence, ROS would hinder Ca 2+ removal from the cell and encourage intracellular Ca +2 accumulation. Muscle contraction can also directly increase intracellular Ca 2+ , which promotes the membrane translocation of GLUT-4 [ 81 ].

Chronic exercise increases the number and activity of mitochondria in muscle [ 159 ], which counteracts the reported decrease in size, function and integrity of mitochondria in people with T2D [ 160 ], and decreases the expression of PGC-1α, a marker of mitochondrial biogenesis [ 161 ]. Furthermore, skeletal muscle mitochondrial dysfunction has been linked with insulin resistance and can have implications on inflammation, senescence, autophagy and retrograde nuclear signaling [ 162 ].

In summary, exercise activates molecular signals that can bypass defects in insulin signaling in skeletal muscle and increase skeletal muscle mitochondria, which are associated with improved insulin sensitivity in skeletal muscle and therefore improve aging-associated effects of T2D.

Summary, perspective and limitations

Exercise is an effective strategy to prevent aging and enhance longevity and health span both on a clinical and a cellular level due to its capacity to modulate all nine hallmarks of aging. Additionally muscle, one of the main systemic effectors of exercise, is recognized as an endocrine organ that produces and releases myokines, implying a complex cross talk between muscles and other tissues. The AMPK pathway ( Figure 2 ), a well-known mediator of exercise effects in muscle could be activated in different tissues and drive many of the health-promoting and lifespan-extending capabilities of exercise. We propose that it is a central effector node able to impact the hallmarks of aging and integrate the effects of exercise on many tissues. T2D, a disease in which cellular aging is accelerated in several tissues, is an ideal candidate to further understand the antiaging effects of exercise ( Figure 4 ).

Conceptual overview. Created in BioRender.

This review has several limitations. As mentioned, the lack of deleterious effects of a sedentary lifestyle upon aging during exercise can sometimes be confused with antiaging effects of exercise. This conundrum can only be solved if aging studies are carried out in non-sedentary older populations. Unfortunately this rarely occurs and should be considered while interpreting the cited studies. Another limitation is the cross-sectional design of studies comparing an exercised and a sedentary population in spite of the knowledge that the rate of aging varies considerably amongst individuals. The ideal design for aging studies is a longitudinal follow up of non-sedentary individuals; this is rarely feasible due to constraints of time and resources.

Although every attempt was made to include the most relevant studies for each subject, the vastness of publications in this area means that some important work may have been unintentionally omitted. We encourage readers to further their searches on specific subjects that have specially interested them.

We propose that future studies should address the effects of exercise on tissues which are not considered its direct targets but do show accelerated aging in T2D, such as pancreatic β-cells. In these, the role of AMPK and its physiological control will become especially significant as exercise is considered a cellular antiaging strategy.

ACKNOWLEDGMENTS

We would like to thank Susan Bonner-Weir for proofreading the manuscript and the reviewers for their comments and suggestions which significantly improved the scope and perspective of this review.

AUTHOR CONTRIBUTIONS: P.V.C. and C.A.M. conceptualized, researched and wrote/edited the manuscript and figures.

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

FUNDING: This study was supported by Institutional Startup Funds to C.A.M. (Joslin Diabetes Center), the Richard and Susan Smith Family Foundation and by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 to P.V.C.

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FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease

FDA News Release

Today, the U.S. Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. 

“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” 

NASH is a result of the progression of nonalcoholic fatty liver disease where liver inflammation, over time, can lead to liver scarring and liver dysfunction. NASH is often associated with other health problems such as high blood pressure and type 2 diabetes. By at least one estimate, approximately 6-8 million people in the U.S. have NASH with moderate to advanced liver scarring, with that number expected to increase. Rezdiffra is a partial activator of a thyroid hormone receptor; activation of this receptor by Rezdiffra in the liver reduces liver fat accumulation. 

The safety and efficacy of Rezdiffra was evaluated based on an analysis of a surrogate endpoint at month 12 in a 54-month, randomized, double-blind placebo-controlled trial. The surrogate endpoint measured the extent of liver inflammation and scarring. The sponsor is required to conduct a postapproval study to verify and describe Rezdiffra’s clinical benefit, which will be done through completing the same 54-month study, which is still ongoing. To enroll in the trial, patients needed to have a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring. In the trial, 888 subjects were randomly assigned to receive one of the following: placebo (294 subjects); 80 milligrams of Rezdiffra (298 subjects); or 100 milligrams of Rezdiffra (296 subjects); once daily, in addition to standard care for NASH, which includes counseling for healthy diet and exercise. 

At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise. The range of responses reflects different pathologists’ readings. In addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings. Demonstration of these changes in a proportion of patients after just one year of treatment is notable, as the disease typically progresses slowly with a majority of patients taking years or even decades to show progression.

The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. 

Use of Rezdiffra should be avoided in patients with decompensated cirrhosis. Patients should stop using Rezdiffra if they develop signs or symptoms of worsening liver function while on Rezdiffra treatment. 

Using Rezdiffra at the same time as certain other drugs, in particular statins for lowering cholesterol, may result in potentially significant drug interactions. Health care providers should refer to the full prescribing information  for additional information on these potentially significant drug interactions with Rezdiffra, recommended dosage and administration modifications. 

The FDA approved Rezdiffra under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious conditions and address an unmet medical need, based on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. The required aforementioned 54-month study, which is ongoing, will assess clinical benefit after 54 months of Rezdiffra treatment. 

Rezdiffra received Breakthrough Therapy, Fast Track and Priority Review designations for this indication. 

The FDA granted the approval of Rezdiffra to Madrigal Pharmaceuticals.

Related Information

• NIH: Nonalcoholic Fatty Liver Disease (NAFLD) & NASH

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This Climber’s Salve Is the Only Thing That Heals My Dry, Cracked Hands

My hands are constantly dry. And when I climb , I use chalk on my hands, which saps them of moisture even more. The gnarliest my hands have ever been was after one long winter climb in New Mexico. After sticking my hands into rough sandstone cracks for six hours, it felt like they had been put through a cheese grater. To make it worse, temperatures had fallen below freezing and winds were gusting around 20 miles per hour. When I got home, I remember wincing as I washed my hands, because it stung to use soap as I washed away dirt from 10,000 tiny cuts.

Then my friend at the climbing gym tipped me off to this tiny tin of hand salve , which is made with aloe, arnica, chaparral, and radish root, among other ingredients. He said it’s made specifically for climbers and works wonders for dry, cracked skin. After the first use, I was sold. My knuckles were immediately less white and chapped. The next day, my hands still felt a bit achy as they were recovering from all the nicks and scrapes, but my skin felt softer and rehydrated, like a desert cactus that finally got a bit of rain. It rejuvenated my wind- and rock- beaten hands in a way that normal lotion hadn’t before. Since 2021, it’s been the only hand salve I’ve found that heals my hands, especially in the winter.

I’ve used regular hand creams for years, but as a climber, they presented an interesting problem. Climbers want as much friction as possible between their skin and the rock, which is why they use chalk, so they can better grip the holds — both on actual rocks outside, and indoors, on plastic holds. On my climbing trips, I would never want to use Jergens or Aveeno, which are often too greasy. The slightest smear of lotion on a hold could ruin another climber’s experience, so I stayed away from them.

But Allez’s cream is different — it’s a bit thicker and slightly clumpy, and has more of a paste consistency. You scoop out a little dollop (a little goes a long way), almost like a hair product, and begin working it onto your skin. I was surprised that it didn’t sting when I first applied it, which is often the case with other creams and lotions. I love that it absorbs quickly, and there’s no filmy layer of cream on top that won’t rub in. The lack of residue is not just good for climbing but also for typing on my laptop or using my phone.

My girlfriend has even drier hands than mine — she says her skin can feel “like a lizard.” During the pandemic, her hands got dried out from washing them constantly, and now that dryness flares up in the winter. After I gave her my pitch about this salve, she tried it and became a believer. She likes how quickly the Allez cream sinks into her skin, and it doesn’t leave it sticky, unlike her other creams that have coconut oil and other similarly moisturizing ingredients.

Even though I’m not applying it every single day, my skin feels better the more I use it. My knuckles and the backs of my hands feel less irritated and itchy when I apply it after hours of being outside. I just wish it didn’t cost $20 for this small tin, because I end up rationing it for when my hands are in the worst shape. And then to tide myself over, I use other hand creams a bit begrudgingly.

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Shop with Google

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Should you buy it?

Google pixel watch 2 review: accurate gps and a fast processor make it a great smartwatch for android users.

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Google's second-generation Pixel Watch 2 has everything you want in an Android wearable. It functions as an effective smartwatch, has fast, reliable GPS, and has a battery that lasts longer than one day.

But before I tested the watch, I doubted it could compete with others in the space like the Samsung Galaxy Watch 6 Classic or the Fitbit Sense 2 , two of the best Android smartwatches you can buy. This is because the original Pixel Watch was a disappointment. It was a great smartwatch but a terrible fitness tracker due to glaring issues with its GPS. 

Thankfully, Google fixed the GPS and the Pixel Watch 2 is a fully functional smartwatch I can actually recommend. It retains what worked with the original but now has a new, faster processor, an updated operating system (which is also compatible with the Pixel 1), and a longer battery.

The Pixel Watch 2 features an always-on display and three sensors for heart-rate tracking, skin temperature measurement, and stress management. It often falls to this price, so we don't recommend paying more for it.

• Check mark icon A check mark. It indicates a confirmation of your intended interaction. Accurate and reliable activity tracking and GPS
• Check mark icon A check mark. It indicates a confirmation of your intended interaction. New chipset delivers faster load times and minimal lag
• con icon Two crossed lines that form an 'X'. Only available in one sizing option
• con icon Two crossed lines that form an 'X'. Some advanced features require a monthly Fitbit Premium subscription

The Pixel Watch 2 has a minimal, lightweight, and comfortable design

Google made no change to the Pixel Watch 2's design compared to the original model, but that's OK. I like the look of its round watch face and soft rolling edges which achieves a sleek on-wrist aesthetic that feels more classy than sporty. My review model came with a rubber sports band but the watch is compatible with a variety of the best Google Pixel Watch 2 bands that do well to change its overall look.

While I appreciate the overall design, I would've liked to see Google offer multiple sizing options. Its 41mm case size works well enough for various wrist sizes but I know some people prefer smaller or bigger smartwatches. The lack of variety fails to cater to that crowd. I'm used to wearing larger wearables like the Apple Watch Ultra 2 and Samsung Galaxy Watch 6 Classic, so the Pixel Watch 2 felt dainty when I first put it on.

This is the best smartwatch for Android users

Smartwatch capability was the original Pixel Watch's strong suit, and the Pixel Watch 2 is even better. This is due in large part to a fast new processor, the debut of Wear OS 4, and a few new native features.

The most noticeable of these changes is the processor. The quad-core Qualcomm Snapdragon W5 processor makes the Pixel Watch 2 noticeably faster than its predecessor. I never experienced any lag while scrolling through menus or opening applications and its notifications would always pop up as soon as they buzzed on my phone.

It's that kind of seamlessness that stood out to me. The watch wasn't just an extension of my smartphone but something I could reliably use as my smartphone. Sending text messages, answering phone calls, and interacting with app notifications is intuitive and incredibly easy to do.

This kind of use case is where the Wear OS 4 operating system also shined, particularly with new features like the native Gmail and Google Calendar access. It was so easy for me to quickly read and respond to emails, and I appreciated being able to look at my calendar without fishing my phone out of my pocket.

Wear OS 4's new phone-switching feature is also a major perk as it allowed me to easily switch between phones without repeating the entire set-up and factory reset process. Since I tested the Pixel Watch 2 on both a Google Pixel 7 and a Samsung Galaxy S23, this feature was used a lot — and it made my life so much easier.

Google also debuted a Pixel Watch 2-specific feature called Safety Check which can alert preset emergency contacts via a text message if you haven't communicated with them within a certain time. I tested it by checking in with my partner while on a particularly long bike ride, but it can also be used by people on first dates or traveling home late at night.

Overall, the Pixel Watch 2 excelled as an extension of my Android smartphone and it's one of the best smartwatches you can buy. Notifications were easy to interact with, responding to texts and emails was a breeze, and I could even take phone calls right on my wrist.

It delivers the same experience across any Android smartphone

Although the Pixel Watch 2 is a Google-branded Android smartwatch, it functions the same on a Google smartphone as it does on something like a Samsung smartphone. I tested the watch using the Google Pixel 7 and the Samsung Galaxy S23 and experienced no difference in performance or usability.

This is a big deal. For example, the Samsung Galaxy Watch 6 Classic offers a far more seamless and complete experience when it's paired with a Samsung smartphone. When that same watch is paired with a Google phone, the performance suffers.

This isn't the case with the Pixel Watch 2. The experience remained the same regardless of which smartphone I had it paired with. There are no exclusives, no missing features, and nothing that would make one phone better to use than the other.

The main reason for this is that you only need to download both the Fitbit app and the Google Pixel Watch app. Since both are downloadable via the Google Play Store, a platform all Android phones have access to, there's no such thing as a preferred use case.

Delivers accurate and reliable health and fitness tracking

The original Pixel Watch's fitness tracking was a letdown. Poor GPS syncing and reliability produced inconsistent results, making it difficult to recommend to active users.

This was the single biggest problem Google needed to fix with the Pixel Watch 2. Thankfully, it did. GPS syncs quicker and is far more accurate, making the data it tracks also a lot more accurate.

I tested it alongside the Samsung Galaxy Watch 5 Pro , our pick as the best Android smartwatch overall, and my favorite active wearable, the Apple Watch Ultra 2. On everything from bike rides and multiple-mile runs, the Pixel Watch 2 produced similar pacing and distance results. I even enjoyed wearing it while working out which I could not say about the original model.

I also appreciated just how much it's able to track. There are the basics like running and cycling but also a variety of advanced workout types like strength training, hiking, and trail running. Its small design and light weight make it particularly valuable on longer outings, too. I wore it for a 10-mile run and a 30-mile bike ride and hardly noticed I was wearing it at all. You can't say that about the Watch 5 Pro or Ultra 2.

The watch is an excellent health tracker, too. It has in-depth sleep tracking, all-day heart rate monitoring, and ECG readings, as well as a new skin temperature sensor and heart rate sensor. These last two were particularly useful as they provided unique insights into my sleep quality. I could see my skin temperature and heart rate variability throughout the night but it also informed me that I have low heart rate levels while I sleep — which is something I now monitor more frequently.

I was also fond of the watch's stress monitor. As someone who goes for several long walks each day, I used this feature often as a way of knowing exactly when to put a pause on my work day. The watch would ping me whenever my stress levels spiked and that was my cue to take a break. This wasn't a perfect system as it would sometimes notify me mid-meeting, but it did make me more aware of managing my stress throughout the day.

It's worth noting that there are several features locked behind the $10 per month Fitbit Premium. These include things like advanced sleep data, additional stress management tools, and Fitbit's unique Daily Readiness Score. While you don't need a membership to use the Pixel Watch 2, I do feel as though it's worth it to those who want the added insight. The watch does come with six free months of the service, allowing you to test drive it before officially signing up.

Solid battery life and fast recharge times

Battery life is yet another area where the Pixel Watch 2 shows marked improvement over its predecessor. While I needed to charge the first-gen model nightly, I could consistently go at least a full day and night before the Pixel Watch 2 needed to be plugged in.

This is an important upgrade because it allowed me to get full usage out of the watch; I could track my activity and workouts during the day and still have enough battery to track my sleep.

Certain features, like the Always-On Display, drain the battery a little quicker, but I could still get a full day of use out of the watch with it turned on. My routine consisted of charging it in the morning after going for a walk, then wearing it the rest of the day and night once it was fully charged. I was only ever not wearing the watch for roughly two to three hours daily.

The watch also charges quickly and often went from 0% battery to 100% charge in around two hours. I could get enough battery for a full day of use with less than an hour on the charger, too.

If you're an Android user looking for a well-rounded wearable that's both a premium smartwatch and a reliable fitness tracker, then yes. The Google Pixel Watch 2 is a quality generational upgrade that's able to compete with the likes of Samsung's Watch 5 Pro and Watch 6 Classic, two of the best Android smartwatches on the market. It's also the best wearable Google makes, as it's far superior to the Fitbit Sense 2 or Versa 4. 

Its most notable upgrade is its capability as a fitness tracker. Poor GPS syncing plagued the first-gen model but the Pixel Watch 2 avoids the same fate. With fast, quick, and consistent GPS, activity-tracking is now one of the wearable's fortes.

The same can be said of the Pixel Watch 2's smartwatch experience. It has an easy-to-navigate interface and a fast, new processor, and its integration with Google's suite of apps, like Gmail, Google Assistant, and Google Calendar, is handy. The fact it can be used on any phone running Android 9.0 or later, without sacrificing any features, is a major plus, as well. 

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