Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence

Abstract

Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5′-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Exercise training reduces β-cell senescence in mice.
Fig. 2: Prevention of β-cell senescence outweighs its reversal.
Fig. 3: Exercise training activates AMPK in pancreatic islets.
Fig. 4: Glucagon activates AMPK in mouse and human islets.
Fig. 5: GLP-1R and GCGR activate AMPK and decrease senescence.
Fig. 6: Gcgr knockdown partially impairs exercise training effects.
Fig. 7: Exercise training promotes the nuclear translocation of NRF2.
Fig. 8: Postexercise serum reduces senescence markers in T2DM islets.

Similar content being viewed by others

Data availability

Bulk RNAseq data are deposited to the Gene Expression Omnibus with accession no. GSE227516. Source data are provided with this paper.

References

  1. Khan, M. A. B. et al. Epidemiology of type 2 diabetes—global burden of disease and forecasted trends. J. Epidemiol. Glob. Health 10, 107–111 (2020).

    PubMed  PubMed Central  Google Scholar 

  2. Sun, H. et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 183, 109119 (2022).

    PubMed  Google Scholar 

  3. Dunning, T., Sinclair, A. & Colagiuri, S. New IDF Guideline for managing type 2 diabetes in older people. Diabetes Res. Clin. Pract. 103, 538–540 (2014).

    PubMed  Google Scholar 

  4. Hooten, N. N., Pacheco, N. L., Smith, J. T. & Evans, M. K. The accelerated aging phenotype: the role of race and social determinants of health on aging. Ageing Res. Rev. 73, 101536 (2022).

    Google Scholar 

  5. Salomon, J. A. et al. Healthy life expectancy for 187 countries, 1990–2010: a systematic analysis for the Global Burden Disease Study 2010. Lancet 380, 2144–2162 (2012).

    PubMed  Google Scholar 

  6. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  7. Bahour, N. et al. Diabetes mellitus correlates with increased biological age as indicated by clinical biomarkers. Geroscience 44, 415–427 (2022).

    CAS  PubMed  Google Scholar 

  8. Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Carapeto, P. V. & Aguayo-Mazzucato, C. Effects of exercise on cellular and tissue aging. Aging (Albany NY) 13, 14522–14543 (2021).

    CAS  PubMed  Google Scholar 

  10. Radák, Z. et al. Exercise training decreases DNA damage and increases DNA repair and resistance against oxidative stress of proteins in aged rat skeletal muscle. Pflugers Arch. 445, 273–278 (2002).

    PubMed  Google Scholar 

  11. Werner, C. et al. Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 120, 2438–2447 (2009).

    PubMed  Google Scholar 

  12. Kaliman, P. et al. Neurophysiological and epigenetic effects of physical exercise on the aging process. Ageing Res. Rev. 10, 475–486 (2011).

    PubMed  Google Scholar 

  13. Ntanasis-Stathopoulos, J., Tzanninis, J. G., Philippou, A. & Koutsilieris, M. Epigenetic regulation on gene expression induced by physical exercise. J. Musculoskelet. Neuronal Interact. 13, 133–146 (2013).

    CAS  PubMed  Google Scholar 

  14. Wohlgemuth, S. E. et al. An exploratory analysis of the effects of a weight loss plus exercise program on cellular quality control mechanisms in older overweight women. Rejuvenation Res. 14, 315–324 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Barclay, R. D., Burd, N. A., Tyler, C., Tillin, N. A. & Mackenzie, R. W. The role of the IGF-1 signaling cascade in muscle protein synthesis and anabolic resistance in aging skeletal muscle. Front. Nutr. 6, 146 (2019).

    PubMed  PubMed Central  Google Scholar 

  16. Lanza, I. R. et al. Endurance exercise as a countermeasure for aging. Diabetes 57, 2933–2942 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Englund, D. A. et al. Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell 20, e13415 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Verdijk, L. B. et al. Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men. J. Gerontol. A Biol. Sci. Med. Sci. 64, 332–339 (2009).

    PubMed  Google Scholar 

  19. Keller, C., Keller, P., Giralt, M., Hidalgo, J. & Pedersen, B. K. Exercise normalises overexpression of TNF-α in knockout mice. Biochem. Biophys. Res. Commun. 321, 179–182 (2004).

    CAS  PubMed  Google Scholar 

  20. de Brachène, A. C. et al. Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes. Diabetologia 66, 450–460 (2023).

    Google Scholar 

  21. Suryadevara, V. et al. SenNet recommendations for detecting senescent cells in different tissues. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-024-00738-8 (2024).

    Article  PubMed  Google Scholar 

  22. Midha, A. et al. Unique human and mouse β-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors. Diabetes 70, 1098–1116 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. Saul, D. et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat. Commun. 13, 4827 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hayashi, T. et al. Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49, 527–531 (2000).

    CAS  PubMed  Google Scholar 

  27. Hayashi, T., Hirshman, M. F., Kurth, E. J., Winder, W. W. & Goodyear, L. J. Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47, 1369–1373 (1998).

    CAS  PubMed  Google Scholar 

  28. Musi, N. et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 50, 921–927 (2001).

    CAS  PubMed  Google Scholar 

  29. Calegari, V. C. et al. Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets. J. Endocrinol. 208, 257–264 (2011).

    CAS  PubMed  Google Scholar 

  30. Kari, S., Vasko, V. V., Priya, S. & Kirschner, L. S. PKA activates AMPK through LKB1 signaling in follicular thyroid cancer. Front. Endocrinol. (Lausanne) 10, 769 (2019).

    PubMed  Google Scholar 

  31. Witters, L. A., Kemp, B. E. & Means, A. R. Chutes and ladders: the search for protein kinases that act on AMPK. Trends Biochem. Sci 31, 13–16 (2006).

    CAS  PubMed  Google Scholar 

  32. Ducommun, S. et al. Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: identification of mitochondrial fission factor as a new AMPK substrate. Cell. Signal. 27, 978–988 (2015).

    CAS  PubMed  Google Scholar 

  33. Urhausen, A., Gabriel, H. & Kindermann, W. Blood hormones as markers of training stress and overtraining. Sports Med. 20, 251–276 (1995).

    CAS  PubMed  Google Scholar 

  34. Chen, Z. et al. Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem. Pharmacol. 177, 113951 (2020).

    CAS  PubMed  Google Scholar 

  35. Wang, Z. et al. Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents. Nat. Commun. 10, 2538 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Garatachea, N. et al. Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 18, 57–89 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. Woods, J. A., Wilund, K. R., Martin, S. A. & Kistler, B. M. Exercise, inflammation and aging. Aging Dis. 3, 130–140 (2012).

    PubMed  Google Scholar 

  39. Stein, G. H., Drullinger, L. F., Soulard, A. & Dulić, V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19, 2109–2117 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee, B. Y. et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell 5, 187–195 (2006).

    CAS  PubMed  Google Scholar 

  41. Apfeld, J., O’Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18, 3004–3009 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. van Vliet, T. et al. Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression. Mol. Cell 81, 2041–2052 (2021).

    PubMed  Google Scholar 

  43. Nguyen-Tu, M.-S. et al. Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase. Diabetologia 65, 997–1011 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, W. et al. Network pharmacology for systematic understanding of Schisandrin B reduces the epithelial cells injury of colitis through regulating pyroptosis by AMPK/Nrf2/NLRP3 inflammasome. Aging (Albany NY) 13, 23193–23209 (2021).

    CAS  PubMed  Google Scholar 

  45. Pisania, A. et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661–1675 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).

    PubMed  PubMed Central  Google Scholar 

  47. Hall, L. G., Thyfault, J. P. & Johnson, J. D. Exercise and inactivity as modifiers of β cell function and type 2 diabetes risk. J. Appl. Physiol. (1985) 134, 823–839 (2023).

    CAS  PubMed  Google Scholar 

  48. Langlois, A., Forterre, A., Pinget, M. & Bouzakri, K. Impact of moderate exercise on fatty acid oxidation in pancreatic β-cells and skeletal muscle. J. Endocrinol. Invest. 44, 1815–1825 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Aguayo-Mazzucato, C. et al. β cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 25, 898–910 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by institutional start-up funds to C.A.-M., National Institutes of Health (NIH) grants 1R01DK132535 to C.A.-M. and P30 DK036836 to Joslin Diabetes Center (Cores), Thomas J. Beatson Jr. Foundation grant 2020-010 and the Richard and Susan Smith Family Foundation Award to C.A.-M. Support was also provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001 (to P.C.), the 2021 STEP-UP (Short-term Research Experience for Underrepresented Persons) programme supported by award number 1R25DK113652 from the NIH-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (to J.K.), NIDDK grant K23-DK114550 and BADERC P&F grant (to R.J.W.M.), NIH grant R01DK099511 and R01 DK112283 (to L.J.G.) and American Diabetes Association grant #1-17-PMF-009 (to A.B.A.-W.). G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grant (MR/R022259/1), Diabetes UK Project grant (BDA16/0005485), CRCHUM start-up funds, an Innovation Canada John R. Evans Leader Award, JDRF, CIHR, NIH-NIDDK multi-PI project grant (R01DK135268) and CIHR-JDRF Team grant (CIHR-IRSC:0682002550; JDRF 4-SRA-2023-1182-S-N). Human pancreatic islets and/or other resources were provided by the NIDDK-funded IIDP (RRID:SCR _014387) at City of Hope, NIH grant #2UC4DK098085.

Author information

Authors and Affiliations

Authors

Contributions

P.C., K.I., F.H., J.K., A.B.A.-W. and R.J.W.M. conducted the experiments. P.C., M.F.H., L.J.G., G.A.R. and C.A.-M. designed the study. P.C. and C.A.-M. wrote the manuscript. All authors reviewed and edited the paper.

Corresponding author

Correspondence to Cristina Aguayo-Mazzucato.

Ethics declarations

Competing interests

G.A.R. has received grant funding from and is a consultant for Sun Pharmaceutical Industries Ltd. C.A.-M. has served as a consultant for eGenesis and Novo Nordisk. The other authors declare no competing interests.

Peer review

Peer review information

Nature Metabolism thanks Sandra Galic and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Distance run per day.

Extended Data Figure 1 refers to Fig. 1. Distance (kilometers) run per day for young 6-weeks-old C57BL/6 females (a, n=5-11/group) and for retired breeders, male 6–9 months-old (b, n=5-10/group) in the wheel-running group (trained). Each line represents an individual mouse.

Source data

Extended Data Fig. 2 Body composition parameters.

Extended Data Figure 2 refers to Figs. 1 and 3. (a) Body weight in grams of female trained mice (6 weeks of age, n=5-11/group) from control and trained (wheel) groups. Relates to Fig. 1a and b. (b) Body weight in grams of sedentary and trained (treadmill) at the end of the protocol for 12 -weeks-old (n=10 animals/group, males), relates to Fig. 1d–h; (c) Representative pictures from DEXA Fat and lean mass were measured by dual-energy X-ray absorptiometry (DEXA) (d-g). (h) Body weight in grams of sedentary and trained (treadmill) animals sedentary and control with insulin resistance induced by S961 (males, n=5/group, 6–9 months-old), relates to Fig. 1i-l; (i) Body weight in grams of sedentary and trained (treadmill) animals sedentary and control (males, n=5/group, 6–9 months-old); relates to Fig. 3a–c.N= 5 animals/group, males, 6–9 months old. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05.

Source data

Extended Data Fig. 3 Glucose and insulin tolerance tests.

Extended Data Figure 3 refer to Fig. 1d–h. AUC for ITT (a) in 12-weeks-old C57BL/6 males after treadmill exercise protocol; n=10/group (a), serum levels from S961 treated mice, n=4-5/group (b), AUC and blood glucose levels for IPGTT (c, e) and ITT (d, f) for trained and sedentary 6–9 months-old animals (n=5/group) from reversibility prevention (c and d) and reversibility groups (e and f). N=4-10/group. Two sided-test and Welch’s correction. Mean ± SD. ***P<0.001.

Source data

Extended Data Fig. 4 Glucose, IL6 and insulin response.

Extended Data Figure 4 refers to Figs. 4 and 5. Glucose levels (a) and concentration of IL-6 (b) after exercise-protocol (6–9-month-old C57BL/6 male mice; n=10/group in A and n=5/group in B). (c) insulin from glucose stimulated insulin secretion performed in islets from male mice (C57BL6, 3–6 months-old, cultured in presence of glucagon and trained serum. N=5 animals/group. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05, **P<0.01, ****P<0.0001.

Source data

Extended Data Fig. 5 AMPK activation and P21CIP1 levels in islets treated with human from exercise participants without T2D.

Extended Data Figure 5 refers to Fig. 8. Experiment conducted in individuals without T2D. The results showed increased AMPK phosphorylation (A and B) but without changes in senescence marker P21CIP1 (A and C). Samples from individuals ranging from 22 to 57 years old, male, n=6/group. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05.

Source data

Extended Data Table 1 Donor information for human pancreatic samples
Extended Data Table 2 Volunteer information for serum from moderate intensity training program
Extended Data Table 3 Primer sequences used for qPCR
Extended Data Table 4 Antibodies for immunostaining and western blot

Supplementary information

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Fig. 7

Statistical source data.

Source Data Fig. 8

Statistical source data.

Source Data Fig. 3

Western blots for Fig. 3d,l.

Source Data Fig. 4

Western blots for Fig. 4g,l.

Source Data Fig. 5

Western blots for Fig. 5e,l.

Source Data Fig. 6

Western blots for Fig. 6a.

Source Data Fig. 7

Western blots for Fig. 7a.

Source Data Fig. 8

Western blots for Fig. 8c.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 3

Statistical source data.

Source Data Extended Data Fig. 4

Statistical source data.

Source Data Extended Data Fig. 5

Statistical source data.

Source Data Extended Data Fig. 5

Western blots.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carapeto, P., Iwasaki, K., Hela, F. et al. Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence. Nat Metab 6, 1976–1990 (2024). https://doi.org/10.1038/s42255-024-01130-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-024-01130-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing