Skip to main content
SpringerLink
Log in

Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis

GeroScience volume 44, pages 1727–1741 (2022)Cite this article

A Correction to this article was published on 20 May 2022

This article has been updated

Abstract

Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced oxidative/nitrative stress, activation of various pro-inflammatory, and cell death pathways are critical in the initiation and progression of the changes culminating in diabetic cardiomyopathy. Cannabinoid 2 receptor (CB2R) activation in inflammatory cells and activated endothelium attenuates the pathological changes associated with atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy. In this study, we explored the role of CB2R signaling in myocardial dysfunction, oxidative/nitrative stress, inflammation, cell death, remodeling, and fibrosis associated with diabetic cardiomyopathy in type 1 diabetic mice. Control human heart left ventricles and atrial appendages, similarly to mouse hearts, had negligible CB2R expression determine by RNA sequencing or real-time RT-PCR. Diabetic cardiomyopathy was characterized by impaired diastolic and systolic cardiac function, enhanced myocardial CB2R expression, oxidative/nitrative stress, and pro-inflammatory response (tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule 1, macrophage inflammatory protein-1, monocyte chemoattractant protein-1), macrophage infiltration, fibrosis, and cell death. Pharmacological activation of CB2R with a selective agonist attenuated diabetes-induced inflammation, oxidative/nitrative stress, fibrosis and cell demise, and consequent cardiac dysfunction without affecting hyperglycemia. In contrast, genetic deletion of CB2R aggravated myocardial pathology. Thus, selective activation of CB2R ameliorates diabetes-induced myocardial tissue injury and preserves the functional contractile capacity of the myocardium in the diabetic milieu. This is particularly encouraging, since unlike CB1R agonists, CB2R agonists do not elicit psychoactive activity and cardiovascular side effects and are potential clinical candidates in the treatment of diabetic cardiovascular and other complications.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Change history

References

  1. Ryder JR, Northrop E, Rudser KD, Kelly AS, Gao Z, Khoury PR, Kimball TR, Dolan LM, Urbina EM. Accelerated early vascular aging among adolescents with obesity and/or type 2 diabetes mellitus. J Am Heart Assoc. 2020;9:e014891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cigolle CT, Blaum CS, Halter JB. Diabetes and cardiovascular disease prevention in older adults. Clin Geriatr Med. 2009;25:607–41, vii–viii.

    Article  PubMed  Google Scholar 

  3. Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB, Huang ES, Korytkowski MT, Munshi MN, Odegard PS, Pratley RE, Swift CS. Diabetes in older adults. Diabetes Care. 2012;35:2650–64.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Milicevic Z, Raz I, Beattie SD, Campaigne BN, Sarwat S, Gromniak E, Kowalska I, Galic E, Tan M, Hanefeld M. Natural history of cardiovascular disease in patients with diabetes. Diabetes Care. 2008;31:S155–60.

    Article  CAS  PubMed  Google Scholar 

  5. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.

    Article  CAS  PubMed  Google Scholar 

  6. Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. J Diabetes Investig. 2015;5:623–34.

    Article  Google Scholar 

  7. Varga ZV, Giricz Z, Liaudet L, Hasko G, Ferdinandy P, Pacher P. Interplay of oxidative nitrosative nitrative stress inflammation cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta (BBA) - Mole Basis Dis. 2015;1852:232–42.

    Article  CAS  Google Scholar 

  8. Pacher P, Obrosova IG, Mabley JG, Szabo C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications Emerging new therapeutical strategies. Curr Med Chem. 2005;12:267–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Obrosova IG, Pacher P, Szabà C, Zsengeller Z, Hirooka H, Stevens MJ, Yorek MA. Aldose reductase inhibition counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications. Diabetes. 2005;54:234–42.

    Article  CAS  PubMed  Google Scholar 

  10. Rajesh M, Mukhopadhyay P, Bátkai S, Mukhopadhyay B, Patel V, Haskó G, Szabó C, Mabley JG, Liaudet L, Pacher P. Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med. 2009;13:2330–41.

    Article  PubMed  Google Scholar 

  11. Rajesh M, Bátkai S, Kechrid M, Mukhopadhyay P, Lee W-S, Horváth B, Holovac E, Cinar R, Liaudet L, Mackie K, Haskó G, Pacher P. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes. 2012;61:716–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Steffens S, Pacher P. Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies. Br J Pharmacol. 2012;167:313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pacher P, Steffens S, Hasko G, Schindler TH, Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol. 2018;15:151–66.

    Article  CAS  PubMed  Google Scholar 

  14. Matyas C, Erdelyi K, Trojnar E, Zhao S, Varga ZV, Paloczi J, Mukhopadhyay P, Nemeth BT, Hasko G, Cinar R, Rodrigues RM, Ait Ahmed Y, Gao B, Pacher P. Interplay of liver-heart inflammatory axis and cannabinoid 2 receptor signaling in an experimental model of hepatic cardiomyopathy. Hepatology. 2020;71:1391–407.

    Article  CAS  PubMed  Google Scholar 

  15. Rajesh M, Mukhopadhyay P, Bátkai S, Patel V, Saito K, Matsumoto S, Kashiwaya Y, Horváth B, Mukhopadhyay B, Becker L, Haskó G, Liaudet L, Wink DA, Veves A, Mechoulam R, Pacher P. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010;56:2115–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Soethoudt M, Grether U, Fingerle J, Grim TW, Fezza F, de Petrocellis L, Ullmer C, Rothenhausler B, Perret C, van Gils N, Finlay D, MacDonald C, Chicca A, Gens MD, Stuart J, de Vries H, Mastrangelo N, Xia L, Alachouzos G, Baggelaar MP, Martella A, Mock ED, Deng H, Heitman LH, Connor M, Di Marzo V, Gertsch J, Lichtman AH, Maccarrone M, Pacher P, Glass M, van der Stelt M. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Nat Commun. 2017;8:13958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc. 2008;3:1422–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Trojnar E, Erdelyi K, Matyas C, Zhao S, Paloczi J, Mukhopadhyay P, Varga ZV, Hasko G, Pacher P. Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome. Free Radic Biol Med. 2020;152:540–50.

    Article  CAS  PubMed  Google Scholar 

  19. Varga ZV, Kupai K, Szucs G, Gaspar R, Paloczi J, Farago N, Zvara A, Puskas LG, Razga Z, Tiszlavicz L, Bencsik P, Gorbe A, Csonka C, Ferdinandy P, Csont T. MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart. J Mol Cell Cardiol. 2013;62:111–21.

    Article  CAS  PubMed  Google Scholar 

  20. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462.

    Article  CAS  PubMed  Google Scholar 

  21. Weis F, Beiras-Fernandez A, Sodian R, Kaczmarek I, Reichart B, Beiras A, Schelling G, Kreth S. Substantially altered expression pattern of cannabinoid receptor 2 and activated endocannabinoid system in patients with severe heart failure. J Mol Cell Cardiol. 2010;48:1187–93.

    Article  CAS  PubMed  Google Scholar 

  22. Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. CB2-receptor stimulation attenuates TNF-{alpha}-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol. 2007;293:H2210-2218.

    Article  CAS  PubMed  Google Scholar 

  23. van Esbroeck ACM, Varga ZV, Di X, van Rooden EJ, Toth VE, Onodi Z, Kusmierczyk M, Leszek P, Ferdinandy P, Hankemeier T, van der Stelt M, Pacher P. Activity-based protein profiling of the human failing ischemic heart reveals alterations in hydrolase activities involving the endocannabinoid system. Pharmacol Res. 2020;151:104578.

    Article  PubMed  Google Scholar 

  24. Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 2011;50:193–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pacher P, Batkai S, Kunos G. Cardiovascular pharmacology of cannabinoids. Handb Exp Pharmacol. 2005;599–625.

  26. Batkai S, Pacher P. Endocannabinoids and cardiac contractile function: pathophysiological implications. Pharmacol Res. 2009;60:99–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease – successes and failures. FEBS J. 2013;280:1918–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Valenta I, Varga ZV, Valentine H, Cinar R, Horti A, Mathews WB, Dannals RF, Steele K, Kunos G, Wahl RL, Pomper MG, Wong DF, Pacher P, Schindler TH. Feasibility evaluation of myocardial cannabinoid type 1 receptor imaging in obesity: a Translational approach. JACC Cardiovasc Imaging. 2018;11:320–32.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mukhopadhyay P, Batkai S, Rajesh M, Czifra N, Harvey-White J, Hasko G, Zsengeller Z, Gerard NP, Liaudet L, Kunos G, Pacher P. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol. 2007;50:528–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mukhopadhyay P, Rajesh M, Batkai S, Patel V, Kashiwaya Y, Liaudet L, Evgenov OV, Mackie K, Hasko G, Pacher P. CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res. 2010;85:773–84.

    Article  CAS  PubMed  Google Scholar 

  31. El-Remessy AB, Rajesh M, Mukhopadhyay P, Horvath B, Patel V, Al-Gayyar MM, Pillai BA, Pacher P. Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia. 2011;54:1567–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rajesh M, Mukhopadhyay P, Hasko G, Liaudet L, Mackie K, Pacher P. Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol. 2010;160:688–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tiyerili V, Zimmer S, Jung S, Wassmann K, Naehle CP, Lutjohann D, Zimmer A, Nickenig G, Wassmann S. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol. 2010;105:465–77.

    Article  CAS  PubMed  Google Scholar 

  34. Sugamura K, Sugiyama S, Nozaki T, Matsuzawa Y, Izumiya Y, Miyata K, Nakayama M, Kaikita K, Obata T, Takeya M, Ogawa H. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation. 2009;119:28–36.

    Article  CAS  PubMed  Google Scholar 

  35. Immenschuh S. Endocannabinoid signalling as an anti-inflammatory therapeutic target in atherosclerosis: does it work? Cardiovasc Res. 2009;84:341–2.

    Article  CAS  PubMed  Google Scholar 

  36. Dol-Gleizes F, Paumelle R, Visentin V, Mares AM, Desitter P, Hennuyer N, Gilde A, Staels B, Schaeffer P, Bono F. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2009;29:12–8.

    Article  CAS  PubMed  Google Scholar 

  37. Gruden G, Barutta F, Kunos G, Pacher P. Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol. 2016;173:1116–27.

    Article  CAS  PubMed  Google Scholar 

  38. Jourdan T, Park JK, Varga ZV, Paloczi J, Coffey NJ, Rosenberg AZ, Godlewski G, Cinar R, Mackie K, Pacher P, Kunos G. Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy. Diabetes Obes Metab. 2018;20:698–708.

    Article  CAS  PubMed  Google Scholar 

  39. Barutta F, Corbelli A, Mastrocola R, Gambino R, Di Marzo V, Pinach S, Rastaldi MP, Perin PC, Gruden G. Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy. Diabetes. 2010;59:1046–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, Song XY, Spillmann F, Riad A, Schultheiss HP and Tschöpe C. Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Research in Cardiology. 2007;102:500–7.

  41. Westermann D, Walther T, Savvatis K, Escher F, Sobirey M, Riad A, Bader M, Schultheiss H-P and Tschöpe C. Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy. Diabetes. 2009;58:1373–81.

  42. Johnson FL. Pathophysiology and etiology of heart failure. Cardiol Clin. 2014;32:9–19.

    Article  PubMed  Google Scholar 

  43. Mandavia CH, Aroor AR, DeMarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. 2013;92:601–8.

    Article  CAS  PubMed  Google Scholar 

  44. Defer N, Wan J, Souktani R, Escoubet B, Perier M, Caramelle P, Manin S, Deveaux V, Bourin M-C, Zimmer A, Lotersztajn S, Fo Pecker, Pavoine C. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. The FASEB Journal. 2009;23:2120–30.

    Article  CAS  PubMed  Google Scholar 

  45. Montecucco F, Matias I, Lenglet S, Petrosino S, Burger F, Pelli G, Braunersreuther V, Fo Mach, Steffens S, Di Marzo V. Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis. 2009;205:433–41.

    Article  CAS  PubMed  Google Scholar 

  46. Montecucco F, Lenglet Sb, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach FO, Steffens S. CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mole Cell Cardiol. 2009;46:612–20.

    Article  CAS  Google Scholar 

  47. Hoyer FF, Steinmetz M, Zimmer S, Becker A, Lütjohann D, Buchalla R, Zimmer A and Nickenig G. Atheroprotection via cannabinoid receptor-2 is mediated by circulating and vascular cells in vivo. J Mole Cel Cardiol. 2011;51:1007–14.

  48. Molica F, Matter CM, Burger F, Pelli G, Lenglet S, Zimmer A, Pacher P, Steffens S. Cannabinoid receptor CB2 protects against balloon-induced neointima formation. Am J Physiol Heart Circ Physiol. 2012;302:H1064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Montecucco F, Di Marzo V, da Silva RF, Vuilleumier N, Capettini L, Lenglet SB, Pagano S, Piscitelli F, Quintao S, Bertolotto M, Pelli G, Galan K, Pilet L, Kuzmanovic K, Burger F, Pane B, Spinella G, Braunersreuther V, Gayet-Ageron AL, Pende A, Viviani GL, Palombo D, Dallegri F, Roux-Lombard P, Santos RAS, Stergiopulos N, Steffens S, Mach FO. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J. 2012;33:846–56.

    Article  CAS  PubMed  Google Scholar 

  50. Pacher P, Szabo C. Role of peroxynitrite in the pathogenesis of cardiovascular complications of diabetes. Curr Opin Pharmacol. 2006;6:136–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315–424.

    Article  CAS  PubMed  Google Scholar 

  52. Barutta F, Piscitelli F, Pinach S, Bruno G, Gambino R, Rastaldi MP, Salvidio G, Di Marzo V, CavalloPerin P, Gruden G. Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes. 2011;60:2386–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Barutta F, Grimaldi S, Franco I, Bellini S, Gambino R, Pinach S, Corbelli A, Bruno G, Rastaldi MP, Aveta T, Hirsch E, Di Marzo V, Gruden G. Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice. Kidney Int. 2014;86:979–90.

    Article  CAS  PubMed  Google Scholar 

  54. Mohnle P, Schutz SV, Schmidt M, Hinske C, Hubner M, Heyn J, Beiras-Fernandez A, Kreth S. MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure. Biochem Biophys Res Commun. 2014;451:516–21.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Intramural Research Program of NIH/NIAAA (to PP). ZVV is supported by the Rosztoczy Foundation. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Author information

Author notes

  1. MR and PM equally contributed to the manuscript.

Authors and Affiliations

  1. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    Mohanraj Rajesh, Partha Mukhopadhyay, Sándor Bátkai, Muhammad Arif, Zoltán V. Varga, Csaba Mátyás, Janos Paloczi & Pal Pacher

  2. Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary

    Zoltán V. Varga

  3. Departments of Hematology and Stem Cell Transplantation, South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Saint Ladislaus Campus, Budapest, Hungary

    Andrea Lehocki

  4. Department of Anesthesiology, Columbia University, New York, NY, USA

    György Haskó

Authors
  1. Mohanraj Rajesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Partha Mukhopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sándor Bátkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad Arif
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zoltán V. Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Csaba Mátyás
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Janos Paloczi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Lehocki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. György Haskó
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pal Pacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MR, PM, GH, and PP designed the experiment. MR, PM, SB, CM, and AM performed the experiments. MR, ZVV, PM, AM, and CM performed the analysis. MR, ZVV, GH, AL, JP, and PP wrote/edited the paper.

Corresponding author

Correspondence to Pal Pacher.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajesh, M., Mukhopadhyay, P., Bátkai, S. et al. Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis. GeroScience 44, 1727–1741 (2022). https://doi.org/10.1007/s11357-022-00565-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-022-00565-9

Keywords

search

Navigation