Endocrinol Metab.  2023 Jun;38(3):295-301. 10.3803/EnM.2023.1727.

Skeletal Senescence with Aging and Type 2 Diabetes

Affiliations
  • 1Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
  • 2Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA
  • 3Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA

Abstract

Osteoporosis and type 2 diabetes (T2D) are common diseases that often coexist. While both of these diseases are associated with poor bone quality and increased fracture risk, their pathogenesis of increased fracture risk differs and is multifactorial. Mounting evidence now indicates that key fundamental mechanisms that are central to both aging and energy metabolism exist. Importantly, these mechanisms represent potentially modifiable therapeutic targets for interventions that could prevent or alleviate multiple complications of osteoporosis and T2D, including poor bone quality. One such mechanism that has gained increasing momentum is senescence, which is a cell fate that contributes to multiple chronic diseases. Accumulating evidence has established that numerous boneresident cell types become susceptible to cellular senescence with old age. Recent work also demonstrates that T2D causes the premature accumulation of senescent osteocytes during young adulthood, at least in mice, although it remains to be seen which other bone-resident cell types become senescent with T2D. Given that therapeutically removing senescent cells can alleviate age-related bone loss and T2D-induced metabolic dysfunction, it will be important in future studies to rigorously test whether interventions that eliminate senescent cells can also alleviate skeletal dysfunction in context of T2D, as it does with aging.

Keyword

Osteoporosis; Aging; Osteoporosis; Fracture; Diabetes mellitus, type 2; Cellular senescence

Figure

  • Fig. 1. Cellular senescence in type 2 diabetes (T2D). Accelerated cellular senescence has been observed in mice with T2D in adipose tissue, pancreatic β-cells, liver, brain, and bone (among potentially other tissues) (created with BioRender.com).


Reference

1. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014; 29:2520–6.
2. Rowley WR, Bezold C, Arikan Y, Byrne E, Krohe S. Diabetes 2030: insights from yesterday, today, and future trends. Popul Health Manag. 2017; 20:6–12.
Article
3. Farr JN, Khosla S. Determinants of bone strength and quality in diabetes mellitus in humans. Bone. 2016; 82:28–34.
Article
4. Shanbhogue VV, Mitchell DM, Rosen CJ, Bouxsein ML. Type 2 diabetes and the skeleton: new insights into sweet bones. Lancet Diabetes Endocrinol. 2016; 4:159–73.
Article
5. Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL, et al. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017; 13:208–19.
Article
6. Sfeir JG, Drake MT, Khosla S, Farr JN. Skeletal aging. Mayo Clin Proc. 2022; 97:1194–208.
Article
7. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194–217.
Article
8. Farr JN, Almeida M. The spectrum of fundamental basic science discoveries contributing to organismal aging. J Bone Miner Res. 2018; 33:1568–84.
Article
9. Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol. 2020; 16:263–75.
Article
10. Farr JN, Khosla S. Cellular senescence in bone. Bone. 2019; 121:121–33.
Article
11. Khosla S, Samakkarnthai P, Monroe DG, Farr JN. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat Rev Endocrinol. 2021; 17:685–97.
Article
12. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25:585–621.
Article
13. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123:966–72.
Article
14. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996; 93:13742–7.
15. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003; 22:4212–22.
Article
16. Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017; 21:21–8.
Article
17. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6:2853–68.
Article
18. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99–118.
Article
19. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013; 15:978–90.
Article
20. Prata LG, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin Immunol. 2018; 40:101275.
Article
21. Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995; 55:2284–92.
22. Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016; 31:1920–9.
Article
23. Saul D, Monroe DG, Rowsey JL, Kosinsky RL, Vos SJ, Doolittle ML, et al. Modulation of fracture healing by the transient accumulation of senescent cells. Elife. 2021; 10:e69958.
Article
24. Chandra A, Lagnado AB, Farr JN, Doolittle M, Tchkonia T, Kirkland JL, et al. Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity. Aging Cell. 2022; 21:e13602.
Article
25. Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017; 23:1072–9.
Article
26. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479:232–6.
Article
27. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362:2260–70.
Article
28. D’Andrea G. Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia. 2015; 106:256–71.
Article
29. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14:644–58.
Article
30. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015; 4:e12997.
Article
31. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018; 24:1246–56.
Article
32. Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019; 18:e12950.
Article
33. Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017; 8:15691.
Article
34. Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, et al. Acceleration of b cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019; 30:129–42.
35. Ogrodnik M, Zhu Y, Langhi LG, Tchkonia T, Kruger P, Fielder E, et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 2019; 29:1061–77.
Article
36. Luo J, Quan J, Tsai J, Hobensack CK, Sullivan C, Hector R, et al. Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism. 1998; 47:663–8.
Article
37. Eckhardt BA, Rowsey JL, Thicke BS, Fraser DG, O’Grady KL, Bondar OP, et al. Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes. JCI Insight. 2020; 5:e135236.
Article
38. Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S. In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res. 2014; 29:787–95.
Article
39. Furst JR, Bandeira LC, Fan WW, Agarwal S, Nishiyama KK, McMahon DJ, et al. Advanced glycation endproducts and bone material strength in type 2 diabetes. J Clin Endocrinol Metab. 2016; 101:2502–10.
Article
40. Nilsson AG, Sundh D, Johansson L, Nilsson M, Mellstrom D, Rudang R, et al. Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res. 2017; 32:1062–71.
Article
41. Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL, Martin DE, et al. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 2022; 34:75–89.
42. Hickson LJ, Langhi Prata LG, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019; 47:446–56.
Article
43. Saul D, Kosinsky RL, Atkinson EJ, Doolittle ML, Zhang X, LeBrasseur NK, et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat Commun. 2022; 13:4827.
Article
44. Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell. 2012; 11:345–9.
Article
45. Nelson G, Kucheryavenko O, Wordsworth J, von Zglinicki T. The senescent bystander effect is caused by ROS-activated NF-kB signalling. Mech Ageing Dev. 2018; 170:30–6.
46. Farr JN, Saul D, Doolittle ML, Kaur J, Rowsey JL, Vos SJ, et al. Local senolysis in aged mice only partially replicates the benefits of systemic senolysis. J Clin Invest. 2023; 133:e162519.
Article
47. Swanson EC, Manning B, Zhang H, Lawrence JB. Higherorder unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol. 2013; 203:929–42.
Article
48. Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun. 2012; 3:708.
Article
49. Ramasamy R, Shekhtman A, Schmidt AM. The multiple faces of RAGE: opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets. 2016; 20:431–46.
50. Litwinoff E, Hurtado Del Pozo C, Ramasamy R, Schmidt AM. Emerging targets for therapeutic development in diabetes and its complications: the RAGE signaling pathway. Clin Pharmacol Ther. 2015; 98:135–44.
Article
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