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Inhibiting Age-related Bone Loss by Eliminating Senescent Cells

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Review of “Targeting cellular senescence prevents age-related bone loss in mice” from Nature Medicine by Stuart P. Atkinson

Recent studies have suggested that the elimination of senescent cells, or the prohibition of their pro-inflammatory capabilities, can reverse many age-related comorbidities, including cardiovascular deterioration [1], lost insulin sensitivity [2], and overall frailty [3]. Now, new research from the laboratories of James L Kirkland and Sundeep Khosla (Mayo Clinic College of Medicine, Rochester, Minnesota, USA) have demonstrated that the elimination of senescent cells can also reverse age-related bone loss [4, 5] and promote healthy aging [6].

To study the consequences of eliminating senescent cells or inhibiting their functions, Farr, Xu, and Weivoda et al. employed three different mouse models of aging:

  • The development of transgenic mice containing a ‘suicide’ transgene that permits inducible elimination of senescent cells in response to drug treatment
  • Treatment with “senolytic” drugs that specifically kill senescent cells without affecting differentiated cells
  • The inhibition of the proinflammatory secretome of senescent cells employing a Janus Kinase inhibitor (JAK) inhibitor

Encouragingly, senescent cell elimination/inhibition in each model system mediated similar improvements to bone mass, strength, and microarchitecture in aged mice (20 to 22 months), but not young mice, in comparison to untreated mice. The authors linked these improvements to the reversal of age-related deficiencies in bone formation after clearance of senescent cells by means of a decrease in osteoclast number, and their associated bone-resorptive (bone breakdown) capabilities, and the maintenance of osteoblast-mediated bone formation.

The authors of this highly encouraging study propose the clearance of senescent cells, or the inhibition of their proinflammatory character, as a novel treatment strategy for age-related bone loss and multiple age-related comorbidities. While the genetic approach is not (currently!) feasible for use in human patients, JAK inhibition or treatment with senolytic drugs may have an exciting clinical future.

It seems that for senescent cells and healthy aging, less is most definitely more! Stay tuned to the Stem Cells Portal to hear much more on this exciting anti-aging strategy!

References

  1. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973-977.
  2. Xu M, Palmer AK, Ding H, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 2015;4:e12997.
  3. Xu M, Tchkonia T, Ding H, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A 2015;112:E6301-6310.
  4. Hamrick MW, Ding KH, Pennington C, et al. Age-related loss of muscle mass and bone strength in mice is associated with a decline in physical activity and serum leptin. Bone 2006;39:845-853.
  5. Glatt V, Canalis E, Stadmeyer L, et al. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res 2007;22:1197-1207.
  6. Farr JN, Xu M, Weivoda MM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 2017;23:1072-1079.