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. 2024 Aug 6;36(8):1795-1805.e6.
doi: 10.1016/j.cmet.2024.07.006.

Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function

Binsheng Wang  1 , Lichao Wang  1 , Nathan S Gasek  1 , Chia-Ling Kuo  2 , Jia Nie  3 , Taewan Kim  1 , Pengyi Yan  1 , Junyu Zhu  1 , Blake L Torrance  4 , Yueying Zhou  5 , Lisa C Flores  6 , Colton Allen  6 , Allison M Andrade  7 , Chun Guo  7 , Rachel L Cohn  1 , Evan R Jellison  8 , Jenna M Bartley  4 , George A Kuchel  7 , Sheng Li  9 , Tamar Pirtskhalava  10 , Tamar Tchkonia  10 , Sumit Yadav  11 , Laura Haynes  4 , James L Kirkland  12 , Yuji Ikeno  13 , Ming Xu  14
Affiliations

Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function

Binsheng Wang et al. Cell Metab. .

Abstract

A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.

Keywords: aging; cellular senescence; frailty; inflammation; morbidity compression.

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Conflict of interest statement

Declaration of interests M.X., T.T., and J.L.K. have a financial conflict of interest with a Mayo Clinic pending patent for p21-Cre mouse model.

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