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Senescent cells and the dynamics of aging

By Omer Karin, Amit Agrawal, Ziv Porat, Valery Krizhanovsky, Uri Alon

Posted 14 Nov 2018
bioRxiv DOI: 10.1101/470500

A causal factor in mammalian aging is the accumulation of senescent cells (SnCs) with age. SnCs cause chronic inflammation, and removing SnCs decelerates aging in mice. Despite their importance, however, the production and removal rates of SnCs are not known, and their connection to aging dynamics is unclear. Here we use longitudinal SnC measurements and SnC induction experiments to show that SnCs turn over rapidly in young mice, with a half-life of days, but slow their own removal rate to a half-life of weeks in old mice. This leads to a critical slowing-down that generates persistent SnC fluctuations. We further demonstrate that a mathematical model, in which death occurs when fluctuating SnC populations cross a threshold, quantitatively recapitulates the Gompertz law of survival curves in mice and humans. The concept of a causal factor for aging with rapid turnover which slows its own removal can go beyond SnCs to explain the effects of interventions that modulate lifespan in Drosophila and C. elegans , including survival-curve scaling and rapid effects of dietary shifts on mortality.

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