Senescent cell accumulation mechanisms inferred from parabiosis
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ORIGINAL ARTICLE
Senescent cell accumulation mechanisms inferred from parabiosis Omer Karin
&
Uri Alon
Received: 16 August 2020 / Accepted: 12 October 2020 # The Author(s) 2020
Abstract Senescent cells are growth-arrested cells that cause inflammation and play a causal role in aging. They accumulate with age, and preventing this accumulation delays age-related diseases. However, the mechanism for senescent cell accumulation is not fully understood. Accumulation can result from increasing production or decreasing removal of senescent cells with age, or both. To distinguish between these possibilities, we analyze data from parabiosis, the surgical conjoining of two mice so that they share circulation. Parabiosis between a young and old mouse, called heterochronic parabiosis, reduces senescent cell levels in the old mouse, while raising senescent cell levels in the young mouse. We show that parabiosis data can reject mechanisms for senescent cell accumulation in which only production rises with age or only removal decreases with age; both must vary with age. Since removal drops with age, senescent cell half-life rises with age. This matches a recent model for senescent cell accumulation developed from independent data on senescent cell dynamics, called the SR model, in which production rises linearly with age and senescent cells inhibit their own removal. The SR model further explains the timescales and mechanism of rejuvenation in parabiosis, based on transfer of spare removal capacity from the young mouse to the old. The present quantitative understanding can help design optimal treatments that remove
O. Karin (*) : U. Alon Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel e-mail: [email protected]
senescent cells, by matching the time between treatments to the time it takes senescent cells to re-accumulate. Keywords Aging . Senescent cells . Parabiosis . Mathematical modeling . Systems biology
Introduction Senescent cells are growth-arrested cells that inhibit tissue regeneration and secrete pro-inflammatory factors called SASP (Senescence-Associated Secretory Phenotype) [1–3]. They have beneficial roles in development and wound healing. However, with age their abundance increases in multiple tissues [4–7], raising the concentration of pro-inflammatory SASP factors. The accumulation of senescent cells plays a causal role in aging, as was demonstrated in mice studies. Continuous senescent cell ablation starting in midlife extended lifespan and delayed age-related disease [8], whereas senescent cell transplantation shortened lifespan and healthspan [9]. Senescent cell ablation in mice, using drugs or genetic means, improved tissue regeneration and delayed disease in a wide range of disease models including models for cardiovascular disease, diabetes, kidney failure, Alzheimer’s disease, and osteoarthritis [10–24]. Senescent cells have a lifetime on the order of days to weeks [25] and are therefore continually produced and removed over the lifespan. Their removal is
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