Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

By D. Baker, Bennett G. Childs, Matej Durik, M. Wijers, Cynthia J. Sieben, Jian Zhong, Rachel A. Saltness, Karthik B. Jeganathan, Grace C. Versoza, A. Pezeshki and 3 more. Nature, 2016

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Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Subfields: Cancer Research, Pediatrics, Perinatology and Child Health, Physiology

View Paper: https://www.semanticscholar.org/paper/386956f00bea69683e4bc5224bae5326a8aabd94

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Citations in the corpus

cGAS is essential for cellular senescence (2017, background): “Recent studies have provided strong evidence that senescence has a causal role in aging and age-related diseases and that genetic deletion of senescent cells increases the lifespan and ameliorates age-related pathologies in mice (50, 51).”
Mechanisms and functions of cellular senescence. (2018, neutral): “Indeed, the elimination of senescent cells reduces levels of proinflammatory cytokines such as IL-6, IL-1 α , and TNF-α in fat, kidneys, and skeletal muscle of aged mice (14, 15, 18).”
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse (2016, background): “Moreover, senescent cells accumulate with age in several vertebrate organisms (1), and their elimination can delay the onset of several age-associated disorders in mice (3, 4).”
Unmasking Transcriptional Heterogeneity in Senescent Cells (2017, background): “Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9].”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “In a subsequent study using naturally aging INK/ATTAC mice, the same authors showed that elimination of p16 cells delays onset of age-associated diseases in later life, but also increases median and maximum lifespans, suggesting senescent cells limit longevity (20).”
Cellular Senescence: A Translational Perspective (2017, background): “…study, an increase in median lifespan was suggested in INKATTAC mice in which p16Ink4a+ cells had been targeted by repeated intraperitoneal (ip) injections of AP20187 beginning in mid-adulthood at the equivalent of 40 years of human age, compared to vehicle-treated controls (Baker et al., 2016).”