Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

By D. Baker, Tobias Wijshake, T. Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, B. van de Sluis, J. Kirkland, Jan M. van Deursen. Nature, 2011

3,430 citations recorded by the source corpus.

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

Subfields: Physiology

View Paper: https://www.semanticscholar.org/paper/5e51683562d4509859d779717a9e90806cd4dade

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Citations in the corpus

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016, positive): “ATTAC MEFs were generated as previously described 4 .”
Senescence is a developmental mechanism that contributes to embryonic growth and patterning. (2013, background): “, 2007), premature aging (Baker et al., 2011; Keyes et al., 2005), fibrotic tissue (Jun and Lau, 2010; Krizhanovsky et al.”
Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors (2016, background): “AP20187 eliminated senescent cells and alleviated age-related dysfunction in progeroid mice producing ATTAC only in p16Ink4a-expressing cells (Baker et al., 2011).”
Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice (2017, positive): “com 957 AGING vascular, frailty-related, osteoporotic, neurological, radiation-induced, and other phenotypes and disorders in chronologically aged, progeroid, and high fat-fed atherosclerosis-prone mice, consistent with our observations in mice from which senescent cells had been removed by inducing”
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs (2015, background): “We previously demonstrated that the healthspan of transgenic mice can be enhanced by selectively killing senescent cells using a transgenic suicide gene (Baker et al., 2011).”
The hallmarks of aging. (2013, background): “Moreover, transgenic mice overexpressing BubR1, a mitotic checkpoint component that ensures accurate segregation of chromosomes, exhibit an increased protection against aneuploidy and cancer, as well as extended healthy lifespan (Baker et al., 2013).”
Senescence and the SASP: many therapeutic avenues (2020, background): “Eliminating senescent cells reduces the levels of proinflammatory cytokines in old mice (Baker et al. 2011, 2016), suggesting that the SASP may also contribute to inflammaging.”