p16INK4a induces an age-dependent decline in islet regenerative potential

Abstract

The p16INK4a tumour suppressor accumulates in many tissues as a function of advancing age. p16INK4a is an effector of senescence and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic beta-cell proliferation in adult mammals. Here we show that p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16INK4a, but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16INK4a accumulation on islet function, we assessed the impact of p16INK4a deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific beta-cell toxin. Transgenic mice that overexpress p16INK4a to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16INK4a deficiency in young mice, but was relatively increased in p16(INK4a)-deficient old mice. Survival after toxin-mediated ablation of beta-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16INK4a demonstrated enhanced islet proliferation and survival after beta-cell ablation. These genetic data support the view that an age-induced increase of p16INK4a expression limits the regenerative capacity of beta-cells with ageing.

Aging by epigenetics—A consequence of chromatin damage?

“…Because of senescence, most primary human cells have a finite proliferative lifespan, and evidence has been presented that senescence contributes to tissue aging in vivo, in part by limiting the self-renewal of tissues [61][62][63]. Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72].…”

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…The senescence biomarker p16 INK4a mediates cell cycle arrest through inhibition of cyclin‐dependent kinase 4 and 6 (CDK4/6), but p16 INK4a expression is not required for production of the SASP (Coppe et al., 2011). Furthermore, in vivo evidence suggests that the primary functional consequence of high p16 INK4a expression with aging is to limit the proliferation of specific cell types during homeostasis or in response to injury (Janzen et al., 2006; Krishnamurthy et al., 2006; Liu et al., 2011; Molofsky et al., 2006; Sousa‐Victor et al., 2014). Several groups, however, have suggested cell cycle independent effects of p16 INK4a and CDK4/6 inhibition (Goel et al., 2017; Murakami, Mizoguchi, Saito, Miyasaka & Kohsaka, 2012), and it is unclear whether reduced p16 INK4a expression can protect tissues from age‐related pathologies that are associated with the SASP but not with replicative failure.…”

Relationships between stem cell exhaustion, tumour suppression and ageing

“…For some tissues, this expectation has been fulfilled, at least in part. Age-related decline in proliferation of the forebrain progenitors, pancreatic b-islet cells and HSCs were rescued significantly upon deletion of p16 INK4A in mice, as were regeneration of the corresponding tissues (Janzen et al, 2006;Krishnamurthy et al, 2006;Molofsky et al, 2006). These studies strongly indicate that naturally occurring upregulation of p16 INK4A levels with age form a ratelimiting block in tissue regeneration and that deletion of p16 INK4A alone is sufficient to remove at least part of this blockade.…”

“…The immediate response to DNA damage and oncogenic stress involves the p53-p21 transcriptional axis; however, once these factors wane, p16 INK4A levels begin to rise to cause irretrievable cell cycle exit through senescence (Campisi, 2005;Kim and Sharpless, 2006). In accord with 16 INK4A -mediated senescence playing an important role in ageing, 16 INK4A has been shown to be upregulated in various tissues in aged humans and rodents, and overexpression of p16 INK4A in mice to a degree observed with ageing leads to decreased b-islet regeneration (Krishnamurthy et al, 2004;Krishnamurthy et al, 2006;Ressler et al, 2006). If p16 INK4A upregulation is a cause of age-associated loss of regenerative capacity, then one would expect that deletion of p16 INK4A would suppress stem and progenitor cell attrition and tissue degeneration with age.…”