Ink4a/Arf expression is a biomarker of aging

Abstract

The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16 INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16 INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16 INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16 INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

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

“…In accord with observations in other murine tissues (Krishnamurthy et al., 2004), there was a significant increase in p16 INK4a expression (48.4‐ and 43.5‐fold, respectively) in the 18‐month and 22‐ to 27‐month groups as compared to skeletally mature mice of 4 months of age ( p  < .01, Figure 1a). A significant but less robust upregulation was seen in the related gene product p19 ARF , with an average fold increase of 24.4‐ and 12.9‐fold at 18 months and 22–27 months of age, respectively ( p  < .01, Figure 1a).…”

Cellular senescence impact on immune cell fate and function

“…This property makes senescent cells clearly different from quiescent cells (Campisi & Robert, 2014). One gene locus, namely CDKN2A, which encodes for two unrelated proteins p16 INK4a and p14/p19 ARF , is involved in this senescence‐induced cell cycle arrest (Krishnamurthy et al ., 2004). Indeed, by inhibiting cyclin‐dependent kinases (CDKs), p16 INK4a maintains the retinoblastoma family members (pRB, p107, and p130) in their transcriptionally repressive forms, thus preventing G1/S cell cycle progression (Gil & Peters, 2006).…”

“…Indeed, after 2 weeks in culture, these cells eventually stop proliferating and concomitantly accumulate p16 INK4a and p14/p19 ARF . It is not known whether B‐cell senescence can naturally occur in vivo in young individuals, but with age, the expression levels of both p16 INK4a and p14/p19 ARF increase in all B lineages, particularly in pro‐B, pre‐B, and IgM+ mature B cells (Krishnamurthy et al ., 2004; Signer et al ., 2008). Ectopic expression of p16 INK4a or p14/p19 ARF in young pro‐/pre‐B cells mimics the effect of aging by decreasing cell growth and survival.…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…Senescent cells accumulate in several tissues during aging in humans and mice (Dimri et al, 1995; Krishnamurthy et al, 2004) and are considered to contribute to tissue aging and aging‐associated disorders through their cell nonautonomous functions (Freund, Orjalo, Desprez, & Campisi, 2010; Watanabe, Kawamoto, Ohtani, & Hara, 2017). Recent studies using transgenic mice designed to eliminate senescent cells from tissues by sensitizing them to specific drugs have more clearly elucidated the roles of senescent cells in tissue aging and disease.…”