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.