title: Ink4a/Arf expression is a biomarker of aging.
abstract: The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a 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 p16INK4a 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 p16INK4a 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 p16INK4a 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.
authors.affiliation: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7295, USA.
authors.forename: Janakiraman
authors.initials: J
authors.lastname: Krishnamurthy
authors.forename: Chad
authors.initials: C
authors.lastname: Torrice
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Grigoriy I
authors.initials: GI
authors.lastname: Kovalev
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Regaiey
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000096:biosynthesis* / Q000235:genetics; D000375:Aging; D000818:Animals; D015415:Biomarkers; D031204:Caloric Restriction; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D001616:beta-Galactosidase; D020823:ADP-Ribosylation Factor 1