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PMID: 15520862 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Ink4a/Arf expression is a biomarker of aging.

The Journal of clinical investigation ·Vol. 114 ·No. 9 ·2004-11-00 ·Pages 1299-307

Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE

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.

MeSH Terms
ADP-Ribosylation Factor 1/biosynthesis,genetics Aging Animals Biomarkers Caloric Restriction Cell Cycle Cyclin-Dependent Kinase Inhibitor p16/biosynthesis,genetics Disease Models, Animal Humans Immunohistochemistry Mice Models, Biological Polymerase Chain Reaction Rats Reverse Transcriptase Polymerase Chain Reaction Time Factors Tissue Distribution beta-Galactosidase/metabolism
Chemicals
Biomarkers Cyclin-Dependent Kinase Inhibitor p16 beta-Galactosidase ADP-Ribosylation Factor 1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Krishnamurthy Janakiraman
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7295, USA.
Torrice Chad
Ramsey Matthew R
Kovalev Grigoriy I
Al-Regaiey Khalid
Su Lishan
Sharpless Norman E
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI22475
Published
2004-11-00
Pages
1299-307
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC524230
Subset
IM
Grants
NCI NIH HHS · K08 CA090679 · United States
NIA NIH HHS · R01 AG019899 · United States
NIA NIH HHS · AG19899 · United States
NCI NIH HHS · CA090679 · United States
Corrections
CommentIn
PMID: 15520854
External Links
PubMed source DOI: 10.1172/JCI22475 PMC Full Text View journal details
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