Work, from our lab and others, has established that the beneficial, anti-cancer function of the p16INK4a tumor suppressor mechanism also untowardly contributes to mammalian aging. In this model, the age-associated expression of p16INK4a compromises organismal fitness by limiting the regeneration and repair of certain self-renewing compartments. In support of this hypothesis, recent data from our lab and collaborators has shown that p16INK4a-deficient animals demonstrate a resistance to certain aging phenotypes in pancreatic -cells, neural stem cells and hematopoietic stem cells, while transgenic animals expressing excess p16INK4a demonstrate an accelerated functional decline with aging in these compartments. Additional support for this model has come from recent human genome-wide and candidate association studies which have linked single nucleotide polymorphisms near the CDKN2a locus, which encodes p16INK4a, to human age-associated conditions such as frailty, type 2 diabetes and atherosclerotic disease (myocardial infarction, ischemic stroke and abdominal aortic aneurysm). In the renewal of this proposal, we seek to extend these prior observations to further enhance our understanding of how p16INK4a influences mammalian aging.
In specific aim I, we propose to further define the role of p16INK4a in pancreatic -cell aging using a novel p16INK4a-conditional allele generated in our lab.
In specific aim II, we will further study the role of p16INK4a in a murine model of atherosclerosis using germline and conditional p16INK4a-deficient mice.
In specific aims III and IV, we will focus on the role of p16INK4a in lymphocyte aging.
In aim III, we will characterize T- and B-cell number and function in mice harboring somatic inactivation of p16INK4a in these tissues.
In aim I V, we will study the expression of p16INK4a in human T-cells with aging and after exposure to age-promoting stimuli such as cytotoxic chemotherapy. Through these approaches, we will further delineate the contribution of p16INK4a to age-associated phenotypes such as type 2 diabetes, atherosclerosis and immune dysfunction in humans in mice.

Public Health Relevance

Some aspects of aging result from a decline in the ability of tissues to repair and regenerate. This decline in tissue regenerative capacity is in part caused, in some cell types, by activation of the cell's intrinsic anti-cancer machinery. Human genetic studies have suggested this process is of particular importance in aging-related diseases such as atherosclerosis and type 2 diabetes. In this work, we use experimental systems in humans and mice to investigate the role of anti-cancer mechanisms in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG024379-10S1
Application #
8850022
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Velazquez, Jose M
Project Start
2004-08-15
Project End
2015-07-31
Budget Start
2014-06-15
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$100,000
Indirect Cost
$34,210
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Souroullas, George P; Jeck, William R; Parker, Joel S et al. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22:632-40
Pustavoitau, Aliaksei; Barodka, Viachaslau; Sharpless, Norman E et al. (2016) Role of senescence marker p16 INK4a measured in peripheral blood T-lymphocytes in predicting length of hospital stay after coronary artery bypass surgery in older adults. Exp Gerontol 74:29-36
Wood, William A; Krishnamurthy, Janakiraman; Mitin, Natalia et al. (2016) Chemotherapy and Stem Cell Transplantation Increase p16(INK4a) Expression, a Biomarker of T-cell Aging. EBioMedicine 11:227-238
Sharpless, Norman E; Sherr, Charles J (2015) Forging a signature of in vivo senescence. Nat Rev Cancer 15:397-408
Souroullas, George P; Sharpless, Norman E (2015) mTOR signaling in melanoma: oncogene-induced pseudo-senescence? Cancer Cell 27:3-5
Jeck, William R; Sharpless, Norman E (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32:453-61
Sanoff, Hanna K; Deal, Allison M; Krishnamurthy, Janakiraman et al. (2014) Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst 106:dju057
Sorrentino, Jessica A; Sanoff, Hanna K; Sharpless, Norman E (2014) Defining the toxicology of aging. Trends Mol Med 20:375-84
Jeck, William R; Sorrentino, Jessica A; Wang, Kai et al. (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19:141-57
Wang, Yang; Sharpless, Norman; Chang, Sandy (2013) p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses. J Clin Invest 123:4489-501

Showing the most recent 10 out of 34 publications