The incidence of age-related diseases continues to rise as the number of Americans over the age of 65 grows. As a result, research is now focused on discovering methods to promote longevity. Although few molecular indicators of biological age have been indentified, we and others have recently shown that p16INK4a serves a robust and accurate marker of mammalian aging. Induction of p16INK4a correlates directly with chronological age in rodents and can be slowed by anti-aging strategies such as caloric restriction. In addition, our preliminary data show that p16INK4a levels are decreased by moderate exercise in healthy human subjects. Despite these data, the mechanisms by which lifestyle modification promotes longevity remain largely undefined. Herein, I will exploit the unique properties of p16INK4a as an aging biomarker to assess the tissue- specificity of anti-aging strategies. To do this, I have developed a novel knockin reporter allele, p16-LUC, which expresses firefly luciferase under control of the endogenous p16INK4a promoter. Importantly, my preliminary data show that induction of this allele correlates with cellular senescence in vitro and can be visualized in living animals. Using these mice I plan to address the following specific aims: 1) Characterize the p16- LUC allele under conditions relevant to the mammalian aging process, 2) Investigate the influence of diet and exercise on the induction of p16INK4a, 3) Determine the time- dependent and organ-specific effects of diet and exercise on p16INK4a promoter occupancy.
These studies will determine the potential of a new mouse model to predict how exercise and diet influence biological aging. In addition, we will gain insight into the processes that cause our bodies to age, helping us to develop new strategies that promote human health and longevity.
|Robinson, Andria R; Yousefzadeh, Matthew J; Rozgaja, Tania A et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273|
|Hennessey, Rebecca C; Holderbaum, Andrea M; Bonilla, Anamaria et al. (2017) Ultraviolet radiation accelerates NRas-mutant melanomagenesis: A cooperative effect blocked by sunscreen. Pigment Cell Melanoma Res 30:477-487|
|Guan, Xiangnan; LaPak, Kyle M; Hennessey, Rebecca C et al. (2017) Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth. Mol Cancer Res 15:237-249|
|Burd, Christin E; Gill, Matthew S; Niedernhofer, Laura J et al. (2016) Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms. J Gerontol A Biol Sci Med Sci 71:1388-1394|
|Rosko, A; Hofmeister, C; Benson, D et al. (2015) Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma. Bone Marrow Transplant 50:1379-81|
|LaPak, Kyle M; Burd, Christin E (2014) The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res 12:167-83|
|Burd, Christin E; Liu, Wenjin; Huynh, Minh V et al. (2014) Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov 4:1418-29|
|Sorrentino, Jessica A; Krishnamurthy, Janakiraman; Tilley, Stephen et al. (2014) p16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J Clin Invest 124:169-73|
|Burd, Christin E; Sorrentino, Jessica A; Clark, Kelly S et al. (2013) Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152:340-51|