Aging is directly or indirectly responsible for an increasingly large amount of death and debilitating disease (Alzheimer's, Parkinson's, Heart Disease, Cancer, etc.) in this and other developed countries, yet there is little that can be done to prevent or treat these diseases. The goal of this project is to learn more about the causes of aging and to discover potential therapeutic targets for its treatment or retardation. There are many proposed causes for aging, including macromolecule damage accumulation, telomere shortening, and our focus: cellular senescence. Recent evidence has implicated a likely role of Wnt signaling in inducing cellular senescence, and this project seeks to elucidate the mechanism by which this occurs. The first step is to identify which genes that are involved in Wnt signaling have altered expression with age by comparing gene expression data from Q-PCR arrays of select tissue types in young, old and calorie-restricted mice. This will be done separately in brain, heart, and lung tissue, and followed by biostatistical analysis and chromatin immunoprecipitation (ChIP) to determine cis-regulatory sites of genes of interest and the proteins that bind to these sites. The second part of this project focuses on causation rather than association;the genes whose expression changes with age as well as their regulators (as determined by ChIP) will be tested in vitro to determine if up- or down-regulating them is able to induce or delay senescence. This will not only confirm that Wnt signaling causes senescence, and thereby aging as well, but will provide a set of genes that are likely to be responsible. In future studies the expression of these genes can be altered in vivo in a tissue specific manner to determine if this modification can retard aging of these tissues. This research is relevant to public health because everyone is affected by aging. Directly, it decreases quality of life and leads to the development of degenerative and deadly disease, and the cost of care of the elderly, particularly people in their last year of life, is astronomical. Finding novel therapies to retard the rate of aging or treat its effects will not only increase average quality of life and healthspan of most people, but will also decrease the cost of health care to society

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F08-F (20))
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Velazquez, Jose M
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Brown University
Schools of Medicine
United States
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Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco et al. (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160:477-88
Hofmann, Jeffrey W; McBryan, Tony; Adams, Peter D et al. (2014) The effects of aging on the expression of Wnt pathway genes in mouse tissues. Age (Dordr) 36:9618
Sedivy, John M; Kreiling, Jill A; Neretti, Nicola et al. (2013) Death by transposition - the enemy within? Bioessays 35:1035-43