In this proposal, I seek an extension of my MERIT award.
The aims of the current funding period were: 1) To assess telomere-initiated cellular senescence in vivo;2) To investigate heterochromatin-associated senescence states. 3) To study the upregulation of p16. In the 3 years and 8 months since the start of this funding cycle, our projects have evolved from a predominant focus on cellular senescence to a much stronger connection with in vivo organismal aging. We do not wish to imply that cellular senescence is not relevant for aging, but rather that our research has led us in directions that include significant components of chronological aging. Our work has coalesced along 2 predominant themes: 1) Physiological changes that accompany a lifespan extension elicited by a hypomorphic allele of the ubiquitous c-Myc transcription factor;2) Age-associated epigenetic changes that lead to chromatin remodeling, and other genome-wide changes. The first project is based on the remarkable discovery that mice heterozygous for a knockout of the c-myc gene have an extended lifespan. We have completed an extensive demographic analysis showing that both median and maximum lifespans are increased in both sexes: 10-11% in males, and 17% in females. In studying these animals we have taken unbiased approaches, assessed known mouse age- associated phenotypes, and investigated specific pathways targeted by c-Myc. Our studies have identified inflammation and lipid metabolism as the major targets of future investigation. Going forward we propose to investigate a large number of physiological phenotypes in the Myc-het mice, how they change with age, and which ones may explain the observed lifespan extension. The second project has revolved mostly around replicative senescence of human fibroblasts in cell culture. We performed high throughput studies of epigenetic changes during senescence, and discovered extensive genome-wide rearrangements of chromatin that culminate in the heterochromatinization of active genes and expression and activation of retrotransposable elements. Interestingly, we have also found that retrotransposable elements and satellite sequences become expressed with age in several mouse tissues. We propose to apply these approaches to study the aging epigenome in the mouse.

Public Health Relevance

First, we have found a novel genetic intervention that significantly extends lifespan in the mouse. Our data indicate that the mechanisms responsible for this effect are likely to be quite different from those studied in other models of longevity. Second, we have discovered that the fundamental architecture of the genome undergoes widespread alterations during cellular senescence. These degenerative changes that profoundly affect genome integrity are likely to be the consequence cellular aging processes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Velazquez, Jose M
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Brown University
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Waaijer, Mariƫtte E C; Gunn, David A; van Heemst, Diana et al. (2018) Do senescence markers correlate in vitro and in situ within individual human donors? Aging (Albany NY) 10:278-289
Sarosiek, Kristopher A; Fraser, Cameron; Muthalagu, Nathiya et al. (2017) Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 31:142-156
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Borghesan, Michela; Fusilli, Caterina; Rappa, Francesca et al. (2016) DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. Cancer Res 76:594-606
Waaijer, Mariƫtte E C; Croco, Eleonora; Westendorp, Rudi G J et al. (2016) DNA damage markers in dermal fibroblasts in vitro reflect chronological donor age. Aging (Albany NY) 8:147-57
Tatar, Marc; Sedivy, John M (2016) Mitochondria: Masters of Epigenetics. Cell 165:1052-1054
Criscione, Steven W; De Cecco, Marco; Siranosian, Benjamin et al. (2016) Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2:e1500882
Giampieri, Enrico; De Cecco, Marco; Remondini, Daniel et al. (2015) Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence. PLoS One 10:e0118442
Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco et al. (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160:477-88

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