(PROJECT 1) The central hypothesis of this program grant is that endogenous DNA damage is a major contributor to the aging process via induction of DNA damage responses and their biological outcomes, such as altered activity of cellular processes, mutations and epigenetic changes, apoptosis and cellular senescence. Project 1 previously established several mouse models with defects in DNA repair, which have an accelerated aging phenotype. In the current grant, we demonstrated with Core B that dietary restriction (DR) enormously prolongs lifespan and health of accelerated aging mouse models. This is important, because this provide us a competitive edge to study the mechanism of DR in a 5-10 fold shorter timeframe. Within the context of this renewal application, we will focus in specific aim 1 on the underlying mechanisms of DR. In collaboration with Project 2 and 3 we will address the hypothesis whether DR acts by reducing the DNA damage load via improved DNA damage repair and signaling including its downstream consequences ((epi)mutations, cellular senescence, apoptosis) or via reduced generation or enhanced scavenging of endogenous reactive metabolites such as reactive oxygen species or advanced glycation endproducts. Furthermore, we will extensively delineate molecular and cellular changes in response to DR with the aim to identify novel therapeutic targets.
In specific aim 2, we will follow up on a recent discovery in which we identified a microRNA signature for aging across several wild type aged mouse organs, which is directly upregulated by transcription- blocking DNA lesions. One of the main functions of these microRNAs is to repress cell death and maintain cell viability in the presence of unrepaired DNA damage, a process we have designated 'cell preservation'. Strikingly, Project 4 has identified induction of many cell preservation microRNAs in extreme human longevity, suggesting that cell preservation is associated with healthy aging. In collaboration with project 2, 3, 4 and core B we will further study microRNA-based cell preservation by silencing these microRNAs in accelerated aging mice to determine a causal role in aging. In addition, we will study the molecular basis of cell preservation and determine associated cellular aging phenotypes such as inflammation, energy metabolism and mutation frequencies. The results from these specific aims will provide new insight into the role of DNA damage in aging and mechanisms underlying DR.

Public Health Relevance

(PROJECT 1) Aging and age-related diseases are one of the major challenges for health care in industrialized societies. Understanding the molecular and cellular basis of aging is a prerequisite for designing interventions. We have established a strong link between DNA damage and aging using accelerated aging mouse models, which will be employed for rapidly intervention screening and delineating the molecular basis of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017242-17A1
Application #
8742952
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-04-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
Hernandez-Segura, Alejandra; de Jong, Tristan V; Melov, Simon et al. (2017) Unmasking Transcriptional Heterogeneity in Senescent Cells. Curr Biol 27:2652-2660.e4
Milholland, Brandon; Suh, Yousin; Vijg, Jan (2017) Mutation and catastrophe in the aging genome. Exp Gerontol 94:34-40
Dong, Xiao; Zhang, Lei; Milholland, Brandon et al. (2017) Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 14:491-493
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Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar et al. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691
Milholland, Brandon; Dong, Xiao; Zhang, Lei et al. (2017) Differences between germline and somatic mutation rates in humans and mice. Nat Commun 8:15183
Andriani, Grasiella A; Vijg, Jan; Montagna, Cristina (2017) Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain. Mech Ageing Dev 161:19-36
Lau, Cia-Hin; Suh, Yousin (2017) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology 63:103-117
Perrott, Kevin M; Wiley, Christopher D; Desprez, Pierre-Yves et al. (2017) Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience 39:161-173

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