(PROJECT 4) Evidence from this program project (PPG) demonstrated that defects in genome maintenance cause premature aging in mice. The contribution of genome maintenance to human longevity, however, remains to be established. The main objective of Project 4 (Previous Project 5) has been to translate the PPG's breakthrough discoveries into the human situation by testing the hypothesis that polymorphic variation at loci involved in genome maintenance relates to longevity and healthy aging phenotypes in humans. Research in Project 4 has led to the discovery of genetic and epigenetic signatures associated with human longevity: (1) enrichment of rare variants predicted to change the function and/or expression of proteins involved in signaling and repair of DNA double strand breaks (DSBs) in centenarians as compared to controls;and (2) upregulated microRNAs (miRNAs) in both immortalized B-cells and plasma of centenarians as compared to controls. Interestingly, some of these miRNAs were found, by Project 1, to induce cell preservation responses and cell death repression in the presence of unrepaired DNA damage. We hypothesize that a cluster of protective (epi)genotypes in the genome maintenance gene regulatory network is necessary to achieve exceptional longevity in humans. To confirm and extend our observations that support this hypothesis, we propose a systematic multidisciplinary approach to validate the longevity-associated (epi)genotype signatures and investigate the underlying molecular mechanisms to ascertain the functional relevance of observed positive associations by testing various parameters of cellular fitness in short-term cell culture studies in collaboration with all other Projects. Functionally relevant gene variants and miRNAs will then be further studied for their in vivo effect during aging by modeling them in the mouse in collaboration with Core B. The information generated in Project 4 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.

Public Health Relevance

(PROJECT 4) Defining the genetic and epigenetic factors that influence longevity in humans may have profound implications for the development of strategies to delay or prevent age-related diseases. Identification of genes that promote longevity and prevent or delay crippling diseases at old age is likely to help us finding novel strategies for prevention and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017242-17A1
Application #
8742955
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2014-09-30
Project End
2019-04-30
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
10461
Lau, Cia-Hin; Suh, Yousin (2018) In vivo epigenome editing and transcriptional modulation using CRISPR technology. Transgenic Res 27:489-509
Wiley, Christopher D; Schaum, Nicholas; Alimirah, Fatouma et al. (2018) Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci Rep 8:2410
Quispe-Tintaya, Wilber; Lee, Moonsook; Dong, Xiao et al. (2018) Bleomycin-induced genome structural variations in normal, non-tumor cells. Sci Rep 8:16523
H├ębert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279
Jeon, Ok Hee; Kim, Chaekyu; Laberge, Remi-Martin et al. (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775-781
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
Vijg, Jan; Dong, Xiao; Milholland, Brandon et al. (2017) Genome instability: a conserved mechanism of ageing? Essays Biochem 61:305-315
Lau, Cia-Hin; Suh, Yousin (2017) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology 63:103-117
Lau, Cia-Hin; Suh, Yousin (2017) In vivo genome editing in animals using AAV-CRISPR system: applications to translational research of human disease. F1000Res 6:2153
Hernandez-Segura, Alejandra; de Jong, Tristan V; Melov, Simon et al. (2017) Unmasking Transcriptional Heterogeneity in Senescent Cells. Curr Biol 27:2652-2660.e4

Showing the most recent 10 out of 253 publications