The aging process can be naturally accelerated and decelerated during evolution leading to significant diversity in lifespan among related species. Rodents represent a particularly convenient system to examine this diversity at the molecular level, because these animals are characterized by a ten-fold difference in lifespan and their tissues and cultured cells are readily available. Unbiased characterization of genes and processes that are associated with natural changes in lifespan within rodents may lead to the development of approaches that target the aging process and possibly delay it. We hypothesize that the lifespan of rodents is adjusted through a combination of order-wide and lineage-specific processes and provide preliminary data in support of this possibility. Project 4 will carry out gene expression and ribosome profiling analyses across rodent tissues and fibroblasts to identify and characterize these processes, focusing on DNA repair and metabolic processes known to regulate lifespan or occur in long-lived rodents. This project will further directly examine the functions of several unique protein forms we identified by sequencing the genome and transcriptome of the longest-lived rodent, the naked mole rat. Project 4 will test if these forms result in reduced mutagenesis in mouse cells and test the hypothesis that the naked mole rat telomeres have a high capacity to protect chromosome ends from genome instability. Finally, we will uncover and analyze gene expression and protein synthesis programs that are coordinately regulated in order to adjust rodent lifespan. This information will be integrated to develop a model featuring key processes which are altered globally and in an organ-specific manner as organisms change their lifespan.

Public Health Relevance

Characterization of genes and processes that are associated with natural changes in lifespan may lead to the development of approaches that target the aging process and possibly delay it. Project 4 will carry out gene expression analyses to uncover these processes, focusing on DNA repair and forms occurring in long- lived rodents. This information will help develop strategies to delay the aging process in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG047200-01
Application #
8707610
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441
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Zhou, Xuming; Sun, Di; Guang, Xuanmin et al. (2018) Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans. Genome Biol Evol 10:967-975
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Sziráki, András; Tyshkovskiy, Alexander; Gladyshev, Vadim N (2018) Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17:e12738
Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279
Tan, Li; Ke, Zhonghe; Tombline, Gregory et al. (2017) Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming. Stem Cell Reports 9:1721-1734
Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406

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