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
Ma, Siming; Upneja, Akhil; Galecki, Andrzej et al. (2016) Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. Elife 5:
Quispe-Tintaya, Wilber; Gorbacheva, Tatyana; Lee, Moonsook et al. (2016) Quantitative detection of low-abundance somatic structural variants in normal cells by high-throughput sequencing. Nat Methods 13:584-6
Dokukin, Maxim; Ablaeva, Yulija; Kalaparthi, Vivekanand et al. (2016) Pericellular Brush and Mechanics of Guinea Pig Fibroblast Cells Studied with AFM. Biophys J 111:236-46
Gorbunova, Vera; Seluanov, Andrei (2016) DNA double strand break repair, aging and the chromatin connection. Mutat Res 788:2-6
Patrick, Alison; Seluanov, Michael; Hwang, Chaewon et al. (2016) Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan. Aging (Albany NY) 8:841-7
White, Ryan R; Vijg, Jan (2016) Do DNA Double-Strand Breaks Drive Aging? Mol Cell 63:729-38
Tian, Xiao; Azpurua, Jorge; Ke, Zhonghe et al. (2015) INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc Natl Acad Sci U S A 112:1053-8
Ma, Siming; Yim, Sun Hee; Lee, Sang-Goo et al. (2015) Organization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. Cell Metab 22:332-43
Ma, Siming; Lee, Sang-Goo; Kim, Eun Bae et al. (2015) Organization of the Mammalian Ionome According to Organ Origin, Lineage Specialization, and Longevity. Cell Rep 13:1319-26
MacRae, Sheila L; Zhang, Quanwei; Lemetre, Christophe et al. (2015) Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human. Aging Cell 14:288-91

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