The Overarching goal of this Program Project Grant (PPG), entitled """"""""Comparative Genomics of Longevity,"""""""" is to identify molecular mechanisms responsible for more efficient DNA repair and high cancer resistance in long-lived rodent species, with implications for human health. Rodents are an Ideal group for comparative aging studies because they are phylogenetically related, even though their lifespans are extremely diverse, ranging from 2-4 years in mice and rats to over 20 years in naked mole rats, beavers, porcupines, and squirrels. The mechanisms responsible for these vast differences in aging rates between species are largely unknown. Characterization of the processes responsible for this disparity in lifespan may enable the development of interventions to extend the human lifespan and prevention of age-related diseases. Preliminary studies show that long-lived rodents have more efficient DNA double-strand break (DSB) repair and that some of the long-lived species are highly resistant to cancer. The central hypothesis of this PPG, therefore, is that long-lived species have evolved more efficient mechanisms to maintain genome stability and prevent cancer. Efforts will focus on testing this hypothesis and understanding the exact molecular mechanisms responsible for more efficient DNA repair and cancer resistance in long-lived rodents. This PPG is comprised of four highly integrated projects. Project 1 (Vera Gorbunova) will identify mechanisms responsible for more efficient DSB repair in long-lived species. Project 2 (Andrei Seluanov) will examine mechanisms responsible for anticancer properties of high molecular weight hyaluronan found in long-lived rodents. Project 3 (Jan Vijg) will test whether more efficient DSB repair and hyaluronan prevent accumulation of mutations in long-lived species using novel high throughput approaches. Project 4 (Vadim Gladyshev) will use genomic and transcriptomic approaches to identify genes and pathways involved in DSB repair and hyaluronan biosynthesis that are differentially regulated in long-lived species. Thus, the research team consists of five investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), cancer-resistance and long-lived rodents (Seluanov), mutagenesis and high throughput approaches (Vijg), comparative genomics (Gladyshev), and bioinformatics (Zhang, Core C). Moreover, the team has developed a collection of primary rodent cells and tissues specifically to facilitate comparative studies of longevity (Seluanov, Core B). This joining of expertise will allow unprecedented insight into the biology of longevity;In summary, this team of investigators is uniquely positioned to pursue integrated studies of longevity across rodent species using a combination of cell, molecular, and genomic approaches.

Public Health Relevance

Mammalian species differ dramatically in their aging rates, but mechanisms responsible for these differences are unknown. This program project will identify mechanisms responsible for more efficient DNA repair and higher cancer resistance in long-lived rodents. This knowledge will enable the development of interventions to extend the human lifespan and delay the onset of age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG047200-01
Application #
8676097
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Guo, Max
Project Start
2014-05-01
Project End
2019-04-30
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
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
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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