Understanding of mechanisms that control lifespan is among the most challenging biological problems. Although not viewed as a medical condition to be treated, aging is the most prevalent disease-related state. Many complex human diseases are associated with aging, which is both the most significant risk factor and the process that drives the development of these diseases. Clinically, extending lifespan would mean delaying the onset of age-related diseases, such as cancer, neurodegenerative diseases, type II diabetes and sarcopenia. Studies of model organisms and centenarians as well as the use of compounds that extend lifespan in model organisms (e.g., rapamycin) as drugs for multiple human diseases associated with aging suggest that these approaches are feasible. It is also clear that the aging process can be naturally accelerated and delayed (e.g., mammals are characterized by >100-fold difference in lifespan, and it can both increase and decrease during evolution). These differences in lifespan and other traits among mammals are much larger than those among natural isolates of the same species of model organisms, between centenarians and controls, or between wild type and longer-lived mutant organisms identified in various laboratories. Moreover, the observed variation in mammalian lifespan occurs naturally, in contrast to laboratory mutants characterized by extended lifespan but unable to compete in the natural setting. We propose to employ this diversity in lifespan and associated life-history traits to uncover mechanisms that regulate species lifespan in mammals. For this, we will utilize methods of comparative genomics to examine pairs of genomes of closely related short- and long-lived organisms, carry out analysis of lifespan, life-history and other traits across a panel f mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators,

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1AG047745-01
Application #
8564159
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Guo, Max
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$882,292
Indirect Cost
$382,292
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Fang, Xiaodong; Seim, Inge; Huang, Zhiyong et al. (2014) Adaptations to a subterranean environment and longevity revealed by the analysis of mole rat genomes. Cell Rep 8:1354-64