Effect of longevity genomes on the GH/IGF-1 phenotype and disease-free survival

DESCRIPTION (provided by applicant): I am a gerontologist physician-scientist, with a Master's degree in Clinical Research Methods and training in Endocrinology, focused on the discovery of genomic mechanisms that protect against age-associated diseases. I completed two years of post-doctoral training in translational gerontology and genetics at the Albert Einstein College of Medicine (Einstein) Institute for Aging Research, under the mentorship of Nir Barzilai, MD, during which time I was funded by the T32 and AFAR grants. Subsequently, I joined the Einstein faculty and was recognized with the Glenn Award for Research in Biological Mechanisms of Aging. I am presently funded by a career development KL2 grant from Einstein. My proposed project will be carried out within the environment of two established studies currently conducted at Einstein: (1) Longevity Genes Project (LGP), a cross sectional study of centenarians and unrelated controls, which serves as the discovery cohort for the genomic elements and phenotypes that are subsequently evaluated in (2) LonGenity, an independent, longitudinal validation study of offspring of centenarians, who are enriched with longevity genomes, and age-matched controls without parental history of longevity. The overarching hypothesis of these studies is that unique genomic elements protect against age-related diseases and result in healthy longevity, which is supported by observational and genetic evidence. My mentoring committee is headed by Dr. Barzilai, who directs the Nathan Shock Center of Excellence in the Biology of Aging, the Glenn Center for the Biology of Human Aging, and leads the longevity studies at Einstein. During the award period I will advance my knowledge in the longitudinal study methods, genetics and aging, as well as enhance my leadership skills, through mentored research and didactic training. Expanding evidence suggests that genomic alterations, which result in the attenuation of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) signaling, result in extended survival and improved health in animal models and humans. My study proposal hypothesizes that longevity- related genomic factors regulate the GH/IGF-1 phenotypes, which in turn, mediate protection against age-related diseases and promote longevity. This hypothesis will be tested prospectively in the LonGenity cohort and will determine the effects of the longevity genomic elements on the GH/IGF-1 phenotypes, in addition to, the prevalence and incidence of cardiovascular disease, cancer, type 2 diabetes mellitus, dementia, frailty, and exceptional longevity. Genomic elements to be tested will include longevity genotypes and microRNAs discovered in LGP by a candidate gene approach, unbiased genome-wide association study approach, and microRNA screening approach. The results of my early work investigating the effect of the GH/IGF-1 phenotype in nonagenarians have recently been published in Aging Cell and received international media coverage. This proposed project presents an opportunity to make discoveries that may lead to drug development for healthy aging, while providing a fertile environment within which I will grow into an independent gerontology investigator and a leader in translational research focusing on genomic regulation of endocrine pathways in aging.