Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. The long-term goal of this Program is to identify genes that contribute to exceptional longevity in humans, and to assess the associations among these genes with age-related diseases and longevity. We have comprehensively characterized over 300 Ashkenazi Jewish (relatively homogenous population) families with exceptional longevity (survival in good health to at least age 95) and have identified several biological markers that may be causative in their longevity. Most robust is our discovery that large particles size of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and increase in HDL levels are highly prevalent in centenarians and their offspring. These lipoprotein particle size are lower in offspring that have age-related diseases. These findings have focused us on candidate gene approach. We have analyzed several hundreds polymorphic exonic SNPs in these candidate genes, and have shown a significant, monotonic increase with aging in the frequency age related increase (from ~5-10% to ~25-30%) in a single polymorphism in the Cholesterol ester transfer protein (CETP), Apolipoprotein C-3 (APOC-3), Adiponectin (ADIPOQ) genes. Altered levels of these genes products, and age-related disease or longevity, have been linked to the favorable genotypes.
We aim to discover more longevity genes, aging genes, and their interactive/protective pathways by high through-out methods (Project 1). Because the GH/IGF pathway seems to be evolutionary conserve pathway for longevity, we will identify new polymorphisms in major genes in this pathway and examine their relationship to levels, function and age-related diseases (Project 2). We also will follow the cohort of offspring of centenarians and age-gender-matched control longitudinally to determine mainly the incidence of CVD (Project 3), and cognitive impairment (Project 4), according to favorable genotypes and their phenotypic expression. We will begin to validate the genetic and clinical data in an independent non-Jewish population and our new recruits. These objectives will be accomplished with assistance of Cores that will coordinate (Core A Administrative), recruit and retain (Core B Clinical) and use state-of-the-art epidemiological, statistical, and bioinformatics approaches (Core C-Statistics and Data Management), and molecular genetic technologies (Core D- Genetic). This program brings together a strong interdisciplinary team of investigators from gerontology, neurology, genetics, epidemiology, statistics and statistical genetics mainly from Albert Einstein College of Medicine, who have a proven track record of collaboration and of successful recruitment from this population. Consequently, implicating this phenotype and genotype in longevity will lead to fundamental insights into the molecular basis of several important age-related diseases. These insights may lead to novel preventive and treatment strategies for these diseases that will have a profound impact on morbidity and mortality, and will enhance the quality of life in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG027734-05S3
Application #
8544705
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (J1))
Program Officer
Rossi, Winifred K
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2012-09-30
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$133,322
Indirect Cost
$53,488
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kato, Kaori; Zweig, Richard; Schechter, Clyde B et al. (2016) Positive attitude toward life, emotional expression, self-rated health, and depressive symptoms among centenarians and near-centenarians. Aging Ment Health 20:930-9
(2016) The genetic architecture of type 2 diabetes. Nature 536:41-7
Strauss, S B; Kim, N; Branch, C A et al. (2016) Bidirectional Changes in Anisotropy Are Associated with Outcomes in Mild Traumatic Brain Injury. AJNR Am J Neuroradiol :
Freudenberg-Hua, Yun; Li, Wentian; Abhyankar, Avinash et al. (2016) Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians. Hum Mol Genet 25:3096-3105
Perice, Leland; Barzilai, Nir; Verghese, Joe et al. (2016) Lower circulating insulin-like growth factor-I is associated with better cognition in females with exceptional longevity without compromise to muscle mass and function. Aging (Albany NY) 8:2414-2424
Baskovich, Brett; Hiraki, Susan; Upadhyay, Kinnari et al. (2016) Expanded genetic screening panel for the Ashkenazi Jewish population. Genet Med 18:522-8
Roshandel, Delnaz; Klein, Ronald; Klein, Barbara E K et al. (2016) New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins. Diabetes 65:2060-71
Norden-Krichmar, Trina M; Gizer, Ian R; Phillips, Evelyn et al. (2015) Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort. Twin Res Hum Genet 18:727-37
Ryu, Seungjin; Teles, Francesca; Minopoli, Giuseppina et al. (2015) An epigenomic role of Fe65 in the cellular response to DNA damage. Mutat Res 776:40-7
Han, Jeehae; Atzmon, Gil; Barzilai, Nir et al. (2015) Genetic variation in Sirtuin 1 (SIRT1) is associated with lipid profiles but not with longevity in Ashkenazi Jews. Transl Res 165:480-1

Showing the most recent 10 out of 90 publications