Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. In this Program Project we plan to expand the evidence indicating that life span is strongly inherited in families with exceptional longevity. We have comprehensively characterized over 300 Ashkenazi Jewish 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. We hypothesize that subjects with exceptional longevity have a 'genetic-hallmark'that provides protection against several age-related diseases. In preliminary data we show that these subjects and their offspring have 2-3 fold increases in rates of polymorphism in 2 genes regulating lipoprotein-cholesterol ester transfer protein (CETP) and apolipoprotein C-3 (APOC-S)-and decrease in plasma levels CETP and APOC-3. These contribute to large particles size of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and increase in HDL levels. We have also demonstrated that these genotypes and phenotypes are associated with less hypertension (HTN), cardiovascular disease (CVD) and metabolic syndrome (MS) (in offspring of the long-term survivors) and improved cognitive function (in probands). Using the strength of this established cohort, we now propose to utilize robust genetic technology with 500,000 SNPs (Genetic Core) and computational systems biology approach to characterize a cluster of genetic markers that will identify subjects with exceptional longevity with great accuracy. Furthermore, we will go back to the phenotypic data and associate this cluster with intermediate plasma phenotype and a reduced prevalence of age-related diseases. In addition, we will study the genetic basis of centenarians to overcome age-related diseases, in known and newly discovered pathways. These objectives will be accomplished using state-of-the-art computational biology, biochemical, molecular genetic, and statistics/bioinformatics (Statistics and Data management Core) approaches. This cohort of Ashkenazi Jews is ideal for this study since it is genetically homogeneous founder population that has been the basis of successful identification of other disease genes. Consequently, implicating this 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 #
8544706
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$19,047
Indirect Cost
$7,642
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Ezzati, Ali; Wang, Cuiling; Lipton, Richard B et al. (2017) Association Between Vascular Pathology and Rate of Cognitive Decline Independent of Alzheimer's Disease Pathology. J Am Geriatr Soc 65:1836-1841
Manning, Alisa (see original citation for additional authors) (2017) A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes 66:2019-2032
Sundermann, Erin E; Katz, Mindy J; Lipton, Richard B (2017) Sex Differences in the Relationship between Depressive Symptoms and Risk of Amnestic Mild Cognitive Impairment. Am J Geriatr Psychiatry 25:13-22
Seng, Elizabeth K; Buse, Dawn C; Klepper, Jaclyn E et al. (2017) Psychological Factors Associated With Chronic Migraine and Severe Migraine-Related Disability: An Observational Study in a Tertiary Headache Center. Headache 57:593-604
Sundermann, Erin Elizabeth; Wang, Cuiling; Katz, Mindy et al. (2016) Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ?4 on memory decline in older adults. Neurobiol Aging 41:200.e7-200.e12
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
Zimmerman, Molly E; Ezzati, Ali; Katz, Mindy J et al. (2016) Perceived Stress Is Differentially Related to Hippocampal Subfield Volumes among Older Adults. PLoS One 11:e0154530
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
Fuchsberger, Christian (see original citation for additional authors) (2016) The genetic architecture of type 2 diabetes. Nature 536:41-47

Showing the most recent 10 out of 97 publications