The Long Life Family Study (LLFS), established in 2005 in response to an NIA RFA, enrolled families enriched for exceptional longevity (EL), to discover factors that contribute to healthy aging and survival. From 2006 to 2009, LLFS enrolled 539 sibships (G1), their offspring (G2) and spouses (total 4,953). Comparison with a referent cohort reveals that LLFS families have strong exceptional clustering of EL. The G2 offspring have a variety of Healthy Aging Phenotypes (HAPs), defined as an unusually low age-specific prevalence of one or more specific conditions or risk factors, compared to population-based cohorts suggesting enrichment of shared (possibly genetic) protective effects in LLFS families. In the second funding period (2010-2013), we conducted a 2.5 million SNP GWAS (dbGaP phs000397); developed a high-throughput technique and sequenced ~450 candidate genes and replicated many variants and found additional ones associated with Healthy Aging Phenotypes (HAP) and longevity. 54% of LLFS G1 and 92% of G2 remain alive. Participant retention has been 94%. We now propose a third funding period to conduct a second in-person examination (V2) to prospectively study rates of change in HAPs with age and identify genetic and other factors contributing to HAPs and longevity. We hypothesize that EL and HAPs entail common and rare variants that individually have modest effects, but which in combinations strongly influence longevity and specific HAPs, and may only be detectable in family studies enriched for HAPs, such as LLFS. HAPs evaluated at the initial in-person visit show strong linkage peaks which are not explained by common haplotypes interrogated by GWAS (HLODs ranging from 6.0-45.1). These are likely driven by rare, lineage-private alleles that will only be found by sequencing specific families, and may point to important new biology.
Specific Aim 1 is to conduct a second in-home examination on all surviving LLFS participants.
Specific Aim 2 is to analyze cross-sectional and longitudinal phenotypes. The goal is to identify pathways for EL and HAPs by characterizing the shared and distinct LLFS phenotypes and environmental factors. We will characterize individual longitudinal patterns of HAPs to identify subgroups showing similar patterns and exceptional phenotypes. We will test whether these HAPs are heritable, and test for differences with internal and external referent groups.
Specific Aim 3 is to find genes/variants associated with cross-sectional and longitudinal phenotypes using a) Whole Exome Sequencing to comprehensively search for coding variants associated with HAPs and EL and b) Targeted Regulatory Sequencing of regions under linkage peaks for HAPs in selected families showing the strongest linkage evidence.
Specific Aim 4 is to replicate our genetic and epidemiological findings in other aging study cohorts. This study could lead to the discovery of pathways and potential therapeutic/prevention targets affecting HAPs and EL. A Data Management and Coordinating Center and 4 Field Centers comprise the major components of the LLFS. This renewal application is submitted by the Duke Uni./Uni. of Southern Denmark Field Center.

Public Health Relevance

The Long Life Family Study (LLFS) proposes a second examination of families enriched for exceptional longevity (EL), to discover genetic and environmental factors that contribute to healthy aging. These studies could lead to the discovery of new pathways and potential therapeutic/prevention targets affecting healthy aging and longevity.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG023712-11
Application #
9096691
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Dutta, Chhanda
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
None
Type
Organized Research Units
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Yashin, Anatoliy I; Zhbannikov, Ilya; Arbeeva, Liubov et al. (2016) Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures. Front Genet 7:188
Sanders, Jason L; Singh, Jatinder; Minster, Ryan L et al. (2016) Association Between Mortality and Heritability of the Scale of Aging Vigor in Epidemiology. J Am Geriatr Soc 64:1679-83
Fagan, Erin; Sun, Fangui; Bae, Harold et al. (2016) Telomere length is longer in women with late maternal age. Menopause :
Sebastiani, Paola; Thyagarajan, Bharat; Sun, Fangui et al. (2016) Age and Sex Distributions of Age-Related Biomarker Values in Healthy Older Adults from the Long Life Family Study. J Am Geriatr Soc 64:e189-e194
Kulminski, Alexander M; Raghavachari, Nalini; Arbeev, Konstantin G et al. (2016) Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study. Biogerontology 17:893-905
Sun, Fangui; Sebastiani, Paola; Schupf, Nicole et al. (2015) Extended maternal age at birth of last child and women's longevity in the Long Life Family Study. Menopause 22:26-31
Pedersen, Jacob K; Skytthe, Axel; McGue, Matt et al. (2015) Low tobacco-related cancer incidence in offspring of long-lived siblings: a comparison with Danish national cancer registry data. Ann Epidemiol 25:569-574.e3
Honig, Lawrence S; Kang, Min Suk; Cheng, Rong et al. (2015) Heritability of telomere length in a study of long-lived families. Neurobiol Aging 36:2785-90
Minster, Ryan L; Sanders, Jason L; Singh, Jatinder et al. (2015) Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index. J Gerontol A Biol Sci Med Sci 70:1003-8
Stevenson, Meredith; Bae, Harold; Schupf, Nicole et al. (2015) Burden of disease variants in participants of the Long Life Family Study. Aging (Albany NY) 7:123-32

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