We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children's generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles.
Our specific aims are to: 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples;2) identiy common genetic variants for healthy aging and excepional survival using GWAS;3) identify rare variants for exceptional survival and healthy aging by targeted sequencing;and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging.

Public Health Relevance

Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AG023749-08S1
Application #
8736046
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (M2))
Program Officer
Dutta, Chhanda
Project Start
2004-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$491,197
Indirect Cost
$184,199
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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Fagan, Erin; Sun, Fangui; Bae, Harold et al. (2016) Telomere length is longer in women with late maternal age. Menopause :
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
Broer, Linda; Buchman, Aron S; Deelen, Joris et al. (2015) GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. J Gerontol A Biol Sci Med Sci 70:110-8
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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