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Background: Identification of genes or fundamental biological pathways that regulate aging phenotypes and longevity could lead to possible interventions to increase healthy longevity.Methods: Using data from the Long Life Family Study, we performed genomewide association analyses on an endophenotype construct, LF1, comprising a linear combination of traits across health domains. LF1 primarily reflected traits from the pulmonary and physical activity domains.Results: We detected a significant association between LF1 and a locus on chromosome 10p15 (p-value = 4.65 × 10-8) and suggestive evidence (p-value < 5 × 10-6) for association on chromosomes 1, 2, 8, 12, 15, 18, and 22. Using data from the Health, Aging and Body Composition Study, we subsequently replicated the association for the 1p13 region near the NBPF6 locus (p-value = 3.65 × 10-4).Conclusions: Our analyses indicate that loci influencing a healthy aging endophenotype construct predominantly comprised of pulmonary and physical function domains may be located on chromosome 1p13 near the NBPF6 locus. Further investigation of this possible locus and other suggestive loci may reveal novel biological pathways that influence healthy aging. [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology ( SAVE), to determine its value for genetic analyses. Design Longitudinal, community-based cohort study. Setting The Long Life Family Study ( LLFS) in the United States and Denmark. Participants Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551). Measurements The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models. Results Heritability of the SAVE was 0.23 ( P < .001) overall (n = 3,599), 0.31 ( P < .001) in probands (n = 1,479), and 0.26 ( P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio ( HR) = 2.83, 95% confidence interval ( CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2). Conclusion The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses. [ABSTRACT FROM AUTHOR]

One method by which to identify fundamental biological processes that may contribute to age-related disease and disability, instead of disease-specific processes, is to construct endophenotypes comprising linear combinations of physiological measures. Applying factor analyses methods to phenotypic data (2006-2009) on 28 traits representing 5 domains (cognitive, cardiovascular, metabolic, physical, and pulmonary) from 4,472 US and Danish individuals in 574 pedigrees from the Long Life Family Study (United States and Denmark), we constructed endophenotypes and assessed their relationship with mortality. The most dominant endophenotype primarily reflected the physical activity and pulmonary domains, was heritable, was significantly associated with mortality, and attenuated the association of age with mortality by 24.1%. Using data (1997-1998) on 1,794 Health, Aging and Body Composition Study participants from Memphis, Tennessee, and Pittsburgh, Pennsylvania, we obtained strikingly similar endophenotypes and relationships to mortality. We also reproduced the endophenotype constructs, especially the dominant physical activity and pulmonary endophenotype, within demographic subpopulations of these 2 cohorts. Thus, this endophenotype construct may represent an underlying phenotype related to aging. Additional genetic studies of this endophenotype may help identify genetic variants or networks that contribute to the aging process. [ABSTRACT FROM AUTHOR]