Launched in 2005, the Long Life Family Study (LLFS) seeks to understand exceptional longevity in some families to discover genetic and environmental factors that contribute to healthy aging. Funded by the National Institute on Aging, the project is a collaboration between researchers at Duke University, Washington University St. Louis, Boston Medical Center, Columbia University, University of Pittsburgh and University of Southern Denmark. CPHA Research Scholar Kaare Christensen is Principal Investigator.
From 2006 to 2009, LLFS enrolled 539 two-generation families (siblings, spouses and offspring) in the United States and Denmark with a history of longevity. Participants totaled 4,953 individuals. First-generation (G1) participants made-up approximately one-third of the cohort, with a mean age of 90 and the other two-thirds, primarily offspring, had a mean age of 61.
All participants underwent biomedical testing and answered extensive questions on health, environment and family history. This initial examination revealed exceptional clustering of longevity in these families and showed lower rates of disease and risk factors than is seen in the general population. The offspring of G1 enrollees, for example, 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.
From 2010 to 2013, we conducted a 2.5 million SNP GWAS; 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.
Understanding the pathways responsible for exceptional longevity in certain families could lead to the discovery of targets for therapy or prevention in the wider population. Exceptional longevity is not simply an extended version of a typical life; longevity is associated with a compression of the period of life in which one is disabled. At extreme ages, morbidity (disease) is compressed as well (Andersen et al. 2012). Why the exceptionally long-lived stay functional and healthier for longer than others is unknown.
Individuals differ markedly in rates of age-related changes in assorted functions that influence risk of morbidities in late life. The exceptionally healthy LLFS population provides a unique resource to identify factors contributing to favorable trajectories of change with age. We have found cross-sectional relationships in LLFS that suggest at least 3 such trajectories, depending on the function: 1) delayed onset of functional decline, 2) slower rate of change, and/or 3) higher baseline functional reserve but a usual rate of decline (Newman et al. 2011). However, to assess the causes of inter-individual variation in these trajectories, and their consequences, longitudinal data are essential.
In 2014, 54 percent of G1 enrollees and 92 percent of their offspring (G2) remain alive. We have checked in with participants in every year of the study and in 2014 we plan to conduct a second in-person examination to prospectively study rates of change in HAPs with age and to identify genetic and other factors contributing to HAPs and longevity.
We hypothesize that exceptional longevity (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.
In this new wave of the study, we will:
- Conduct a second in-home examination on all surviving LLFS participants
- 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.
- 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.
- Replicate our genetic and epidemiological findings in other aging study cohorts.