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. From 2006 to 2009, LLFS enrolled 539 two-generation families (siblings, spouses and offspring) in the United States and Denmark, all with histories 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 those 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, the study team 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.
In 2014-2017, the study team conducted a second in-person examination of all living LLFS participants to prospectively study rates of change in HAPs with age. This examination also identified genetic and other factors contributing to HAPs and longevity. At this time, 54 percent of G1 enrollees and 92 percent of their offspring (G2) were alive. Participants are continuing to be followed-up annually to track vital and health status.
The third in-person visit, collecting all information at Visit 2 was completed from 2020-2024. Biological samples were repeated at Visit 3 and are also stored for future studies. All biochemical assays performed at Visit 1 were completed on stored Visit 2 and newly collected Visit 3 samples. Whole genome sequencing was performed on all participants baseline blood collection. Baseline samples were also used for baseline transcriptomic and methylomic assays on everyone. Specific families were selected to perform longitudinal transcriptomic and methylomic assays. Metabolomics was completed on all participants at all timepoints.
Visit 3 was designed to measure longitudinal change from Visits 1 and 2. Therefore, at the Visit 3 examination, we repeated measures that were expected to change over time, updated medical history and medications and repeated a blood draw. Visit 3 started during the COVID pandemic, and as such we did not collect spirometry data on anyone due to safety concerns. Additionally, we used video and split visits in order to facilitate a third visit with as many participants as possible.
During Visit 3 we also enrolled as many grandchildren from these families as possible (grandchildren of the probands), thereby making many of the pedigrees in our study three generations.
Project PI: Kaare Christensen