The LC was organized in 1999 to identify genes that affect longevity and aging in humans. In its initial phase (Phase I), members of a LC planning committee exchanged information about research methods and results from several disciplines, formed cross-disciplinary collaborations, and identified potential biological pathways that may harbor genetic variants that affect human lifespan. This phase, which was supported by a planning grant from the NIA, brought together researchers interested in longevity and aging from a variety of disciplines, including laboratory scientists who study longevity in model systems; epidemiologists who have enrolled and followed large cohorts of elderly people; experts in genomic methods; biostatisticians interested in the analysis of the associations between genetic data and complex traits; demographers who study patterns of mortality and life expectancy; and gerontologists and geriatricians. The planning committee included many members of the current LC.
The planning process led to a number of successful collaborations and led to Phase II of the Consortium, also supported by the NIA. In Phase II, the LC took three approaches to study longevity: a.) identify common genetic variants associated with survival in candidate pathways in adults > 90 years old; b.) identify genes association with long life span in mice; and c.) study the associations between telomere length and human longevity. Phase II included 5 projects and 3 Cores, involved a broad consortium of scientists to test hypotheses that: 1. common single nucleotide polymorphisms (SNPs) in insulin signaling pathways are associated with exceptional survival; 2. common SNP’s in pathways involved in inflammation and thrombosis are associated with exceptional survival; and 3. longer telomere length is associated with exceptional survival; 4. the effects of growth hormone and insulin signaling in lifespan determination of mouse models, and 5. analyzed genetic variants associated with cellular stress resistance and longevity in wild-type mice.
Phase III of the consortium pursued more refined studies focusing on Centenarians, cross-species studies, and integrated data analyses. The cross-species analysis includes RNA-seq analysis of fibroblasts to find transcriptional signatures associated with the large variation in lifespan across bird species.
Historically, the Consortium has provided support for many smaller opportunity fund research endeavors. These projects represented state-of-the art, often cutting edge research on aging and longevity. For example, one the major projects explored the use of QTL analysis to identify genes associated with stress and aging in mice. Still another focused on telomere length in human aging and longevity while a third assessed associations between stress, inflammation and the genetics of human aging. Among the smaller one year projects, some of the efforts were devoted to better understanding the exceptional longevity of Okinawans, others to identifying rare sirtuin variants in the extremes of adult lifespan and still others to using chemical mutagenesis of murine embryonic stem cells to generate stress resistant (and potentially long-lived) mice. In Phase III of the LC, a Translational Research Core contained two working groups (focused on APOE and FOXO3) that regularly review the progress of opportunity fund projects, discuss current literature and, most importantly, identify and help develop new research projects for opportunity fund support.
Since 2001, the LC has organized 20 meetings involving a total of 179 speakers, some presenting on more than one occasion. Until recently, the average meeting involved about 50 attendees, including speakers, discussants and NIA staff. Over the years, a wide range of topics related to aging and longevity have been covered (see link to previous programs), representing some of the most exciting and cutting edge work being done at the time. For example, LC meetings were among the first to consider Klotho as a longevity regulating gene, to consider the role of heat shock proteins in aging, to explore the role of epigenetics and DNA methylation in regulating aging and to consider the role of cellular senescence in cancer and aging. Most recently, the LC held a workshop to discuss, in depth, the genetics and functional genomics of FOXO3, one of few genes whose variants are most consistently with exceptional longevity.
By design, most meetings provided an almost unique interdisciplinary approach and included a combination of basic, translational, computational and clinical science. The symposia also provided a platform for LC funded investigators to present and discuss the progress of their research. Equally importantly, they also provided an essential venue for informal discussions leading, in a number of cases, to new collaborations and joint research projects.
The LC will continue its focus on identifying genetically-mediated factors that contribute to human longevity, both in terms of lifespan and healthspan. However, the newly-framed LC will have a much stronger emphasis on the integration, validation and pre-clinical translation of results than before, using a wide- variety of approaches (see Projects and Cores here). The central and guiding theme of the LC will be to identify genetic and molecular factors that, in aggregate, causally influence human longevity and that, either individually or as part of a broader molecular pathway or process, might be amenable to pharmacological manipulation. LC investigators have, over the previous two decades, made substantive contributions to the state-of-the-knowledge of human aging and longevity.