The LonGenity research study builds upon the Longevity Genes Project, initiated in 1998 at the Albert Einstein College of Medicine by Dr. Nir Barzilai. Dr. Barzilai's early observations of the phenotypes of healthy, vital centenarians led him to ask a series of questions. The project's primary focus questioned why some people enjoy extremely long life spans, with physical health and brain function far better than expected in the 9th and 10th decades of life.
In 2006 Dr. Barzilai and his team increased their efforts to conduct a large program, "Roles of genes in exceptional longevity in humans" (LonGenity), funded by the National institute of Aging.
In the LonGenity program, genetic analysis (GWAS and candidate gene approach) is performed in an already established cohort (centenarians, their offspring, and age-match unrelated control to these offspring), and genetic findings are validated in a newly established cohort of offspring of parents with exceptional longevity (OPEL) vs. offspring of parents with usual survival (OPUS).
Over the past ten years Dr. Barzilai's team has assembled and characterized families with exceptional longevity and have identified several biological markers that may explain their longevity. Their hypothesis is that unique genotypes and phenotypes protect against age-related diseases (Figure 1). In order to comply with the steps to prove the causality suggested by the figure 1, novel genetic, epidemiologic, and statistical approaches are used to identify genetic markers in subjects with exceptional longevity, and test the impact of these markers on biological measurements and clinical out comes. The long-term objectives are to identify genes that contribute to exceptional longevity in humans, and assess associations among these genes with age-related diseases and longevity.
The LonGenity research study aims:
- To discover "hallmark" genes for exceptional longevity, and their target "killing" genes (Project 1).
- To discover genotypes for exceptional longevity in humans in the GH/IGF pathway (Project 2).
- To support a causative role of distinct genetic and biochemical markers for exceptional longevity in the prevention of cardiovascular diseases (CVD, Project 3).
- To support a causative role of distinct genetic and biochemical markers for exceptional longevity in the prevention of cognitive decline (Project 4).
To date, a unique cohort of over 500 proband with exceptional longevity (~100 y/o), over 700 of their offspring (ages 60-85), and over 600 unrelated subjects ages 60-95 have been assembled and characterized.
Findings
Results of the research to date have been encouraging and enthusiastically received by the medical research community. Among the findings, the team has learned that longevity is:
- Highly likely to be inherited from generation to generation
- Highly correlated to high HDL ("good") and low LDL ("bad) cholesterol levels
- Likely to occur among people with larger HDL and LDL molecule sizes resulting in lower incidences of cardiovascular disease,insulin resistance, and hypertension.
Additionally, they have learned that:
- A mutation in the lipoprotein gene Cholesterol Ester Reverse Transferase (CETP) is associated with gene.
- The (CETP) gene is involved in prevention of cognitive decline and Alzheimer’s disease.
- A mutation in the apo lipoprotein C-3 gene (APOC3) modulates lipoproteins and their particle sizes and is associated with extensive survival. Subjects with a certain genotype live on average 4 years longer than those without.
- A deletion in an intrastate area of adiponectin (ADIPOQ), a recently discovered fat-derived peptide that has been shown in vivo to have actions that improves insulin action and decreased arterial wall inflammation, is associated with exceptional longevity.
- We discovered new, non-synonymous, polymorphisms in the insulin-like growth factor -1 (IGF-1) signaling pathway in selected groups of relatively short women centenarians. Relative dwarfism was shown to be conserved in order to achieve longevity in lower species and genetic rodent models.
- We showed that the telomeres, those parts of DNA at the edge of chromosomes that are shortening every time the cell divides, are longer in centenarians. These are also longer telomeres seem to be inherited in their offspring. Moreover, some mutations in the telomeres genes seem to be responsible for these.
