Critical Anti-Aging Pathways from Inter-Species Comparisons
PI: Richard A. Miller, MD, PhD
University of Michigan
This project starts from the assumption that the evolutionary processes that create long-lived species might involve fundamental changes in cell biology that affect many cell types throughout the organism. The project is assembling a collection of skin-derived fibroblasts from healthy young adults of long-lived and short-lived species, including primates, rodents, birds, and bats, and test them in tissue culture for properties that might be involved in postponing aging and multiple age-dependent diseases in the long-lived species. Longevity Consortium’s sequencing and bio-informatics cores are using RNA-sequencing methods to develop information about patterns of gene expression associated with slow aging and disease resistance, and work in the Miller laboratory will focus on mechanisms of cellular resistance to oxidation damage, heavy metal toxicity, and control of autophagy. The data produced will (a) suggests new traits, measurable in human volunteers, for which genetic associations might usefully be sought, (b) suggests new biochemical pathways, for example those related to defenses against specific categories of cellular stress, that might play a role in postponing one or several age-related diseases in long-lived people, and which might be regulated by common polymorphisms or rare alleles among humans, and (c) independent of genetic correlations, the data may suggest pharmacological targets, related to exceptional longevity among related sets of species, that deserve investigation as loci for prevention of multiple age-linked diseases.
Rich Miller, MD, PhD
millerr [AT] umich.edu
Subphenotypes of Exceptional Longevity and Environmental and Genetic Associations
PI: Thomas Perls MD, MPH, Boston Medical Center and Boston University School of Medicine
Co-PI: Paola Sebastiani PhD, Boston University School of Public Health
The overarching hypothesis of this project is that in humans, surviving to the oldest 1 percentile and beyond entails an increasingly influential genetic component and as a result it should be possible to discover patterns of inheritance as well as genetic contributors to slower aging and compression of morbidity and disability towards the ends of exceptionally long lives. Along with genetic signatures associated with specific patterns of exceptional survival, we also expect to find biomarker signatures that are also specific and sensitive for multiple subphenotypes of this advantageous trait. Findings supported by this project include:
- Analysis of clinical data from the New England and Elixir Centenarian Studies support the “Compression of Morbidity Hypothesis”, that is, humans who survive towards the limit of life span compress the period of time they experience age-related diseases and disability.1 For example, people living to 110+ years on average spent only the last 5 years at the end of their lives with at least one of six major age-related diseases (heart disease, hypertension, stroke, cancer, diabetes, or dementia). Compression of morbidity was also demonstrated with increasing ages of exceptional survival in another NIA-funded study, the Long Life Family Study (LLFS).2 These findings support the existence of protective genetic variants that slow aging and subsequently decrease risk for a broad range of age-related diseases associated with mortality. The compression of diseases into a very short period of time at ~110+ years also suggests a biological limit to life span when these protective mechanisms are maxed-out.3
- A genome wide association study of genetic data from the above two centenarian studies (one was a discovery set, the other was a replication set) identified patterns of variations of 281 genetic markers (pointing to 130 genes) called “genetic signatures” that could be used to differentiate, based on genetic data alone, centenarians from non-centenarians.4 The ability to pick out a centenarian (called sensitivity) increased with their age such that the sensitivity was modest (61%) for 95 year olds, but very high (84%) for 105+ year olds. 90% of 801 centenarians clustered into 28 distinct genetic signatures and some of these in turn were associated with specific subphenotypes of exceptional longevity (e.g. survival free of cardiovascular disease, or free of dementia). These findings support the hypothesis that the genetic influence upon survival to oldest ages increases with age, particularly beyond the top 0.1 percentile of survival. They also are consistent with the hypothesis that this genetic influence is made up of many genetic variants (and the pathways they modulate) that individually have modest effects, but as a group can have a very strong effect. Approximately 50 of the 281 SNPs were found to be associated with longevity in one or more of 3 ethnically distinct centenarian studies and the LLFS,5
Building upon the above work and to continue research efforts that are synergistic with studies performed by other Longevity Consortium investigators, we are engaged in the following:
- To complete validation of pedigree data of ~1,500 participants of the New England Centenarian Study, use the data for estimation of heritability of human extreme longevity, and generate a model for risk prediction of human longevity based on various familial patterns of such longevity. In collaboration with FamilySearch.org, we are in the process of constructing and validating a much larger set of centenarian pedigrees using automated search procedures developed by this effort.
- To produce a catalogue of genes/loci associated with human extreme longevity by combining data from 2 linkage studies of long lived individuals, and association studies based on imputed data sets. The catalogue will include genes in the insulin signaling pathway, and genes in the RNA editing pathway both of which are of keen interest to the Longevity Consortium. Network modeling will be used to identify subphenotypes of longevity that can suggest experimental validation of the findings. Candidates will be presented at the monthly Longevity Consortium meetings.
- To continue development of Bayesian statistical methods for integrative analysis of genetic data. In particular we will develop efficient approaches for family-based association studies in the Bayesian software OpenBUGS.
- Andersen SL, Sebastiani P, Dworkis DA, Feldman L, Perls TT. Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J Gerontol A Biol Sci Med Sci 2012;67:395-405.
- Sebastiani P, Sun F, Andersen SL, et al. Families Enriched for Exceptional Longevity also have Increased Health-Span: Findings from the Long Life Family Study. Front Public Health 2013:doi: 10.3389/fpubh.2013.00038. URL: http://www.frontiersin.org/Journal/10.3389/fpubh.2013./abstract
- Sebastiani P, Perls. The genetics of extreme longevity: lessons from the New England Centenarian Study. Front Genet 2012;3:277.
- Sebastiani P, Solovieff N, Dewan AT, et al. Genetic signatures of exceptional longevity in humans. PLoS ONE 2012;7:e29848. URL: http://dx.plos.org/10.1371/journal.pone.0029848
- Sebastiani P, Bae H, Sun FX, et al. Meta-analysis of genetic variants associated with human exceptional longevity. Aging (Albany NY) 2013;5:653-61.
Tom Perls, MD, MPH, thperls [AT] bu.edu, 617-638-6688
Paola Sebastiani, PhD sebas [AT] bu.edu, 617-638-5877