Genetic cartography of longevity in humans and mice: Current landscape and horizons

Abstract

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA variants that modulate aging. We argue that the problem in mapping longevity genes is mainly one of low power and the genetic and environmental complexity of aging. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40 years of linkage studies using murine cohorts and 15 years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan.

Multi-Omic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

“…Earlier studies have demonstrated that lifespan across the BXD family of mice varies by ~3-fold-from 11 to 32 months [19][20][21]. These differences among strains are consistent across studies, even twenty years apart (rho = 0.61, Figure S1A [1,20,21]). Here, 1418 individuals lived out their natural lifespans and were used for the calculation of longevity, permitting comparisons across diets ( Figure 1C) and strain ( Figure 1D).…”

“…Aging is a dynamic and diverse process driven over a lifetime of interactions between genetic variants, environmental factors, and stochastic processes. Despite its complexity, lifespan is a heritable trait, with genotype explaining 30-50% of its variation across laboratory mice [1,2] and ~25% in humans [1]. Because age is the most prominent "risk factor" for a wide range of metabolic diseases, such as diabetes, heart disease, neurodegeneration, and most cancers [3,4], it is critical to understand the cellular and molecular changes that accumulate and lead to these diseases.…”

PGC‐1a integrates a metabolism and growth network linked to caloric restriction

“…The genetics of human longevity has been an active area of investigation, and genes associated with longevity include ApoE, FOXO3a, and AdipoQ. A recent meta‐analysis of longevity‐associated quantitative trait loci identified PPARg as a potential longevity factor (Hook et al, ). The close relationship between growth inhibition and activation of mitochondrial oxidative pathways could be a more general mechanism for cellular homeostasis.…”

Gene-by-environmental modulation of longevity and weight gain in the murine BXD family

“…Longevity is among the most complex and heterogeneous of traits. Differences in lifespan are dependent on interactions among many genetic and environmental factors, and innumerable gene-by-environmental (GXE) interactions (de Magalhães et al, 2012), (Kuningas et al, 2008), (McDaid et al, 2017), (Hook et al, 2018). Nutrition, of course, has a profound influence on health and lifespan (Fontana and Partridge, 2015).…”

“…Studies of BXDs by Gelman, Lang, and colleagues (Gelman et al, 1988;Lang et al, 2010) demonstrate at least two-fold variation in lifespan on a standard diet-from approximately 12-15 months for the shortest lived strains to 30 months for the longest lived strains. In these studies conventional heritabilities of lifespan are as high as 25-45%, but the effective heritabilities (h 2 RI ) that accounts for the depth of resampling (n = 8 to 12 replicates/genome) are as high as 80% (Belknap, 1998;Hook et al, 2018). The BXD family is particularly well suited to study GXE interactions because diverse but perfectly matched cohorts can be treated in parallel using different diets , (Hall et al, 2014), (Andreux et al, 2012), (Williams et al, 2016;Wu et al, 2014).…”