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

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 40years of linkage studies using murine cohorts and 15years 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

Gender and hormonal status modulate the hypolipidemic mechanisms of dietary soluble fiber in the guinea pig

Coronary heart disease (CHD) is the single leading cause of death in the United States. Elevated plasma cholesterol levels and gender constitute two of the major risk factors for CHD. Dietary soluble fiber (SF) has consistently been shown to reduce plasma LDL cholesterol concentrations. ^ The purpose of these studies was to assess distinctive effects of gender and hormonal status on secondary mechanisms by which dietary SF lowers plasma LDL cholesterol. Guinea pigs were used as the animal model because their lipoprotein profile and response to dietary fiber are similar to humans. ^ Male, female and ovariectomized (to mimic menopause) guinea pigs were allocated to two dietary treatments differing only in fiber source: control diet contained 10% cellulose and 2.5% guar gum while SF diet contained 5% psyllium, 5% pectin and 2.5% guar gum. SF intake significantly reduced plasma total and LDL cholesterol, triacylglycerol (TAG) and apo B concentrations. ^ However, ovariectomized guinea pigs, in both diet groups, had highest plasma LDL cholesterol, apo B and TAG concentrations. SF treatment yielded smaller cholesteryl ester-depleted LDL. Susceptibility of LDL to oxidation was reduced in males and females following SF intake but remained unaffected in ovariectomized guinea pigs. Female guinea pigs had higher plasma HDL and LDL α-tocopherol concentrations, compared to males. ^ Dietary SF altered hepatic cholesterol metabolism by effectively reducing hepatic free cholesterol, TAG and microsomal free cholesterol concentrations, while activities of HMG-CoA reductase and cholesterol 7α-hydroxylase (CYP7) were upregulated. Guinea pig CYP7 cDNA was cloned and partially sequenced for the first time. The nucleotide sequence showed 86% homology to the human CYP7 cDNA. Hepatic CYP7 mRNA abundance paralleled the increase in enzyme activity in guinea pigs fed the SF diet. Ovariectomized guinea pigs had the lowest activity and expression of hepatic CYP7 even after intervention with SF. ^ From these studies we conclude that induction of hepatic CYP7 activity and mRNA abundance by dietary SF intake is one of the major secondary mechanisms that may account, in large part, for the hypocholesterolemic effect of soluble fiber. Gender and hormonal status influence metabolic responses to dietary SF with estrogen deprivation leading to the most detrimental lipid profile for CHD risk.

Body weight and high-fat diet are associated with epigenetic aging in female members of the BXD murine family.

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic strains from the BXD family of mice that exhibit over twofold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from predominantly female cases, 6-25 months old, that were maintained on normal chow or high-fat diet (HFD). We defined subsets of CpG regions associated with age, BW at young adulthood, and strain-by-diet-dependent life span. These age-associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites such as promoters and exons that have high CpG density and low average methylation. CpG regions associated with BW were enriched in introns, tended to have lower methylation in mice with higher BW, and were inversely correlated with gene expression (i.e., higher mRNA levels in mice with higher BW). CpG regions associated with life span were linked to genes involved in life span modulation, including the telomerase reverse transcriptase gene, Tert, which had both lower methylation and higher expression in long-lived strains. An epigenetic clock defined from age-DMRs revealed accelerated aging in mice belonging to strains with shorter life spans. Both higher BW and the HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier BW. Furthermore, we demonstrate that the measure of epigenetic aging derived from age-DMRs can predict genotype and diet-induced differences in life span among female BXD members

Body weight and high‐fat diet are associated with epigenetic aging in female members of the BXD murine family

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic strains from the BXD family of mice that exhibit over twofold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from predominantly female cases, 6-25 months old, that were maintained on normal chow or high-fat diet (HFD). We defined subsets of CpG regions associated with age, BW at young adulthood, and strain-by-diet-dependent life span. These age-associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites such as promoters and exons that have high CpG density and low average methylation. CpG regions associated with BW were enriched in introns, tended to have lower methylation in mice with higher BW, and were inversely correlated with gene expression (i.e., higher mRNA levels in mice with higher BW). CpG regions associated with life span were linked to genes involved in life span modulation, including the telomerase reverse transcriptase gene, Tert, which had both lower methylation and higher expression in long-lived strains. An epigenetic clock defined from age-DMRs revealed accelerated aging in mice belonging to strains with shorter life spans. Both higher BW and the HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier BW. Furthermore, we demonstrate that the measure of epigenetic aging derived from age-DMRs can predict genotype and diet-induced differences in life span among female BXD members

Multiomic profiling of the liver across diets and age in a diverse mouse population

We profiled the liver transcriptome, proteome, and metabolome in 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wildtype and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into dietary and aging effects. Candidates were cross-examined in an independent Diversity Outbred mouse liver dataset segregating for similar diets, with ~80–90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections

Multiomic profiling of the liver across diets and age in adiverse mouse population

We profiled the liver transcriptome, proteome, and metabolome in 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wild-type and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into dietary and aging effects. Candidates were cross-examined in an independent diversity outbred mouse liver dataset segregating for similar diets, with 80%-90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections.ISSN:2405-472

Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations