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

Abstract

Summary 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 in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort sacrificed 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 ~4–6 days/g. At 500 days, animals on a HFD typically gain 4× 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 high fat diet are substantially modulated by gene-by-environmental interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

“…For the BXDs, life expectancy is highly dependent on the background genotype, and mean lifespan varies from under 16 months for strains such as BXD8 and BXD13, to over 28 months in strains such as BXD91 and BXD175. 19,22,24 While the EAA from the universal was inversely correlated with strain lifespan data, the predicted-maxLS had a direct correlation with observed strain maxLS. We note that the predicted-maxLS overestimated the strain max-LS by 0.7 to 3 years (median error of +1.6 years).…”

“…276 cases with DNAm data also had fasted serum glucose and total cholesterol, 18,19 and we examined whether these metabolic traits are associated with three of the DNAm readouts: the univ.EAA, predicted-maxLS, and DNAm entropy. We applied linear regression with age, diet and final body weight as covariates, and this showed significant effects of cholesterol on predicted-maxLS (p = 0.002), and entropy (p = 9E-06) (Table S1).…”

“…We next obtained longevity data from a parallel cohort of female BXD mice that were allowed to age on CD or HFD. 19 We evaluated whether the DNAm readouts were informative of strainlevel lifespan. Since the strain lifespan was determined from female BXDs, we restricted this to only the female cases.…”

“…17 Here, we test the performance and applicability of these novel DNAm clocks and lifespan predictor in a genetically diverse cohort of mice belonging to the BXD family. 18,19 The BXDs are a well-established mouse genetic reference panel that were first created as a family of recombinant inbred (RI) strains by crossing two inbred progenitors: C57BL/6J (B6) and DBA/2J (D2). The family has been expanded to ~150 fully sequenced progeny strains.…”

“…20,21 The BXD population incorporates significant genetic variation, and likewise, show considerable phenotypic variability in their metabolic profiles, response to diet, aging rates, and natural life expectancy. [18][19][20][22][23][24] The availability of genetic data, and accompanying deep multi-omics and phenomics, make the BXDs a powerful experimental population to evaluate the DNAm biomarkers, and to dissect the genetic modulators of epigenetic aging. Previously, we explored the aging methylome in a small number of BXD cases and found that high fat diet (HFD) and higher body weight were associated with higher age-dependent changes in methylation.…”