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

Abstract

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.

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Fig. 1: Study overview.
Fig. 2: Diet influence on lifespan in female mice.
Fig. 3: Effect of body weight on lifespan.
Fig. 4: Diet effect on serum metabolites.
Fig. 5: Diet effect on serum metabolic hormones.

Data availability

All data conform fully to findable, accessible, interoperable and reusable standards94 and Supplementary Table 1 provides research resource identifiers (www.rrids.org) for all strains. Mean, median and 75% quantile lifespan data from cases and controls are available at GN (www.genenetwork.org) under the headings Species: Mouse; Group: BXD Family; Type: Traits and Cofactors and Dataset: BXD Published Phenotypes (for example, GN traits BXD_18435, 18441, 19451, 19452, 21302 and 21450). Body weight data at 6, 12, 18 and 24 months is also available in GN (for example, traits BXD_19126, 19130, 19131, 19167, 19168, 19169, 19170 and 19171). For example, the following URL with query string parameters will retrieve mean lifespan data for HFD cases: www.genenetwork.org/show_trait?trait_id=18435&dataset=BXDPublish, where the number can be replaced with other ID numbers to obtain and download any data from this work. Organ weight data for a large subset of cases and controls that were euthanized between 6 and 24 months of age (liver, heart, kidneys and brain) are available but these data are only covered briefly here (for example, GN traits BXD_20156, 20157, 20158, 20159, 20353, 20354, 20148, 20149, 20150, 20151, 20146 and 20147). Individual data are also available for all cases, both in the Supplementary table (the precise data used in all analyses here) and in GN under the headings Species: Mouse; Group: BXD NIA Longevity Study; Type: Traits and Cofactors and Dataset: BXD-NIA-Longevity Phenotypes. For example, individual data for lifespan, irrespective of diet, is accessible at www.genenetwork.org/show_trait?trait_id=10002&dataset=BXD-HarvestedPublish. Note that lifespan datasets in GeneNetwork are part of a long-term, and still active genetic study of lifespan in the BXD family, and some datasets will therefore include additional strains as well as outliers excluded from the fixed Supplementary table. Source data are provided with this paper.

Code availability

Source code and raw data used for the fixed-effects linear model, random-effects meta-analysis model, and survival analysis in R are available at https://github.com/genenetwork/bxd_gxelongevity_2020. We have generated a Jupyter notebook as well, detailing our source code with computational and statistical output.

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Acknowledgements

We thank J.F. Nelson for helpful discussion on the LXS dietary restriction datasets. We thank P. Prins, Z. Sloan and other members of the GeneNetwork team for superb informatics support. Finally, we thank Dr. Elizabeth A Fitzpatrick and team at the Regional Biocontainment Laboratory at UTHSC for generating serum hormone data. This work was supported by grants from the NIH nos. R01AG043930 (R.W.W.), NIH R01AG070913 (R.W.W.), the University of Tennessee Center for Integrative and Translational Genomics (L.L.), the Ecole Polytechnique Fédérale de Lausanne, the European Research Council (AdG-787702) (J.A.), the Swiss National Science Foundation (310030B-160318) (J.A.) and the AgingX programme of the Swiss Initiative for Systems Biology (RTD 2013/153) (J.A.). S.S. was supported by NIH grant no. P30 DA044223-04. E.G.W. was supported by NIH F32 Ruth Kirchstein Fellowship (grant no. F32GM119190). K.M. was supported by NIH grant no. R21 AG055841. R.W.R. was supported by TriMetis Life Sciences, Memphis, TN, USA. L.M. was supported by the American Heart Association and Methodist Mission Support Fund. C.K. was supported by grant no. NIH R01AG054180.

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Contributions

E.G.W., S.R., J.A., L.L. and R.W.W. were responsible for the conceptualization. Aging colony management and informatics was done by S.R., J.F.I., C.J.C., M.S.M., A.G.C. Investigations were carried out by S.R., D.G.A., J.F.I., C.J.C., M.S.M., A.G.C., K.M., M.K.M., J.D.Z., W.Z., J.H., S.M.N., L.A.W., T.M.S., C.C.K., Y.C., L.L. and R.W.W. Formal analysis and data curation were done by S.R., D.G.A., M.B.S., P.J., E.G.W., A.S., M.H., R.W.R., S.S. and R.W.W. The original draft was written by S.R. and R.W.W. Review and editing of the paper was done by S.R., M.B.S., E.G.W., K.M., L.M., D.G.A., S.S., R.A.M., J.A. and R.W.W. Companion web resources were provided by A.G.C., S.R., S.S. and R.W.W.

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Correspondence to Robert W. Williams.

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Extended Data Fig. 1 Diet effect on lifespan and body weight at 500 days of age.

Related to Fig. 1 and Fig. 3. Diet effect on lifespan and body weight at 500 days of age (A) Data points represent lifespan of animals on low-fat chow diet (CD) in BXDs with n ≥ 4 per strain. Red + denotes the strain median. (B) Data points represent lifespan on the high-fat diet (HFD) in BXDs with n ≥ 4 per strain. Blue + denotes the strain median. (C) Data points represent body weight on CD at 500 days of age in BXDs with n ≥ 4 per strain. Red + denotes the strain median. (D) Data points represent body weight on HFD at 500 days of age in BXDs with n ≥ 4 per strain. Blue + denotes the strain median.

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Extended Data Fig. 2 A Bayesian Network model of the impact of diet on serum metabolites and lifespan and peak body weight at 500 days age.

Edge weights in this network are the weighted fraction of best 1000 Bayesian models that have the same edge and polarity. A value of 1.0 means every one of 1000 “top-ranked models” has this edge. The upper 6 nodes are serum metabolites, and lifespan and body weight at 500 days age are the final outcomes.

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Roy, S., Sleiman, M.B., Jha, P. et al. Gene-by-environment modulation of lifespan and weight gain in the murine BXD family. Nat Metab 3, 1217–1227 (2021). https://doi.org/10.1038/s42255-021-00449-w

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