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

Sandoval-Sierra, Jose Vladimir; Helbing, Alexandra H. B.; Williams, Evan G.; Ashbrook, David G.; Roy, Suheeta; Williams, Robert W.; Mozhui, Khyobeni

doi:10.1111/acel.13207

Cited by 36 publications

(54 citation statements)

References 48 publications

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“…For biological age prediction, three different types of mouse DNAm clocks were computed, each as a pair: liver-specific, and pan-tissue ( Table 1 ). These are: (1) a general DNAm clock (referred to simply as DNAmAge): clock trained without pre-selecting for any specific CpG subsets; (2) developmental clock (dev.DNAmAge): built from CpGs that change during development; and (3) interventional clock (int.DNAmAge): built from CpGs that change in response to aging related interventions such as caloric restriction, HFD, or dwarfing alleles 9,11,25 . These clocks were trained either in an independent mouse dataset that did not include the BXDs and were therefore unbiased to BXD characteristics (unbiased mouse clocks), or trained in a subset of the BXD CD mice and used to estimate age in the full BXD cohort (BXD-biased clocks).…”

Section: Resultsmentioning

confidence: 99%

“…The genetic variation, and the availability of accompanying deep -omic data make the BXDs a unique experimental population for dissecting the genetic modulators of epigenetic aging. Previously, we explored the aging methylome in a small number of BXD cases and found that HFD and higher body weight were associated with higher age-dependent changes in methylation 25 . In the present work, our goals were to (1) test the accuracy of the DNAm measures in predicting age, lifespan, and association with diet and metabolic characteristics, and (2) apply quantitative trait locus (QTL) mapping and gene expression analyses to uncover loci and genes that contribute to these DNAm biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Mozhui

et al. 2021

Preprint

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DNA methylation (DNAm) clocks are accurate molecular biomarkers of aging. However, the clock mechanisms remain unclear. Here, we used a pan-mammalian microarray to assay DNAm in liver from 339 predominantly female mice belonging to the BXD family. We computed epigenetic clocks and maximum lifespan predictor (predicted-maxLS), and examined associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. The epigenetic age acceleration (EAA) derived from the clocks, and predicted-maxLS were correlated with lifespan of the BXD strains. Quantitative trait locus (QTL) analyses uncovered significant QTLs on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and on Chr19 that contains a cytochrome P450 cluster. Both loci harbor candidate genes associated with EAA in humans (STXBP4, NKX2-3, CUTC). Transcriptome and proteome analyses revealed enrichment in oxidation-reduction, metabolic, and mitotic genes. Our results highlight loci that are concordant in human and mouse, and demonstrate intimate links between metabolism, body weight, and epigenetic aging.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Mozhui

et al. 2021

Preprint

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“…Sandoval-Sierra et al [ 30 ] analyzed epigenetic aging of female mice from a group of recombinant inbred strains that differ in multiple phenotypic characteristics including bodyweight and longevity. Recombinant inbred strains are produced by crossing animals from two different inbred strains (in this case, C57BL6 and DBA2) and then inbreeding their progeny by repeated brother X sister mating.…”

Section: The Rate Of Epigenetic Aging Is Related To Bodyweight a Growth Hormone-dependent Traitmentioning

confidence: 99%

“…Epigenetic age was calculated from age-related differentially methylated regions and age acceleration (negative or positive) was calculated by relating epigenetic age to chronological age. The results revealed age-accelerating effect of greater adult bodyweight [ 30 ]. These findings relating epigenetic aging to bodyweight represent a significant addition to previous evidence for a negative association of body size and longevity among members of the same species [ 1 31 ].…”

Section: The Rate Of Epigenetic Aging Is Related To Bodyweight a Growth Hormone-dependent Traitmentioning

confidence: 99%

Growth Hormone and Aging: New Findings

Bartke

Hascup

et al. 2021

World J Mens Health

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Complex relationships between growth hormone (GH) signaling and mammalian aging continue to attract attention of many investigators. Recent results include evidence that the impact of GH on genome maintenance (DNA damage and repair) is drastically different in normal as compared to cancer cells, consistent with GH promoting aging and cancer progression. Impact of GH on DNA methylation was studied as a possible mechanism linking actions of GH during early life to the trajectory of aging. Animals with reduced or enhanced GH signaling and novel animals with adipocyte-specific deletion of GH receptors were used to elucidate the effects of GH on white and brown adipose tissue, including the impact of this hormone on lipolysis, fibrosis, and thermogenesis. Effects of GH on adipose tissue related to lipid and energy metabolism emerge as mechanistic links between GH, healthspan, and lifespan. Treatment of healthy men with a combination of GH, dehydroepiandrosterone, and metformin was reported to restore thymus function and reduce epigenetic age. Studies of human subjects with deficiency of GH or GH receptors and studies of mice with the same endocrine syndromes identified several phenotypic changes related (positively or negatively) to the previously reported predisposition to healthy aging. Results of these and other recent studies advance present understanding of the mechanisms by which GH influences aging and longevity and of the trade-offs involved.

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“…Rodents, especially mice, have been the species most prominently used for biomedically relevant traits. Amongst these, the BXD family of recombinant inbred (RI) mouse strains, have been extensively used for almost 50 years in fields such as neuropharmacology [4,5,6,7,8,9,10], immunology [11,12,13,14,15], behavior [16,17,18,19,20,21,22,23], aging [24,25,26,27,28], neurodegeneration [29,30,31,32,33], and gut microbiome-host interactions [34].…”

Section: Introductionmentioning

confidence: 99%

Old data and friends improve with age: Advancements with the updated tools of GeneNetwork

Chunduri

Ashbrook

2021

Preprint

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Understanding gene-by-environment interactions is important across biology, particularly behaviour. Families of isogenic strains are excellently placed, as the same genome can be tested in multiple environments. The BXD's recent expansion to 140 strains makes them the largest family of murine isogenic genomes, and therefore give great power to detect QTL. Indefinite reproducible genometypes can be leveraged; old data can be reanalysed with emerging tools to produce novel biological insights. To highlight the importance of reanalyses, we obtained drug- and behavioural-phenotypes from Philip et al. 2010, and reanalysed their data with new genotypes from sequencing, and new models (GEMMA and R/qtl2). We discover QTL on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We narrowed down the candidate genes based on their ability to alter gene expression and/or protein function, using cis-eQTL analysis, and variants predicted to be deleterious. Co-expression analysis ('gene friends') and human PheWAS were used to further narrow candidates. Prominent candidate genes include: Slitrk6 in a Chr 14 QTL for locomotion in the center of an open field, we show to be part of a coexpression network involved in voluntary movement, and association with neuropsychiatric phenotypes in PheWAS; and Cdk14, one of only 3 genes in a Chr 5 QTL for handling induced convulsions after ethanol treatment, that is regulated by the anticonvulsant drug valproic acid. By using families of isogenic strains, we can reuse and reanalyse data to discover novel and highly plausible candidate genes involved in response to the environment.

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

Cited by 36 publications

References 48 publications

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Growth Hormone and Aging: New Findings

Old data and friends improve with age: Advancements with the updated tools of GeneNetwork

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