Global remodeling of the mouse <scp>DNA</scp> methylome during aging and in response to calorie restriction

Sziráki, András; Tyshkovskiy, Alexander; Gladyshev, Vadim N.

doi:10.1111/acel.12738

Cited by 62 publications

(64 citation statements)

References 41 publications

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“…In the present study, we parsed the variance in the methylome and defined site-specific methylation differences that may be attributed to a strain-level phenotype, median lifespan, and two individual-level variables—age and BW0. For the age-DMRs, the time-dependent patterns were consistent with previous reports 14,30 . As in Sziráki et al 14 , methylation loss over time occurred mostly in regions with higher average DNAm, and methylation gains occurred mostly in regions with lower average DNAm.…”

Section: Discussionsupporting

confidence: 91%

“…For the age-DMRs, the time-dependent patterns were consistent with previous reports 14,30 . As in Sziráki et al 14 , methylation loss over time occurred mostly in regions with higher average DNAm, and methylation gains occurred mostly in regions with lower average DNAm. Since DNAm was quantified over 150 bp nonoverlapping bins, we were also able to relate the differential methylation patterns to the local CpG density.…”

Section: Discussionsupporting

confidence: 91%

“…In the mouse model, lifespan extending interventions such as calorie restriction (CR) and treatment with rapamycin, or strong genetic mutations that drastically reduce body weight (e.g., Ames and Snell dwarf mice), have been shown to significantly decelerate the epigenetic clock 5,7,8,13,14 . However, to date, most DNAmAge estimations in the mouse have been modeled on the canonical C57BL/6J (B6) background strain 5–8,13 .…”

Section: Introductionmentioning

confidence: 99%

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Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Sandoval-Sierra

Helbing

Williams³

et al. 2019

Preprint

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SummaryDNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and lifespan in 12 inbred mouse strains from the BXD panel that exhibit over two-fold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from mice ranging in age from 6 to 25 months 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 expectancy. The age associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites with high CpG density and low average methylation. CpG regions associated with BW were enriched in introns and generally showed lower methylation in mice with higher BW, and inversely correlated with gene expression such that mRNA was higher in mice with higher BW. Lifespan-associated regions featured no distinct genomic characteristics but were linked to genes involved in lifespan regulation, including the telomerase reverse transcriptase gene, Tert, which showed lower methylation and higher gene expression in long-lived strains. An epigenetic clock defined from the age-DMRs conveyed accelerated aging in mice belonging to strains with shorter lifespans. Both higher BW at young adulthood and HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier body weight. Furthermore, the study demonstrates that the measure of epigenetic aging derived from age-DMRs can predict strain and diet-induced differences in lifespan.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Sandoval-Sierra

Helbing

Williams³

et al. 2019

Preprint

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“…Clock‐type CpG age markers have recently been referred to as “age‐related DNA methylation positions” (aDMPs) (Lowe et al, ; Slieker et al, ). aDMPs are generally located within the promoter or first exon of a gene (Bekaert, Kamalandua, Zapico, Voorde, & Decorte, ; Grönniger et al, ; Horvath, ; Sziráki, Tyshkovskiy, & Gladyshev, ; Zbieć‐Piekarska et al, ). Epigenetic drift is thought to occur due to a decline or imperfect replication of DNAm by an epigenetic maintenance system with increasing age (Horvath, ; Horvath & Raj, ).…”

Section: Introductionmentioning

confidence: 99%

Age estimation in a long‐lived seabird (Ardenna tenuirostris) using DNA methylation‐based biomarkers

Paoli-Iseppi

Deagle

Polanowski

et al. 2019

Molecular Ecology Resources

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Age structure is a fundamental aspect of animal population biology. Age is strongly related to individual physiological condition, reproductive potential and mortality rate. Currently, there are no robust molecular methods for age estimation in birds. Instead, individuals must be ringed as chicks to establish known‐age populations, which is a labour‐intensive and expensive process. The estimation of chronological age using DNA methylation (DNAm) is emerging as a robust approach in mammals including humans, mice and some non‐model species. Here, we quantified DNAm in whole blood samples from a total of 71 known‐age Short‐tailed shearwaters (Ardenna tenuirostris) using digital restriction enzyme analysis of methylation (DREAM). The DREAM method measures DNAm levels at thousands of CpG dinucleotides throughout the genome. We identified seven CpG sites with DNAm levels that correlated with age. A model based on these relationships estimated age with a mean difference of 2.8 years to known age, based on validation estimates from models created by repeated sampling of training and validation data subsets. Longitudinal observation of individuals re‐sampled over 1 or 2 years generally showed an increase in estimated age (6/7 cases). For the first time, we have shown that epigenetic changes with age can be detected in a wild bird. This approach should be of broad interest to researchers studying age biomarkers in non‐model species and will allow identification of markers that can be assessed using targeted techniques for accurate age estimation in large population studies.

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“…It is important to note that changes in methylation also occur in pathways implicated to be dysregulated with aging systemically, such as the insulin signaling pathway and cellular senescence [36][37][38][39]. Recent studies show that age-related DNA methylation changes in blood [40,41], kidney [42], liver [35,39], and the hippocampus [26], can be prevented by dietary, genetic, and pharmacological pro-longevity interventions providing further support for the association between DNA methylation and aging.…”

Section: Introductionmentioning

confidence: 97%

Early life DNA methylation profiles are indicative of age-related transcriptome changes

Hadad¹,

Masser²,

Blanco-Berdugo³

et al. 2019

Preprint

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Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions, are observed with aging and can be prevented by anti-aging interventions, but the functional outcomes of altered methylation on transcriptome profiles are poorly understood with brain aging.Integrated analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers, but not promoters. Methylation levels at young age of genes altered with aging are positively associated with age-related expression changes even in the absence of significant changes to methylation with aging, a finding also observed in mouse Alzheimer's models. DNA methylation patterns established in youth, in combination with other epigenetic marks, are able to predict changes in transcript trajectories with aging. These findings are consistent with the developmental origins of disease hypothesis and indicate that epigenetic variability in early life may explain differences in age-related disease.

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Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction

Cited by 62 publications

References 41 publications

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Age estimation in a long‐lived seabird (Ardenna tenuirostris) using DNA methylation‐based biomarkers

Early life DNA methylation profiles are indicative of age-related transcriptome changes

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