Tissue-Specific GHR Knockout Mice: An Updated Review

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

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“…3e). Unlike full-body GHRKO mice, liver-specific GHRKO mice do not possess a longevity advantage 38,39 .…”

Section: Transgenic Mice For Studying the Somatotropic Axismentioning

confidence: 99%

Universal DNA methylation age across mammalian tissues

Fei

Haghani

et al. 2023

Nat Aging

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“…It should be noted that Snell dwarf mice and full-body GHRKO mice show extended maximum life spans (25)(26)(27). On the other hand, liver-specific GHRKO mice, despite exhibiting reduced serum IGF-1 levels, do not show a corresponding increase in maximum life span (28,29).…”

Section: Weak Effect Of Mutations In the Somatotropic Axismentioning

confidence: 99%

Epigenetic predictors of species maximum life span and other life-history traits in mammals

Li,

Haghani,

Yan

et al. 2024

Sci. Adv.

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By analyzing 15,000 samples from 348 mammalian species, we derive DNA methylation (DNAm) predictors of maximum life span ( R = 0.89), gestation time ( R = 0.96), and age at sexual maturity ( R = 0.85). Our maximum life-span predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species including humans. The DNAm maximum life-span predictions are not affected by caloric restriction or partial reprogramming. Genetic disruptions in the somatotropic axis such as growth hormone receptors have an impact on DNAm maximum life span only in select tissues. Cancer mortality rates show no correlation with our epigenetic estimates of life-history traits. The DNAm maximum life-span predictor does not detect variation in life span between individuals of the same species, such as between the breeds of dogs. Maximum life span is determined in part by an epigenetic signature that is an intrinsic species property and is distinct from the signatures that relate to individual mortality risk.

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“…It should be noted that Snell dwarf mice and full-body GHRKO mice show extended maximum lifespans (25)(26)(27). On the other hand, liver-specific GHRKO mice, despite exhibiting reduced serum IGF1 levels, do not show a corresponding increase in maximum lifespan (28,29).…”

Section: Weak Effect Of Mutations In the Somatotropic Axismentioning

confidence: 99%

Epigenetic predictors of species maximum lifespan and other life history traits in mammals

Li,

Haghani,

Yan

et al. 2023

Preprint

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Maximum lifespan is an intrinsic characteristic of a biological species and is defined as the longest time an individual of a species has been reported to survive. By analyzing 15K samples derived from 348 mammalian species representing 25 taxonomic orders we previously identified CpG methylation sites associated with maximum lifespan. Here we present accurate DNA methylation-based (DNAm) predictors of maximum lifespan (r=0.89), average gestation time (r=0.96), and age at sexual maturity (r=0.85). Our DNAm maximum lifespan predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species such as humans, red deer, and cattle. The DNAm maximum lifespan predictions do not vary significantly by caloric restriction and partial reprogramming. Genetic disruptions in the somatotropic axis, which includes growth hormone, IGF-1, and their related receptors, have an impact on DNAm maximum lifespan only in select mouse tissues. Cancer mortality rates in major mammalian orders show no correlation with our epigenetic estimates of life history traits. The DNAm maximum lifespan predictor does not detect variation in lifespan between individuals of the same species, such as between the breeds of dogs. We also present the first prototypes of accurate pan mammalian DNAm predictors of sex and tissue type.Collectively, our findings indicate that maximum lifespan is determined, at least in part, by an epigenetic signature that is an intrinsic property of each species and is distinct from the signatures that relate to individual lifespan, which is unaffected by interventions influencing the mortality risk of individuals.

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Tissue-Specific GHR Knockout Mice: An Updated Review

Cited by 6 publications

References 33 publications

Universal DNA methylation age across mammalian tissues

Universal DNA methylation age across mammalian tissues

Epigenetic predictors of species maximum life span and other life-history traits in mammals

Epigenetic predictors of species maximum lifespan and other life history traits in mammals

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