Abstract
The naked mole-rat, Heterocephalus glaber (NMR), the longest-lived rodent, is of significance and interest in the study of biomarkers for ageing. Recent breakthroughs in this field have revealed ‘epigenetic clocks’ that are based on the temporal accumulation of DNA methylation at specific genomic sites. Here, we validate the hypothesis of an epigenetic clock in NMRs based on changes in methylation of targeted CpG sites. We initially analysed 51 CpGs in NMR livers spanning an age range of 39-1,144 weeks and found 23 to be significantly associated with age (p<0.05). We then built a predictor of age using these sites. To test the accuracy of this model, we analysed an additional set of liver samples, and were successfully able to predict their age with a root mean squared error of 166 weeks. We also profiled skin samples with the same age range, finding a striking correlation between their predicted age versus their actual age (R=0.93), but which was lower when compared to the liver, suggesting that skin ages slower than the liver in NMRs. Our model will enable the prediction of age in wild-caught and captive NMRs of unknown age, and will be invaluable for further mechanistic studies of mammalian ageing.
Highlights
The naked mole-rat (Heterocephalus glaber) is arguably unique among mammals in the extent of its social insect-like behaviour, first highlighted by Jarvis [1]
In an extensive study of naked mole-rats, we identify 23 CpGs in liver tissue that are significantly associated with age, and build a predictor of age model with a root mean squared error of 166 weeks, or approximately 10% of the published maximum possible lifespan
In profiling skin samples from the same individuals, we found a striking correlation between the predicted age of these samples versus their actual age
Summary
The naked mole-rat (Heterocephalus glaber) is arguably unique among mammals in the extent of its social insect-like behaviour, first highlighted by Jarvis [1]. Little more than mouse-sized (mean body mass is around 35g), naked mole-rats are the longest-lived rodent with a maximum possible lifespan exceeding 31 years [5] They resist all of the normal signs of ageing and are emerging as an important non-model organism for the study of longevity and healthspan. These unusual mammals uniquely do not show an increase in age-specific hazard of mortality, in defiance of Gompertz’s law [8] They show no decreased physiological capacity with age, maintaining vascular elasticity, cardiac function, gastrointestinal function, glucose tolerance, and reproductive capacity www.aging-us.com well into the third decade of life [2, 9, 10], and resist sarcopenia, the progressive loss of skeletal muscle with age [11]. Such CpG sites at which DNA methylation dynamics show significant correlations with age can potentially enable accurate age estimates for tissues across the life span of an individual, and it has been shown in humans that most tissues and organs from the same body exhibit broadly similar epigenetic ages [19]
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