Epigenetic Clocks for Mice Based on Age-Associated Regions That are Conserved Between Mouse Strains and Human

Abstract

Aging of mice can be tracked by DNA methylation changes at specific sites in the genome. In this study, we used the recently released Infinium Mouse Methylation BeadChip to compare such epigenetic modifications in C57BL/6 (B6) and DBA/2J (DBA) mice. We observed marked differences in age-associated DNA methylation in these commonly used inbred mouse strains, indicating that epigenetic clocks for one strain cannot be simply applied to other strains without further verification. In B6 mice age-associated hypomethylation prevailed with focused hypermethylation at CpG islands, whereas in DBA mice CpG islands revealed rather hypomethylation upon aging. Interestingly, the CpGs with highest age-correlation were still overlapping in B6 and DBA mice and included the genes Hsf4, Prima1, Aspa, and Wnt3a. Notably, Hsf4 and Prima1 were also top candidates in previous studies based on whole genome deep sequencing approaches. Furthermore, Hsf4, Aspa, and Wnt3a revealed highly significant age-associated DNA methylation in the homologous regions in human. Subsequently, we used pyrosequencing of the four relevant regions to establish a targeted epigenetic clock that provided very high correlation with chronological age in independent cohorts of B6 (R2 = 0.98) and DBA (R2 = 0.91). Taken together, the methylome differs extensively between B6 and DBA mice, while prominent age-associated changes are conserved among these strains and even in humans. Our new targeted epigenetic clock with 4 CpGs provides a versatile tool for other researchers analyzing aging in mice.

The immunity and redox clocks in mice, markers of lifespan

“…However, since our models are developed in peritoneal leukocytes, which can be isolated without sacrificing the animals, they allow us to monitor the animals until their natural death, so we can analyze the relationship between estimated BA and lifespan. Other models such as the Epigenetic Clock or the Telomere Clock are developed in blood samples or different tissues [30][31][32] , which implies the sacrifice of the animals and does not allow us to study the link with longevity. Moreover, some of the BA www.nature.com/scientificreports/ models developed in humans cannot be applied to mice, such as the Telomere Clock.…”

Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

“…CADASIL mice display accelerated epigenetic ageing when compared to an established reference cohort of wild type mice [ 28 ] (Figure 6). This phenotype may be CADASIL specific or may be caused by the different genetic backgrounds of the CADASIL mice and the reference cohort, [ 39 ] but in any case Cerebrolysin treatment significantly reduced accelerated aging in CADASIL mice and expanded the overall chronological lifespan of these animals. This is of specific relevance, since epigenetic age was reported to be closely correlated with cognitive function and frailty [ 33 ] and to reflect overall biological age and health better than chronological age.…”

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…In humans, epigenetic clocks have been shown to accurately estimate chronological and biological age and predict survival [ 9 , 10 , 11 , 12 ]. In mice, a three CpG clock, analyzing methylation sites in Prima1, Hsf4 and Kcns1 genes, was recently demonstrated to be highly correlated with chronological age [ 13 , 14 ]. This kind of epigenetic clock provides exceptional advantages in terms of time and costs, especially in longitudinal studies involving hundreds of mice.…”