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

Date Published: March 25, 2018

Publisher: John Wiley and Sons Inc.

Author(s): András Sziráki, Alexander Tyshkovskiy, Vadim N. Gladyshev.


Aging is characterized by numerous molecular changes, such as accumulation of molecular damage and altered gene expression, many of which are linked to DNA methylation. Here, we characterize the blood DNA methylome across 16 age groups of mice and report numerous global, region‐ and site‐specific features, as well as the associated dynamics of methylation changes. Transition of the methylome throughout lifespan was not uniform, with many sites showing accelerated changes in late life. The associated genes and promoters were enriched for aging‐related pathways, pointing to a fundamental link between DNA methylation and control of the aging process. Calorie restriction both shifted the overall methylation pattern and was accompanied by its gradual age‐related remodeling, the latter contributing to the lifespan‐extending effect. With age, both highly and poorly methylated sites trended toward intermediate levels, and aging was accompanied by an accelerated increase in entropy, consistent with damage accumulation. However, the entropy effects differed for the sites that increased, decreased and did not change methylation with age. Many sites trailed behind, whereas some followed or even exceeded the entropy trajectory and altered the developmental DNA methylation pattern. The patterns we observed in certain genomic regions were conserved between humans and mice, suggesting common principles of functional DNA methylome remodeling and its critical role in aging. The highly resolved DNA methylome remodeling provides an excellent model for understanding systemic changes that characterize the aging process.

Partial Text

Aging is characterized by the gradual reduction in the ability to cope with physiological challenges, which ultimately leads to death (Johnson, Sinclair, & Guarente, 1999). It is clear that the genome defines species lifespan, but the DNA sequence in itself cannot fully explain the aging process. Analyses of epigenetic phenomena, which affect gene expression and chromatin structure and link environmental and genetic factors, may offer a better understanding of the aging process. DNA methylation, histone posttranslational modifications, and microRNA expression show complex changes during aging (Huidobro, Fernandez, & Fraga, 2013). For example, DNA methylation is gradually decreased during aging in different species, including humans, but certain genomic regions, such as CpG islands, are known to gain methylation with age. There is an emerging need for deep analyses of the DNA methylome across ages to define the specific patterns and determine whether the changes are uniform across the genome and its regions, and whether they are consistent during aging. Increased mortality with age in humans supports the idea of acceleration, and this is also consistent with the current understanding of the aging process (Gladyshev, 2016), although experimental analyses are needed to clarify these issues.

None declared.




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