Contributing mechanisms of aging form an interconnected network of cause and consequence. For most such mechanisms there is considerable debate over relative importance to the manifestations of aging, as well as over whether a mechanism is upstream or downstream of its peers. The step by step “A causes B causes C causes D” view of aging and age-related disease is very unclear in the middle reaches of the chain of cause and effect, despite a good list of first causes and a growing understanding of proximate causes for many age-related conditions. Progress is slow, as no biochemical mechanism exists in isolation, and it is a challenge to pick apart the complexities of cellular metabolism to find the important relationships.

Thus for DNA methylation, epigenetic changes that alter expression of proteins, at the high level one can argue that this is downstream of forms of damage and dysfunction, a response on the part of cells. One can also argue that some of these changes are harmful and cause further issues. Connecting DNA methylation to causes and consequences is an enormous undertaking, given the number of methylation sites that are now connected to aging as a result of work on epigenetic clocks. Nonetheless, some inroads are being made.

During aging, predefined genes constantly undergo epigenetic modifications and exhibit altered expression in response to internal and external environmental stress. Changes in DNA methylation may occur hundreds of times over the lifespan of an individual in the form of a fully adaptive response. However, in some cases, this methylation acts as a switch for the acceleration of pathological aging, resulting in negative consequences. Thus, global fluctuations in DNA methylation are not only a consequence but also a cause of aging. Understanding the biological mechanisms underlying the observed associations may reveal novel targets for reversing aging-related phenotypes and ultimately prolonging lifespan.

Evidence has emerged showing that decreased autophagic activity is involved in DNA methylation. DNA methylation inhibits autophagy processes in two ways, one of which is the direct modification and silencing of autophagy-related genes by DNA methyltransferases. The promoter regions of Atg5 and LC3 are hypermethylated in aged mice, which suppresses gene expression and disrupts the completion of autophagosomes. Whole-body overexpression of Atg5 results in antiaging phenotypes, extending the median lifespan of mice by 17.2%. Furthermore, researchers have recently shown that DNA methylation inhibitors can rescue phenotypic changes associated with aging by reactivating autophagy-related genes.

Identification of the target genes modified by DNA methylation-related regulatory elements in aging individuals is highly informative to figure out the hormone-like effectors and signal pathways that mediate these alterations as well as related diseases. The interaction among epigenetic regulators during aging should also be highly valued. Further studies should focus on the cross-talk among these epigenetic regulators, such as DNA methylation, RNA methylation, histone methylation, and noncoding RNAs, which will aid in providing a full picture of epigenetics and aging. The results of such studies may pave the way for antiaging interventions as well as treatments for related diseases, enabling human life extension.