Mutations and Epigenetics: The Dynamic Duo of Aging

Highlights

• Among 9,331 individuals studied, mutations in the genetic sequence coincided with epigenetic changes.
• DNA mutations were associated with pervasive remodeling of epigenetic alterations in surrounding regions of DNA.
• Incorporating such DNA mutations to develop an aging clock worked about as well as previously established epigenetic clocks to predict age.

As published in Nature Aging, Ideker and colleagues from the University of California, San Diego demonstrated that certain DNA mutations coincided with epigenetic alterations. Not only that but these changes to the DNA sequence were associated with pervasive epigenetic remodeling, leading to molecular tagging modifications in surrounding regions of DNA. With the application of these DNA mutations to an aging clock, Ideker and colleagues predicted age almost as well as established epigenetic aging clocks. These findings suggest that these two hallmarks of aging—mutations in the DNA sequence and epigenetic modifications—are somehow intertwined.

Theories of aging have posited that either mutations to the DNA sequence or epigenetic alterations contribute to aging. As such, the debate as to which of these cellular processes underpins aging most has continued, and previous studies so far have not uncovered how tightly linked they may be.

Explaining why DNA mutations seem to coincide with epigenetic alterations with age has to do with epigenetic alterations called methylation, which increases the probability of a mutation. With a subsequent mutation, methylation at the site of mutation becomes much less likely, also, conferring a snowball effect where methylation initiates mutations and mutations then inhibit further methylation. Future research will be necessary to disentangle whether methylation causes mutations, mutations lead to alterations in methylation patterns, or whether both processes work together to drive aging. Furthermore, according to the Stanford researchers, further research may identify other underlying contributors to both of these processes, such as the activation of cellular DNA damage repair mechanisms.

Methylation Makes Mutations Likely, and Mutations Inhibit Further Methylation

Since both the accumulation of DNA mutations and epigenetic alterations have been linked to characteristics of aging, Ideker and colleagues hypothesized that both processes are related. To test this notion, they compared DNA mutation and epigenetic profiles in tumor cells of cancer patients to those from the patients’ blood cells.

At sites of DNA where mutations accumulate most—certain repeated sequences of nucleotide bases—they measured whether a mutation had occurred and whether these mutations correlated with elevated methylation. They found that indeed mutations at these sites tended to be more heavily methylated. This finding supports the notion that methylation at certain sites of DNA increases the likelihood of mutations.

Ideker and colleagues then sought to find whether mutations in the repeated sequences affect methylation at surrounding regions of DNA. The Stanford researchers found that mutated DNA sequences were associated with lower methylation in surrounding DNA regions, supporting their hypothesis.

The researchers attempted to find the extent to which mutations at the repeated DNA sequences modify methylation at surrounding DNA regions. In cancer cells, mutations were associated with methylation changes reaching nearly 10,000 bases from the site of mutation. In non-cancerous cells, mutations were associated with DNA methylation changes about 1,000 bases from the site of mutation. These findings suggest that DNA mutations are associated with methylation pattern alterations in the surrounding DNA.

To find whether the identified DNA mutations associated with methylation alterations can be used to design an aging clock, Ideker and colleagues created a clock with the mutations. They compared the predicted ages of individuals based on mutations to epigenetic clocks based on methylation patterns. Interestingly, the mutations- and epigenetics-based aging clocks nearly aligned in predicting which individuals were aging faster or slower than average. This result supports that researchers can use DNA mutation and/or epigenetics aging clocks to predict people’s age.

“This is very clear evidence of a relationship,” said Dr. Steven Cummings, one of the paper’s authors, in a press release.

Parsing Out Underlying Drivers of Aging

Since genetic mutations and epigenetic profiles can both predict biological age, this suggests that both play a role in the processes of aging. According to Ideker and colleagues, heavy methylation makes mutations more likely at certain DNA sites. Once these mutations occur, the study’s findings suggest that alterations in methylation patterns occur in surrounding DNA regions. Thus, the question of whether DNA mutations cause epigenetic alterations or whether methylation drives mutations needs further research. It seems likely that both processes occur at once, so perhaps other underlying causes of methylation alterations and mutations drive these processes, such as cellular DNA damage responses.

If future research uncovers that cellular DNA damage responses do drive aging, pinpointing ways to improve DNA damage responses may help alleviate aging. Moreover, if such cellular DNA damage responses drive aging, then restoring epigenetic profiles to more youthful states, as suggested by the Information Theory of Aging from Harvard’s David Sinclair, may only treat a symptom of aging.

One complication with attributing aging to something other than epigenetics comes from explaining why restoring younger epigenetic profiles in aged cells rejuvenates them. Evidence suggests that researchers have rejuvenated cells and restored younger epigenetic profiles in these cells by treating them with proteins called Yamanaka factors.

In this light, the mechanism by which cellular rejuvenation occurs in Yamanka factor-treated cells may not come solely from restoring younger epigenetic profiles. Instead, Yamanaka factors may modulate other factors related to aging, such as cellular DNA damage responses. The only way to uncover whether this is the case would be to test whether treating cells with Yamanaka factors enhances cellular DNA damage responses. All the same, with the new findings from this study, a clear picture of what cellular factors drive aging may be more complex than attributing aging to either mutations or epigenetics alone.