Findings from a study are challenging the established views on aging by uncovering a direct link between somatic mutations and epigenetic modifications. Researchers found that random genetic mutations drive predictable changes in DNA methylation. This offers new insights into the relationship between mutation accumulation and epigenetic clocks. Specific findings are detailed in an article published in Nature Aging in January 2025.
A Genome-Wide Analysis Exploring the Causal Relationship Between Somatic Mutations and Age-Related Methylation Changes
Background
There are two prevailing theories about the relationship between aging and the DNA. The somatic mutation theory suggests that aging is a result of the accumulation of random mutations in the DNA sequence. The epigenetic clock theory posits that aging is caused by the accumulation of epigenetic modifications or minor changes to the chemical structure of the DNA that do not alter the sequence but change which genes are activated or inactivated.
Furthermore, companies like Altos Labs, backed by billionaires such as Jeff Bezos, have invested billions in an approach based on the discovery of Shinya Yamanaka in 2006 which identified four key proteins that can be used to send a cell back to its embryonic state and remove all biomarkers of aging. Most of the research undertakings of the anti-aging industry have focused on resetting epigenetic markers to turn cells back to their youthful state.
A team of biologists and epidemiologists at the University of California San Diego challenged the aforementioned core foundation of current anti-aging research. Researchers Z. Koch, A. Li, D. S. Evans, S. Cummings, and T. Ideker underscored the notion that the epigenetic clock theory and the resulting models based on the Yamanaka discovery might be insufficient. This means that focusing on reversing epigenetic markers may be the wrong approach.
“Major research institutions and companies are betting on turning back the epigenetic clock as a strategy to reverse the effects of aging, but our research suggests that this may only be treating a symptom of aging, not the underlying cause, said co-corresponding author and professor Ideker. “If mutations are in fact responsible for the observed epigenetic changes, this fact could fundamentally change the way we approach anti-aging efforts in the future.”
Methods and Findings
DNA methylation or the addition of a methyl group to cytosine, often at CpG sites of a DNA sequence, has been used to develop epigenetic clocks. These biological clocks can predict the calendar age of an individual based on methylation patterns. However, since methylation promotes C-to-T mutations, the researchers hypothesized that age-related methylation changes might correspond with the accumulation of somatic mutations in DNA.
Nevertheless, to test their hypothesis, the researchers analyzed data from 9,331 patients cataloged in the Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. They compared genetic mutations to epigenetic modifications and found that mutations were predictably correlated with changes in DNA methylation. They also found that a single mutation could cause a cascade of epigenetic changes across the genome. Below are the specific details:
• There is a connection between CpG mutations and methylation changes. The changes occurred not only at the mutation site but extended across a ±10 kilobase region. This suggests that a single mutation can cause widespread changes in methylation.
• They were able to predict age based on these mutations. These predictions are aligned with predictions from epigenetic clocks. They could even identify individuals who were aging faster or slower than expected based on both methylation and mutation data.
• The researchers also found that areas of the genome where mutations accumulate with age also tend to have methylation patterns that are highly predictive of age. This promotes the idea that mutations and methylation changes are linked to the aging process.
Implications
The epigenetic clock theory and the Yamanaka discovery led researchers to treat epigenetic clocks as the fundamental driver of aging. The assumption is that resetting the clock would reset the aging process. However, newer insights are emerging. These epigenetic clocks, as determined by epigenetic markers, now appear to be merely a byproduct of changes in DNA damage
Researchers Z. Koch et al. concluded that there is a strong connection between the accumulation of sporadic somatic mutations and the widespread changes in DNA methylation that occur as people age. This reinforces the idea that both processes contribute to biological aging. Findings further suggest that mutations might be a key driver of the age-related changes observed in the methylome or the complete set of methylation modifications in a cell.
Moreover, based on the findings, if mutations are the fundamental cause of aging, then reversing epigenetic changes alone may not halt the aging process. Focusing on epigenetic reversal may be considered merely treating a symptom rather than the cause of aging. This redirects the focus of anti-aging research from a programmed process to random cumulative changes over time.
Further studies are needed to fully understand the relationship between somatic mutations and epigenetic changes in aging. Nonetheless, based on the findings alone, reversing aging may require addressing somatic mutations, which are random and cumulative, making the process more complex than previously thought. Billionaire-funded efforts focusing on reversing epigenetic markers may be misguided if mutations are the true drivers of aging.
FURTHER READING AND REFERENCE
- Koch, Z., Li, A., Evans, D. S., Cummings, S., and Ideker, T. 2025. “Somatic Mutation as an Explanation for Epigenetic Aging.” In Nature Aging. Springer Science and Business Media LLC. DOI: 1038/s43587-024-00794-x