Summary: A new study has discovered a direct link between somatic mutations and epigenetic changes, challenging established ideas about aging. Researchers have discovered that random genetic mutations lead to predictable changes in DNA methylation, providing new insights into the relationship between mutation accumulation and epigenetic clocks.
This suggests that epigenetic changes may follow aging rather than cause it, making it more difficult to reverse aging than previously thought. These findings redefine our understanding of aging at the molecular level and have significant implications for future anti-aging therapies.
Key facts:
- Mutation-epigenetic link: Random genetic mutations lead to predictable epigenetic changes.
- Complexity of aging: Epigenetic clocks can track aging caused by somatic mutations.
- Therapeutic impact: Reversing aging may require tackling mutations, not just epigenetics.
Source: UCSD
Researchers at the University of California San Diego School of Medicine have published findings that shed new light on an old question: What causes aging at the molecular level?
Their findings, published in Natural agingdescribe a never-before-seen link between the two most accepted explanations: random genetic mutations and predictable epigenetic modifications.
The latter, also known as the epigenetic clock theory, has been widely used by scientists as a consistent quantitative measure of biological aging.
However, new research suggests the process may not be so simple.
“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 it may just be treating a symptom of aging , not the underlying cause,” said the co-corresponding author. Trey Ideker, Ph.D., professor at UC San Diego School of Medicine and UC San Diego Jacobs School of Engineering.
“If mutations are indeed responsible for the observed epigenetic changes, this could fundamentally change how we approach anti-aging efforts in the future.” »
There are two dominant theories about the relationship between aging and DNA. Somatic mutation theory suggests that aging is caused by the accumulation of mutations, permanent changes in our DNA sequence that occur randomly.
The epigenetic clock theory suggests that aging occurs due to the accumulation of epigenetic modifications, minor changes in the chemical structure of DNA that do not alter the underlying sequence, but rather alter the genes that are activated or disabled. Unlike mutations, epigenetic modifications can also be reversed in some cases.
Because epigenetic modifications only occur at specific sites in our genome rather than random locations, they are easier to quantify and have become a go-to way for scientists to determine the “biological age” of cells.
However, scientists have long wondered about the source of these epigenetic changes.
To answer this fundamental question, researchers analyzed data from 9,331 patients cataloged in the Cancer Genome Atlas and pan-cancer analysis of whole genomes.
By comparing genetic mutations to epigenetic modifications, they found that the mutations correlated predictably with changes in DNA methylation, a type of epigenetic modification.
They found that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. Through this relationship, researchers have been able to make similar predictions about age using either mutations or epigenetic changes.
“Epigenetic clocks have been around for years, but we are only now beginning to answer the question of why epigenetic clocks work in the first place,” said first author Zane Koch, a Ph.D. candidate in bioinformatics at UC San Diego.
“Our study demonstrates for the first time that epigenetic changes are linked in complex and predictable ways to random genetic mutations. »
The study authors note that additional research is needed to fully understand the relationship between somatic mutations and epigenetic changes associated with aging.
However, the study results represent a major advance in our understanding of the aging process and have important implications for the development of new therapies aimed at preventing or reversing aging.
“If somatic mutations are the fundamental driver of aging and epigenetic changes simply follow this process, it will be much more difficult to reverse aging than we previously thought,” added co-corresponding author Steven Cummings, MD , executive director of the San Francisco study. Coordinating Center at UC San Francisco and Principal Investigator at Sutter Health’s California Pacific Medical Center Research Institute.
“This leads us to view aging as a programmed process, but rather as one largely influenced by random and cumulative changes over time.”
In addition to Ideker, Cummings and Koch, the study was co-authored by Adam Li of UC San Diego and Daniel S. Evans of the California Pacific Medical Center Research Institute and UC San Francisco.
Funding: This study was supported by the National Institutes of Health (grants U54 CA274502 and P41 GM103504).
About this research news in genetics and aging
Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Picture: Image is credited to Neuroscience News
Original research: Closed access.
“Somatic mutation as an explanation of epigenetic aging” by Trey Ideker et al. Natural aging
Abstract
Somatic mutation as an explanation of epigenetic aging
DNA methylation marks have recently been used to create models called epigenetic clocks, which predict calendar age.
As cytosine methylation favors C-to-T mutations, we hypothesized that methylation changes observed with age should reflect the accumulation of somatic mutations and that both should yield analogous aging estimates. .
In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site, but also with widespread remodeling of the methylome up to ±10 kilobases.
This one-to-many mapping allows age predictions based on mutations that match epigenetic clocks, including individuals who age faster or slower than expected. Additionally, genomic loci where mutations accumulate with age also tend to exhibit methylation patterns that are particularly predictive of age.
These results suggest a strong link between the accumulation of sporadic somatic mutations and the widespread methylation changes observed over the lifespan.
