In late 2021 a Russian-born billionaire named Yuri Milner gathered some of the most celebrated scientific minds of our time at his lavish US$100-million-dollar mansion in California. The topic of conversation was reversing aging. Could our cells be reprogrammed into a younger state? And, perhaps most importantly for the aging billionaire, how quickly could this technology be developed?
The unusual event resulted in the development of Altos Labs, a biotech startup with aspirations to produce an anti-aging treatment that can extend human life. By the next year Altos Labs had amassed around $3 billion dollars in funding, with figures including Jeff Bezos dropping cash into the fund.
One of the key research areas Altos Lab is focusing on is reversing aging by removing the epigenetic markers that accumulate on cells as time passes. Based on the landmark findings of Shinya Yamanaka in 2006, the idea is that four key proteins can be used to send a cell back to its embryonic state, essentially removing all biomarkers of aging.
A new study from a team of biologists and epidemiologists at UC San Diego is calling into question this core foundation of much anti-aging research. The findings suggest a focus on reversing epigenetic markers may be the wrong approach for trying to reverse aging, and a competing hypothesis around the relationship between aging and DNA mutations may be a better 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,” explains Trey Ideker, co-corresponding author on the new study. “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.”
The study interrogates what is known as the epigenetic clock theory. For decades scientists have observed that chemical changes tend to accumulate on DNA as we age. These changes follow a process called DNA methylation. This is basically a mechanism where methyl groups are added to segments of DNA, essentially turning a gene on or off.
In 2011, geneticist Steve Horvath, along with a team of researchers at UCLA, homed in on a system that could accurately estimate a person’s biological age based on several DNA methylation markers in the blood. The system was dubbed Horvath’s epigenetic clock, and it was presented as a grand unifying theory of aging. These epigenetic markers on DNA were more than just a downstream sign of cellular aging but actually the driving factor behind a whole host of age-related cellular dysfunctions. Basically, this epigenetic dysregulation of gene expression is at the top of a domino effect that affects cellular function and other degenerative processes. So underlying a great deal of modern anti-aging research is the quest to reverse, or remove, these age-related methylation markers. If we could scrub a cell clean of these marks then in theory we can return the cell back to a youthful state.
Both Horvath and Yamanaka are among the many scientists tapped by Altos Labs to work on an anti-aging treatment.
Contrasting the epigenetic clock theory is a competing grand unifying theory that argues somatic mutations in DNA are the fundamental cause of aging. This idea suggests that as cells replicate, mutations naturally arise and over time these mutations accumulate causing all the expected signs of aging. Backing this theory was the discovery that somatic mutations tend to accumulate in a linear way across the lifespans of most mammalian species. In other words, tracking somatic mutations turned out to be an equally effective way of measuring age.
Researchers ended up facing a chicken or the egg question. What came first? The somatic mutations or the methylation markers? And what is the relationship between these two processes?
The new research zoomed in on this relationship by studying genetic data from more than 9,000 people. It found a distinct relationship between somatic mutations and DNA methylation. So much so that age predictions made using either metric led to similar results.
Although DNA methylation can be shown to lead to somatic mutations, the researchers note this model does not account for observations where mutations were detected in areas of the genome with low levels of methylation. In other words, the local probability of mutations should be decreased in the presence of hypomethylation if methylation was the driver of mutations. But that wasn’t what the researchers saw.
Here the researchers propose their radical theory – mutations are possibly the upstream driver of DNA methylation. And what this ultimately means is that anti-aging work focusing on scrubbing a cell of methylation markers may be futile.
"If somatic mutations are the fundamental driver of aging and epigenetic changes simply track this process, it’s going to be a lot harder to reverse aging than we previously thought," says co-corresponding author Steven Cummings. “This shifts our focus from viewing aging as a programmed process to one that's largely influenced by random, cumulative changes over time.”
Focusing on epigenetic reversal could be akin to treating a symptom and not a cause, the study concludes. What does this mean for the many multi-billion dollar anti-aging projects? We’ll know soon enough when companies like Altos Labs start pushing their experiments into clinical studies. Everything is of course just speculation at this point, but would it be a surprise if we discovered reversing such a fundamental biological process like aging was harder than we thought?
The new study was published in Nature Aging.
Source: UCSD
