What role will epigenetic clocks play in measuring and intervening in aging processes?
Steve Horvath doesn’t like the term “anti-aging.” The father of modern epigenetic clocks has sparked a new boom in slowing, halting, and even reversing aging. If you google the term “anti-aging,” you’ll get pages of results teeming with wrinkle creams, dietary supplements, and serums—so it’s not hard to understand why Horvath shies away from the term.
When Horvath first described epigenetic clocks, scientists began to speculate that altering these clocks could reverse aging. After all, if certain patterns of DNA methylation at specific sites in cells in specific tissues of the body are hallmarks of aging, could altering these patterns somehow reverse aging?
The simple answer: it is possible.
Horvath’s clock predicts biological age based on activity at a selection of DNA methylation sites that regulate gene expression. Similar to a volume control, turning different sites on or off can upregulate or downregulate gene expression. It is a complex process involving millions of switching points.
In Horvath’s case, he found that the combined effect of 353 sites provides an exceptionally accurate test for chronological age. Using data from 8,000 samples from 82 DNA methylation datasets compiled by other researchers, Horvath examined methylation patterns in 51 tissues and cell types. Using these datasets, Horvath developed a biomarker-based clock for aging and then proved its accuracy. In practice, two 25-year-olds would have the same chronological age, but the Horvath clock could assign one to be 20 and the other to be 30, based on individual DNA methylation patterns. The implication, though not yet proven, is obvious: people who age faster may die earlier and live less healthy lives.
As a senior researcher at the Altos Labs campus in San Diego, Horvath is at the center of a well-funded race to answer questions related to epigenetic clocks. He hopes to make these clocks and other offshoots of his findings useful, even though there are so many possibilities that one career is not enough to explore them all. For now, he is focusing on researching epigenetic age as a means of slowing aging, backed by the $3 billion provided by Altos investors and an all-star team. These include Nobel Prize winner Jennifer Doudna, who co-invented the genome editing tool CRISPR, and Shinya Yamanaka, another Nobel Prize winner who discovered a way to transform differentiated cells into a stem cell-like state by manipulating four gene regulators—now known as Yamanaka factors.
“The fact that we age and get wrinkles is really a problem of our generation that will be solved sooner or later,” says Horvath.
Epigenetic clocks: Just a marker of time?
Despite their obvious potential and growing popularity, epigenetic clocks still have some notable shortcomings. First, it is difficult to say exactly how accurate biological age measurements are. According to one expert, epigenetic clocks can predict life expectancy much better than previous techniques such as oxidative damage or telomere length. However, the problem with longevity research is that studies designed to determine whether biological age predictions translate into actual life expectancy take decades to complete. In other words, will a 25-year-old with a biological age of 30 die five years earlier than average? Second, scientists have not yet figured out which changes are directly caused by aging. It is possible that, regardless of age, some changes in older people occur by chance. In other words, some changes that we associate with aging may have no impact on the length or quality of our lives. Finally, some scientists suspect that epigenetic clocks are more a measure of biological age than a factor influencing it.
Horvath is a little more optimistic. “I would say that there are areas that are very important,” he says of the DNA methylation sites that control his clock. “If you change the right sites, you can actually rejuvenate the cells. I’m not claiming that, I’m just saying that no one knows.”
Since his clock is considered extremely reliable, dozens of others have joined it, although according to Horvath, it doesn’t matter which clock you use. Thanks to machine learning, each epigenetic clock measures DNA methylation rates at so many sites that the results usually match.
There are improved versions that focus on healthspan and predict, among other things, the risk of age-related events such as physical dysfunction, cancer, or Alzheimer’s disease. Meanwhile, Altos Labs has developed another second-generation clock that predicts age-related diseases and decline.
However, there is one caveat. Different anti-aging or rejuvenation measures—especially those targeting a single tissue type—can have different effects on the various DNA methylation sites. In these cases, Horvath says, “you have to be very careful about which clock you use,” and hopes that over time, other scientists will develop increasingly complex, accurate, and explainable epigenetic clocks whose results could be interpreted not only as reliable indicators of the speed of aging, but also as definitive clues to the body’s response to various stressors.
One big question remains. Do we need individual epigenetic clocks for each body system? Or is a systemic, cross-tissue clock better?
Rejuvenation is in our DNA
Aging is surprisingly poorly defined. Scientists disagree on why we age or how aging evolved. Current ideas include increased mortality, loss of function, accumulation of damage over time, continued development, age-related changes, or now also an increase in biological age as measured by epigenetic clocks. Although there is no consensus, they are all true, and they all seem to go hand in hand. Nevertheless, there must be a single, important characteristic that defines aging, but there is currently no agreement on what that characteristic is.
Any type of life-extending intervention requires a way to measure rejuvenation. Which epigenetic clock is best suited to measure the reversal of the aging process has not yet been determined. The clocks were basically developed to measure the transition from young to old, but the transition from old to young is not necessarily the same.
Epigenetic clocks as test endpoints
Epigenetic clocks remain an effective tool in the science of rejuvenation. According to researchers, they are best suited in the short term as a measuring instrument, a kind of epigenetic yardstick that can be used to determine whether other interventions are successful. Although there are still unanswered questions about how we define aging, how we measure rejuvenation, and how this could unfold economically , epigenetic clocks are “a real revolution,” says Harvard biomedical researcher Vadim Gladyshev, calling Horvath “a hero.” He adds that the clocks represent a major advance in quantifying the complicated aging process.
In human aging research, epigenetic clocks could help quantify the effectiveness of a treatment while the subjects are still alive. In other words, once epigenetic clocks are mature enough for the FDA or EMA to accept them as a surrogate endpoint, researchers could demonstrate a drug’s effectiveness within months by measuring methylation—rather than waiting years to see how the drug affects survival. Longevity research could advance more quickly and would no longer rely on death as the primary endpoint.
Partial cellular reprogramming
One of the most promising—and potentially dangerous—therapies that could take advantage of epigenetic clocks is partial reprogramming of cells. This technique is a bit like taming a wild horse. If you can calm the animal long enough to swing into the saddle, you could be in for a wild ride.
Yamanaka factors are four specific proteins that regulate the transcription or expression of four specific genes. Stem cell researcher (and later Nobel Prize winner) Shinya Yamanaka discovered that altering these four proteins can transform a differentiated cell, such as a muscle, liver, or kidney cell, into a completely undifferentiated cell, similar to an embryonic stem cell. These are called induced pluripotent stem cells.
Like other epigenetic breakthroughs, induced pluripotent stem cells have a downside: they are very, very good at forming ugly, cancer-like tumors called teratomas. Similar to embryonic stem cells, induced pluripotent stem cells have the potential to differentiate and become anything.
“The problem with stem cells is that you take them out of context and remove the control, the feedback mechanism,” says Horvath. The result is “chaos, chaotic growth.” That means a high cancer rate, which is a major safety risk.
But scientists have made another breakthrough. It turns out that specialized cells can be partially reversed. This process returns the cells to a younger state that prevents dedifferentiation, reducing the risk of cancer. Thanks to epigenetic clocks, scientists have a measure—albeit imperfect—of how well this partial reprogramming works. Although this technology is still in its infancy, it has shown promise in mice and frogs.
The mystery of aging
And there is one last caveat that Horvath raises, a kind of scientific dilemma. “The question is why we age. Well, maybe it serves a purpose, namely to prevent malignant transformation . Maybe we age to suppress the risk of cancer. And if you reverse it, you might even increase the risk of cancer.”
Horvath’s research findings have been cited nearly 90,000 times. And he himself does not seem to view his colleagues as competitors, but rather as representatives of a shared mission: to find out what role epigenetic clocks can play in the race for a longer, healthier life. Without wanting to rank them, he considers the most important main candidates for rejuvenation to be: interrupted cellular reprogramming by Yamanaka factors; senolytic drugs that eliminate “senescent” cells that do not die when they should; drugs that mimic the effects of calorie restriction; autophagy, in which damaged proteins are eliminated; and parabiosis, the connection of the circulatory systems of two organisms.
Right now, Horvath is working in a bold new field with generous new funding, and he’s like a kid in a candy store that he created himself.