Aging researchers can now use characteristics of aging such as DNA damage, along with long-lived animal models and so-called aging clocks to unravel how we age.
“Finally, finally,” says Vera Gorbunova, an aging researcher and co-director of the Rochester Aging Research Center at the University of Rochester. Gorbunova says it has taken decades for aging “to be recognized as a legitimate area of research.”
Along those lines, a funding surge is transforming the aging research field, according to bio-gerontologist Steve Horvath, who moved from UCLA to Altos Labs in San Diego, CA. Moreover, aging research has become a more mature, dynamic field with promising results and has attracted some bright minds. The financial boost along with having a trove of intelligent researchers has enabled “a more ambitious, more precise exploration of the mechanisms of aging,” according to Horvath.
Many hallmarks or features of aging have been identified. Some of these include the deterioration of cells and tissues due to increased inflammation. Another is the damage to DNA, proteins, and fats (lipids) from highly reactive molecules called reactive oxygen species generated by metabolic processes. Aging can also be partially characterized by telomere shortening, a process that occurs each time a cell divides.
It is easy for people to cling to one of these hallmarks as the sole contributor to aging; however, as research progresses, many of the hallmarks get knocked off their pedestal. An example is the proposal that oxidative damage from reactive oxygen species accumulates with age, spurring aging, an idea that Horvath was once enamored with. Nonetheless, research has shown that reactive oxygen species play positive roles in cell signaling, knocking this theory’s credulity down a notch.
Essentially, one must appreciate that multiple aging mechanisms play a role to drive aging. What we need now, according to Peter Sudamant, a biologist at the University of California, Berkeley, are ways to find which hallmarks of aging correlate with aging and which cause aging. “That’s tricky,” he says. Some are a bit causative; “however, it is unclear which are the most important.” In the past, Sudamant says some members of the aging research community were too quick to say, “This thing is it! This is the cause.” He adds that some members are still too quick in this regard. He adds that it is likely that all factors of aging matter to some degree. The question becomes to what degree specific factors of aging matter and how much of an effect would be gained by therapeutically targeting one of them.
Finding ways to translate aging research findings that benefit humans should not be rushed, according to Gordan Lauc, an aging researcher from the University of Zagreb. He says private investors approach him who “want to have a magic solution,” such as a pill that works against aging. In a similar way, at scientific conferences, he sees vendors selling consumer products that he perceives as mostly ‘snake oil’ without scientific credibility. “There is so much hype in longevity research,” says Lauc. “There is no regulation because aging is not a disease,” he adds. As such, he and other aging researchers are skeptical of hastily-devised anti-aging antidotes.
Horvath, often referred to as the ‘father of epigenetic clocks,’ developed the first of its kind epigenetic aging clock in 2011. Epigenetics entails the molecular tagging patterns on DNA, and these patterns can be read to predict one’s biological age — where a lower or higher value compared to chronological age represents decelerated or accelerated aging, respectively.
The method of predicting biological age with epigenetic aging clocks was seen as delivering an important biological indicator of aging. As such, the concept of predicting biological age with molecular tagging patterns on DNA has gained traction. Since 2011, Horvath has developed different species-specific aging clocks based on epigenetics, along with clocks based on multiple tissues for research purposes.
Horvath’s latest aging clock based on epigenetics is called GrimAge — based on the Grim Reaper. In Horvath’s view, it is an important molecular predictor of mortality risk.
“We are very interested in developing more accurate clocks,” says Gorbunova, referring to work she has done with Horvath.
Based on his epigenetic clock research, after 30 years of debating whether aging is “wear and tear” or determined by some as-yet-unknown biological mechanism(s), Horvath says, “now we know, at least in mammals, there is something deterministic.” Indeed, only a weak relationship exists between epigenetic changes and gene products, on the one hand, and changes in proteins and shifts in metabolism, on the other. Biology happens at the level of proteins, so it is not clear what exact role methylation has. “And to this day, we struggle with that question,” says Horvath.
Gorbunova’s lab studies naked mole rats — rodents that look like mice, except they have large incisor teeth, tiny ears, live underground mostly, and have no fur. Intriguingly, naked mole rats live up to 40 years in contrast to mice that live around two and a half years. Pertaining to rodent lifespan, Gorbunova says, “It would be as if you would find a type of human that would live 800 years.”
Interestingly, naked mole rats do not seem to get cancer. Gorbunova and her lab identified one potential anti-cancer mechanism in naked mole rats that appears to confer striking elasticity to this rodent’s skin. Their skin cells secrete high molecular mass hyaluronan, a molecule that serves as a structural component to skin cells. This form of hyaluronan is likely an adaptation to life below ground in tunnels. Its anticancer properties likely arise from the anti-inflammatory and antioxidant benefits that it confers.
In a recent article from her lab, Gorbunova showed that genetically engineered mice that have an enzyme that produces high molecular weight hyaluronan live longer lives. Moreover, these mice had lower inflammation levels. In their paper, Gorbunova and colleagues note that this finding “opens new avenues for cancer prevention and lifespan extension.” Nonetheless, she goes on to say that we are still a long way from applying this finding to humans.
Keeping the findings from naked mole rats in mind, Gorbunova thinks that cross-species analyses in aging research will deliver new, tantalizing findings. Utilizing such species, aging researchers no longer need to limit themselves to using, for example, single-cell models like yeast to study aging.
The burgeoning field of aging research has greatly shifted from when researchers started conducting studies in the field 12 years ago. Gone are the days when researchers in the field were studying in small, disparate labs in varying research sectors like stem cell science or physiology. Referring to aging research, Salvador Benitah, an aging researcher for Research in Biomedicine in Barcelona, says, “Now, it’s huge.” With more funding allocated to aging research, scientists can now refer to hallmarks of aging, aging clocks based on epigenetics, and various animal models like naked mole rats to tackle how we age and discover new anti-aging therapeutics based on their findings.