he same four molecules that revolutionized research on stem cells can also reverse aging in mice, scientists reported Thursday, a finding that could herald new approaches to trying to extend human life.
Mice genetically modified to have a devastating human disease of premature aging lived longer after getting the molecular mixture, and mice that grew old normally became more youthful.
Although the discovery is unlikely to find its way into medical practice for years, if ever, it is a significant advance in understanding the basic biology of aging at the molecular and cellular level, experts said, and might eventually lead to ways to slow that process in a way that not only extends lifespan but also “healthspan,” the number of years someone can live without the usual diseases that accompany multiplying birthday candles.
Biologist Lenny Guarente of MIT, a prominent aging researcher who was not involved in the study, called the discovery “rather amazing” but cautioned that it is brand-new and so must be confirmed. That the four molecules “exert a system-wide effect on aging in whole, adult animals is remarkable,” he said, “and if this turns out to be true it would be a breakthrough.”
The effect of the molecules is similar to that of proteins called sirtuins, which biotechs including Elysium Health are targeting as ways to improve health and youthfulness, said Guarente, who is also chief scientific officer and cofounder of Elysium.
“The phenomenon is striking, that aging is reversible,” said neuroscientist Rusty Gage of the Salk Institute of Biological Studies, who was not involved in the research. “At this point it is a complicated procedure and restricted to mice, but things move fast these days.”
The four molecules became biological superstars a decade ago, when Kazutoshi Takahashi and Shinya Yamanaka of Kyoto University reported that they made adult cells growing in lab dishes essentially travel back in time, becoming embryonic stem cells — with the capacity to produce any of the organs or tissues in the body.
That eased the pressure to get stem cells from embryos, which was difficult and raised ethical concerns. But Juan Carlos Izpisua Belmonte of Salk wondered about a different use of the four “Yamanaka” factors: If a large dose caused adult cells to revert to an “induced pluripotent stem cell” akin to an embryonic cell, could a lower dose shave only a few years off cells’ biological age — and even off the biological age of adult animals?
He and his colleagues answered that question in three systems, they reported in Cell: isolated cells from old mice and humans; mice given the human gene that causes progeria, in which aging is so accelerated young children look like 70-year-olds; and just plain geriatric mice.
In the isolated mouse and human cells, exposure to the four molecules rolled back several telltale signs of age, such as DNA damage and defects in cellular machinery. That suggested that the manipulation, called reprogramming, “may potentially modify the aging process,” the authors wrote.
In mice that were genetically engineered to have progeria, the molecules extended their lifespan by an average of one-third: from 18 weeks to 24. The animals’ spleens, skin, kidneys, blood vessels, and stomachs all looked and acted younger, such as by regaining the ability to regenerate cells. Even the mice’s spine curvature — like the “dowager’s hump” that some elderly women develop — was reduced.
The mice still had the progeria mutation. But somehow reprogramming their cells overcame that, at least partly; normal lab mice usually live about two years. The four factors were able to “slow the aging process by preventing molecular changes associated with aging,” the scientists wrote.
In healthy but old mice, introducing the Yamanaka factors also rolled back the calendar. The animals’ muscle cells regained the ability to regenerate, something that is lost in old age. Their pancreatic cells — whose aging can cause diabetes in the elderly — performed like youngsters. The scientists killed the mice to study their organs, and so don’t know if the four molecules made them live longer, however.
Analysis of the cells’ genomes showed that the Yamanaka factors — molecules called transcription factors, which activate various genes — had altered “epigenetic marks.” Those are molecules that affect which genes a cell turns on or off. The marks change with age, “making cells less functional” as an animal gets old, Izpisua Belmonte said.
His study suggests that epigenetic changes drive normal aging, and that those changes may be reversible. “Cellular reprogramming acts by remodeling many of these epigenetic marks,” Izpisua Belmonte said. “As consequence, it has the capacity to rejuvenate and restore these marks back to a younger state.” Reprogramming, he added, “improved tissues and organs, enhanced regeneration, and extended lifespan.”
One key to his success was exposing the mice to only low doses of the Yamanaka factors and for only two days per week. Earlier studies, using high doses (like those needed to produce embryonic stem cells) and longer exposures, triggered the formation of extensive tumors. In this research, none of the mice developed tumors.
Izpisua Belmonte said his lab is now “trying to develop novel ways to achieve cellular rejuvenation using chemicals and small molecules” and “focusing on the rejuvenation of specific tissues and organs.” The idea is to find simple molecules that mimic the Yamanaka factors, which are probably too complicated to use outside a lab.
“I do foresee the use of chemicals that induce cellular reprograming and rejuvenation of tissues and organs in humans,” he said. “These chemicals could be administered in creams or injections to rejuvenate skin, muscle or bones. We think these chemical approaches might be in human clinical trials in the next 10 years.”