If creaky old humans were more like dilapidated old kitchens, rejuvenation would be as simple as replacing cracked and faded Formica with gleaming new granite. But perhaps, a booming new scientific field hypothesizes, biological renovation might be more possible than one might expect.
The field, called “senolytics,” studies compounds that might kill senescent cells, which have become dysfunctional due to aging yet, paradoxically, refuse to die. Research published on Monday suggests the approach might actually work one day: When scientists at the Mayo Clinic eliminated senescent cells from old mice, not only did the animals’ lifespan increase but so did their “healthspan.” That is, during their extra years of life they were spry, strong, and healthy, not frail, decrepit, and sick — as is the case with nearly half of people over 85.
“As a concept [for slowing or reversing aging], senolytics is completely valid,” said Felipe Sierra, director of the National Institute on Aging’s Division of Aging Biology. “This study is really impressive,” he added, and hardly an outlier: “A couple dozen senolytics have been identified and companies are working on it. This is a very hot area.”
The reason eliminating senescent cells might slow aging is that the old cells do not simply fail to pull their weight in the heart, bones, immune system, or elsewhere. They also actively pump out inflammatory compounds that both kill young cells and disable progenitor cells that give birth to new cells, explained Dr. James Kirkland of the Mayo Clinic, who led the research published in Nature Medicine.
“Senescent cells put the brakes on the production of new cells,” he said. That double whammy means that in old animals, including people, fewer and fewer cells are young and functional.
Yet because senescent cells are quite rare even in the elderly, reaching their highest proportion — about 8 percent — in the skin, eliminating them should not leave any organs with too few cells to function. “It had been argued that if you remove senescent cells it might be deleterious,” NIA’s Sierra said. “But the data say it’s not.”
For their mouse research, Kirkland and his team first transplanted half a million Methuselah cells (made ultra-old with drugs or radiation) into young (6 months old) or middle-aged (17 months old) mice. Though only one-ten-thousandth of the animals’ total cells, the transplanted cells were enough to age them, making the mice slower, weaker, and frailer within two weeks. The 17-month-olds were also five times more likely to die within a year than 17-month-olds not given senescent cells.
Although the transplanted cells survived only about 40 days, the mice’s premature aging lasted for months. That supports the idea that senescent cells punch way above their weight in the damage they do, such as by killing young cells and preventing progenitor cells from making replacements.
“They have an outsize effect,” Kirkland said. “They produce poisons that attract [cell-killing] immune cells and spread senescence to younger cells around them.” But not only around them: Although the transplanted senescent cells mostly wound up in the mice’s fat, they caused premature aging of distant muscle cells. Just a handful of senescent cells produced “profound, long-lasting, and deleterious systemic effects,” the researchers wrote.
The scientists then gave both the young mice with transplanted senescent cells and naturally old mice two senolytics: dasatinib, a leukemia drug, and quercetin, a plant compound found in many fruits and vegetables (as well as dodgy dietary supplements). These were the first senolytics Kirkland and his team identified, based on their ability to disable the half-dozen or so biochemical pathways by which senescent cells cleverly postpone their own death.
In young mice, the compounds killed enough of the transplanted senescent cells to keep the animals from becoming prematurely slow, weak, and frail. As for naturally old (20 months) mice, akin to 80-year-old people, those given the compounds walked faster, scampered longer on a treadmill, gripped objects more strongly, and were generally more active than their peers. Truly ancient mice — 24-to-27-month olds, comparable to 75-to-90-year-old people — given the senolytics lived 36 percent longer than their peers, again without the poor health and frailty that usually mark late life. NIA Director Dr. Richard Hodes called that “compelling evidence that targeting … cell senescence in mice can delay age-related conditions, resulting in better health and longer life.”
Aging research has identified enough seemingly promising compounds, from resveratrol to “young blood,” to fill Ponce de Leon’s hoped-for fountain several times over. Yet almost all eventually come up short. Kirkland does not take quercetin supplements: “People should absolutely not be taking this until we have the results from clinical trials,” he said.
Biologist Leonard Guarente of the Massachusetts Institute of Technology, who discovered a key aging mechanism involving proteins called sirtuins, agreed that eliminating senescent cells in mice “is a net plus” for health and lifespan. “Since the senescent cells are a small fraction of total cells, tissue still functions. I think it is an interesting approach but it is still too early to know the extent of the possible benefits in people.”
Clinical trials to answer that are underway, as is research on about a dozen other serolytics. Some “are even better” than dasatinib and quercetin, Kirkland said. That cocktail removes 20 percent to 70 percent of senescent cells from mice, he estimates, but other senolytics can remove more.
Although senolytics were only recently “kind of a backwater,” NIA’s Sierra said, they are becoming a business. California-based Unity Biotechnology (UBX) went public in May. Its pipeline of senolytics is based on six biological mechanisms that allow senescent cells to survive and which different experimental compounds target, said Nathaniel David, Unity’s co-founder and president.
Unity has launched a clinical trial of one senolytic, in osteoarthritis, and is on track to request Food and Drug Administration approval next year to test two more. The FDA does not count aging as a disease, so any anti-aging drugs would have to show they treat other diseases. Different senolytics will work better against certain diseases than others, David predicted, but “by targeting specific diseases of aging, you might also target aging itself.”