An effort to slow effects of aging
Mice lived longer and kept their strength up after five days on drug cocktail, study finds.
Aging might be perfectly natural. But as practiced by the human body, it is beginning to look more and more like a disease — and a treatable one at that.
In a new study, scientists reveal aging to be a process set in motion by the rise of malign forces called senescent cells, which progressively hijack the body and take it on a nightmarish joyride. With advancing age, senescent cells take the wheel, and the human body careens into disease states ranging from cancer and diabetes to arthritis, vision loss and dementia.
As senescent cells mount, our walking pace and cognitive processing speed slow, our grips weaken and disabilities mount. Eventually, driven by this accumulation of insults, we are driven off a cliff.
The final plunge cannot be avoided. But scientists are exploring a range of tantalizing new ways to make the odyssey of sickness and frailty that precedes it a little shorter and less degrading. They may even put the cliff a bit further in the distance.
It’s a science called senolytics — the dissolution or gradual decline of old age.
In research published this month in the journal Nature Medicine, a group led by Mayo Clinic anti-aging researcher James Kirkland offers not only a clear look at the power of senescent cells to drive the aging process, but also a pharmaceutical cocktail that, in mice, can slow and even reverse it.
Even in mice that were well along aging’s path, the senolytic cocktail — a dose of the leukemia drug dasatinib and the dietary supplement quercetin — reduced senescent cells’ numbers, the inflammation they cause and the level of disability that comes with age-related diseases.
When given to younger mice in which the aging process was jump-started with a transfer of senescent cells, the anti-aging cocktail forestalled the onset of agerelated diseases. And the anti-aging effects of a fiveday course of the cocktail lasted for months, the equivalent in humans of more than a decade.
Compared with mice that aged normally, those that started the drugs at an age equivalent to 75 to 90 years in humans ended up living roughly 36% longer, and with better physical function.
That extra lifespan did not come with an extra dose of misery either: In their final two months of life, the physical function of the treated mice was at least as good as that period in the lives of normally aging mice that died earlier.
And after all the mice in both groups had died, Kirkland’s team could find no difference in the mix of diseases that had caused their demise.
In human cells in a test tube and in mice bearing human senescent cells, the drug cocktail showed promising results, targeting senescent cells while leaving other cells intact.
The senolytic cocktail used on mice in the new study is already being tested in a human clinical trial aimed at gauging its safety in patients with chronic kidney disease, one of many diseases linked to aging. The trial is expected to be completed by 2021.
Other proposed trials may test senolytic compounds using “optimized derivatives” of dasatinib and quercitin in patients with a variety of age-related diseases, the study authors said. Those trials may also explore the usefulness of senolytic compounds in younger patients, including certain cancer survivors who tend to develop age-related disease prematurely.
Researchers are also exploring the use of the diabetes drug metformin as a senolytic agent.
The objective, Kirkland said, is not so much to extend the human lifespan as to extend the “healthspan” — the period during which a person can live a life largely free of disease or other impairments.
“What I want for myself, my mother and anyone I care for is a way to be independent and as healthy as possible in later years,” Kirkland said. “Most people don’t want to live to 130 and feel like they’re 130. They’d rather feel like they’re 60.”
Dasatinib and quercitin appear to work synergistically to target senescent cells, which seem not over time to develop a resistance to them, Kirkland said. He cautioned that people hoping to forestall aging should not start taking the leukemia drug or the dietary supplement on their own.
“This is not a place for self-experimentation,” Kirkland said. Until safety trials are completed, he added, “we don’t know what’s going to happen.”
If they prove effective, he said, senolytic drugs could change how many diseases are treated and the way we age.
“You’re not playing whack-a-mole,” Kirkland said — treating a patient’s cancer, for instance, only to have heart disease strike her a few years later. That, in turn, could reduce the social and financial costs of caring for the frailest elderly. The appeal is obvious. Compounds that target aging’s basic processes “have now become the hottest thing” in aging research, said Harvard University aging scientist David Sinclair, who was not involved in the new study.
“There’s a really exciting potential of senolytic drugs being used to treat a whole range of aging-related diseases,” he added.
In March, a team led by Sinclair published research linking frailty and other diseases of aging to a decline in the production of blood vessels that feed the muscles.
In elderly mice, the team showed that administering a compound called nicotinamide mononucleotide improved blood flow, increased endurance and reversed signs of aging. It did so by boosting the very cellular processes that are, in younger animals, spurred by vigorous exercise.
A handful of biotech firms are aiming to coax basic findings like these into human clinical trials. One of them, Unity Biotech, is set to launch an early clinical trial of a drug candidate for osteoarthritis, one of aging’s earliest, most ubiquitous and most disabling diseases.
The firm’s candidate drug, dubbed UBX0101, is described as “a potent senolytic” that eliminates senescent cells by disrupting a protein interaction they need to survive. Unity Biotech is also working toward clinical trials of drugs for glaucoma, macular degeneration and diabetic neuropathy — all considered diseases of aging.
Sinclair is advising a firm in Barcelona, Spain, in the development of senolytic compounds that would restore the body’s mechanisms of cellular repair, which falter with age.
One obstacle all potential senolytics face is the Food and Drug Administration, which would have to approve such drugs for sale in the U.S., but does not recognize aging as an illness to be treated.
The potential reward is great, Sinclair said.
“These drugs offer the possibility of keeping every part of the body healthier for longer,” he said. In the end, people will die quickly, perhaps when their heart or kidneys give out.
“The chronic, slow processes of death are pushed out and the fast ones take over,” Sinclair said. “The last thing we want to do is keep people sicker for longer.”