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Senolytics: The science of the gradual decline of old age

By MELISSA HEALY
Los Angeles Times

July 16. 2018 9:51PM
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. (Dreamstime/TNS)



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 last week in the journal Nature Medicine, a group led by Mayo Clinic anti-aging researcher James Kirkland not only offers a clear look at the power of senescent cells to drive the aging process, but also a pharmaceutical cocktail that, in mice at least, can slow and even reverse it.

Even in mice who were already well along aging’s path, the senolytic cocktail — a dose of the leukemia drug dasatinib and the dietary supplement quercetin — drove down senescent cells’ numbers, tamped down the inflammation they cause, and reduced 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 age-related diseases. And the anti-aging effects of a single five-day course of the cocktail lasted for months, the equivalent in humans of more than a decade.

Compared to mice who aged normally, those who started getting the dasatinib-quercitin cocktail at an age equivalent to 75 to 90 years in humans ended up living roughly 36 percent 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 who died earlier. That was seen in tests of walking speed, grip strength and hanging endurance given to the animals in their last weeks and months of life.

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.

Extending the ‘healthspan’

In human cells in a test tube and in mice bearing human senescent cells, the dasatinib-quercitin cocktail showed equally 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.

Does this suggest the researchers have found a fountain of youth?

No, said Kirkland, who is a geriatrician at the Mayo Clinic in Rochester, Minn. “And we’re not looking for one.”

The objective, he 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 my patients want, and 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.”

Clinical trials

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 by the company 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 another 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 U.S. Food and Drug Administration, which would have to approve such drugs for sale in the United States, but does not recognize aging as an illness to be treated.

“Our biggest problem is regulation,” Sinclair said. “It’s no more difficult to make an anti-aging drug than it is to make a cancer drug.”

But 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.”


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