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A drug cocktail could help us live longer healthily

A drug cocktail could help us live longer healthily

Ageing might be perfectly natural. But as experienced 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 ageing 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 tantalising 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 on July 9, 2018, in the journal Nature Medicine, a group led by Mayo Clinic anti-ageing researcher Dr James Kirkland not only offers a clear look at the power of senescent cells to drive the ageing 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 ageing’s path, the senolytic cocktail – a dose of the leukaemia 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 ageing process was jump-started with a transfer of senescent cells, the anti-ageing cocktail forestalled the onset of age-related diseases.

And the anti-ageing 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% 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-ageing 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, Dr 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 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 ageing. The trial is expected to be completed by 2021.

Other proposed trials may test senolytic compounds using “optimised 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 Dr Kirkland, who is a geriatrician at the Mayo Clinic in Rochester, Minnesota. “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,” he 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 do not seem to develop a resistance to them over time, Dr Kirkland said.

He cautioned, however, that people hoping to forestall ageing should not start taking either the leukemia drug or the dietary supplement on their own.

“This is not a place for self-experimentation,” he said. Until safety trials are completed, he added, “we don’t know what’s going to happen.”

If they do prove effective, senolytic drugs could not only change the way many diseases are treated, they could change the way we age, Dr Kirkland said.

“You’re not playing whack-a-mole,” he 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 ageing’s basic processes “have now become the hottest thing” in ageing research, said Harvard University ageing scientist Dr 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 2018, a team led by Dr Sinclair published research linking frailty and other diseases of ageing 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 (NMN) improved blood flow, increased endurance and reversed signs of ageing.

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 ageing’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 ageing.

Dr 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 US Food and Drug Administration, which would have to approve such drugs for sale in the United States, but does not recognise ageing as an illness to be treated.

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

But the potential reward is great, he 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,” Dr Sinclair said. “The last thing we want to do is keep people sicker for longer.” – Los Angeles Times/Tribune News Service

Want to look younger than your age? It’s largely up to you

Want to look younger than your age? It’s largely up to you

People the world over pay a pretty penny to look young. Many don’t realise, however, that staving off wrinkles, age spots and thinning hair has little to do with cosmetic creams and lotions.

Take, for instance, the skin, the body’s largest organ. “Twenty to 30% of changes in the skin are attributable to genetics,” says Jean Krutmann, director of the Leibniz Research Institute for Environmental Medicine in Dusseldorf, Germany. “The other 70% to 80% are caused by environmental factors, for example ultraviolet radiation and air pollution.”

Your skin says a lot about you, too., “Ageing never affects a single organ only – it’s always the entire organism that ages,” points out Martin Denzel, research group leader at the Cologne-based Max Planck Institute for Biology of Ageing in Germany. “Outward changes are therefore linked to the ageing process as a whole and can be a sign of the body’s condition.”

A fatty diet, alcohol consumption, smoking and overexposure to the sun subject the body to biological stress. In people young and old, this causes molecular damage in cells – in DNA, for example – a thousand every minute. While a young body can repair the damage quickly, an older one is increasingly unable to.

“Ageing means the body is less and less capable of dealing with stress,” Denzel says. “As a result, DNA mutations accumulate in the body’s cells, making organs more likely to fail or tumours to develop.” Denzel says.

These cell alterations have two visible effects on the skin. “For one thing, pigmentation changes,” says Krutmann. “It becomes inhomogeneous, and age spots can form. Secondly, the skin’s elasticity decreases, so wrinkles appear. Everyone gets fine wrinkles from ageing. If environmental influences are added, the wrinkles become much deeper. More collagen, a protein in connective tissue, degrades.”

Krutmann and his colleagues test the effects of various substances on skin in the laboratory. While the harmful and even carcinogenic impact of ultraviolet radiation and tobacco smoke are already proven, research on air pollutants is still in its early stages. “If you coat skin with airborne particulates, it quickly browns,” Krutmann says. “Soot from diesel engines, in particular, has been shown to be harmful.”

Along with environmental influences on the skin, a major factor in how old we look is what we ingest.

A recent study by the National Institute of Public Health at the University of South Denmark, published in the London-based Journal Of Epidemiology And Community Health, found that high alcohol consumption and smoking encourage “visible age-related signs” including earlobe creases, yellowish plaques on the upper or lower eyelids, and a greyish-white arc or ring around the cornea.

A harmful lifestyle or environment doesn’t affect everyone’s health and appearance equally, of course. “People have different genetic makeups. Some live to be well over 100 years old although they smoked and drank alcohol,” notes Denzel. “The chronological and biological clocks can be decoupled. A youthful appearance can be a sign that a person has remained biologically young.” – dpa

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