- By figuring out how to manipulate the human ageing process, researchers hope they might be able to delay ageing-associated diseases such as Alzheimer’s, cancer, osteoporosis, heart disease, and diabetes.
- Researchers from the National Institute on Ageing (NIA) are working to decipher how ageing happens on a cellular level and develop therapies based on those findings.
- The director of the NIA’s division of ageing biology says he is optimistic about two treatments for ageing that are in the pipeline.
What if there were a way to tackle Alzheimer’s, heart disease, diabetes, and cancer in one fell swoop?
Underlying all of those common causes of death is one shared factor: ageing. So new insight into the ageing process could act like a skeleton key that could unlock cures for all of these conditions, according to Felipe Sierra, director of the division of ageing biology at the National Institute on Ageing.
“We’re not trying to become immortal. That is not our goal,” Sierra, whose agency resides within the National Institutes of Health (NIH), told Business Insider. “The goal of the NIH is to improve the health of the elderly. Of course, a side effect of being healthy is that you’re not going to die.”
Research on ageing has gained a lot of momentum in the last decade. But of all the drug targets for ageing-related to disease that are being investigated right now, Sierra said, two potential avenues for treatment are most exciting to him. The first is a drug called rapamycin, which blocks a pathway in the body related to energy, metabolism, and immune function. The other is a class of drugs known as senolytics, which can kill a certain type of cell in the body that causes inflammation and damage.
“The idea is by understanding ageing, we can do manipulations. By doing that, we don’t just delay one disease of ageing, we delay them all,” Sierra said. “It’s a better solution.”
All roads lead to TOR
In studies on animals and humans, restricting caloric intake has been shown to help protect against diabetes, cancer, and cardiovascular disease, and even potentially extend lifespans.
Sierra said the drug rapamycin may produce a similar outcome by targeting a signalling pathway in the body called TOR (target of rapamycin), which is connected to cell growth and ageing.
“Rapamycin mimics, to some extent, calorie restriction. It creates a state in the body where there is a reduction of nutrients,” Manuel Serrano, who wrote a widely cited review of studies on ageing, told Business Insider. “Even though you are eating the same amount, the biochemical machinery of the cells think there are no nutrients, and that is beneficial.”
Rapamycin was initially used as an immuno-suppressive drug for patients who got organ transplants. But after scientists found that it could block the TOR pathway, researchers started studying the compound in the lab.
A recent study conducted by Novartis was especially noteworthy, Sierra said. It looked at how a drug similar to rapamycin that acted on the TOR pathway affected elderly patients’ immune response and risk for infection.The results showed that the patients’ rate of respiratory-tract infections went down by more than 65% during winter cold and flu season.
“This is significant because it is done in humans and it shows that these approaches that address ageing are useful against disease of the elderly, which is this whole paradigm that we are working with,” Sierra said.
Joan Mannick, the researcher behind Novartis’ study, said that going forward, she wants to see whether the drug offers any benefits for other ageing-related dysfunctions like heart disease and neurodegenerative diseases.
“Novartis had realised that the science in the ageing field had progressed enough that we could actually start translating it to humans, and there’s increasing data that ageing is not just due to random wear and tear but it’s actually a biology that is regulated by signalling pathways,” she told Business Insider. “And you can actually target fundamental pathways that seem to contribute to ageing as a new way to treat ageing-related conditions.”
Killing ‘zombie cells’
The TOR pathway is the most popular avenue when it comes to ageing research. But scientists are also looking into a group of drugs known as senolytics, which selectively eliminate a type of cells called senescent cells.
These cells, nicknamed “zombie cells” by some scientists, lose many important functions as they age but don’t die the way normal cells do. Senescent cells can become cancerous and damage neighbouring cells, possibly causing them to become senescent as well.
According to Dr. James Kirkland, a physician and researcher at the Mayo Clinic, our immune systems take out some senescent cells. But the zombie cells can accumulate in tissue as a result of ageing, chronic diseases, chemotherapy, or exposure to radiation. Senescent cells are also closely associated with osteoporosis; in fact, frailty in the elderly is correlated with the accumulation of these cells.
To figure out how to kill these persistent zombie cells, Kirkland and his colleagues used a computer analysis to pinpoint pathways in the cells that protect them against their own inflammatory, toxic secretions. The researchers then attempted to eliminate senescent cells in lab experiments, usinga leukemia drug called Dasatiniband and a flavonoid called Quercetin, which is found in apple peels.
This drug combo appeared to help old mice live 36% longer.
“To me that’s amazing for a mouse that is that old and has lived with all the damages that’s accumulated with age,” Sierra said.
Kirkland said that eliminating senescent cells alleviated radiation-induced injury and frailty in the mice. It also increased cardiac function and blood flow, improved symptoms of diabetes, and relieved osteoporosis.
“We want to get [senolytics] to clinical trials to treat those who are older with serious pulmonary fibrosis or other age-related dysfunctions. Hopefully it can improve lung and other physical functions,” Kirkland said.
One of the only side effects of senolytic drugs, Kirkland noted, is that they could delay wound healing.
A controversial contender
A somewhat controversial but important third ageing treatment option is a modern-day version of parabiosis, the transfusion of blood from a young animal into an old animal.
Although it may seem like a technique out of science fiction, Sierra thinks it’s an important approach to research, if only as a proof of principle.
Tony Wyss-Coray, a neurology professor at Stanford University who studies Alzheimer’s, came up with the idea to use this technique to treat this disease after studying differences in the blood composition of patients who had Alzheimer’s and people without the disease.
Wyss-Coray’s research in mice showed that blood from young mice rejuvenated older mice’s brains, and blood from old mice inflamed younger mice’s brains.
“We found that it’s not the cells that are responsible for this effect, but it’s the soluble factors in the blood, specifically proteins. And we’ve identified a few proteins that have either beneficial effects in the old or detrimental effects in the young,” he said.
Other researchers have used parabiosis to restore function in the liver, kidney, skin, bone, heart, and muscles.
Wyss-Coray founded a company called Alkahest, which uses a specific part of blood plasma to treat Alzheimer’s disease. After a positive early trial in late 2017, the treatment is now in a phase-two trial.
A new outlook for an ageing population
Since 1964, humans globally have been extending their average lifespan by one day every week – an impressive feat.
But Sierra pointed out that there has also been a rapid increase in the number of diseases and disabilities, which indicates that we haven’t been doing a great job of expanding healthspan along with lifespan.
“Imagine a 75-year-old that was supposed to die of a heart attack. But we give him statins and he didn’t get the heart-attack,” Sierra said. “This person did not die when he was supposed to die, but he’s living longer with all the other diseases that we’re not treating.”
Because of that, he said, it’s now more expensive to care for the ageing population.
Approximately 80% of older adults have at least one chronic disease, and 77% have at least two. Chronic diseases account for 75% of the money the US spends on health care, according to the National Council on Ageing.
But targeting ageing could allow scientists to intervene earlier in the chain of events that leads to many chronic and age-affiliated diseases like heart disease, cancer, stroke, and diabetes, which cause almost two-thirds of all deaths each year.
“Ageing is the biggest risk factor for almost every chronic disease. And we never understood that it might be a modifiable risk factor that you can target with a drug,” Mannick said. “I think if future studies continue to be positive, it will open up a whole new area of medicine.”
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