Life-Extending Discovery Renews Debate Over Aging as a ‘Disease’

Even if a new drug proves to prolong human life, it won’t receive regulatory approval for that purpose unless the FDA accepts that aging is a treatable medical condition.

 

David Sinclair and his UNSW team. Britta Campion

 

David Sinclair has been reverse-engineering the aging process for two decades. As the co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, Sinclair and his colleagues have identified several key enzymes and interactions inside cells that cause them to “lose their identity” over time, making our bodies more susceptible to diseases like cancer, heart disease, and dementia.

But what if aging itself is the real disease?

“Aging is the one disease that we all get if we live long enough,” Sinclair told Seeker. “I define it as a disease. Most doctors are trained that aging is something separate from disease. But the only difference in the medical textbooks is that if the majority of people get an age-associated disorder, we call it aging. If less than half of people get something over time, it’s a disease.”

Sinclair is part of a growing movement of “geroscientists” who believe that aging is not inevitable. What we once thought of as a natural process is in fact a degenerative condition — a condition that cannot be cured, but can in fact be slowed. With greater understanding of the molecular and cellular mechanisms of aging, they insist, we can delay the onset of age-related diseases, keeping us healthier longer.

Last week, Sinclair and a team of researchers from Harvard Medical School and the University of New South Wales announced the discovery of a molecule that significantly boosts a cell’s ability to repair damaged DNA. In a paper published March 23 in the journal Science, the authors describe how a molecule called NAD+ blocks a protein that inhibits the body’s natural ability to repair DNA.

“We’re not going to see people spend longer in nursing homes. We’re going to see them spend more time out of nursing homes.”

As we get older, NAD+ levels decrease, allowing DNA damage to build up. These mutations aren’t a direct cause of the progressive deterioration associated with aging, Sinclair said. “Cells cope with the damage by turning on the wrong genes at the wrong time,” he explained.

If NAD+ levels could be increased, Sinclair and his team hypothesized, perhaps the damage could be reversed.
They tested their theory on a group of older mice with low NAD+ levels. For a week, the mice drank a special serum of water mixed with NMN, a precursor of NAD+ that’s small enough to pass through the cellular wall. Once inside the mice’s cells, the NMN bonded with NMN molecules to form more NAD+.

“After just a week, we couldn’t tell the difference between the young mice and the old mice when we looked at their tissues,” said Sinclair.

Now Sinclair’s team is moving toward human trials of the NAD+ booster, with the hope of getting a drug on the market within the next five years.

“Our technology in the animals slows down the appearance of diseases, and that’s how we know that it’s slowing down aging itself. And as a consequence of being healthier, the animals live longer,” said Sinclair. “We think the same will happen in people. If we can delay all major diseases, then we will extend people’s lives, but only because they’re healthier. We’re not going to see people spend longer in nursing homes. We’re going to see them spend more time out of nursing homes.”

But even if Sinclair’s drug proves to delay the onset of age-related diseases in humans — effectively prolonging the human lifespan — it won’t be marketed as an “anti-aging” pill. That is, not unless the US Food and Drug Administration (FDA) accepts that aging is a treatable condition.

The FDA approves drugs for specific “indications” or recognized medical conditions. For example, the indication for a statin drug like Lipitor is cardiovascular disease, and one of the indications for Xanax is anxiety disorder. While the FDA approves drugs indicated for age-related diseases like cancer, type-2 diabetes, and dementia, it doesn’t recognize aging as its own indication… yet.

In June 2015, a group of scientists working under the American Federation for Aging Research (AFAR) met with FDA officials to make an ambitious proposal. Instead of approving a drug for one or two indications, they wanted the FDA to give their blessing to a clinical trial that would test a single drug’s effectiveness at preventing all of the major age-related illnesses at once: cancer, cardiovascular disease, dementia, and type-2 diabetes.

“We worked for weeks honing our arguments and our strategies for trying to convince them,” said Steven Austad, science director at AFAR and chair of the biology department at the University of Alabama Birmingham. “When we actually got into the meeting, within the first 15 minutes they said, ‘OK, that sounds good. Now let’s talk about the design of your study.’ We were kind of taken aback that they had accepted our logic so easily.”

“I think this is probably the most exciting thing to happen in aging research yet, and I think that’s going to be true no matter how the trial results turn out.”

Austad and his colleagues carefully avoided any mention of the words “anti-aging,” which they believe carry a whiff of hyperbole. Instead, they focused on making a sound scientific case for approving a “multimorbidity drug” that extends the so-called health span by delaying the onset of the most common age-related illnesses.

The drug in question is metfornin, a generic medication already approved by the FDA for type-2 diabetes. Metfornin has been taken by thousands of patients worldwide for decades and carries no side effects, except for a few unexpectedly positive ones. When researchers study people taking metfornin, they report startlingly lower incidence rates of cognitive impairment, cancer, and cardiovascular disease. And they live longer.

“By accident, metfornin seems to be a drug that affects most of the processes that we think are critical in determining how well or how poorly someone ages,” said Austad, including improved mitochondrial function, inhibition of free radicals, protection of DNA, and stimulation of something called the mTor pathway.

The metfornin study proposed to the FDA, called Targeting Aging with Metfornin (TAME), would track 3,000 elderly participants over six years and collect detailed health data across a range of illnesses and conditions associated with aging. The trial will cost an estimated $66 million. AFAR is waiting to hear back about an NIH grant, and has a benefactor waiting in the wings with $35 million to cover any shortfalls.

“I think this is probably the most exciting thing to happen in aging research yet, and I think that’s going to be true no matter how the trial results turn out,” said Austad. “But if they turn out to be positive, then this is a game-changer in the health business.”

Austad envisions a day when older people take metfornin preventatively like a multivitamin.

“This has the potential of giving the average person another five to 10 years of healthy life,” he remarked. “Whether it will make them live longer remains to be seen. But even if it doesn’t, it will be a great advance if it were simply to shorten the period of ill health before the end of life. An extra five to 10 years of healthy life for the average person is huge.”

Sinclair at Harvard Medical School also serves on the board of AFAR and is hopeful that the TAME trial will open the door for the FDA to fully recognizing aging as a disease.

“No question, that’s one the biggest things that this administration could do for medicine, to allow biotechnology companies to work toward [an aging drug] as a goal,” said Sinclair, who has co-founded several biotech companies of his own. “Right now, it’s not considered a realistic business model for that very reason. And if that were changed, the investment would go up exponentially.”

 

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