By Steve Spencer

In recent years, there has been growing interest in the science of aging with researchers focused on why people age and how we can combat it. According to Matt Kaeberlein, PhD, a biologist at the University of Washington School of Medicine, “biological aging is the root cause of most major diseases in developed countries.” Therefore, if scientists can find therapies to slow biological aging, we might be better protected from debilitating illnesses like cardiac disease and cancer.

Exercise

Nothing, other than calorie restriction, is as beneficial to healthy aging as exercise. For example, 10 years ago, researchers in the UK examined 125 amateur cyclists between 55 and 79, and compared them to adults in the same age range who didn’t exercise regularly. The cyclists didn’t lose muscle or much bone mass, both of which have been assumed to be inevitable in aging. The biggest surprise was related to the thymus gland, which affects immune function. It normally shrinks in older people, but it didn’t in the cyclists.

Another marker of fitness is VO2 Max. This is a measure of how much oxygen you can consume and use during cardiovascular exercise. A study in JAMA8 that followed over 120,000 people found that a person in the bottom quartile for their age and sex in VO2 Max is at double the risk of all-cause mortality than someone in the top quartile. You can improve your VO2 Max with regular cardio exercise.

Rapamycin and Metformin

There are currently two drugs that a number of Americans are using off-label in an attempt to stay healthier longer.

Rapamycin is an antifungal compound that was discovered on Easter Island in the 1960s. It’s used in high doses in organ transplants to help prevent rejection of the donor organ. About 20 years ago, information began to emerge suggesting that at lower doses rapamycin extended lifespan in mice. About 30 studies have been done, including six with the rigorous Interventions Testing Program, and all yielded positive results. One study found that Rapamycin, which inhibits mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23 percent for males to 26 percent for females.

It’s estimated that around 5,000 people take Rapamycin off-label in an effort to extend health/lifespan. Unfortunately, because the patent on Rapamycin has expired, pharmaceutical companies aren’t interested in performing studies.

The other popular off-label longevity drug is Metformin which is used as a treatment for diabetes. In 2017, Jared Campbell at the University of New South Wales in Sydney, Australia ran a meta-analysis on Metformin, finding that it reduced all-cause mortality and diseases of aging, independent of its effect on diabetes control.

Preliminary studies suggest that metformin’s positive effect on life expectancy may result from improving the body’s responsiveness to insulin, antioxidant effects, and improving blood vessel health, but more research needs to be done. With that in mind, Nir Barzilai, MD, the director of the Institute for Aging Research at the Albert Einstein College of Medicine, leads a group that wants to conduct the Targeting Aging with Metformin (TAME) trial to test whether metformin is capable of delaying the onset of age-related diseases including cancer, cardiovascular disease, and Alzheimer’s. The group has had a difficult time raising money for the trial because, like Rapamycin, Metformin is off patent. At this time, they may begin with trial with partial funding.

Polypill

“About 20 years ago, a couple of British physicians said that if everybody in Britain over age 55 took one pill a day, they could cut cardiovascular deaths by 80 percent,” said Steven Austad, PhD, Chair of the Department of Biology at UAB. “The pill consisted of three low dose anti-hypertensives, a statin, and a couple of other things like aspirin and folic acid. The National Health Service wouldn’t buy into it so it didn’t go anywhere.

“Since then, there have been around a dozen small studies all over the world, including one here in Alabama, that showed it always works. The Alabama study included the most disadvantaged people, and it lowered their blood pressure and their cholesterol. The researchers calculated that it would have lowered heart attacks by 30 percent over the next 10 years.

“With so many disadvantaged people in Alabama, I would create a polypill with anti-hypertensives, a statin, and low dose metformin. The idea is to do a low dose of three anti-hypertensives that all work through different mechanisms. The polypill has several advantages: because these are generic drugs, it’s inexpensive, and it has all your medications in one pill which should help people stick with it. I want to work up a study with this in Alabama.”

Yamanaka Factors

In 2006, Shinya Yamanaka, a geneticist at Kyoto University in Japan, found that four proteins, now called Yamanaka Factors, could reset epigenetic markers which turned adult cells back into pluripotent stem cells. Researchers across the globe were excited about this finding, which earned Yamanaka the Nobel Prize in Medicine, because it opened the possibility of resetting people’s cells which might allow scientists to treat diseases using cells derived from patients’ own tissues, and possibly even reverse some aspects of aging.

However, pluripotent stem cells can turn into cancerous cells, making the endeavor incredibly risky. Recently, some researchers have approached this problem by using only three of the four Yamanaka Factors, while others have limited the time that adult cells are exposed to Yamanaka Factors.

Recently, San Diego–based Rejuvenate Bio injected 124-week-old mice with adeno-associated viruses (AAVs) carrying genes for three of the factors. These mice lived another 18 weeks on average, compared with nine weeks for a control group They also partially regained patterns of DNA methylation that are typical of younger animals. “I would say it’s provocative - possibly a breakthrough,” Austad said. “But it will need to be replicated and the mechanism explored before we can say for sure.”

A Plan to Improve Mice Study Results

Even with some of these encouraging results, it’s been very difficult to translate positive findings in mice studies to humans with a failure rate of over 90 percent.

“We keep them in cages where they get no stimulation, and little to no exercise,” Austad said. “We protect them from microbes so they have a neonatal immune system. It’s like they’ve been raised in a bubble. Some friends of mine did a study with some drugs to see if they improved COVID outcomes with mice. They bought some mice from the pet store and they put their laboratory mice in the cage with the pet store mice, and the lab mice were all dead within two weeks. All they did was put them on the bedding of the pet store mice that were perfectly healthy. It exposed the lab-bred mice to microbes they’d never seen. So it’s not surprising that mice to human studies rarely pan out.

“I would like to make a more natural environment. If I get funding, I’m going to build an environment like that for testing, and use rats instead of mice. I would build an indoor/outdoor thing, like a small barn. I wouldn’t put it outdoors because of rain, but I would allow for temperature variations, daily and seasonal variations. I would use dirt rather than bedding to give the rats exposure to normal microbes.”

The Future

Longevity research is moving fast. There’s no guarantee that research will yield significant benefits, but by tackling the challenges of an aging population head-on, anti-aging research holds the promise of transforming the way we age, enhancing our overall wellbeing, and fostering a healthier and more vibrant global community.