CU Boulder lab is working to determine if results seen in aging mice could apply to humans

Researchers at the University of Colorado Boulder have successfully reversed vascular dysfunction in aging mice with a dietary supplement. The findings have implications for preventing cardiovascular dysfunction and disease during aging in humans.

The supplement, nicotinamide mononucleotide (NMN), acts on cellular processes that are involved in the positive effects of caloric restriction — an intervention that has long been shown to slow the aging process, at least in animals.

Scientists in CU Boulder’s Integrative Physiology of Aging Laboratory previously shown that both exercise and restricting calories in aging mice prevents vascular changes that lead to increased risk of cardiovascular disease.

Now, they are designing and testing potential “healthy lifestyle mimicking” interventions: pharmacological and behavioral approaches that may recapitulate some of the health benefits of exercise and eating a healthy diet.

The reason this is necessary is that it’s difficult to get people to exercise regularly or to cut their calories for the length of time that would be necessary (likely years) to slow aging.

“Physicians have been asking us for years to provide them with evidence-based alternative strategies for patients who will not exercise or eat a healthy diet,” said Doug Seals, a professor in the Department of Integrative Physiology and the lab’s director.

The results of the Seals’ lab research were published this year in the journal Aging Cell.

Seals recognizes the potential these results have for humans. If similar outcomes are observed in people, the compound could be viewed as a complementary approach in patients with poor adherence to conventional healthy lifestyle recommendations.

The mice are step one in a method that seeks to apply the animal-research results to human populations. Seals’ lab is unique in that it is capable of performing fully “translational research” on the CU Boulder campus, often starting in cells and mice before testing novel interventions in people.

Chris Martens, an author on the paper and post-doctoral fellow working in Seals’ lab, is now overseeing a clinical trial assessing a very similar compound, nicotinamide riboside (NR), in middle-aged and older adults. Testing in that study was recently completed, and he is currently analyzing the results.

“We’re expanding upon the findings of our mouse study and measuring artery, neuromuscular, cognitive and metabolic functions. We’re also assessing a wide variety of processes known to be impaired with aging,” said Martens.

The compounds act by raising levels of an important molecule involved in metabolism known as “NAD⁺” and are thought to broadly slow the basic biological processes of aging — sometimes called the “10 hallmarks of aging.” These include cellular effects such as inflammation and oxidative stress, as well as detrimental damage to DNA.

The CU Boulder scientists have demonstrated that raising NAD⁺ appears to activate a key longevity enzyme called SIRT1, resulting in the reduction of damaging free radicals and an improvement in the function and health of arteries. SIRT1 is a protein related to metabolism that has been linked to vascular, metabolic and even cognitive dysfunction with aging. The study notes that SIRT1 activity decreases with age and contributes to artery dysfunction.

In the long term, scientists hope to establish the effectiveness of new interventions that broadly treat several, if not all, of the 10 hallmarks of aging, not only the specific cellular processes that NR targets. For now, eating less (or simulating eating less) is a good bet.

“Caloric restriction and regular exercise are the only methods we have of slowing the fundamental processes of aging,” said Seals.

However, it is important to note that the goal of these pharmacological interventions is not to extend lifespan. Rather, the scientists aim to delay the potential onset of common diseases.

“Our goal is not to increase lifespan, but to extend healthspan” said Martens. Health-span is the number of years that a person spends in good health, not necessarily how long they live.

If a person is diagnosed with a chronic disorder such as heart disease at age 50, but they live to be 80, then much of their life is spent in poor health. This is not uncommon in developed societies.

With a combination of healthy lifestyle practices and “mimetics,” it might be possible to extend healthspan and delay chronic disease. People would still live long lives, but would spend far less time spent grappling with illness and disability.

“The problem is, most chronic diseases are tightly linked with aging,” said Seals. By slowing down the process of aging, novel pharmacological or behavioral interventions could lessen the personal and family-related burdens of aging. These approaches might also lessen stress on the health-care system.

The latter is important, given that the U.S. health-care system is about to absorb the impact of rapidly aging demographics. The U.S. Department of Health and Human Services projects that 20 percent of the population will be over the age of 65 by 2020.

For those struggling with dieting and exercise, innovative pharmacological compounds such as NR might help extend healthspan.

“The medical community is asking us to provide research-based treatment options,” said Seals, “We’re trying to meet that need.”