Scientists 'reverse' ageing in mice by improving endurance

Australian and US researchers have discovered that replacing two naturally occurring molecules in the body can reverse symptoms of ageing, potentially influencing how the body responds to and performs exercise.

In a paper published in the journal Cell, a research team led by UNSW and Harvard Medical School found that a decline in the blood flow to tissues and organs with age can be reversed by restoring molecules that improved exercise capacity and physical endurance in mice. The researchers found that the two molecules replicate the benefits of exercise — a breakthrough that could lead to better athletic performance, improved mobility in the elderly and the prevention of ageing-associated diseases.

The study’s senior author was Dr David Sinclair, head of laboratories at Harvard Medical School Boston and a professor at the UNSW School of Medical Sciences. In a study published last year, he identified that the metabolite NAD+, which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. Furthermore, treating old mice with the NAD+ booster NMN improved their cells’ ability to repair DNA.

The latest study shows that as levels of NAD+ decline with age, the body’s capacity to exercise decreases because of fewer blood vessels and reduced blood flow. Dr Sinclair explained that endothelial cells, the cells that line the blood vessels, are the main culprit here and the likely reason we feel tired and have less energy as we age.

However, by treating mice with NMN and increasing levels of hydrogen sulfide (H₂S), Dr Sinclair and his team managed to extend physical endurance in mice by over 60%, no matter what their age. “Remarkably,” Dr Sinclair said, “by feeding mice NMN and H₂S it restores NAD+ levels in endothelial cells and makes them believe they are young and exercised.

“With exercise, the effect is even more dramatic. We saw 32-month-old mice, roughly equivalent to a 90-year-old human, receiving the combination of molecules for four weeks run, on average, twice as far as untreated mice. Mice treated only with NMN alone ran 1.6 times further than untreated mice.”

The scientists identified that this mechanism is due to a restoration of capillary formation in muscle by stimulating the activity of the protein SIRT1, a key regulator of blood vessel formation. Lead author Dr Abhirup Das, from UNSW’s School of Medical Sciences, explained, “Age plays a critical role in the links between blood vessels and muscle, and points to a loss of NAD+ and SIRT1 as the reason people lose the capacity to exercise.

“Our bodies already make NAD+ in our cells, but after 50 its levels drop dramatically,” said Dr Das. “Exercise is a way to prevent decline in blood flow, but these findings show that by restoring the levels of NAD+ in mice equivalent to 60-year-old humans, we can get the same benefits of exercise.”

Dr Sinclair and Dr Lindsay Wu, co-head of the Laboratory for Ageing Research at UNSW, have been working for five years to make NAD+ boosters into therapeutic agents with their companies MetroBiotech NSW and MetroBiotech International. The goal is to work towards developing NMN-based drugs that mimic the benefits of exercise, increasing blood flow and oxygenation of muscles.

“If these findings translate from mouse to human, we could have a revolutionary impact on the quality of life of older people — not to mention the benefits of avoiding diseases of ageing,” said Dr Wu.

Human trials with a NAD+ booster called MIB-626 were completed in Boston in 2017, with the second phase predicted to begin later this year. According to Dr Sinclair, “NAD+ boosters, particularly when combined with H₂S, are some of the most promising molecules in medical research today.”

Illustration: Researchers found that two molecules could replicate the benefits of exercise. Credit: Kevin Krull.