Longevity Briefs: Combining Two Treatments To Extend Mouse Lifespan

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Ageing is a complex process, with many different components that may each need to be targeted individually in order to have a meaningful impact on human health. This perhaps explains why, while scientists have discovered many treatments that can be given to adult mice to extend their lifespan, none of these treatments have been more successful than calorie restriction (a sharp reduction in calorie intake without causing malnutrition). More research needs to be done to figure out how multiple biological processes can be targeted at once to delay ageing more effectively.

In this study, researchers combine two different approaches to see if they could extend mouse lifespan. They targeted both oxytocin, the so-called ‘love hormone’, and the TGF-β pathway, which plays many important roles including in cell growth, wound healing and the immune system.

The discovery:

Researchers conducted their study in 25 month-old mice, which are roughly equivalent to 75 year-old humans. 12 male and 13 female mice were in the control group, while 14 male and 13 female mice were treated with a combination of oxytocin (OT) and and a compound called Alk5 inhibitor (A5i), which targets the TGF-β pathway. These were chosen because of previous research suggesting that they were important factors whose levels in the blood changed with age, and that they might underpin some of the health benefits of blood plasma exchange. In brief:

• Oxytocin is a hormone produced by the hypothalamus and that declines with age. Mouse studies suggest it may reverse some signs of ageing. You can read more about the potential mechanisms here.
• A5i inhibits TGF-β, which usually increases with age. While the TGF-β pathway is necessary for wound healing, overactivity causes fibrosis (the production of scar tissue instead of functional tissue).

The treatment consisted of subcutaneous injections of either OT and A5i or a control injection three times a week for two weeks, continuing this cycle for the duration of the study.

For male mice, the effect on lifespan appeared to be substantial. Treatment with OT+A5i resulted in a statistically significant 14% increase in their overall median lifespan (the age by which 50% of the mice are dead) compared to the control group. Their maximum lifespan also appeared to be increased – by the time all of the male mice in the control group were dead, 4 of the treated male mice were still alive. Beyond just living longer, the male mice also experienced a substantial increase in their healthspan, demonstrating improved physical performance (measured by treadmill endurance) and enhanced short-term memory (assessed through novel object recognition tests).

Intriguingly, these benefits were observed exclusively in male mice; female mice treated with OT+A5i showed no significant improvements in either lifespan or the studied health parameters. Researchers didn’t just look at health and lifespan – they also examined the protein profiles of the mice’s blood over time. They found that treatment with OT+A5i was actually associated with a more youthful balance of proteins in both sexes initially, but this effect wore off in females after four months of treatment.

The implications:

OT+A5i treatment appears to have significant benefits for both health and lifespan in male but not female mice. Why exactly the effects of OT+A5i wore off in the female mice will require further investigation. Oxytocin is already clinically approved and is used to induce labour, while A5i drugs are currently under investigation for the treatment of various diseases and so far appear safe. It might therefore be feasible to conduct a clinical trial for this combination in humans in the not-too-distant future.