Longevity Briefs: Can Exercise Slow Ovarian Ageing?

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:

The ovaries are among the fastest ageing human organs, becoming unable to fulfil their primary function of producing eggs after around 50 years. Yet ovarian ageing doesn’t just matter for reproductive health – the menopause also comes with hormonal changes that influence ageing in a wide range of organs, from the brain to bone tissue. Ovarian ageing puts women at greater risk of osteoporosis (age-related loss of bone density), exacerbates autoimmune disease and may also contribute to greater risk of Alzheimer’s disease compared to men. While hormone replacement therapy can reduce these risks, it doesn’t prevent ovarian ageing itself.

One of the few interventions that we can say with reasonable certainty slows ageing in humans is physical exercise. Exercise is associated with reduced risk of age-related disease and increased lifespan in animals and humans alike. However, exercise affects different organs in different ways, and the effects of exercise on ovarian ageing specifically are debated. In this study, researchers provide animal evidence that exercise may indeed delay ovarian ageing, and that this effect could be mimicked by targeting the underlying mechanism.

The discovery:

Researchers began by looking at data from over 150,000 women from two different observational datasets and found that on average, premenopausal women reported doing more exercise than the postmenopausal women of the same age. This of course doesn’t prove that physical inactivity caused earlier menopause as opposed to the other way around. It’s also likely that women undergoing faster ovarian ageing are also ageing faster in other ways, possibly resulting in a decline in physical activity. To test whether there was a causal relationship, researchers put adult female mice through 1 month of treadmill exercise training and compared them to untrained mice. They found that trained mice had significantly more primordial follicles (the structures in the ovaries that contain immature oocytes), higher levels of growth factors produced by oocytes, and higher levels of AMH – a marker of ovarian reserve, the capacity of the ovaries to produce viable egg cells.

Researchers hypothesised that a hormone called adiponectin might be responsible for these benefits. Adiponectin is mainly produced by fat tissue, but some is also produced by the ovaries. Adiponectin is produced during exercise and had previously been found to extend lifespan and delay ageing in some organs in mice. To test the effects of adiponectin on ovaries, researchers cultured ovaries from newborn mice with varying levels of adiponectin and found that higher adiponectin levels slowed down follicle growth. They also found that adult mice deficient in adiponectin had fewer follicles and benefited less from exercise than normal mice, together suggesting that adiponectin produced during exercise may preserve follicles by slowing down their growth. Interestingly, using genetic techniques to reduce adiponectin production by ovaries specifically had similar effects, suggesting that ovary-derived adiponectin is particularly important.

Finally, researchers tried feeding adult mice AdipoRon, a compound that binds to and activates adiponectin receptors. They found that treated mice had significantly more follicles in their ovaries, better markers of ovarian reserve and had more offspring compared to controls, suggesting that this treatment may improve ovarian and reproductive health by mimicking some of the benefits of exercise.

The implications:

This research provides more evidence that exercise may slow ovarian ageing, at least in mice. It also identifies adiponectin production by the ovaries as an important contributor to these effects, and shows that the benefits of exercise can be mimicked through treatment with AdipoRon, a drug that targets the same receptors as adiponectin. AdipoRon has previously been studied for its ability to replicate other benefits of exercise and is of interest for the treatment of a variety of conditions including obesity and diabetes. Unfortunately, AdipoRon remains an experimental research compound at the time of writing, as no human clinical trials have been conducted so far.

This study pointed to suppression of the mTOR pathway as a possible mechanism of adiponectin’s effects on ovarian ageing. mTOR is a protein that regulates how cells respond to the availability of energy, with mTOR activation promoting cell growth and generally accelerating ageing. In addition to exercise, forms of dietary restriction such as fasting and protein restriction are effective ways of suppressing mTOR. Some of these practices have also been found to slow ovarian ageing in mice.