Longevity Briefs: Why Are Women More Resistant To Brain 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:

Men and women do not appear to age at the same rate or in the same ways. Women suffer from a higher risk of autoimmune disease, as well as age-related hormonal disruption in the form of the menopause, contributing to higher risk of osteoporosis (loss of bone density) and sarcopenia (loss of muscle mass). Men on the other hand have shorter lifespans on average compared to women, which is in large part due to a higher incidence of cardiovascular disease. Another area in which women appear to come out on top is cognitive ageing. Research suggests that cognitive decline in old age progresses at a slower pace than in men, and that their brains appear younger at a molecular level.

In this study, researchers ask if the X chromosome could hold the key to this resilience to cognitive ageing. The X chromosome is unusual due to the phenomenon known as X chromosome inactivation. Females inherit one X chromosome from each parent, but during development, one of those chromosomes is randomly silenced in each cell. This means that roughly 50% of cells use the genetic code of the X chromosome from the male parent exclusively, while the others only use the code from the female parent. However, some genes on the inactivated chromosome are able to escape silencing, which can in some cases compensate for defects in the active chromosome, such as a disease-causing genetic mutation. The researchers wanted to investigate whether something similar might be happening during ageing to help maintain cognitive function.

The discovery:

Researchers started by breeding together two strains of mice, one of which had been genetically engineered so that its X chromosome would always be the active X chromosome when inherited by female offspring. This way, if they detected the expression of X chromosome genes originating from the other strain, they would know that these genes had escaped inactivation. They then took cells from the hippocampus (a brain region involved in memory, particularly spatial memory) from the brains of four young and four old female offspring. Upon analysing genes whose expression is known to be impacted by ageing, they found that in cells from the old mice, some of these genes escaped silencing on the inactive X chromosome. Many of those were known to be related to cognitive function, with mutations in some of them capable of causing intellectual disability in humans.

They then focused in on one of these identified genes called Plp1, which is responsible for producing a component of the myelin sheath – the insulating material that wraps around nerve fibres to speed up electrical impulses. Studying human brain samples showed that Plp1 was expressed at higher levels within the parahippocampus (the region surrounding the hippocampus) in elderly women than in elderly men. To test whether Plp1 expression might be related to improved cognitive health, the researchers engineered a virus that would deliver the Plp1 gene to myelin producing cells, and then used this to treat both male and female mice. They found that treated mice from both sexes benefited, displaying enhanced learning and memory compared to mice treated with a control virus.

The implications:

While limited to mice, this study demonstrates how studying sex-specific differences in ageing might eventually lead to benefits for everyone. Inherited genetic mutations in the X chromosome always affect males, since that’s the only copy they inherit. In females, inheriting a single defective X-linked gene will at worst result in 50% of cells being affected, with the further possibility of the healthy copy on the other chromosome escaping silencing. Having two copies of the X chromosome may protect against cognitive ageing in a similar way. Since the X chromosome contains genes important for cognitive function, silenced copies of these genes becoming active in old age might help maintain the production of important proteins that would otherwise decline.