Longevity Briefs: Why Do Some People Stay Sharp In Old Age?

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:

Cognitive decline is inevitable with age, yet while some individuals maintain relatively sharp minds well into old age, others experience significant cognitive decline or early onset dementia. Why? One possible explanation is that people who maintain cognitive function into old age had healthier, better-functioning brains to begin with. They can afford to lose more cognitive function without it impacting them significantly – a concept known as cognitive reserve. However, it is also likely that the underlying causes of cognitive decline progress at different rates in different people. One such underlying cause is thought to be cellular senescence. Senescence is a state in which cells are unable to divide but also unable to die. Senescent cells release a cocktail of inflammatory signalling molecules that, over time, cause damage to surrounding tissues. In this study, researcher ask how much of the variability in cognitive function might be explained by senescence in the brain, at least in mice.

The discovery:

Researchers used a cognitive testing system called PhenoTyper, which they had previously developed themselves, to assess spatial memory in aged mice (22-24 months old). This involved a task in which mice were trained to go through one of three holes in order to receive a reward. After learning which hole was the correct one, the reward was switched to a different hole. They found that there was significant variation in how quickly the mice were able to relearn which hole was the correct one. Based on this, researchers were able to group male mice into cognitively intact or cognitively impaired groups, but not female mice as the variability in their cognitive function was not as stark.

Researchers then examined the hippocampus (a brain region that is important for spatial memory). They found that cognitively impaired mice exhibited significantly increased reactive gliosis, which is the brain’s response to damage, compared to their cognitively intact counterparts. They also had higher levels of molecular markers for senescent cells. The presence of these markers indicated senescence specifically among glial cells and astrocytes, which play maintenance roles in the brain and are heavily involved in reactive gliosis. To find out whether senescent cells were responsible for the variability in cognitive function, researchers then treated 22 month-old mice with either dasatinib and quercentin (a combination treatment that removes senescent cells) or a control treatment. 8 weeks later they repeated the previous test, and found that dasatinib and quercetin significantly improved relearning, with nearly all of the treated mice qualifying as cognitively intact according to the same criteria as before, while also displaying reduced markers of senescence.

The implications:

This research suggests that cellular senescence may be an important driver of cognitive decline in ageing mice. Since mice do not get Alzheimer’s disease or other forms of dementia, the variability observed was natural variability in cognitive function in old age, and seemed to be attributable to senescence. More importantly, drugs that remove senescent cells appeared to restore cognitive function. One of the advantages of this study was the testing system, PhenoTyper, which continuously monitors mice in their cages (including at night). This has multiple advantages, including reducing stress placed on the mice, which means their behaviour is more likely to represent natural cognitive performance.

The big caveat here is that this research comes from mice, and not just any mice but BL6 mice. This is a highly inbred strain that is very unhealthy and not representative of natural ageing in mice, let alone humans. It would therefore be very premature to conclude that dasatinib and quercetin would be beneficial for us. Some recent evidence does hint at potential benefits for the most cognitively impaired, but this was only a pilot study with no control group, so we must wait for larger trials.