Longevity Briefs: How Does Calorie Restriction Affect 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:

Calorie restriction or CR – a sharp reduction in calories without causing malnutrition – has been shown to consistently extend lifespan in animals. It also significantly delays the age-related deterioration of many different organs, including the brain. This is because when nutrients are scarce, cell division and growth slow down while damage repair and survival are prioritised. This response probably evolved as a way to keep an organism alive for longer when food is too scarce for reproduction – any offspring produced now are unlikely to survive, so the organism’s best bet for passing on its genes would be to survive through the famine.

For this reason, scientists suspect that CR might not have the same lifespan effects in humans as it does in shorter-lived organisms, since our reproductive lifespans are already far longer than any seasonal food shortage. We don’t actually know if CR extends human lifespan, but we do know that it leads to short-term improvements in health beyond the obvious benefit of weight loss. We also know that the molecular mechanisms behind the benefits of CR are similar between mice and humans. It might be possible to leverage these mechanisms in order to enhance human health in old age and prevent age-related diseases, but first we need a better understanding of how calorie restriction affects different organ systems. In this study, researchers focus on the brain – an organ in which prevention of ageing would be highly valuable, since neurodegenerative diseases are currently incurable.

The discovery:

Researchers used transcriptomics to analyse brains from 36 mice aged 12 months (adult), 18 and 24 months (aged), half of which had their calorie intake reduced to 60% of normal. Transcriptomics measures the complete set of RNA ‘templates’ that are being produced by a cell’s genome, which gives scientists an overall picture of the activity levels of different genes. When transcriptomics is performed on many cells in bulk, information about individual cells is lost as the differences in transcription between cells are ‘averaged out’. However, researchers in this study used a technique called spatial transcriptomics, which allowed them to measure not only transcription within individual cells, but also what type of cell that data came from and their spatial location within the brain.

The researchers found that CR significantly reduced the age-related expansion of inflammatory glial cell populations. Glial cells are non-neuronal cells that support and protect neurons, but can switch to an inflammatory state in old age. CR also preserved neural stem and progenitor cells (cells that can develop into new brain cells) for longer, and broadly reduced molecular markers of DNA damage and cellular senescence (a state in which cells can no longer divide) across various brain regions and cell types. Nearly all age-related gene expression changes that occurred in mice fed a normal diet were reduced by CR. In some cases, gene expression was not significantly different between adult and aged CR mice. CR appeared to maintain the activity of genes related to cognitive function, maintenance of myelin (the nerve’s protective ‘wrapping’), and circadian rhythm.

The implications:

This study suggests that CR has a broad impact on genes related to different aspects of brain function in different brain regions. Furthering our understanding of these genes may open up new opportunities to mimic the effects of CR through the use of drugs. Some existing drugs like rapamycin are already known to replicate the benefits of CR in mice, but it is not yet known whether they have the same effects in healthy humans.

While we do not know if calorie restriction extends lifespan in humans, it is likely to benefit brain health if done safely. One important point to note is that in this study, CR was started at 4 months of age – in other words, when the mice were still quite young. While CR has been shown to extend lifespan even when started much later than this, CR might do more harm than good in elderly humans because they are more at risk of nutrient deficiencies. Muscle loss during CR is also more problematic in the elderly due to overall frailty.