Longevity Briefs: Calorie Restriction May Affect Age-Related Protein Modifications In The Brain

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:

After having been assembled, proteins within our cells can undergo all kinds of further modifications that alter the way they function, primarily by changing their shape. Some of these modifications are a necessary part of how the protein functions, while others are unwanted modifications or damage that prevents the protein from functioning correctly. Such dysfunctional proteins need to be recycled, and the cell’s ability to maintain a healthy balance of protein production, modification and recycling is called proteostasis. Proteostasis declines with advancing age, meaning that an increasing proportion of proteins within a cell are not functioning as they should.

Proteostasis may be particularly important in the brain, where damaged proteins can contribute to inflammation and form various plaques thought to contribute to neurodegenerative diseases. One important protein modification is ubiquitylation (attachment of small ubiquitin tags to proteins), which can mark proteins for degradation or change how they behave. Here, researchers investigate exactly how protein modifications like ubiquitylation change across ageing brains, and discover that these modifications are modifiable through diet, at least in mice.

The discovery:

In the study, researchers used mass-spectrometry to look at three major types of protein modification (ubiquitylation, phosphorylation and acetylation) in the brains of young vs old mice. They found that of these three modifications, ubiquitylation showed the largest change with age, with most ubiquitylation sites increasing in abundance in old brains. The authors also compared the accumulation of ubiquitylated proteins in aged brains vs the liver, and found that the brain showed a stronger skew toward increased ubiquitylation.

Researchers suspected that the accumulation of ubiquitylated proteins with age could be caused by reduced protein degradation. To test this, they used human stem cell-derived neurons and treated them with molecules to inhibit proteasome activity. Proteasomes are protein complexes that degrade proteins tagged with ubiquitin. They found that this treatment mimicked many age-related ubiquitylation changes.

Finally, the researchers conducted a small mouse study to see if dietary restriction could reverse some ubiquitylation changes. Male mice aged 26 months (roughly equivalent to a human in their 60s) were split into two groups: a group of 4 that were fed normally, and a group of 6 that had their calorie intake reduced by 30% for 4 weeks. After that, they were returned to a normal diet for 7 days. The researchers observed that this dietary restriction followed by re-feeding had a significant impact on ubiquitylation, though not all changes were in the same direction. Some proteins, like those present within synaptic membranes and ribosomes (the structures where new proteins are built) showed overall reduced ubiquitylation, while others, such as proteins associated with mitochondria (the power plants of the cell) and myelin (the protective coating surrounding some nerve fibres) showed increased ubiquitylation. This wasn’t fully explained by changes in levels of the proteins themselves, which remained mostly unaltered.

The implications:

The study suggests that shifts in protein ubiquitylation are a prominent feature of brain ageing that could potentially be modified through diet. This last point will require further research, as this study only used a handful of mice, and it’s not clear whether the changes in ubiquitylation that occurred would actually be a net benefit for brain health in mice, let alone humans. Scientists mostly agree that dietary restriction is beneficial for general health and longevity in younger humans, but the benefits in older adults are less clear, as there are additional risks such as muscle loss and nutrient deficiencies in older age groups.

Changes in ubiquitylation occurred after only one ‘cycle’ of calorie restriction, which would be good news if those ubiquitylation changes turned out to be beneficial. However, it’s worth noting that 4 weeks of calorie restriction is a long time relative to the lifespan of a mouse – ‘equivalent’ to over a year as a proportion of human lifespan.