Longevity Briefs: Can Protein Quality In The Brain Be Enhanced Through Diet?

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:

Inside our cells, proteins are assembled by linking together amino acid subunits to form a chain, with the sequence of amino acids determining the protein’s shape. However, things don’t end there: once a protein has been built, it can be further modified via the addition of chemical tags in a process called post-translational modification (PTM). For example, phosphorylation can alter the shape of a protein and thereby change its function, while ubiquitination usually marks damaged or misfolded proteins for degradation.

With increasing age, our cells’ ability to ensure the correct balance and quality of its proteins decreases. This is known as ‘loss of proteostasis‘ (proteo referring to proteins, stasis referring to maintenance). This means that an increasing proportion of proteins within our cells are damaged, misfolded and not functioning in the way they are supposed to. Worse yet, they may contribute to disease. This is particularly relevant in the brain, where misfolded proteins such as amyloid beta and tau are thought to contribute to neurodegenerative diseases like Alzheimer’s. Finding ways to enhance protein quality control could be valuable for preventing such diseases and promoting healthy ageing in general. In this study, researchers show that dietary restriction or DR (a sharp reduction in nutrient intake without causing malnutrition) appears to help the brain fix age-related disruptions in protein degradation, at least in mice.

The discovery:

Researchers used mass‑spectrometry in order to compare PTMs in young versus old mouse brains. They measured three major types of PTM – ubiquitination, phosphorylation and acetylation – alongside total protein levels. As anticipated, the levels of post-translational modification (as a proportion of total protein abundance) changed with age, but changes in ubiquitination levels were far more pronounced than for the other forms of PTM. Some proteins displayed an increase in ubiquitination while others showed a decrease, indicating a general disruption in protein quality control. Researchers found that around a third of these changes were replicated in human neurons when they inhibited the proteosome – the structure responsible for degrading proteins tagged by ubiquitin. This suggests that the changes in ubiquitination levels with age could be partly due to loss of proteosome function, causing ubiquitinated proteins to accumulate.

Next, researchers investigated whether diet could have an impact on proteostasis. They took six 26‑month‑old mice (roughly equivalent to 70-something humans) and reduced their dietary intake by 30% for 4 weeks, while another 4 were fed normally as a control group. 7 days after they were returned to a normal diet, they found that ubiquitination levels in the dietary-restricted mice were significantly altered compared to control mice, even restoring the ubiquitination levels of some proteins to ‘youthful’ levels.

The implications:

These results suggest that altered ubquitination that occurs with age, partly due to the dysfunction of the cell’s ‘waste disposal systems’, can be semi-restored through dietary restriction. Sharp reductions in nutrient intake result in an emergency stress response by cells. Since nutrient supply has been cut down, cells must make better use of what they have and react by enhancing self-repair and recycling processes at the expense of cell growth and division.

While the study only looked at molecular effects, many of the identified proteins were involved in synaptic function and energy metabolism, so it is plausible that these changes could translate into protection against age-related disease and enhanced cognitive function. One small caveat is that 4 weeks of dietary restriction represents a rather long time relative to the lifespan of a mouse. If a mouse lives 30 months, the 4 weeks is proportionally speaking about 2.5 ‘human years’. There have not been many human dietary restriction studies lasting this long, and especially not in the elderly for whom such restriction carries additional risks of nutrient deficiency.