Posted on 10 May 2022
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.
Why is this research important: Within each cell, proteins are built by structures called ribosomes. Proteins emerge from the ribosome as linear chains, and must subsequently fold upon themselves to produce a molecule with a three dimensional structure. If proteins don’t fold into the correct structure, they might not function properly, or worse, they may become harmful. Amyloid beta, the protein that forms the amyloid plaque that accumulates in the brains of people with Alzheimer’s disease, is one example of a misfolded protein.
As we age, proteins misfold more frequently, and our cells become less effective at removing them. This has been proposed as one of the hallmarks of ageing – the 9 fundamental processes thought to drive the ageing process. Chaperone proteins can help other proteins to fold correctly. Could chaperone proteins be used therapeutically to slow some aspects of the ageing process?
What did the researchers do: In this study, researchers took 24 mice 18-22 months old (this is old for a mouse, roughly equivalent to a 70 year-old human) and 23 mice 2-6 months old (roughly equivalent to humans aged 10-20). Half of the mice in each group were given a placebo injection, while the others were given an injection of sodium 4-phenyl butyrate (PBA), a molecule that mimics the effects of natural chaperone proteins, into the abdominal cavity. PBA was also introduced into their drinking water. This treatment continued for 10-12 weeks, following which the mice underwent cognitive testing, and their brain activity was monitored during sleep.
Key takeaway(s) from this research: Aged mice had more fragmented sleep/wake patterns, meaning they awoke more often for shorter periods of time, while younger mice were awake less frequently for longer periods. However, old mice receiving PBA had sleep and wake patterns that were more similar to those of the younger mice: their sleep/wake patterns were less fragmented, they switched between different sleep phases less frequently and they spent longer in each sleep phase.
Using fluorescent staining techniques, researchers were able to study brain cells from the mice at the molecular level. They found that molecules associated with damage to the area of the cell in which protein folding occurs (the endoplasmic reticulum) were reduced in the hippocampi and cerebral cortices of aged mice treated with PBA. What’s more, these mice performed better in cognitive tasks dependent on these brain regions, such as maze navigation. They also showed increased levels of molecules indicating an increased ability for brain rewiring, aka synaptic plasticity.
Finally, researchers tried another method of reducing protein misfolding to see if it would also lead to improved cognitive function. They genetically modified one group of aged mice to produce increased levels of binding immunoglobulin protein (BiP), a naturally produced chaperone protein, while another group of mice were given a control treatment. As before, treated mice performed better in cognitive tests.
PBA had previously been found to have similar effects in fruit flies, but this is the first study showing that it can improve cognition in mammals. Both cognitive function and sleep quality decline with age, but the interactions between sleep, cognition and ageing aren’t well understood. In this study, the treatment may have led to improved sleep which then led to improved cognitive performance, or both effects could have resulted from the same underlying mechanisms. Either way, this study suggests that protein misfolding is indeed relevant to brain ageing, and that targeting it at its root may be a viable way to slow cognitive decline. Worthy of note is that treatment in the ageing group began when the mice were already old, which is encouraging because it suggests that chaperone therapy can reverse some of the changes associated with sleep/cognitive decline after they have occurred.
Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice: https://doi.org/10.1111/acel.13598