Longevity Briefs: Could This Clinically Approved Drug Slow 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:

Inflammation is the body’s first line of defence and most inaccurate weapon against pathogens. It causes a lot of ‘collateral damage’, but is able to keep infection at bay until the more precise and effective (though slower) T and B cell responses can get going. Inflammation stops once an infection is dealt with, but in old age low levels of inflammation simmer constantly, contributing to the progression of age-related diseases. This age-related chronic inflammation is sometimes called inflammageing.

Inflammageing is thought to be particularly important in the brain, and is likely to be one of the main fundamental drivers of both neurodegenerative diseases and general cognitive ageing. Inflammation in the brain has a specific name: neuroinflammation. In this study, researchers investigate the potential of a drug called rapamycin to suppress neuroinflammation when given to mice long-term. Rapamycin is known to be safe, as it is already approved for use in humans for preventing organ transplant rejection by suppressing the immune system. However, rapamycin does not necessarily suppress the immune system at low doses – on the contrary, it seems to rebalance the immune system away from inflammation. However, the effects of long term, low dose rapamycin in healthy humans is unknown.

The discovery:

Researchers fed groups of 3-9 mice (depending on the experiment) rapamycin in their food for 5 months at a concentration of 14 parts per million (ppm). This amount of rapamycin is considered to be in the middle of the range in relation to other mouse lifespan extension studies, and has previously been shown to correlate with an increase in maximum lifespan of up to 22%. In this study, blood and tissue samples from a variety of organs were collected, including from the brain, in order to investigate whether there were any effects on immune function compared to mice given a control treatment.

Researchers started by looking at the proportions of different immune cell types. They found no significant change in the overall percentage of white cells typically associated with inflammation in the rapamycin group, nor were there significant changes in the concentrations of inflammatory molecules in the blood. There was a slight increase in the number of naive T cells (cells capable of recognising and responding to new infections that the immune system hasn’t seen before) in the rapamycin-fed mice, as well as a reduction in a specific type of T cell that promotes inflammation.

Researchers then looked at the brain’s resident immune cells and ‘housekeepers’, microglia. Not only do these cells protect the brain from pathogens, but they also play a role in repair and support learning and memory by ‘pruning’ weak synaptic connections. With age, neuroinflammation impairs these cells’ repair roles, which is thought to be a contributor to neurodegenerative disease. Unfortunately, rapamycin did not significantly impact microglial function. Researchers then injected mice with lipopolysaccharide (LPS), a molecule that forms part of the cell walls of many gut bacteria and that causes a strong inflammatory response if it gets into the blood. They found that in response to this strong inflammatory insult, the microglia of mice fed a rapamycin-containing diet did not respond as strongly as in control mice, suggesting less neuroinflammation.

The implications:

This study suggests that while long-term rapamycin treatment in mice did have some favourable effects on T cell populations, it didn’t appear to suppress neuroinflammation or chronic inflammation in general. It did however prevent some neuroinflammation in the context of an acute inflammatory stimulus in the form of LPS. It has been speculated that, in old age, small amounts of LPS and other bacterial products making their way into the blood from the gut might contribute to chronic inflammation, though this is nowhere near the amount of LPS that was given to mice in this study. There’s also no telling whether any of the changes in inflammatory responses that were observed here would translate into actual health benefits (though as already mentioned, mice given comparable doses of rapamycin have been very conclusively shown to live significantly longer).

Some people take rapamycin in the hope that it will delay ageing, though there is no proof of this in humans as of yet. Rapamycin exerts most of its benefits through the suppression of a molecule called mTOR, a ‘metabolic switch’ that regulates how cells spend their energy. mTOR can also be suppressed through calorie restriction (a sharp reduction in calorie intake without causing malnutrition, achieved by, for example, intermittent fasting).