Does Rapamycin Slow Ageing In Humans?

Getting your Trinity Audio player ready...

The drug rapamycin comes from an unlikely place – it is produced by bacteria found in the soil on the island of Rapa Nui (the native name for Easter Island and the namesake of the compound). For the bacteria, rapamycin serves as an antifungal agent. For humans, it might just be our ticket to longer, healthier lives.

What Is It?

Rapamycin is often described as the most promising candidate anti-ageing drug we currently have, and for a few reasons. Originally used in humans for its antifungal properties, scientists quickly found that rapamycin suppressed the immune system. This turned out to be a blessing rather than a curse, however, and rapamycin entered use as an immune suppressant to prevent the rejection of organ transplants. As a result, rapamycin had already been extensively studied in humans and had a well established safety profile by the time by the time its potential as an anti-ageing drug emerged.

It has now been shown that rapamycin can extend the lifespans of many organisms by upwards of 10%, as well as slowing age-related deterioration. This is largely due to rapamycin’s ability to inhibit a protein called mTOR (mammalian target of rapamycin), which is thought to play a central role in the ageing process. mTOR is a ‘master regulator’ of cellular metabolism, controlling how cells respond to the availability of energy. When energy is scarce, mTOR is inhibited, causing cells to slow their rate of division and enter a kind of ‘survival mode’ in which cellular repair and defence mechanisms against damage are activated. This is thought to underpin some of the health benefits of calorie restriction, but by artificially inhibiting mTOR with drugs like rapamycin, these benefits may be replicated.

It’s not hard to see why a lot of people are excited about rapamycin, but there is unfortunately little human research investigating the effects of rapamycin in healthy people. Of late, there has also been some reason for pessimism. One of the most publicised stories concerning the drug emerged last year when entrepreneur Bryan Johnson, who has been self-experimenting in a number of ways in an attempt to slow ageing, stopped taking rapamycin due to concerns it may have achieved the opposite. This came not long after an observational study indicated that rapamycin was associated with more rapid ageing according to epigenetic clocks (algorithms that estimate age according to changes to the DNA molecule).

The gold standard method for determining whether a drug causes a certain outcome is a randomised, double blind placebo-controlled trial. This is when participants are randomly assigned to receive either the real drug or a ‘fake’ placebo drug, and neither the participants nor the people giving out the drugs know which is which. Some such trials have been conducted for rapamcyin, but mainly to study the effects on a specific age-related disease, rather than on general health and ageing.

That makes today’s study – the PEARL trial – a rarity. PEARL (Participatory Evaluation of Aging with Rapamycin for Longevity) is a randomised, double blind placebo-controlled trial of rapamycin that was crowd-funded by Lifespan.io. They have now reported the results.

The Experiment

The trial followed 114 people with a mean age of 60, randomised to receive weekly rapamycin doses of 5mg, 10mg, or a placebo. For reference, 2mg per day is a typical dose given for immune system suppression, but considerably higher doses have also been shown to be relatively safe. The trial lasted 48 weeks, during which time participants were monitored for side effects, as well as potential benefits.

The Good:

There was no significant difference in adverse events between the three groups, suggesting that rapamycin was generally safe. Taking rapamycin was also associated with some statistically significant benefits, though some of these benefits were limited to the female participants, which is consistent with previous research showing that rapamycin benefits males less. Women in the 10mg group reported significantly lower levels of pain and also had significantly more lean mass.

The researchers also assessed general health and emotional wellbeing via a survey (the 36-Item Short Form Survey, SF-36). Interestingly, while the scores of both male and female participants increased after taking rapamycin, this increase was only statistically significant for general health in the 5mg group, not in the 10mg group. Blood tests revealed that participants in the 5mg group had higher red blood cell counts, while those in the 10mg group had lower levels of blood carbon dioxide.

The Bad:

While there were benefits to taking rapamycin, there were also some downsides. Men in the 10mg group had lower blood calcium levels and higher blood urea nitrogen (BUN). BUN is a measure of how much urea (the waste product of protein metabolism that is filtered in the kidneys where it enters the urine) is in the blood, so elevated BUN could indicate reduced kidney function. Men in the 5mg group also had slightly higher HbA1C, which is a marker of long term blood sugar levels.

The study also raised another area of concern: the gut. For female participants, there was a trend towards higher intestinal permeability (which is generally regarded as a bad thing) in the 10mg group, while in male participants in the 10mg group, there were increased markers of gut dysbiosis (a disruption in the balance of gut microbes).

There was no significant change in visceral fat mass in the rapamycin groups compared to placebo (unpublished data had suggested that rapamycin might reduce visceral fat). There was no statistically significant change in self reported physical function or osteoarthritis metrics. A small subset of 21 participants also had their epigenetic age measured, but no statistically significant effect of rapamcyin was detected.

The Implicatoins:

While the results of this study may not be Earth shattering, they are an important step forwards, showing that rapamycin can be safely given to healthy adults. The apparent downsides of taking rapamycin were slight in comparison to the potential benefits and need to be confirmed and studied further in larger trials. The main goal of this trial was to assess safety and doses were kept relatively low in order to avoid immunosuppressant effects, whereas doses used in animals to extend lifespan were (relative to body weight) many times higher. This means that higher doses could be necessary to produce more substantial benefits. Overdoses as high as 103mg have been found to have only mild effects, but the long term effects of high doses in healthy humans are unknown.

The main limitations of this study were the use of self-reported data and the participants being a non-representative sample of the population, given that they volunteered for the study. This means that they were most likely concious of lifespan extension research prior to the study and probably represented a healthier-than-average group. Rapamycin might have had a stronger impact on a less healthy population.