Can we slow ageing in humans? Can humans achieve immortality? These questions have piqued mankind’s curiosity since time immemorial. However, it was not until the beginning of the twentieth century that scientists actually began studying mortality curves of different cellular organisms including humans, which provided solid evidence that human lifespan can be extended in the absence of evolution. This paved the way for early studies conducted in the 1900s that focused on slowing the process of ageing instead of stopping it all together. Studies conducted by Michael Klass discovered the first set of genes posited to be involved in the process of ageing. And it was in 2009 that a breakthrough was made in the search for an anti-ageing compound and the role of rapamycin in slowing ageing was first reported.

Introduction to Rapamycin

Rapamycin (also known as Sirolimus) is a macrolide produced by Streptomyces hygroscopicus, which was first isolated in 1975 from the soil samples of South Pacific island of Rapa Nui. Its clinical use stems from its ability to block the mTOR pathway that controls cell growth and metabolism.

Initially, Rapamycin was identified as an antifungal agent but later its immunosuppressive and anti-cancerous properties were established. It was only in 2009 that a study conducted by Harrison et al. demonstrated its anti-ageing property. This study has since lead to multiple studies being conducted globally to establish rapamycin's potential as an anti-ageing compound.

Studies supporting Rapamycin’s role in anti-ageing

The TOR (target of rapamycin) pathway, which senses nutrients, contributes to cellular and organismal ageing. Invertebrates, such as yeast, nematodes, and fruit flies, have longer lifespans when the TOR signalling pathway is inhibited through genetic or pharmaceutical intervention. In many model organisms, including mice, rapamycin has been shown to increase lifespan by inhibiting this TOR pathway, with the most pronounced effects on longevity reported in females.

According to a study by Harrison et al., when rapamycin was given to 19-month-old mice, an increase in the median lifespan of 14% for females and 9% for males was observed. In a different multi-centre study, genetically heterogeneous mice were given rapamycin in food starting at the age of 9 months, and at each of the three study centres, there was an appreciable increase in life span. Female median survival increased by 18% and male median survival increased by 10%. Further, a study by Bitto et al. showed that treating 20-month-old mice with a high dose of rapamycin for only 3 months resulted in a dramatic increase in the median lifespan of both the sexes. Female median lifespan increased by 39% and male median lifespan increased by 45%. Additionally, it was also interestingly observed that changes induced by rapamycin such as those in the microbiome were not transient but persisted after rapamycin treatment was discontinued.

Rapamycin’s conclusive role in increasing mammalian lifespan led researchers to probe the next most important question. Does rapamycin impact only lifespan or does it also potentially delay age-related diseases? Several studies conducted over the years corroborated this theory and demonstrated that rapamycin not only extended lifespan but also delayed age-related diseases such as cardiac diseases, cancer, and neural degeneration, amongst others. In a study conducted by Flynn et al., 24-month-old female mice were given rapamycin for 3 months, and health outcomes were assessed using a range of non-invasive tests. In comparison to the mice that were fed a control diet, rapamycin treatment not only reversed the age-related decline in cardiac function but also led to advantageous behavioural, skeletal, and motor changes in the test mice. It was also noted that the improvement in cardiac function persisted for 2 months after rapamycin treatment was discontinued.

In another study, a two-year experiment was performed by Anisimov et al. using inbred mice that received rapamycin three times per week for two weeks, then a break of two weeks beginning at the age of two months. The study showed that rapamycin reduced ageing-related weight gain, lengthened life expectancy, and postponed spontaneous cancer.

Furthermore, in a study carried out by Urfer et al., 24 healthy, middle-aged dogs were given either a placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. Results revealed that when compared to dogs who received a placebo, the rapamycin-treated group experienced no clinical side effects. In the dogs treated with rapamycin, echocardiography indicated improvement in both diastolic and systolic age-related measures of heart function.

Future Implications

As an mTOR inhibitor, rapamycin, the first drug with demonstrable anti-ageing effect in mammals, exhibits exceptional potential for extending lifespan. Based on the studies conducted over the past 10 years, three major findings surrounding rapamycin’s role in anti-ageing have been identified. Firstly, it has been determined that rapamycin increases the lifespan of both male and female mice, which is unique because all other anti-ageing interventions are sex specific. Secondly, rapamycin is effective over a wide range of doses; it does not have a negative effect on lifespan, even at high doses. Lastly, rapamycin not only reverses many of the adverse aspects of ageing late in life but also need not be administered continuously; its effect might persist well after it is discontinued.

Given these promising results, the imminent next step is to take rapamycin to clinical trials for use in humans. However, there is always a veritable concern around how well would the results generated in mice models translate in humans. Extensive studies, therefore, need to be conducted to determine the long-term side effects, dosage, and route of administration of rapamycin in humans before the age-old quest of increased lifespan may finally become a reality.