Rapamycin – disputed potential longevity drug

You might have heard that some people take a drug called rapamycin to decrease their biological aging processes.

However, rapamycin is still mainly in the preclinical stage of development for longevity intervention, and potential side effects and long-term effects in humans are not yet established. But what is it with rapamycin that make scientists determined to push it to clinical studies?

From Rapa Nui to kidney transplants and cancer therapy

Rapamycin (also known as sirolimus) is a natural product discovered in soil samples from Rapa Nui, Easter Island, in the 1960s and isolated from bacteria found in these samples in the 1970s (1). It took nearly 20 years of intensive research to determine the correct structure of the compound, as well as to investigate its biological activity. Rapamycin was discovered to have antifungal, immunosuppressive, and antitumor properties. It was first approved by the FDA in 1999 to prevent acute rejection in kidney transplant recipients (2). It was later discovered that the drug could be repurposed, and it is now approved for use in drug-eluting stents.

Although rapamycin showed antitumor properties, it has poor solubility (ability to dissolve) making it unsuitable for treating human cancer. So several other compounds with similar structures to rapamycin, known as rapamycin analogs (rapalogs), have been developed (3). Everolimus and temsirolimus are two of the most well-known rapalogs, both of which are FDA-approved anti-cancer drugs. They are used in combination therapy with other treatment modalities due to their modest efficacy as a monotherapy (when used alone). Other compounds that act in a similar way in the body to rapalogs, called mTOR inhibitors (see below), are also being studied alone or in combination with chemotherapy, radiotherapy, and targeted therapy, and there are many completed or ongoing clinical trials for treating various types of human cancer (4). Rapamycin, and other mTOR inhibitors, have also been studied in relation to their effects on age-related diseases and the aging process (2). From a public health perspective, it is desirable for the window near the end of life, when illness typically occurs, to be compressed. It is, however, too early to know whether rapamycin, and other mTOR inhibitors could represent such an intervention (2).

Rapamycin and its potential of longevity intervention in humans

Rapamycin and its analogues have attracted the attention to researchers in the longevity field due to its connection to the aging process.

Rapamycin and its analogues inhibit the mammalian target of rapamycin (mTOR), a key factor in the aging process. mTOR is considered an important part of protein synthesis. mTOR is involved in many processes associated with aging, including cellular senescence, immune responses, cell stem regulation, autophagy, mitochondrial function, and protein homeostasis (proteostasis), read more here (5). High mTOR can promote growth in the body, including cancer growth. At low levels, the body is in repair and maintenance mode, stimulating autophagy (which recycles damaged and old proteins into new amino acids to build new tissue). Inhibition of mTOR by rapamycin and its analogs has been shown to extend lifespan and reduce aging and disease progression in multiple organs in various model organisms. Therefore, rapamycin and its analogs are potential repurposed drug candidates for longevity interventions in humans (3).

Preclinical studies of rapamycin and increased life span

Evidence that rapamycin can slow aging and extend healthy lifespan comes primarily from studies in experimental organisms such as yeast, nematodes, fruit flies and mice (6). We wanted to share two examples of preclinical studies that show promising indications for the use of rapamycin for longevity, and one of the reasons scientists are eager to move forward with rapamycin studies in humans as well.

Increased lifespan in mice

Study 1 -Short rapamycin treatment can increase lifespan and health span in middle-aged mice (7)

A recent study reported that rapamycin prolongs lifespan and delays age-related dysfunction in rodents (7). The study showed that 3-month treatment with rapamycin increased life expectancy by up to 60% compared to control group (mice not treated with rapamycin) and improved healthy life expectancy in middle-aged mice. The researchers gave a group of 20-month-old mice a small dose of rapamycin for three months, then stopped the drug treatment and observed how long the mice lived. The researchers also had a control group of mice that received a placebo. The drug-treated mice lived on average two months longer compared to the control group (6 % increase in lifespan) (7). One of the mice survived to 3 years and 8 months, which is 6o% longer than controls. The study also showed that the microbiome was altered. Data suggests that short-term treatment with rapamycin has lasting effects in later life that can sustainably slow aging, influence cancer prevalence, and modulate the microbiome (7).

Improved cardiac function in dogs

Study 2- The Dog Aging project (7)

Another study we wanted to share is part of “The Dog Aging Project” based at the University of Washington in Seattle. Compared to the commonly used model organisms, companion dogs have a unique translational potential for geroscience as they share many aspects of human aging, as well as living in a similar environment, having access to medical care, and availability of detailed medical records. Although dogs suffer from similar age-related declines, their lifespans are much shorter, making research more practical. By understanding how companion dogs age, researchers hope to understand more about how humans age. The Dog Aging project aims to identify the biological and environmental factors that influence their lifespan by following tens of thousands of companion dogs for 10 years.

A small study of 24 healthy middle-aged dogs received either a placebo (control group) or rapamycin for 10 weeks (6). The results showed no adverse effects in the rapamycin-treated group compared to placebo-treated dogs, and some of the same positive effects described for mTOR inhibition in mice were also observed in the rapamycin-treated dogs. Additionally, studies have shown improved cardiac function in dogs treated with rapamycin (6).

Due to the small size and short duration of the study, it is not possible to draw firm conclusions as to whether rapamycin-treated dogs have an improved lifespan compared with controls. Unlike these prior studies, however, the dogs in the study lived in a normal home environment, providing significant evidence that rapamycin can be safely administered to companion dogs and may provide significant health benefits (6). Despite the small sample size, the results are encouraging and studies using larger numbers of dogs are planned to validate the effects of rapamycin on cardiac function and see if it can significantly improve health and longevity.

Clinical studies of rapamycin for longevity

Despite the rapamycin’s promising results in experimental organisms and the fact that the drug is already FDA-approved for certain diseases, rapamycin is still not administered to humans to improve longevity. That is due to the side effects of the drug, which are considered to outweigh the benefits. Some of the side effects could be serious, such as hyperlipidaemia and hyperglycaemia, anaemia and stomatitis (2). The effects of mTORC1 inhibition on immune function and wound healing are also of particular concern (2). Although it is unclear whether rapamycin alone has substantial immunosuppressive effects in healthy individuals, it undoubtedly changes the immune response. It would be unfortunate to take a drug that slows the rate of ageing, only to succumb to infection from an otherwise not harmful bacterium or virus. Optimal dosage and duration of treatment are also unknown factors (2).

There are, however, a few clinical trials investigating the effect of rapamycin on longevity in humans. We will address one phase 2 clinical trial in this article (8). The aim of the clinical trial is to establish the long-term safety and efficacy profile of rapamycin in reducing the signs of aging and declining health in 150 healthy participants (aged 50 to 85) (8). The study is double-blinded, and placebo controlled which means that neither the participant nor the doctor knows if the participant is given the drug or placebo. Although the trial is not investigating lifespan, the study will provide us insights on different biochemical and physiological measures that are associated with aging. The study is currently undergoing and set to be completed by the end of 2023. We are going to follow the study and are eager to see the results.

In conclusion, rapamycin has increased the lifespan of mice and showed improved cardiac function in dogs in pre-clinical studies making it a promising intervention for longevity. We do not yet know the effects (negative or positive) rapamycin will have on the lifespan of humans. But we know it will be exciting to follow the movement from pre-clinical to clinical studies for longevity intervention. Perhaps it will be possible to see the same effect in humans and thus improve healthy aging and extend life span.

References

1. Vézina C, Kudelski A, Sehgal SN. RAPAMYCIN (AY-22, 989), A NEW ANTIFUNGAL ANTIBIOTIC I. TAXONOMY OF THE PRODUCING STREPTOMYCETE AND ISOLATION OF THE ACTIVE PRINCIPLE. J Antibiot (Tokyo). 1975;28(10):721–6.
2. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013 Jan 17;493(7432):338–45.
3. Kuerec AH, Maier AB. Why Is Rapamycin Not a Rapalog? Gerontology. 2023 Jan 7;1–3.
4. Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol OncolJ Hematol Oncol. 2019 Jul 5;12(1):71.
5. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette FA, Topisirovic I, et al. mTOR as a central regulator of lifespan and aging. F1000Research. 2019 Jul 2;8:F1000 Faculty Rev-998.
6. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DEL, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience. 2017 Apr 1;39(2):117–27.
7. Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016 Aug 23;5:e16351.
8. AgelessRx. Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL): A Prospective, Double-Blind, Placebo-Controlled Trial for Rapamycin in Healthy Individuals Assessing Safety and Efficacy in Reducing Aging Effects [Internet]. clinicaltrials.gov; 2022 Oct [cited 2023 Mar 9]. Report No.: NCT04488601. Available from: https://clinicaltrials.gov/ct2/show/NCT04488601.