Consider a drug capable of reversing the effects of aging on the heart, restoring its youthful function. That's what researchers observed when they gave dogs rapamycin—a drug traditionally used to treat certain cancers and prevent organ transplant rejection. The findings were striking: The dogs exhibited marked improvements in heart function, effectively reversing the age-related changes typically seen in aging.

While these findings are remarkable, they add to a growing body of research indicating that rapamycin might enhance healthspan and promote longevity in various species, from worms to mice. This has sparked considerable interest in the scientific community regarding rapamycin’s potential as an anti-aging agent. However, the question of whether rapamycin can slow aging in humans remains a subject of intense debate, with concerns about its broader effects and long-term safety still unresolved.

Rapamycin targets a cellular pathway called mTOR, which is crucial for growth, repair, and healing. When mTOR gets deregulated, it can lead to chronic diseases like cancer and diabetes. This dual nature of mTOR makes rapamycin both fascinating and controversial in the quest for longevity. Of course, like any drug, rapamycin carries risks, some of them severe.

In this article, we'll explore rapamycin's discovery and isolation, its role and function in the mTOR pathway, how it promotes longevity, and the adverse effects associated with its use.

Rapamycin at a glance

In brief, evidence suggests that rapamycin affects multiple organ systems and physiological processes in the body, including^{[1] [2]}

Cancer suppression:

• Reduces growth of various cancer types, including carcinomas, breast cancer, pancreatic cancer, and mesothelioma.

Cardiovascular health:

• Decreases heart enlargement and fibrosis.
• Improves heart function.

Cellular senescence (aging):

• Reduces the number of senescent cells.
• Prevents senescence.
• Suppresses pro-aging secretory phenotype.
• Reduces senescence in a mouse model of progeria.

Hematopoiesis:

• Increases red blood cell numbers.

Immune function:

• Decreases T helper cells.
• Increases pro-inflammatory gamma-delta T cells.
• Mixed effects: Improves infection resistance, vaccine effectiveness, and bacterial clearance in some studies; increases infection loads and reduces survival in others.

Musculoskeletal effects:

• Exacerbates age-related bone loss.
• Increases tendon strength.

Neurological benefits:

• Alzheimer's disease: Improves cognition, strengthens blood-brain barrier, reduces amyloid-beta and tau.
• Parkinson's disease: Decreases dopamine cell loss, reduces inflammation, improves motor function, reverses depression and anxiety behaviors.
• Neurovascular disease: Strengthens blood-brain barrier, increases vascular density and blood flow.
• Brain injury: Improves cognition, rescues learning and memory deficits.
• Neurodevelopmental: Increases synaptic plasticity, improved behavior in autism model, reduced anxiety and depression in multiple models.

Reproductive effects:

• Decreases endometrial tumors in females.
• Causes testicular degeneration in males.

Rapamycin's discovery and isolation

In the early 1970s, scientists discovered that bacteria in soil samples taken from Easter Island produced a powerful antifungal compound. They named it rapamycin, after Rapa Nui, the name given to Easter Island by its indigenous people.^[3] Further research on rapamycin found that the drug prevented cells from multiplying—a critical aspect of cancer initiation and development—but it also prevented organ transplant rejection, securing it as a breakthrough immunosuppressant. However, rapamycin worked differently from other anti-rejection drugs, inhibiting the action of a newly identified protein called the mechanistic target of rapamycin, or mTOR.

Role and function of mTOR

mTOR is a kinase—a type of enzyme—that participates in essential cellular pathways involved in growth, proliferation, motility, survival, protein synthesis, autophagy, and gene transcription.^[4] It sits in the core of two multiprotein complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both complexes are found in the cytosol, the watery part of the cell outside the nucleus, where they respond to distinct stimuli and regulate different processes.

mTORC1 regulates protein synthesis and cell growth, which are necessary for developing, maintaining, and repairing the body's tissues. It is highly sensitive to changes in nutrient and oxygen levels, allowing it to act as a cellular energy/redox sensor. Various cellular stressors activate mTORC1, including reactive oxygen species, growth factors,^[5] and molecules that indicate damage or the presence of pathogens.^[6]

mTORC2 regulates cellular metabolism and plays a crucial role in maintaining both healthy and cancer cells.^[7] Various growth factors regulate mTORC2, including insulin, insulin-like growth factor, and vascular endothelial growth factor. These growth factors bind to cell surface receptors and activate essential mediators such as phosphatidylinositol 3-kinases (PI3K), phosphatase and tensin homolog (PTEN), and protein kinase B (Akt) to increase mTORC2 activity.^[8]

mTOR's two-sided nature

The mTOR pathway is essential for growth, wound healing, and muscle growth in healthy adults and children. However, in some people, it promotes cancer initiation and development.^[9] These seemingly contradictory functions arise from the different roles of mTORC1 and mTORC2.

The processes that regulate muscle growth provide a perfect example of these differing roles. When a person uses their bicep muscle to pick up a heavy weight, the muscle fibers contract, compressing the muscle cell contents and physically altering organelles. These two actions briefly suspend normal protein synthesis.^[10] During the rest period after exercise, protein synthesis increases dramatically to compensate for the suspension and repair any damage that might have occurred during the training.^[10]

• mTORC1 drives the rapid increase in protein synthesis and cell growth by activating key translation factors. It responds to growth factors, nutrient availability, and energy status, ensuring the cell has the necessary resources to build new proteins. During the post-exercise recovery period, mTORC1 ramps up the production of proteins needed for muscle repair and growth.

• mTORC2 regulates the cytoskeleton, cell survival, and metabolism. It enhances the cellular environment to facilitate efficient protein synthesis and growth. mTORC2 also activates Akt, a protein that further promotes cell survival and growth pathways. While mTORC1 directly drives protein synthesis, mTORC2 ensures that the cellular machinery and environment are optimized for this process.^[7]

It's worth mentioning that only mTORC1 is sensitive to rapamycin. However, chronic rapamycin exposure indirectly suppresses mTORC2 activity by reducing the amount of mTOR protein available for use by either mTORC1 or mTORC2.

How rapamycin promotes longevity

The remarkable effects of mTOR inhibition on the aging process first came to light just over 20 years ago when scientists discovered that rapamycin extended the lifespan of worms. Unfortunately, attempts to demonstrate that rapamycin improves human health and lifespan have yet to materialize. However, abundant data demonstrate the role of mTOR inhibition in aging and disease in mice and other animals. This section will focus on these findings.

Worms and mice

In 2003, researchers reported that mTOR inhibition extended the lifespan of C. elegans, a type of roundworm commonly used in biological research. The worms, which typically live about 10 days, lived 25 days—more than doubling their average lifespan. Some of the ways that mTOR inhibition likely slows aging in this species is by slowing protein synthesis^[11][12][13] and increasing autophagy^[1]—a crucial cellular recycling program that helps cells get rid of old, defective components, facilitating survival when nutrient availability is low.

A 2009 study conducted by scientists at the National Institutes of Aging identified rapamycin as the first drug to extend the maximal lifespan in mammals of both sexes.^[14] Scientists at three separate research sites fed young and old mice a highly bioavailable form of rapamycin at a concentration of 14 parts per million (ppm).

Treatment began for one group of mice at about nine months of age and another group at about 20 months of age and continued until the mice reached the end of their natural lives (about 26 to 30 months). Both groups experienced an increase in maximal lifespan with little difference in effect size between groups.

The average lifespan of young female mice increased by 15%, 16%, and 7% across the three separate testing facilities, and the lifespan of older female mice increased by 45%, 48%, and 22%. The average lifespan of young male mice increased by 5%, 8%, and 15%, and for older male mice, by 16%, 23%, and 52%. The researchers suggested that the variation in lifespan extension between study sites may have been due to differences in the chow used at various study points.

Follow-up studies have shown that giving oral rapamycin to young mice at concentrations of 4.7, 14, or 42 ppm extends lifespan in females. In contrast, males only show increased lifespan at the two higher doses, a finding that aligns with other research suggesting that females benefit more from lifespan extension treatments. However, scientists don't fully understand the mechanisms behind these sex-specific differences.

Some studies in mice have varied the age at which rapamycin treatment begins (from two to 24 months old) and the dose (ranging from 4.7 to 126 ppm), observing lifespan increases of 58% to 100%. However, other studies have found no increase in lifespan. These results suggest that rapamycin's effect on longevity can vary considerably based on the study protocol.^[2].

mTOR and cancer suppression

When interpreting these studies, an important aspect to consider is the natural occurrence of cancer in mice. Roughly three-fourths of mice like the ones used in these studies—a common strain of wild-type mice—die from cancer, primarily lymphomas and blood cancers like leukemia.^[15] Given this fact of mouse biology, the primary means by which rapamycin exposure/mTORC1 inhibition extended lifespan in mice was probably cancer suppression and delayed cancer-related death.^[1]

Increased mTORC1 activity is a critical player in many cancers due to its activation of cancer-causing genes like Akt and Ras, which promote tumor growth and metastasis, and the loss of tumor-suppressing proteins such as PTEN and serine-threonine liver kinase B1.^[16] It also facilitates nutrient uptake—a crucial aspect of cancer growth and proliferation.

Although mice with altered mTOR function may have lower cancer rates, they also face a higher risk of infection. This underscores the complex relationship between mTOR and cancer and highlights potential risks associated with rapamycin use.^[17]

Distinguishing between lifespan extension and slower biological aging

Following these early rapamycin studies, scientists weren't sure whether lifespan extension was due to a delay in death from cancer and other preventable causes or if it was a consequence of slowing the rate of biological aging. If rapamycin merely delays death due to cancer in older animals, then younger animals wouldn't experience any benefit. However, if rapamycin slows the aging process, those changes should be detectable in younger and older animals.

Canines

Studies in larger animals have had mixed findings; however, those in dogs have been particularly encouraging. Dogs are ideal models for studying human aging because they live in environments similar to humans and often eat diets that include or are similar to human food. In a study where 24 middle-aged healthy dogs received either a placebo or a non-immunosuppressive dose of rapamycin three times a week for ten weeks, researchers found that dogs that received the rapamycin exhibited improvements in multiple aspects of heart function, including how well the heart filled and pumped out blood.^[18]

A later study in dogs failed to see any improvements in heart function. However, this difference was likely due to the lower dose of rapamycin, the small sample size, the younger age of the dogs, and the insensitivity of the tests used to assess cardiac function.^[19]

Monkeys

Researchers administered rapamycin to old marmosets for three weeks or 14 months to measure its safety and effects on longevity. Although the rapamycin was safe and well-tolerated, none of the animals experienced longevity effects.^[20]

Humans

Rapamycin was first introduced in the clinical setting as a coating on implantable medical devices, such as vascular stents, to suppress the immune response to foreign objects.^[21] Physicians later used it to prevent organ and tissue transplant rejection.^[22]

Rapalog development

Rapamycin is insoluble in water, so scientists have developed multiple classes of rapalogs—compounds that suppress mTOR but are readily absorbed and utilized by the body. These include everolimus, temsirolimus, zotarolimus, and ridaforolimus.^[23] Currently, rapamycin and rapalogs are FDA-approved for the following indications:

Rapamycin

• Organ rejection prevention
• Lymphangioleiomyomatosis (rare lung disease) treatment
• Stent coating
• Vascular malformations
• Angiofibroma

Everolimus

• Organ rejection prevention
• Renal cell carcinoma
• HER2-negative breast cancer
• Neuroendocrine tumors of pancreatic origin
• Renal angiomyolipoma
• Subependymal giant cell astrocytoma

Temsirolimus

• Renal cell carcinoma

Zotarolimus

• Stent coating

Ridaforolimus

• This drug has no approved FDA uses currently but is under investigation in clinical trials.

Next-generation rapalogs

Unfortunately, rapalogs have been largely unsuccessful in clinical trials. Scientists are still unsure why, but one possible reason involves the feedback loops that maintain proper mTOR levels. A newer class of drugs called ATP-competitive mTOR inhibitors overcome some of these challenges by blocking the activity of mTORC1 and mTORC2, preventing feedback mechanisms that activate PI3K/Akt.^[16].

Investigators assessed the effects of an ATP-competitive mTOR inhibitor called RTB101 on the incidence of acute respiratory illness in older people in phase 2b and phase 3 trials. In the phase 2b trial, participants received RTB101 in varying doses (5 milligrams once daily, 10 milligrams once or twice daily, or 10 milligrams combined with everolimus daily) or a placebo for 16 weeks. Interestingly, the 10-milligram once-daily dose reduced the incidence of acute respiratory illness more effectively than the twice-daily or combination therapy. The investigators proposed that intermittent mTOR inhibition was more effective than persistent inhibition. Although they didn't replicate their findings in the phase 3 trial, they did note that RTB101 consistently upregulated antiviral genes and was well-tolerated across all trials.^[24]

An even newer generation of drugs includes RapaLink-1, which work via bivalent mTOR inhibition,^[25] meaning they can inhibit both mTORC1 and mTORC2 in cells that are rapamycin-resistant.^[26]

Adverse effects of rapamycin

Like most drugs, rapamycin use carries minor risks, including stomatitis (inflammation of the mouth), leukopenia (low leukocyte count), anorexia (appetite loss), anemia, and fatigue.^[27]. Potentially more severe effects included altered blood lipids and impaired muscle protein synthesis.

Altered blood lipids

Early studies suggested that rapamycin promoted minor increases in cholesterol and triglycerides, but longer-term studies revealed more substantial increases, particularly at higher doses. These effects peaked after roughly two months and improved with lower doses and statin administration.^[22] Interestingly, a study found that people with high triglycerides and low HDL cholesterol who received a vascular stent coated with everolimus were more likely to require repeat procedures, especially if their original stent was small.^[28] Another study found that 13 percent of patients who received a sirolimus-coated stent experienced increased cholesterol and triglycerides.^[29]

Impaired muscle protein synthesis

Some studies have reported adverse effects on muscle protein synthesis for even low-dose rapamycin. A single 12-milligram dose of rapamycin blocked the increase in muscle protein synthesis typically seen with resistance training, while a single 16-milligram dose blocked the increases typically seen with protein intake. Consequently, 20 milligrams daily could effectively block all aspects of muscle protein synthesis associated with dietary protein intake and resistance training. Impaired muscle protein synthesis is problematic for older adults, for whom disability from age-related muscle loss is a genuine concern.^[30]

Conclusions

Rapamycin is an immunosuppressant drug known for its potent anti-aging effects. It targets mTOR, a protein whose activity is vital for cellular growth. mTOR functions within two complexes, mTORC1 and mTORC2, each activated by different stimuli and having distinct, sometimes opposing effects on the body.

While most research on rapamycin's effects on longevity has been conducted in animals, a few clinical trials have been completed for various diseases, with more on the horizon. Future studies will further elucidate the molecular effects of rapamycin, explore different methods of mTOR inhibition, and expand the range of diseases treatable with mTOR inhibitors.

Evidence suggests that casual use of rapamycin (outside of clinical need) carries considerable risks. However, if a person chooses to take rapamycin, they should consider taking it in a pulsatile (non-continuous) manner, as with most anti-aging drugs. Continuous dosing, longer periods of use, and higher doses all increase the risk of side effects, which can be severe with rapamycin—including immune suppression, metabolic disease, and, paradoxically, some forms of cancer.

Lifestyle behaviors can mimic many of rapamycin's beneficial effects. For example, sedentary people can selectively inhibit mTORC1 to reduce cancer risk through intermittent fasting, prolonged fasting, carbohydrate restriction, and BCAA/leucine restriction (achievable by consuming plant-based proteins). By engaging in exercise and resistance training, growing children, active adults, and older adults can support mTORC2 activity, which is needed for development and naturally declines with age.