Rapamycin

From Longevity Wiki
The chemical structure of rapamycin.

Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.[1]

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.[2] At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.[3] The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.[4]

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.[5] Some physicians and scientists have thus suggested that rapamycin may slow down aging.[6][7][8]

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.[6][9] It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.[10]

Evidence of increased healthspan or lifespan

Dogs

There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.[11] As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.

Mice

In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.[12]

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).[13] Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.[13] This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.[14]

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.[15]

Rapidly aging mice models

Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.[16] In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.[17]

Middle-aged mice

Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.[18] A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.[19] Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.[20] These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

Yeast

Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as Saccharomyces cerevisiae.[21]

Flies

Rapamycin extends the lifespan of the fruitfly, Drosophila melanogaster. The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).[22] Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing Drosophila lifepsan by 48%.[23]

Roundworms

TOR inhibition by rapamycin extends lifespan in Caenorhabditis elegans, a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in C. elegans seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.[24]

Age-related diseases

Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.[25]

Cancer

In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.[26] Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.[26] The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.[26]

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.[27][28][29]

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.[30] A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.[31] Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.[31][32][33]

Heart Disease

One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.[34] This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.[34] Additionally, improvements in behaviour and physical function were demonstrated.[34] Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.[35] Improvements in heart function were shown with only a brief treatment course of 8 weeks.[35] Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.[35]

Alzheimer's

Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.[36] In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.[37] This led to alleviation of AD-like symptoms, such as restored cognition and memory.[37] Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.[38] The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.[38]

Dose response

Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.[39][40] Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.[40]

Mechanism

Manipulating metabolic pathways - differences to calorie restriction

Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.[41][42] This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.[43] mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.[43][44] However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.[41][42] For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.[41] This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.[42]

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.[45][46] However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.[13][47] Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.[48][49][50] Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.[51]

mTORC1 and mTORC2

In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast Saccharomyces cerevisiae.[52][53] mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.[43] There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.[54][55] In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.[55]

Effects on glucoregulatory control

A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.[54] This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.[56] Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.[57][58][59][60] Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.[61]

Reducing the effects of cellular senescence

The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.[62][63] A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.[64]

Human clinical trials

Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.[6]

PEARL study

Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.[65]

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.[66]

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

Dog clinical trials

The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.[67] The project is led by Professor Matt Kaeberlein at the University of Washington.[68]

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.[11][68]

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.[68] Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.[69]

Heart disease

One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

Regulatory approval

Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.[70] The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.[71] It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

Safety

Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.[72][73]

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.[74] These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.[75] In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.[76][77]

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.[78] The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.[6] In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.[6]

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.[79] However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).[80] This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.[79]

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

Rapalogs

Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.[81] Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, TKA001, selected based on in silico predictions, extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.[82] However, only one rapalog, everolimus, has published clinical data in this context.[83] RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.[84][85] Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, DL001, with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.[86] Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The in silico molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.[87]

Antiemetic; piperazine-derivative antihistamine meclizine, which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by 8%.[88] Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.[89]

mTOR inhibition improves immune function in the elderly

In a phase 2 randomized clinical trial published in Science Translational Medicine in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.[90]

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.[90] One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.[90] These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

TORC1 inhibition enhances immune function and reduces infections in the elderly

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in Science Translational Medicine in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.[91]

A) Number of patients with laboratory-confirmed RTIs of any severity caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with severe symptoms caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection

Improving immune function in older adults for respiratory tract infections, including coronaviruses

Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non COVID-19) incidence, as well as reductions in severe symptoms.[92] However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.[92]

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to COVID-19.[92]

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.[92]

See also

References

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  30. ↑ Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. The Journal of clinical investigation, 123(8), 3272-3291.
  31. ↑ 31.0 31.1 Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? Science translational medicine, 5(211), 211fs40.
  32. ↑ Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell, 13(3), 468-477.
  33. ↑ Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? Journal of genetics and genomics, 41(9), 459.
  34. ↑ 34.0 34.1 34.2 Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. Aging cell, 12(5), 851-862.
  35. ↑ 35.0 35.1 35.2 Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell, 19(2), e13086.
  36. ↑ https://www.science.org/doi/10.1126/scitranslmed.aar4289
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  38. ↑ 38.0 38.1 Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PloS one, 8(5), e62459.
  39. ↑ Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell, 13(3), 468-477.
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  91. ↑ Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Science translational medicine, 10(449).
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  93. ↑ Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142
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