Rapamycin, the only drug that has been consistently demonstrated to in

By Zelton Dave Sharp, Randy Strong

^{Published in:}

Experimental Gerontology

Volume 176, 1 June 2023, 112166

1. Introduction

Prior to 2009 the consensus of scholars was that aging could not be treated or if it could be it must be a youth factor (e.g., growth hormone). Numerous advertised non-scientific approaches that absconded with a lot of folk's money mostly confused people and were counterproductive for the field. However, there were two scientific settings in which aging could be reproducibly delayed. Unfortunately, neither was optimal for use in people. They were restrictions of diet and/or growth factors by genetic means. Since people do not like restricting anything, especially food, progress toward a deeper understanding of aging and potential ways to delay its effects was slow.

In recognition of this bottleneck, the National Institute of Aging did a smart thing. It established a program to identify compounds that could be tested for aging effects under rigorous and standard conditions. The goal was to determine drug effects on lifespan of genetically heterogeneous mice of both sexes. A major advantage of this new Intervention Testing Program is that the three test sites are geographically separated, the test mice are by design genetically heterogeneous and included both sexes and importantly, the site directors are recognized experts in aging studies in rodents but had no stake in the outcomes. More information about the ITP can be found here.¹

It has been exceptionally successful. To date, the ITP website indicates they have tested or in the process of testing 64 different compounds, some at varied doses and in combination. Twenty publications from the ITP have reported increases in lifespan from ten compounds. Importantly, the ITP also reports compounds that do not extend lifespan.

In this section, we focus of the ITP 2009 test of what was then an unlikely candidate drug called rapamycin. Results showing increased median and maximum lifespan in advanced aged males and females in this paper reset the paradigm for aging studies. It suggested that pharmacological agents can prevent, delay and/or reduced the severity of age-caused morbidities. In this lifespan, we will first briefly remind readers about the biology of the cell systems affected by rapamycin, better known as the targets of rapamycin or TOR. Next, we will review the results of several studies on the effects chronic rapamycin has on lifespan in both sexes including our recollection of the first study (Harrison et al., 2009). Following that, we will relate selected examples of the effects chronic rapamycin has on age-caused diseases. We conclude with our view of what rapamycin effects are telling us about aging and how it might be working. We confess at the outset that we have only a faint picture of rapamycin's function as an anti-aging agent and suggest that it will be as complicated and mysterious as the studies to determine how restriction of food and growth factors work, which after half a century still have a way to go.

1.1. TOR story

The discovery of rapamycin, its characterization and development have been covered previously (Sharp and Strong, 2010). The discovery of its intracellular receptor FKBP (FK506 binding protein; a proline rotomase) was concomitant with the genetic identification of the target of rapamycin TOR1 and TOR2 in yeast (Heitman et al., 1991). The big question then was what do these genes encode? When obtained the cDNAs for yeast TOR1 and TOR2 turned out to look like large novel kinases, which at first were thought to regulate the cell cycle. However, in a now classic paper and one we feel set the stage for TOR's role in aging, Barbet et al. (1996) showed that inactivation of TOR either by rapamycin or deletion led to a starved phenotype and G1 arrest. After identification of TOR in budding yeast, multiple labs reported the identification of one gene encoding mammalian target of rapamycin (Brown et al., 1994; Chiu et al., 1994; Sabatini et al., 1994). Each lab named it differently but eventually got merged into mammalian TOR (mTOR), then mechanistic TOR followed, with some reservations (Hall, 2013). Thus, it was these discoveries that led one of us (zds) to envision chronic rapamycin as a potential antiaging compound that would mimic diet restriction. However, there was another clue that centered on the issue of cell and organism size that also played a big role in the thinking.

Although it's hard to imagine, the prevailing view up to that time was that cells and organisms somehow just naturally grew given sufficient nutrients. How cell size was determined was unknown. In the aging world, thoughtful investigations of ideas about organism size indicated that mass is somehow involved in lifespan determination. Small dogs live healthier. Longer lives than big dogs. Many factors determine body size, including cell size and/or number. That no definitive mechanism(s) (such as cellular antioxidant production) explains the relationship between body size and longevity (Barja, 2014) suggests that this idea has led to investigations barking up the wrong tree. More about this in a moment.

At that time, there were two interventions known to extend lifespan: diet restriction and pituitary dwarfs. One of us (zds) wondered about a common phenotype that linked both interventions, which was that they both resulted in smaller animals compared to controls. How could size play a role in age retardation? As mentioned, multiple factors regulate body size, two being either fewer cells or smaller cells. For the long-lived Snell pituitary dwarf (Flurkey et al., 2001), they have the same number of skeletal muscle fibers (cells) as wild type, but the fiber size is significantly smaller (Stickland et al., 1994). This suggested that pituitary dwarfs lacking in growth hormone (plus TSH and prolactin) could result from reduced mTOR activity which was shown in liver and muscle by one of us (zds) in collaboration with Andrzej Bartke (Sharp and Bartke, 2005). Thus, reduced mTOR due to growth factor (or factors) restriction in mice and by diet restriction or rapamycin in yeast were both linked to aging. Could chronic rapamycin mimic both processes to slow aging?

It was a crazy idea. The main objection then and now is that rapamycin is a potent immunosuppressant in people and is, therefore a dangerous drug for chronic use in humans, especially in elders. Rapamycin was and still is used (in various formulations and combinations) for cancer treatment, and chronically as an agent to suppress rejection of transplants. Interestingly in this last group of patients, the incidence of cancer is reduced (Knoll et al., 2014; Salgo et al., 2010). Despite the black label warning on sirolimus, the ITP agreed to test it. Now it was up to us, to make this test happen.

1.2. The test

It was not smooth sailing at first. We were aiming for rapamycin blood concentrations like those in transplant patients (10 ng/ml). Although rapamycin in food had the expected reduction of mTOR activity in visceral adipose, the drug degraded too fast for use in an ITP trial. Fortunately, one of us (rs) recognized that we needed a method to stabilize rapamycin in food for storage and use if we were ever going to complete the first experiment. In consultation and collaboration with an expert in drug microencapsulation at the Southwest Research Institute, encapsulation with an excipient called Eudragit S100 was recommend for this purpose. This formulation releases rapamycin at close to a neural pH, which is found in distal small intestine and colon in rodents. To our delight, blood levels exceed expectations for our 14 ppm diet (Nadon et al., 2008), and the three sites of the ITP began the trial with this diet on the first cohorts of mice at all three sites. Because of the time it took to develop encapsulated rapamycin (now called eRapa), the cohorts in the three test sites had aged to 20 months. There was a real concern that these older mice could not tolerate our ITP rapamycin diets but it turned out to be not true.

As mentioned in the introduction, the results published of this first experiment reported in Nature (Harrison et al., 2009), showed median and maximum lifespan extension in both sexes. It was remarkable, especially such a response in older mice that were expected to die from treatment. Since this paper, the ITP has performed 5 trials (one in progress), all with the same results; mice live longer and healthier on this drug (Table S1, labeled ITP studies). One of the more remarkable results showed a dose response, with females showing the greatest benefit (Miller et al., 2014). The question is however, will it perform this well in people? We will return to this question in a bit, but it seemed that this would be a good point to briefly review what's known about its target, TOR.

Two complexes assemble that both contain mTOR. mTORC1 and mTORC2 each promote autonomous cell and non-autonomous cell-specific functions (Albert and Hall, 2015). mTORC1 initially was the main focus of aging research with many studies indicating that it is a key regulator of gaining and age-caused diseases (Laplante and Sabatini, 2012). When nutrients and growth factors are replete, mTORC1 promotes anabolic pathways for cell mass accumulation. When opposite conditions are prevalent, it promotes catabolic processes for survival of cells (Liu and Sabatini, 2020).

As shown in Fig. 2, there are activating factors for mTORC1 and stresses that cells encounter that repress mTORC1 both of which that lead to activation of its downstream effectors that function in aging and cancer. Fig. 2 is highly simplified, and there are excellent reviews that provide detailed discussions of mTORC1 and mTORC2 structure, function and signaling networks (Bar-Peled and Sabatini, 2014; Betz and Hall, 2013; Cornu et al., 2013; Dibble and Manning, 2013; Huang and Fingar, 2014; Jewell and Guan, 2013; Laplante and Sabatini, 2012; Ochocki and Simon, 2013; Rexin et al., 2015). Lamming et al. (2014) proposed that active mTORC1 represses longevity, while a functioning mTORC2 promotes longevity in males.

2. How does rapamycin work?

In structure and function, the mTOR genes discussed earlier are conserved in eukaryotes, including plants (John et al., 2011). The protein belongs to a larger family of what has been referred to “‘giant’ phosphatidylinositol 3-kinase (PI3K)–like protein kinases (PIKKs)” (Smerdon, 2014). The conserved structure function domains of this family and the one specific for mTOR are shown linearly in Fig. 1. Aylett et al. (2016) identified the horn and bridge areas of the heat-repeat-containing N-terminal domain, which is common to other members of the PIKK family as are the FAT, FAT-C and kinase domains (Smerdon, 2014). The unusual (and defining) feature of mTOR is the FRB region located on the N-terminus of the kinase domain, with which the FKBP12-rapamycin complex interacts. Evidently, the FRB domain evolved, at least in part, to interact with phosphatidic acid (PA) thereby stabilizing and activating one of the complexes containing mTOR (mTORC1), reviewed by Foster (Foster, 2013; Frias et al., 2023) showed that PA binding prevents rapamycin-FKBP12 binding to FRB domain and promotes mTORC1 translocation to the exosome(Frias et al., 2023). Frias et al. propose that PA acts a “gate keeper” for FRB interactions. For example, PA promotes interaction of S6K1 (a principal suberate of mTORC1) with the FRB but hinders PRAS 40 (an inhibitor of mTORC1) and rapamycin. PA also stabilizes the other mTOR complex (mTORC2), which is less sensitive to acute rapamycin-FKBP12 competition (Frias et al., 2023). But what are the effects on diseases and aging?

3. Effects of chronic rapamycin on age-associated diseases

In response to these results, labs worldwide began testing eRapa and other formulations on various types of age-associated diseases. A common question studied by the ITP and others was: does eRapa delay signs of aging? For example, starting eRapa at 9 months of age slows aging traits in UM-HET3 mice, although noting a higher incidence of testicular degeneration (Wilkinson et al., 2012). In an inbred strain, C57BL/6, starting the diet at 19 months of age, Zhang et al. (2014) investigated this question and concluded eRapa extended life and health span, with no differences noted in testicular degeneration or cataracts in older mice. In a follow up study of long-term effects of chronic eRapa starting at 4 months of age and continued to the end of life, Fischer et al. (2015) data indicated that lifespan and health span are not necessarily correlated. In another study by Neff et al. (2013) eRapa extended lifespan but improved only a few of a wide range of age-associated phenotypes. In addition, the treated mice exhibited two adverse events: testicular degeneration and nephrotoxicity. Ehninger et al. (2014) proposed that chronic eRapa does not slow aging but suppresses cancer, the major cause of mortality in mice. In a rebuttal to this paper Johnson et al. (2013a) stated results “supports the model that rapamycin promotes longevity by targeting some, but perhaps not all, core molecular processes that drive cellular and systemic aging.” A very large field of study quickly grew. Since the ITP's 2009 paper, a weekly search from the NCBI titled “What's new for mTOR” report of new papers ranges from 50 to 100 per week. Most of these papers are disease oriented showing mTOR involvement (mostly up regulated). The concept of mTOR-opathies has emerged.

In the supplementary information Table S1 lists a compendium of papers illustrating the wide variety of aging associated diseases and phenotypes studied using rapamycin or its sister formulations have been used. In cancer alone the number of papers returned by PubMed search using rapamycin or sirolimus, cancer article published since 2016 returned over 260 papers. The same increases were seen in other categories such as neuro degenerative diseases. One that is noteworthy for this review in the cancer lifespan is from Brown's group at The University of Texas MD Anderson Cancer Center, reported for the first time that a rapalog, everolimus showed promise as a breast cancer prevention agent (Mazumdar et al., 2022) This is significant since most agents for cancer are for treatments (and rightly so), but one for prevention is that is also works as an antiaging agent is momentous.

This is in line with the cancer prevention preclinical studies conducted by our group in several murine models of cancer. In these studies, we treated then with our enteric formulation of rapamycin we call eRapa. In a previous study of diet restriction in the Rb1^+/− neuroendocrine tumorigenic model, we showed that this intervention had only a minimal effect on lifespan and tumor prevention (Sharp et al., 2003). In contrast, chromic eRapa treatment showed a highly significant extension of lifespan and delay of tumor development in both sexes (Livi et al., 2013). This is an interesting difference in the in vivo response to diet restriction versus mTORC1 inhibition. The next model was another one with an altered tumor suppressor gene p53 including +/+, +/− and −/− genotypes. We found that p53 and rapamycin are additive in lifespan effects (Christy et al., 2015).

To round out our work on murine tumor suppressor models that spontaneously generate cancer we chose Apc^Min/+ mice that are heterozygous for the adenomatous polyposis coli gene (Apc), which is a model for familial adenomatous polyposis or FAP. In humans, APC inhibits pro-growth WNT signaling through the regulation of β-catenin transport to the nucleus. APC mutations results in the development of numerous adenomatous colorectal polyps at a young age. The polyps inevitably progress to colorectal cancer if left untreated. The standard of care is total colectomy, which is a morbid and life altering treatment.

In collaboration with Paul Hasty, we tested the postulate that enterically delivered rapamycin by eRapa in Apc^Min/+ mice would intervene in the tumorigenic processes in the small intestine crypts to extend lifespan. The results were impressive with some treated animals outliving wildtype female mice (Hasty et al., 2014). We repeated this experiment in both males and females and found the observed the same results, except that in this experiment males lived longer than females (Parihar et al., 2020). To determine if eRapa was effective in preventing malignant tumors in this model, we pretreated with eRapa followed by dextran sodium sulfate treatments. This setting converts Apc^Min/+ mice from a polyposis small intestine model to a colorectal cancer model. Again, eRapa prevented tumors in this model and extended lifespan equally in both sexes (Parihar et al., 2021). This work set the stage for testing eRapa in humans.

3.1. eRapa clinical trials

Based on ours and other's work with eRapa the following clinical trials are underway.

•
Phase IIa (NCT04230499) dose-escalation FAP study
- ○
  Study population: patients with FAP who have previously undergone colectomy or subtotal colectomy and have residual polyps in the remnant colon/rectum
- ○
  Study size: 10 patients per dosing cohort (30 patients total)
- ○
  Study status: open to enrollment
•
Phase 1b (NCT03618355) dose-escalation prostate cancer study
- ○
  Study population: patients with low-grade prostate cancer (Gleason 6 or 7 [3 + 4]) under active surveillance
- ○
  Study size: 3–6 patients per dosing cohort (9–18 patients total)
•
Phase II (NCT04375813) double-blinded, randomized bladder cancer trial
- ○
  Study population: patients with non-muscle invasive bladder cancer

Study size: 75 patients per treatment arm (150 patients total).

As mentioned, mTORC1 has been a focus in aging. A recent exciting paper by Frei et al. (2022) shows that mTORC2 is likely to have a big role also. The study focused on the sympathetic and possibly sensory communication of the central nervous system with white adipose tissue (WAT). This elegant study reported that adipose mTORC2, (a major component of the insulin signaling) is necessary for arborization of sensory neurons in WAT. A bigger point is that this work suggests WAT may affect systemic energy homeostasis via this sensory network. WAT is also one of the most responsive tissues to rapamycin, which showed an opposite adaptation to other tissues such as colon (Dodds et al., 2016).

Another side of the aging coin is processes that contribute to declines associated with age. Early interventions that extended longevity were accompanied by a decrease in the rate of mitochondrial reactive oxygen species and derived damage (Barja, 2013). Marinez-Cisuleo et al. found that rapamycin mimicked these declines and increased autophagy in male livers of middle-aged mice (Martinez-Cisuelo et al., 2016). These studies indicated that in addition to preventing age associated diseases, rapamycin could be promoting positive longevity effects.

4. When rapamycin was not good

While most outcomes to chronic rapamycin are anti-aging, the results in one experiment is noteworthy for its opposite effect and relevance to a large patient population in the elderly, type-2 diabetes. Chronic eRapa resulted in an increase in mortality in a mouse model (db/db) of this disease due to suppurative inflammation (Sataranatarajan et al., 2015). Another major failure of mTOR inhibition by rapamycin was a trial studying intravitreal sirolimus in age-related macular degeneration (AMD) (Petrou et al., 2014). This was unexpected since hyperactivated mTORC1 was widely viewed as playing a major role in development and progression of AMD (Go et al., 2020; Huang et al., 2019; Kaur et al., 2018; Zhang et al., 2020; Zhao et al., 2011; Zigler et al., 2011). Why an intravitreal approach lead to adverse events is somewhat mysterious since systemic sirolimus cured AMD-like symptoms in a mouse model when administer iP (Zhao et al., 2011). In hyperglycemic rats, an IP injection of rapamycin reduced diabetes -induced VEGF overexpression that controls vascular permeability and angiogenesis (Kida et al., 2021). One wonders if systemic intervention with mTORC1 inhibitors would have better success in prevention or treatment in people. It is also noteworthy that the use of mTOR inhibitors in diseases not associated with aging is increasingly wide spread (summarized in Johnson et al., 2013b).

5. Where to from here?

In a recent review published in Cell, López et al., a paper titled: “Hallmarks of aging: An expanding universe” (López-Otín et al., 2022). They proposed 12 hallmarks of aging and three of health. We submit that chronic rapamycin (and diet restriction) likely mitigates the former and promotes the latter. If true, this bodes well for an extremely exciting future for research deeper into mTOR system in aging and its diseases. We also think the ongoing studies of rapamycin effects on a non-human primate, the common marmoset (Callithrix jacchus) will provide vital information to the practical application to clinical practice. Combined these studies indicate that chromic rapamycin has minimal detrimental effects (Lelegren et al., 2016; Ross et al., 2015; Tardif et al., 2015). A long term study of chronic rapamycin (1 mg/kg/body weight/day) in middle age animals was also encouraging since it showed few differences in morphology, hematological markers of blood cell counts, metabolism or inflammation (Sills et al., 2019).

We end with our selection for the most interesting question in aging research. It is, will synthetic organism age? This is related to the deeper question, is life possible without aging? More relevant to this article, Fig. 3 illustrates our view of the present and future as it relates more specifically to mTOR modulators and the future of aging prevention.

The following is the supplementary data related to this article.Download: Download Word document (29KB)

Table S1. Studies of aging, associated diseases and phenotypes.

Declaration of competing interest

The University of Texas Health Science Center at San Antonio has been awarded a patent, U.S. Patent Application No. 13/128,800, by inventors Zelton Dave Sharp and Randy Strong, for an encapsulated rapamycin formulation used in this paper. Under a licensing agreement between Emtora Biosciences and the University of Texas Health Science Center San Antonio, R. Strong and Z.D. Sharp, the University is entitled to milestone payments and royalty on sales of microencapsulated rapamycin. The university has a plan for managing conflicts of interest under its “Policy and Procedures for Promoting Objectivity in Research by Managing, Reducing or Eliminating Conflicts of Interest.”

Acknowledgements

This work was funded in part by NIA grant AG013319. Randy Strong is supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Development. We are also much obliged to the anonymous reviewers for their time and many helpful suggestions for improvement in the paper.

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