Doses and schedules of rapamycin for longevity: does aging exist or only age-related diseases?
This is a brief version of “groundbreaking paper” that I have no time to finish.
Rapamycin for life-limiting disease/condition
Current doses and schedules of rapamycin for longevity are based on the wrong objective: to minimize side effects.
Side effects of rapamycin are not remarkable and less dangerous than the side effects of many other drugs . Since 1999, millions of patients with serious illnesses tolerated rapamycin well. Continuous (everyday) even high doses were studied successfully in patients . A failed suicide attempt (103 tablets or 103 mg) caused no effects except elevated blood lipids . In some studies, side effects were higher in the placebo group than in the rapamycin-treated group .
The most popular schedule of rapamycin for longevity is 5-7 mg once a week. The schedule is well tolerated, according to yet unpublished results. It is based on the assumption that the intermittent schedule has fewer side effects than everyday doses. But this never was compared. For example, 1 mg rapamycin every day was also well tolerated in a clinical trial in healthy elderly . So, both schedules have negligible side effects. But are they equally effective for life extension? We do not know.
In mice, the higher the dose, the longer lifespan [6-9]. Therefore, in humans, the highest dose that does not yet cause unacceptable side effects (maximal tolerated dose) may be optimal for longevity. If (unacceptable) side effects develop, the dose should be decreased. In other words, anti-aging doses are maximal doses without side effects in a particular person . Then anti-aging doses are individual and side-effect-free by definition. Furthermore, if we do not know what exact doses are needed, there is no need to use doses that may cause potential side effects.
In one study in mice, the longevity plateau was reached in female (but not male) mice. Bitto et al. demonstrated that very high doses of rapamycin (probably unachievable in humans) did not extend lifespan in female mice, while lower doses did . Also, high doses were less effective than low doses in cancer prevention in prostate epithelium-specific Pten-knockout mice .
In 2006, when the hyperfunction theory of aging was published , I initially envisioned that rapamycin should be administrated at continuous (everyday), low doses (0.5 mg/day) to prevent age-related diseases. By 2008, I recognized that this not the only one way to use rapamycin. In theory, intermittent treatment may rejuvenate stem and wound healing cells .
Since 2009, data accumulated in mice that not only everyday treatment [13-17], but also various types of intermittent and even transient treatments [18- 24, 7] with rapamycin successfully extended life span in mice.
In theory, high intermittent dose of rapamycin (for example, 30 mg every 3 weeks) may produce a high peak level to ensure that even rapamycin-resistant cells will be targeted. (Probably, everolimus is better for this purpose because of short half-life). A high peak concentration may affect neurons, protected by the blood brain barrier, and stem cells in their niches. A high single dose of rapamycin was shown to maintain lower body weight by shifting the set point long-term in rats .
However, intermittent therapy may have some disadvantages. Such schedules include drug-free periods. During these periods, mTOR can be over-activated in compensation and may, in theory, cause acute harmful events. (I believe that rebound of mTOR in endothelial cells may increase thrombosis, arterial permeability and arterial spasm)
I suggest that optimal dose/schedules are individual, depending on age, gender and spectrum of pre-diseases in each particular person.
Consider an analogy with aspirin. Aspirin was given at high doses (3600 mg/day) every day for one year to patients with rheumatoid arthritis . On the other hand, to prevent thrombosis and CVD, low doses of aspirin (81 mg) are usually used daily. Furthermore, aspirin can be used intermittently or continuously depending on pathology [27, 28].
Similar, doses and schedules of rapamycin may depend on pathology and therefore on the cell type that needs to be targeted.
No one dies from aging per se, everyone (including centenarians) dies from age-related diseases . (We will discuss in the next section that this has a deep meaning. Aging does not exist independently of pathology; aging is an abstraction, describing all pathologies together).
Aging is a process that drives all age-related diseases. By targeting “aging”, we may delay or prevent age-related diseases [11, 30]. This approach was later named the geroscience hypothesis.
The goal of rapamycin treatment is to prevent particular life-limiting age-related diseases that would kill a particular person.
The key word is “life-limiting”. To extend lifespan, the treatment must delay the life-limiting disease. In medical science, it’s simple. If a patient is dying from cancer, it is cancer (a life-limiting disease in this patient) that is treated. It would make no sense to treat Alzheimer’s disease, which is not yet present in this patient.
A similar approach should be employed in geroscience. Although rapamycin may prevent both cancer  and Alzheimer’s disease , optimal doses and schedules may be different for each of them. If an aging healthy person is a smoker, whose parents had died from cancer, schedules of rapamycin should be designed to delay lung cancer rather than Alzheimer’s disease. If an aging healthy person has an APOE ɛ4 allele and family history of Alzheimer’s disease, then schedules of rapamycin should prevent Alzheimer’s disease. In theory, high intermittent doses may target brain cells despite the blood brain barrier (BBB). Designing doses is complex, because, for example, rapamycin affects the BBB by targeting endothelial cells (EC).
Aging is driven by hyperfunctional signal-transduction pathways including mTOR. These pathways are the same in age-related diseases. They render cells hyperfunctional, and these cells drive age-related diseases. But it is different sets of cells that drive particulate diseases.
Different sets of cells participate in hair loss, prostate enlargement, menopause, atherosclerosis, Parkinson’s disease and so on (see “diseases of hyperfunction” . And doses and schedules of rapamycin should be different, adjusted to targeted cell type or organ.
Each disease can be described in the term of hyperfunctional cells and pathways. Pathogenesis of atherosclerosis involves arterial smooth muscle cells (aSMC), endothelial cells (EC), macrophages, blood platelets plus distant hepatocytes and fat cells (secretion hormones, lipids and lipoproteins).
Thus, optimal doses and schedules of rapamycin are different, depending on the life-limiting pathology expected in an individual.
Does aging exist?
In the previous chapter, we discussed that anti-aging treatment should be disease-oriented. Here I suggest that theory of aging should be disease-based. The notion of aging is not needed. Figuratively, aging does not exist, if we look at it under magnifying glass. Instead, we see age-related diseases (ARD) and conditions. (Note: For brevity, I will refer to all age-related pre-diseases, diseases and benign conditions as ARD . In this article “diseases” mean only age-related quasi-programmed diseases.)
What are current views on the relationship between aging and ARD?
According to a dominating notion, aging is caused by accumulation of molecular damages, leading to functional decline and death. Age-related diseases (ARD) are caused by other causes, such as unhealthy lifestyle and “genetics” (Fig. 1A). (Clearly, hypertension is not caused by mutations, for example). Accordingly, aging is just a risk factor for diseases (but this explains little. Why is it a risk factor?). With a healthy lifestyle, aging will cause a “healthy” death (I slightly inflate). Otherwise, a person will die prematurely from age-related diseases (Fig 1A).
This point of view was unchallenged until 2006, when the hyperfunction theory of quasi-programmed aging was published . Aging is a quasi-program, a continuation of developmental growth programs. When developmental growth is completed, the mTOR growth-promoting pathway drives aging instead of growth. Its activity is optimal for growth but higher than necessary post-developmentally. Hyperfuntional signaling renders cells hyperfunctional, driving age-related pre-diseases and diseases ,  . Age-related diseases (ARD) in turn lead to secondary loss of functions and failure (late manifestations of aging) . Hyperfunction theory explains why quasi-programmed aging is life-limiting, whereas accumulation of molecular damage is not limiting-limiting  .
According to hyperfuction theory, aging is a common driving cause of all ARD, not just a risk factor (Fig. 1B). These diseases are obligatory manifestations of aging. Diseases, not aging per se, cause death in animals from humans to C. elegans [37-39]/ . Aging and, therefore, ARD, such as hypertension, are not caused by molecular damage. (Note: Hypertension is a continuation of developmental increase of BP started from birth driven by hyperfunctions.)
The hyperfunction theory of aging is a convenient approximation. Here, I attempt a major revision of hyperfunction theory. It is a hyperfunction theory of quasi-programmed (age-related) diseases.
At first glance, aging behaves as a complex disease and can be treated as a disease by potential anti-aging drugs, but such treatment should individualized (see section 1).
Under magnification, aging is not a disease but a set of all diseases, in mathematical sense, and a set of diseases is not a disease. In analogy, a zoo consists of animals, but a zoo is not an animal .
Aging is correctly defined as an exponential (at least in humans) increase of the probability of death with age, because aging consists of age-related diseases that kill exponentially with age. Although an exponential increase is not perfect for each disease, as a sum, it gives a perfect exponential curve.
Aging is a useful abstraction, which mathematically behaves as an age-related disease but does not exist as independent entity. It’s a sum of all age-related pre-diseases, age-related diseases and conditions. Fragility, gray hair, atherosclerosis and numerous condition and diseases, all together are called aging. But aging does not exist without these diseases.
In analogy, consider a collection of different flowers. This collection of flowers we can call a bouquet. In this analogy, a flower is a disease, and the bouquet is aging. However, we do not need to use the word “bouquet,” we can use a descriptive term—collection of flowers. Similarly, the notion of aging is not necessary. Each flower exists, but the bouquet does not exist without flowers. If we want to describe a bouquet, we describe all the flowers—colors and texture, state of decay and so on. To describe the decay of bouquet, we should focus on individual flowers; for example, some tulips may rot first. We may remove these rotten tulips (analogies to treatment of life limiting disease)
Let us compare two versions of hyperfunction theory of: (i) quasi-programmed aging and (ii) age-dependent (quasi-programmed) diseases.
First, aging is a quasi-program, it is a continuation of developmental growth and reproductive programs. Aging drives age-related diseases. Genetic variability and environmental hazards also contribute (see). Diseases terminate lifespan.
Second, age-related diseases are quasi-programs, they are continuations of developmental growth and reproductive programs. Developmental programs directly drive age-related diseases (no intermittent “virtual aging”). Genetic variability and environmental hazards also contribute (see). Diseases terminate lifespan.
Now we look at “aging” under a microscope and see separate grains: diseases. Aging (a set of diseases), driven by but multiple quasi-programs, multiple off developmental programs that are not switched off. Although mTOR-driven cellular hypertrophy, hyperplasia, hyperfunctions are involved in prostate enlargement and atherosclerosis, quasi-programs are different, because different cell types participate in them (see ). Age-related diseases (ARD) are partially quasi-programmed (some more some less, see ), because external and genetic factors contribute to them. Not all quasi-programs are TOR-dependent; for example, our epigenetic clock seems to be mTOR-independent.
Aging is a set (an analogy with mathematical sets) of members: all age-related diseases and conditions. The “set” is an abstraction. Aging is not a disease, it’s a set of diseases .
A quasi-program of aging is impossible to describe in detail without describing the distinct pathological processes aging consists of. In analogy, a bouquet can be described as beautiful and colorful, but to describe in detail, we need to focus on the individual flowers.
By focusing on potentially life-limiting diseases in a particular person, we may design appropriate doses and schedules of rapamycin and its combinations with other drugs.
This is half medicine and half geroscience, and will call it geromedicine.
- Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019; 11: 8048-8067.
- Cohen EE, Wu K, Hartford C, Kocherginsky M, Eaton KN, Zha Y, Nallari A, Maitland ML, Fox-Kay K, Moshier K, House L, Ramirez J, Undevia SD, et al. Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients. Clin Cancer Res. 2012; 18: 4785-4793.
- Ceschi A, Heistermann E, Gros S, Reichert C, Kupferschmidt H, Banner NR, Krahenbuhl S, Taegtmeyer AB. Acute sirolimus overdose: a multicenter case series. PLoS One. 2015; 10: e0128033.
- Brattstrom C, Sawe J, Jansson B, Lonnebo A, Nordin J, Zimmerman JJ, Burke JT, Groth CG. Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers. Ther Drug Monit. 2000; 22: 537-544.
- Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018; 105: 53-69.
- Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014; 13: 468-477.
- Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016; 5.
- Johnson SC, Yanos ME, Bitto A, Castanza A, Gagnidze A, Gonzalez B, Gupta K, Hui J, Jarvie C, Johnson BM, Letexier N, McCanta L, Sangesland M, et al. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front Genet. 2015; 6: 247.
- Johnson SC, Kaeberlein M. Rapamycin in aging and disease: maximizing efficacy while minimizing side effects. Oncotarget. 2016; 7: 44876-44878.
- Antoch MP, Wrobel M, Gillard B, Kuropatwinski KK, Toshkov I, Gleiberman AS, Karasik E, Moser MT, Foster BA, Andrianova EL, Chernova OV, Gudkov AV. Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer. Oncotarget. 2020; 11: 1373-1387.
- Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5: 2087-2102.
- Blagosklonny MV. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res. 2008; 11: 801-808.
- Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460: 392-395.
- Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011; 66: 191-201.
- Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, Gudkov AV, Antoch MP. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis. Aging (Albany NY). 2012; 4: 715-722.
- Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD. Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013; 5: 100-110.
- Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schroder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, et al. Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest. 2013; 123: 3272-3291.
- Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009; 2: ra75.
- Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010; 176: 2092-2097.
- Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011; 10: 4230-4236.
- Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013; 342: 1524-1528.
- Leontieva OV, Paszkiewicz GM, Blagosklonny MV. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell. 2014; 13: 616-622.
- Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J Gerontol A Biol Sci Med Sci. 2016; 71: 876-881.
- Strong R, Miller RA, Bogue M, Fernandez E, Javors MA, Libert S, Marinez PA, Murphy MP, Musi N, Nelson JF, Petrascheck M, Reifsnyder P, Richardson A, et al. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects. Aging Cell. 2020; 19: e13269.
- Hebert M, Licursi M, Jensen B, Baker A, Milway S, Malsbury C, Grant VL, Adamec R, Hirasawa M, Blundell J. Single rapamycin administration induces prolonged downward shift in defended body weight in rats. PLoS One. 2014; 9: e93691.
- Davis JD, Struth AG, Turner RA, Pisko EJ, Ruchte IR. Pirprofen and aspirin in the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 1979; 25: 618-623.
- Garland LL, Guillen-Rodriguez J, Hsu CH, Yozwiak M, Zhang HH, Alberts DS, Davis LE, Szabo E, Merenstein C, Lel J, Zhang X, Liu H, Liu G, et al. Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial. Cancer Prev Res (Phila). 2019; 12: 809-820.
- Mohammed A, Janakiram NB, Madka V, Zhang Y, Singh A, Biddick L, Li Q, Lightfoot S, Steele VE, Lubet RA, Suen CS, Miller MS, Sei S, et al. Intermittent Dosing Regimens of Aspirin and Naproxen Inhibit Azoxymethane-Induced Colon Adenoma Progression to Adenocarcinoma and Invasive Carcinoma. Cancer Prev Res (Phila). 2019; 12: 751-762.
- Blagosklonny MV. No limit to maximal lifespan in humans: how to beat a 122-year-old record. Oncoscience. 2021; 8: 110-119.
- Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY). 2009; 1: 281-288.
- Blagosklonny MV. Cancer prevention with rapamycin. Oncotarget. 2023; 14: 342-350.
- Kaeberlein M, Galvan V. Rapamycin and Alzheimer’s disease: Time for a clinical trial? Sci Transl Med. 2019; 11.
- Blagosklonny MV. Are menopause, aging and prostate cancer diseases? Aging (Albany NY). 2023; 15: 298-307.
- Blagosklonny MV. Disease or not, aging is easily treatable. Aging (Albany NY). 2018; 10: 3067-3078.
- Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am J Pathol. 2012; 181: 1142-1146.
- Blagosklonny MV. The hyperfunction theory of aging: three common misconceptions. Oncoscience. 2021; 8: 103-107.
- de la Guardia Y, Gilliat AF, Hellberg J, Rennert P, Cabreiro F, Gems D. Run-on of germline apoptosis promotes gonad senescence in C. elegans. Oncotarget. 2016; 7: 39082-39096.
- Wang H, Zhao Y, Ezcurra M, Benedetto A, Gilliat AF, Hellberg J, Ren Z, Galimov ER, Athigapanich T, Girstmair J, Telford MJ, Dolphin CT, Zhang Z, et al. A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans. NPJ Aging Mech Dis. 2018; 4: 6.
- Gems D, de la Guardia Y. Alternative Perspectives on Aging in Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction? Antioxid Redox Signal. 2013; 19: 321-329.