Doses and schedules of rapamycin for longevity: does aging exist or only age-related diseases?

Doses and schedules of rapamycin for longevity: does aging exist or only age-related diseases? 


Mikhail Blagosklonny

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 [1]. Since 1999, millions of patients with serious illnesses tolerated rapamycin well. Continuous (everyday) even high doses were studied successfully in patients [2]. A failed suicide attempt (103 tablets or 103 mg) caused no effects except elevated blood lipids [3]. In some studies, side effects were higher in the placebo group than in the rapamycin-treated group [4].

            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 The schedule is well tolerated, according to yet unpublished results.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 [5]. 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 [1]. 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 [7]. Also, high doses were less effective than low doses in cancer prevention in prostate epithelium-specific Pten-knockout mice [10].

In 2006, when the hyperfunction theory of aging was published [11], 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 [12].

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 [25].

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 [26]. 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 [29]. (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 [31] and Alzheimer’s disease [32], 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” [33]. 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 [34]. 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).

Figure 1

This point of view was unchallenged until 2006, when the hyperfunction theory of quasi-programmed aging was published [11]. 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 [11], [35] [33]. Age-related diseases (ARD) in turn lead to secondary loss of functions and failure (late manifestations of aging) [11]. Hyperfunction theory explains why quasi-programmed aging is life-limiting, whereas accumulation of molecular damage is not limiting-limiting [11] [36].

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 [33].

Figure 2

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 [33]). Age-related diseases (ARD) are partially quasi-programmed (some more some less, see [33]), 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 [33].

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.




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