Rapamycin for Longevity: series 2, part 2

Rapamycin is a proven anti-aging drug

The evidence that rapamycin can function as an anti-aging drug is the culmination of thousands of scientists working independently all over the world, studying mTOR and its respective inhibitors for a variety of different reasons in a variety of different organisms, such as yeast, worms, flies, and mice, and have revealed components of the TOR signaling pathway [142–145]. We know from the work of Harrison et al that inhibition of the TOR signaling pathway by way of rapamycin treatment extends median and maximal lifespan in both genders of mammalian species. Harrison et al continued with the assertion that rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of aging, or both simultaneously. Harrison et al’s study produced the first results to demonstrate a role for mTOR signaling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings pave the way for further development of treatments geared towards targeting mTOR for the treatment and prevention of age-related diseases. Continuing on, Blagosklonny had predicted, in 2003, that conversion from quiescence to senescence, known as geroconversion, is driven by growth-promoting mediators, such as mTOR, when the cell cycle is blocked [147]. Just a quick reminder, quiescence is the inactive but healthy state of a cell in the G0 phase of the cell cycle. While cell senescence is hallmark for the aging processes of a cell and is a state in which cellular resistance to apoptosis is higher, the production of senescence-associated secretory phenotype (SASP) is taking place, mitochondrial dysfunction occurs, as well as changes within the cell's DNA and its supporting molecules; essentially the cell remains alive in a non-functional, static state. Ok, back to the matter at hand, geroconversion. Figuratively, geroconversion can be considered “twisted” growth, according to Blagosklonny, when actual growth is completed [2], [147]. In cell culture, mTOR is maximally activated quickly and geroconversion lasts 3-6 days, whereas in the human body it may take decades to achieve the same results. mTOR drives geroconversion, rendering viable cells hypertrophic and hyperfunctional (e.g. SASP), which eventually leads to the development of age-related pathologies [2]. Clinical researchers have studied rapamycin for the prevention and treatment of nearly every age-related disease, including cancer, obesity, atherosclerosis and neurodegeneration. If a drug is indicated for all age-related diseases, it must be an anti-aging drug in that it targets the common driver of age-related diseases – that is, it targets aging. This is because aging is the sum of all age-related diseases, which limit lifespan [148–150]. So, does rapamycin suppress aging thereby extending lifespan by preventing diseases, or does it prevent diseases by slowing the process of aging? Actually, both explanations are applicable and reflect the same process.

By 2006, an extensive body of work from several independent fields all pointed to rapamycin as an anti-aging drug [2]. According to the hyperfunction theory, aging is an unintended continuation of the developmental growth program, driven in part by mTOR [2,120,121,151,152]. Testable predictions have been formulated [2,153] and confirmed in numerous independent studies [150,154].

In two dozen studies using different strains of mice, rapamycin extended life span. Starting from a thorough study by Harrison et al. [155] and followed by nearly simultaneous studies by others [33,108], the anti-aging effects of rapamycin have been confirmed many times over within several studies [113,150,156,157]. Importantly, rapamycin and everolimus are indicated to have the capacity to treat many, if not all, age-related diseases, from cancer to neurodegeneration [2,158].

Conventional drugs as anti-aging agents

Several conventional drugs used to treat age-related diseases (e.g., hypertension, ischemic heart disease, diabetes, cancer, prostate enlargement) can be somewhat classified as anti-aging drugs [150,154]. First, these drugs extend lifespan in the same model organisms [159]. For example, metformin extends lifespan not only in mice, but also in the worms, which do not suffer from human diseases [160,161]. ACE inhibitors prolong life not only in hypertensive rats, but also in healthy normotensive rats [162]. If these drugs were not already ordinary drugs for human diseases, then gerontologists (biologists who study aging)  would classify them as anti-aging agents.

Furthermore, these drugs have the capacity to prevent or treat more than one disease. For example, metformin is indicated to treat type 2 diabetes as well as pre-diabetes, obesity, metabolic syndrome, cancer, and polycystic ovarian syndrome [163–168]. Another example, aspirin, not only reduces inflammation which is a hallmark of aging, it also reduces the risk of cardiovascular disease, thrombosis, and cancer. Additionally, low-dose aspirin, prevents one-third of colorectal, gastric, and esophageal cancers [169]. PDE5 inhibitors such as Sildenafil and Tadalafil, which are widely used for erectile dysfunction, are also quite effective at treating benign prostate hyperplasia and pulmonary arterial hypertension in humans and suppress inflammation-driven colorectal cancer in mice [170]. We know aging is the summation of all these age-related diseases and given that humans and animals die from age-related diseases, a given human lifespan can be extended via the treatment of multiple pre-diseases and diseases. Rapamycin and these drugs may complement each other in an anti-aging formulation by further extending lifespan and/or by mitigating each other's possible side effects [159]. One example of this type of drug complementation is that of rapamycin and metformin with the later counteracting rapamycin-induced hyperglycemia [171]. Another example would be that of rapamycin and aspirin, which in regards to inhibition of T-cell all proliferation is more effective than just rapamycin treatment. The two agents in combination reduced numbers of CD4(+)IFN-γ(+) Th1 and CD4(+)IL-17(+) Th17 effector cells while maintaining Foxp3(+) regulatory T cells. The results  suggest aspirin may moderately enhance rapamycin-mediated inhibition of DC allostimulatory capacity. Roehrich ME, Wyss JC, Kumar R, Pascual M, Golshayan D, Vassalli G. Additive effects of rapamycin and aspirin on dendritic cell allostimulatory capacity.

^^^ Immunopharmacol Immunotoxicol. 2015;37(5):434-441. doi:10.3109/08923973.2015.1081606

Not taking rapamycin may be as dangerous as smoking

Unsurprisingly, the fear of rapamycin is greater than the fear of smoking. The CDC itself states that cigarette smoking is estimated to cause more than 480,000 deaths annually. Additionally the CDC states that smoking is the leading cause of preventable death and more than 16 million Americans are living with a disease caused by smoking. But whereas smoking shortens both healthspan and lifespan, rapamycin extends them. While smoking increases the incidence of cancer and other age-related diseases, rapamycin prevents cancer in mice and humans. As heavy smoking shortens life expectancy by 6-10 years. In other words, simply not smoking prolongs life by 6-10 years. In middle-aged mice, just 3 months of high-dose rapamycin treatment was sufficient to increase life expectancy up to 60% [109]. When taken late in life, rapamycin increases lifespan by 9-14% [155], despite the dosage being suboptimal [111]. This possibly equates to more than 7 years of human life. By comparison, smokers who quit late in life (at age 65 years), gain between 1.4 -3.7 years [172]. Considered in those terms, one could say that in the elderly, not taking rapamycin may be even more “dangerous” than smoking. Finally, rapamycin may be especially beneficial to smokers and former smokers. While the carcinogens from tobacco cause lung cancer in mice, rapamycin decreases tobacco-induced lung cancer multiplicity by 90% [28]. Which, if you’re a smoker, is possibly the greatest news, to reduce the possibility of developing lung cancer is something to keep in mind if you are considering rapamycin treatment.

Diet and rapamycin

Calorie restriction and intermittent fasting extend both the lifespan as well as the healthspan in a comprehensive selection of species. However, caloric restriction is of little benefit when started during old age [73,173–178]. While intermittent fasting inhibits the mTOR pathway in young but not old mice [179,180]. In contrast to both calorie restriction and intermittent fasting, rapamycin strongly inhibits mTORC1 at any age. Rapamycin also extends lifespan, whether started late or early in life [108,155,181], even if used transiently [109]. So, whereas caloric restriction is more beneficial early in life, rapamycin may be indicated later in life. In addition, the beneficial effects of rapamycin and calorie restriction may be additive, given that they are exerted through overlapping but distinct mechanisms [182–186]. Intermittent rapamycin treatments and calorie restriction (24-48 hours after) can be combined, to avoid potential hyperglycemia. Additionally, the benefits of physical exercise are highest immediately after rapamycin use, which takes advantage of rapamycin-induced lipolysis, which serves as a fuel for muscles. By itself, chronic rapamycin treatment does not compromise muscle endurance [187] and even prevents muscle loss [188–190].

Do we need safer rapalogs to start aging prevention?

Despite the metabolic side effects seen in some mouse models, mice treated with rapamycin live longer and are healthier. Humans in general, may also want to live longer and healthier lives, regardless of rapamycin’s possible side effects. A few outspoken researchers believe that rapamycin should not be routinely used to treat aging in humans due to the possible metabolic effects and have called for the development of safer rapalogs. In defense of rapamycin, both it and the rapalog, everolimus, are FDA-approved drugs, safe for human use. Another bulwark against its detractors, is the simple fact that since 1999, rapamycin has been used by millions of patients without complications.

First, healthy elderly people who are chronically treated with rapamycin or other mTOR inhibitors showed no ill effects like hyperglycemia [8,9,86]. Logically, more threatening adverse effects could be expected in cancer and transplant patients, who are often more heavily pre-treated and more often terminally ill than in healthy people. Second, there are no truly healthy people among the elderly; otherwise, they would be “immortal”, given that all humans will die from age-related diseases, not from healthy aging. Thus, the sooner they would be treated with anti-aging drugs, the longer they would remain relatively healthy.

That said, it is, of course, important to develop new rapalogs, but not because current rapalogs are unsafe. It is important because such research will help us to learn more about mTOR and aging and may lead to the discovery of agents capable of inhibiting the rapamycin-insensitive functions of mTORC1. These future rapalogs could potentially complement our current set in order to further extend lifespan. Non-rapalog rapamycin analogs are also being developed, with the goal to identify nutraceuticals, which are naturally-occurring compounds, that will mimic the anti-aging effects of metformin and rapamycin without adverse effects [191]. The limitation of current rapalogs is not that they are unsafe but that their ability to extend life is limited. The goal should be to develop new drugs that extend life span further.

Rapamycin is a natural anti-fungal antibiotic produced by soil bacteria of Easter Island. The patent on rapamycin has already expired, and pharmaceutical companies have developed other rapalogs such as everolimus. At equipotent doses, rapamycin and everolimus exert almost identical therapeutic and adverse effects; although, everolimus is weaker and has a shorter half-life within the organism when compared with rapamycin.

All current rapalogs exhibit the same side effects as rapamycin and everolimus with the side effects being mTORC1-dependent. Inhibition of mTORC1 decreases cell proliferation and function, which is manifested as lower blood cell counts and insulin levels, especially when rapalogs are chronically administered at high doses. We could develop weaker rapalogs, which would have no side effects if used at the same dose as rapamycin. But then why not just use a lower dose of rapamycin? Given to mice at the same doses as rapamycin, weaker analogs would likely have neither side effects nor any therapeutic effects. Consequently, their metabolic effects would be diminished and so would their therapeutic effects. However, the same negative result can be achieved simply by decreasing the dose of rapamycin. While waiting for our proverbial silver bullets, we need to use the currently available treatments, such as rapamycin and everolimus, to live longer. When “safer” rapalogs are clinically available, we may use them too.

The time is now unless it's too late

The overwhelming evidence suggests that rapamycin is a universal anti-aging drug – that is, it extends lifespan in all tested models from yeast to mammals, suppresses cell senescence and delays the onset of age-related diseases, which are manifestations of aging which is further discussed by Blagosklonny in [148,149,158,192]. Although rapamycin may reverse some manifestations of aging [181,193], it is more effective at slowing down aging than reversing it. Therefore, rapamycin will be most effective when administered at the pre-disease, or even pre-pre-disease stages of age-related diseases [150]. For example, Carosi et al suggested that mTOR inhibitors could be useful in treating Alzheimer disease, but only in the earliest stages [194,195]. In addition, rapamycin and everolimus are more effective at preventing cancer as opposed to treating cancer. Rapamycin may also be useful for treating osteoporosis, though its usefulness in treating a broken hip after an osteoporotic fracture will probably leave much to be desired. Rapalogs may slow atherosclerosis, thereby preventing myocardial infarction, but they are unlikely to help reverse an infarction itself. In other words, anti-aging drugs like rapamycin, extend your healthspan and are most effective before overt diseases cause organ damage and loss of function.

So, is it really too late to take rapamycin once aging reaches an unhealthy stage? Actually, it is not too late. Even if one or a few age-related diseases renders aging unhealthy, other potential diseases are still at pre-disease stages, and anti-aging drugs may delay their development. Moreover, they may slow down further progression of existing overt diseases.

In addition to rapamycin/everolimus, the anti-aging formula metformin, aspirin, ACE inhibitors, angiotensin receptor blockers and PDE5 inhibitors, each of which can prevent or treat more than one age-related disease [159]. Note that Blagosklonny mentions only clinically-approved drugs because they can be used now. Later, perhaps, we may be able to consider further life extension through the use of low doses of pan-mTOR [196,197], mdm-2 [198,199] and MEK inhibitors [200,201], lithium [201,202], as well as next-generation rapalogs.

There is currently no consensus around the short-term markers of anti-aging effects. Therefore, rapamycin trials should be focused on its potential side effects rather than anti-aging effects. We must be sure that the therapy is safe. In the future, the treatment should be conducted as a life-long phase I/II trial, with dose escalation of rapamycin/everolimus until the side effects are reached in an individual patient. The tailored optimal dose (see Figure 2) should be determined individually for each patient and may vary widely on a case to case basis. Doses and frequencies should be limited by the side effects: stomatitis/mucositis, anemia, thrombopenia, leukopenia, edema, and pneumonitis. To be safe, even mild hyperglycemia should be avoided or mitigated with metformin. Treatment is intended to be life-long, unless discontinued due to side effects.

For the next crucial steps of research we need endeavors such as Healthspan as well as anti-aging clinics that can implement the entire anti-aging recipe, including a complementary low carbohydrate diet and lifestyle changes. Blood levels of rapamycin should be measured, as the rapamycin concentration in blood varies greatly among individuals taking the same dose. Doses of rapamycin should be tailored: personalized dosing and schedules. There is no shortage of potential patients who unfortunately already employ self-medication with rapamycin, but there is a shortage of physicians to treat them. Fortunately, a prototype clinic already functions in the USA, demonstrating that it is feasible from a regulatory standpoint. We cannot wait for results from others if we want to live longer and healthier ourselves. The time is now.