Over the past several years there have been many significant discoveries regarding drugs which can affect the rate of aging. Research has sometimes led to confusing or conflicting results, but it is now becoming increasingly clear that certain agents have a definite action with regards to modifying the aging process. Examples include metformin, certain senolytics, carnosine, resveratrol, and mTOR inhibitors such as rapamycin, (note; thepharmacological inhibition of mTOR is an FDA-approved clinical principle).
mTOR (mammalian/mechanistic Target Of Rapamycin) is a well-known term to those who have an interest in the mechanisms of aging. In technical circles, mTOR is also known as the FK506-binding protein 12-Rapamycin-Associated Protein 1 (FRAP1), a term that has featured in increasingly more scientific papers in recent years. Basically, it is a kinase (a protein and, specifically, an enzyme) which is linked to a variety of other specific proteins and, together, they regulate cell function. Examples of processes which are regulated by mTOR include cell growth and motility, synthesis of other proteins, and importantly, autophagy (the process by which the cell degrades itself).The mTOR network senses signals from the environment, as well as signals originating from inside the cell regarding nutrition and energy requirements. Rapamycin is a well-known modulator of the mTOR process and it is the only existing pharmacological treatment which may increase lifespan in animals, including mammals (but not yet proven in humans) (1).
Apart from rapamycin itself, there exist several analogues which inhibit the immune response by blocking the proliferation of T-cells, by blocking the formation of new blood vessels (and thus block the blood supply to cancer cells), and by reducing the impact of inflammation.
The issue of side effects
A cause for concern has been the side-effects which are associated with the use of rapamycin and its analogues. Common side-effects include immunosuppression, lipid and glucose abnormalities and pneumonitis, all of which greatly depend on the dose used, and usually improve after the dose is decreased. These side-effects however may not be directly related to rapamycin itself. In clinical trials, the side-effects were more evident because rapamycin was given to already severely diseased patients who were also taking other drugs. Lower doses given to healthy patients for preventative purposes may not be associated with such side-effects. In addition, taking the drug in alternate dosing (one day on, the next day off) may still have positive benefits with an even lower risk of side effects.
However, there is still a lot to learn about the clinical use of rapamycin with regards to slowing aging in humans. Some of the difficulties include the different isoforms (variants) of the components which participate in the mTOR pathway, the exact location of mTOR complexes inside the cell, and other cell functions which depend directly or indirectly on the action of rapamycin.
For instance, and just to go into some detail, it is known that rapamycin interferes with senescent cells, which are cells that have lost their ability to divide any longer. These cells activate the senescence-associated secretory phenotype (SASP), which essentiallycreates a situation whereby normal cells cannot function properly and thus degeneration becomes evident. Rapamycin inhibits cell senescence through a complicated mechanism, and so it increases longevity (2).
Rapamycin in Humans
While human trials specifically for preventing aging are missing, the following research may give us some useful insights regarding clinical use of mTOR inhibitors.
Natural mimetics of rapamycin
Researchers have tried to identify other compounds which replicate some of its physiological actions. In a recent study it was suggested that compounds such as epigallocatechin gallate, (in green tea for example), isoliquiritigenin (found in licorice), and withaferin A (used in Ayurvedic medicine) may act as mimetics of rapamycin (7). Another compound is oxaloacetate (oxaloacetic acid), which was featured in the Aging Matters™ magazine, issue 3, 2015.
The bottom line
Rapamycin is a drug that has benefits and drawbacks. It is not a nutritional supplement to be taken without supervision. For the specific purpose of preventing age-related degeneration, it is used in low, irregular doses, closely monitoring its response and side effects. This can only be achieved with the help of a knowledgeable professional, and not by the patient on his/her own.
There is great potential in the clinical effects of this and similar drugs, but one must be able to separate hype from science, and not take sensational press news as true facts that are applicable on humans. There is a difference between using rapamycin for established illnesses (cancer) and using it for prevention in healthy people, to avoid aging.
Although in this article I am concentrating on rapamycin, this is not to say that it is one of the few potential treatments for aging. It is important to realize that aging will not be stopped using one, two or more kinds of different pills, but it is a matter of a wider approach, involving a generally appropriate lifestyle, positive attitudes, mental exercises, suitable exposure to positive stress, and many other interdependent factors and processes. In any case, rapamycin and its analogues or mimetics are useful agents to consider in this respect.