Easter Island in the Pacific off the coast of Chile is famous for the giant stone statues that were erected by natives some 500-700 years ago. The thinking is that the statues were designed to honour eminent ancestors by providing a home for their spirits to inhabit. In the 1960s, Easter Island made it into headlines for a totally different reason. Soil samples were found to contain聽Streptomyces hygroscopicus, a bacterium that produces a chemical with antifungal activity. Rapamycin, as the compound was named, also turned out to have an immunosuppressant effect and was introduced into clinical practice as a drug to prevent the rejection of transplanted organs.
In 1991, Dr. Michael Hall at the University of Basel discovered the mechanism by which rapamycin suppresses the immune system. The compound binds to a protein that was rather unimaginatively named 鈥渕echanistic target of rapamycin鈥� or 鈥渕TOR.鈥� That protein turns out to be a critical player in determining how cells function. It behaves as a 鈥渃ellular switch,鈥� determining if cells should grow and build muscle by synthesizing proteins, or whether they should switch to cleaning up old waste.
That 鈥渃leaning up old waste鈥� is termed 鈥渁utophagy,鈥� literally meaning 鈥渟elf -eating.鈥� In autophagy cells degrade and consume their own damaged or dysfunctional components such as misfolded proteins that are linked to neurodegenerative diseases like Alzheimer's and Parkinson's.聽Waste is broken down into amino acids and lipids, which can be reused by the cell to build new, healthy components or be burned for vital energy. By cleaning out dead and defective cellular machinery the process promotes the regeneration of younger, healthier cells.
Activation of mTOR means that muscle protein is being synthesized, cells grow, and tissues are being repaired. That happens in response to an influx of nutrients, mostly amino acids and carbohydrates, or to muscles being exercised as in weight lifting. However, if this activation is constant, then cells do not get a rest, they keep multiplying at an accelerated rate which leads to aging and possibly cancer.
On the other hand, if calories are restricted or energy is depleted due to intense cardiovascular exercise, then cells respond by decreasing mTOR activity. That in turn shuts down growth processes that consume energy and triggers a shift to survival mode. Cell multiplication, including that of cancer cells and immune cells is decreased. Also, the lack of incoming nutrients triggers autophagy and its associated rejuvenation effects. Indeed, calorie restriction is the only intervention that has consistently shown a longevity enhancing effect in various species. However, reducing mTOR activity also has a downside. It can lead to muscle wasting and a weakened immune system. Of course, a weakened immune system is desired when it comes to preventing organ rejection.聽
What does all of this mean practically? Hyperactivity of mTOR, as stimulated by overeating, should be avoided, and mTOR inhibitors like rapamycin can be used to slow the growth of some cancers. Mildly suppressing mTOR through calorie restriction, such as through intermittent fasting, can allow cells to temporarily turn off the growth machinery and engage in life-extending autophagy.
Using rapamycin to mimic calorie restriction has been promoted as a longevity enhancing intervention. So far though, the only real evidence comes from yeast, fruit flies, worms and mice. For now, inhibiting mTOR to downregulate cellular growth and upregulate autophagy through consuming fewer calories and lifting weights is a better bet than wrangling a prescription for rapamycin from a physician.
