Rapamycin for longevity: opinion article

Abstract

From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.

Keywords: aging; anti-aging; fasting; health span; lifespan; metformin; rapalogs; rapamycin.

Figure 1

Potential risk vs benefits of rapamycin-based anti-aging therapy. Pros and Cons: Potential benefits of rapamycin may outweigh its risks.

Figure 2

Optimal dose of rapamycin for maximal net benefits. Life extension by rapamycin is dose-dependent in rodents. The higher the dose, the higher the anti-aging benefits, including cancer prevention and life extension. In humans, side effects are dose-dependent and net benefits could potentially decrease at very high doses. This point of the highest net benefit is the optimal dose. The optimal dose varies in different individuals due to the variability of potential side effects. Thus, the optimal dose in a particular individual is determined by the emergence of side effects. The treatment can be viewed as life-long phase I/II clinical trial.

Figure 3

Effects of standard and anti-aging medicine on health- and life-span. (A) The relationship between health- and life-span. Aging is a sum of all age-related diseases, pre-diseases and pre-pre-diseases. Before overt age-related diseases become apparent, there is a seemingly healthy period of aging (so-called healthy aging). Starting from adulthood, pre-pre-diseases progress towards pre-diseases and then towards overt diseases. Unless treated with modern standard medical practice, the diseased stage is relatively brief. From (A) to (B) Standard medical treatment is usually started when overt diseases are diagnosed. Standard medicine extends life span mostly by preventing death from diseases, thus extending “unhealthy” phase of life, especially terminal stages of diseases, characterized by organ damage, failure and loss of functions. Standard medicine extends lifespan. From (B) to (C) Anti-aging medicine is most effective at the stage of pre-diseases and initial stages of diseases, characterized by increased functions before complications and organ damage occur. In terminal stages of deadly diseases, anti-aging therapy may not be useful. Thus, anti-aging medicine increases both health span and life span. Anti-aging medicine and standard medicine are additive when aging becomes unhealthy. The schema is simplified because, in reality, age-related diseases start at different ages (presbyopia vs sarcopenia), progress at different paces (atherosclerosis vs cancer), and most are not lethal, and some are well treated (cataract). Therefore, healthspan is an abstraction.