Fight Aging!

The path to understanding that pharmacological inhibition of mTOR replicates some of the calorie restriction response to cause a slowing of aging started with studies of rapamycin. The primary mechanism of interest is upregulation of autophagy, a cellular housekeeping mechanism that is involved in a range of interventions that slow aging in short-lived species. Other mechanisms may well turn out to be involved, as altering metabolism is a complex business and still incompletely understood.

The various mTOR inhibitors are collectively one of the most studied, and arguably best of the existing approaches to alter metabolism in order to modestly slow aging in mammals. This isn't rejuvenation, and isn't anywhere near as good as the effects of first generation senolytics when it comes to rapidly reversing aspects of aging in old animals. Rapamycin and other mTOR inhibitors are quite robust in their effects in comparison to many of the other alleged calorie restriction mimetics, however, so there is that.

Rapamycin, the only drug that has been consistently demonstrated to increase mammalian longevity. An update.

Prior to 2009 the consensus of scholars was that aging could not be treated or if it could be it must be a youth factor (e.g., growth hormone). Numerous advertised non-scientific approaches absconded with people's funds, mostly confused people, and were counterproductive for the field. However, there were two scientific settings in which aging could be reproducibly delayed. Unfortunately, neither was optimal for use in people. They were restrictions of diet and/or growth factors by genetic means. Since people do not like restricting anything, especially food, progress toward a deeper understanding of aging and potential ways to delay its effects was slow.

In recognition of this bottleneck, the National Institute of Aging established the Interventions Testing Program (ITP) to identify compounds that could be tested for aging effects under rigorous and standard conditions. To date, the ITP website indicates they have tested or in the process of testing 64 different compounds, some at varied doses and in combination. Twenty publications from the ITP have reported increases in lifespan from ten compounds. Importantly, the ITP also reports compounds that do not extend lifespan.

Here we focus of the ITP 2009 test of what was then an unlikely candidate drug called rapamycin. Results showing increased median and maximum lifespan in advanced aged males and females in this paper reset the paradigm for aging studies. It suggested that pharmacological agents can prevent, delay, and/or reduce the severity of age-caused morbidities. We will first briefly remind readers about the biology of the cell systems affected by rapamycin, better known as mTOR. Next, we will review the results of several studies on the effects chronic rapamycin has on lifespan in both sexes including our recollection of the first study. Following that, we will relate selected examples of the effects chronic rapamycin has on age-caused diseases.

We conclude with our view of what rapamycin effects are telling us about aging and how it might be working. We confess at the outset that we have only a faint picture of rapamycin's function as an anti-aging agent and suggest that it will be as complicated and mysterious as the studies to determine how restriction of food and growth factors work, which after half a century still have a way to go.