It has been reasonably well-established that the practice of “caloric restriction” (fasting or intermittent fasting) has a favorable impact on overall health and well-being and possibly the extension of life. Recent research studies have identified the genetic pathway (mTORC1) that is impacted by caloric restriction and offered insights into how the benefits of CR might be realized without the difficulty of adapting to fasting practices.
CR METABOLIC PATHWAYS:
It comes as no surprise that humans have a gene-based survival system to prolong survival during periods of prolonged famine, and that this system serves as a sensor for nutrient and energy levels, and a regulator of biomass formation. What is surprising is the fact that regulation of this system can have long-term beneficial effects on health and possibly on lifespan. The discovery of this system had it’s origins in an antifungal/immunosuppressant substance that was isolated from a soil sample from the Easter Islands (Rapa Nui). It was named Rapamycin in reference to the place it was discovered. Work on microorganism resistance to Rapamycin led to the later discovery in yeast that Rapamycin inhibits a gene that produces a serine/threonine protein called mTOR (mammalian target of rapamycin), and that like CR, Rapamycin extended lifespan.
The key regulator in this metabolic pathway is a complex of mTOR and co-factors that is identified as mTORC1. mTORC1 is a signaling hub that integrates nutrient and energy signaling with growth factor signaling. Generally mTORC1 stimulates protein synthesis and anabolic growth and inhibits autophagy. Conversely, CR and Rapamycin inhibit mTORC1 which reduces protein formation, and ATP formation, and increases autophagy.
mTORC1 is a complex system that stimulates numerous downstream processes including messenger RNA translation and the transcription factor C/EBPbeta-LIP. LIP is a protein that binds to DNA metabolic regulating sites. The LIP protein can be suppressed by removing an upstream regulatory element (uORF), which produces an effect equivalent to CR or Rapamycin. As is usually the case in this type of situation, developing a drug that inhibits uORF or another critical step in the mTORC1 pathway could theoretically lead to a drug to extend health-span and lifespan.
PHARMACOLOGIC INTERVENTION IN mTORC1 PATHWAY:
The scientific community and the media are conditioned to judge the value of a research finding by the possibility of developing a drug to achieve a therapeutic objective. History, while uniformly disregarded, has shown that drugs designed to block physiological processes rarely act on only the process being targeted. The result is an effective drug, with serious side effects that emerge during clinical trials or after the drug is marketed. To my amazement, society is becoming more accepting of these serious side effects as reflected in the marketing of most biologics. I believe that Rapamycin fits this description as a drug to combat aging. Rapamycin clearly inhibits mTORC1, but has many serious side effects that make it unsuitable for widespread chronic use. This hasn’t stopped the media from touting Rapamycin as the Fountain of Youth drug, and I sense that drug companies will eventually promote the drug for this use and attempt to justify the side effects as reasonable vs. the benefits.
There are many naturally-occurring substances that have epigenetic effects similar to the actions of more powerful drugs, and generally without the serious side effects. One such substance is the widely researched and less widely used alpha lipoic acid. In addition to its favorable effects on oxidative stress and diabetic neuropathy, more recent research has recognized the multi-functional properties of alpha lipoic acid, with particular emphasis on the stimulation of AMPk and the corresponding inhibition of mTORC1 activity. As described in the research reports referenced below, alpha lipoic acid, along with other energy restriction mimetics (resveratrol, rapamycin, metformin and spermidine) stimulates formation of kinase activated AMP, that in turn signals that the cell is in an energy restricted state, and mTORC1 is inhibited. The paper by Nikolai et.al. states that these CR mimetics can have serious side effects and have not been proven safe for long-term use. Contrary to this position it should be noted that alpha lipoic acid has been studied extensively for several decades and has been cited in almost 5000 scientific papers, the vast majority of which report beneficial effects. It is true that alpha lipoic acid has not been subjected to extensive controlled, double-blind studies in humans, but it is commonly used by many health conscious consumers, with no reports of adverse events. Because alpha lipoic acid is a naturally occurring substance that cannot be patented, it is unlikely that funding will be made available for controlled clinical studies or education of the public regarding its many benefits.