Research on caloric restriction (CR) covers a span of 80 years and study results have fluctuated between negative, to sometimes positive, to consistently positive under the right conditions, and presently to positive but of little value beyond a normal caloric intake. Recent research, in addition to confirming the value of CR on health-span and possibly longevity, has identified the genetic pathways that are activated in CR, and opened the door to interventions such as alpha lipoic acid that might mimic the positive effects of CR, without the difficulty of adhering to a low calorie diet. The most recent research on CR has highlighted the importance of the macronutrient ratio in achieving positive health effects, particularly the ratio of protein to carbohydrate.
EARLY CR STUDIES:
The first study on CR was conducted in 1935, but was based on societal problems with malnutrition, and had nothing to do with possible beneficial effects on health and aging. To the contrary, the study demonstrated retarded growth during development, poor health and a shorter lifespan. Some years later, a study was performed in rats by McKay et. al., that only restricted calories, but still provided the vitamins, minerals and micronutrients required to maintain health. Like the earlier study, developmental growth was retarded, but the animals experienced a considerably longer lifespan. During this time period, researchers concluded that the beneficial effects of CR are the result of delayed developmental growth. This conclusion was a clue to the mechanism behind the health benefits of CR, but was later proven incorrect.
Studies in the 1950’s and 1960’s demonstrated that intermittent fasting was as effective as chronic CR, providing a more user-friendly way to achieve the health benefits of CR. Considerable research, with varying results continued for several decades, but the real breakthrough came in 1996 in research that was performed on simple animal models (worms and flies) that elucidated the molecular pathways involved in CR.
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.
PROTEIN: The FINAL NAIL in the CR COFFIN:
Research on CR has focused attention on all of the factors in the design of studies that have had unexpected outcomes. One of these factors was the macronutrient composition used in the study, with particular attention to the ratio of protein to carbohydrate. Using a research tool designated the Geometric Framework nutritional modeling method, researchers Raubenheimer and Simpson (Sydney, Australia), found that diets that were low in protein and high in carbohydrates produced a health-span comparable to CR. A low protein diet was defined as <5% calories from protein, a moderate protein diet as 10% – 20%, and a high protein diet as >20%. Disease and mortality was surprisingly high for the high protein diet, but ameliorated by substituting plant protein for animal protein. This effect was observed in persons under age 65, but the reverse was true for people over age 65, who had higher disease and mortality with a low protein diet and better health and longevity with a high protein diet. The mechanism behind the negative effects of a high protein diet appear to be related to stimulation of the mTORC1 pathway by nutrient sensing of the high availability of amino acids in the cells. It isn’t clear why this protein effect reverses at age 65, but presumably has to do with the accelerated loss of muscle mass with aging, which would be exacerbated with inhibition of the mTORC1 pathway.
CONCLUSION:
It is well-established that under the right conditions, CR is an effective way to lose body mass, extend health-span and possibly extend lifespan. Research studies on CR have contributed to the discovery and understanding of the mTORC1 pathway, which is the major regulator of metabolic activity in humans. While CR is beneficial in itself in reducing chronic disease, it is a difficult regimen to follow and certainly not in sync with modern lifestyles. CR research has led to the discovery that equivalent beneficial effects can be realized with a normal diet, provided that the ratio of protein and carbohydrate are optimized for age. Elucidation of the mTORC1 pathway has also opened the door to user-friendly means of inhibiting the mTORC1 pathway through design of drugs that block or inhibit steps in the regulatory process, or preferentially the application of naturally-occurring molecules such as alpha lipoic acid that stimulate formation of AMPk and down-regulation of mTORC1.
REFERENCES:
- The ratio of macro-nutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum fed mice. Solon-Biet, SM et. al., Cell Metab. 2014 Mar 4: 19 (3); 418-430.
- Alpha-Lipoic Acid Supplementation Reduces mTORC1 Signaling in Skeletal Muscle from High Fat Fed, Obese Zucker Rats. Zhuyun Li, Cory M. Dungan, Bradley Carrier, Todd C. Rideout, David L. Williamson. Lipids. Dec 2014, Volume 49, Issue 12, pp 1193-1201.
- Energy restriction and potential energy restriction mimetics. Nikolai, S et. al., Nutr Res Rev. 2015 Dec;28(2):100-120. Epub 2015 Sep 22.
