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How Can Calorie Restriction Help Support Mitochondrial Function, Anti-Aging and Chronic Disease?

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The benefits of calorie restriction (CR) have been studied for over 70 years. It has been the only proven method to extend the maximal lifespan of mammals. Numerous studies have found reducing total calories by 30 to 50% while maintaining proper nutrition can not only extend lifespan but also create impressive improvements in metabolism, energy production and neuroprotection in both animals and humans. There are number of reasons that CR has a beneficial effect including burning fats (ketones) as fuel but ultimately the mitochondria is where the positive effects occur. This has sent the scientific community in search of finding ways to harness the benefits CR not only for longevity but also as a treatment for diseases that have mitochondrial dysfunction such as neurological disorders.

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The key role of the mitochondria is to produce energy (in the form of ATP) through a complex process that occurs inside each mitochondria called the citric acid cycle and series of steps that requires glucose, oxygen, minerals, b-vitamins, and CoQ10. One of the key lynch-pins in the mitochondrial energy pathways is a substance called NAD (nicotinamide adenine dinucleotide). It is present in 2 forms, NAD+ (the oxidized form) and NADH (the reduced form). What is becoming clear is that the NAD+ to NADH ratio plays powerful role in controlling how much energy the mitochondria and produce. Higher NAD+ levels are thought to have a stimulatory effect on beneficial genes and energy production while a high NADH concentration is thought to inhibit beneficial genes and limit energy production. This is now referred to as the NAD+/NADH ratio theory of aging and chronic disease.

However, despite this fact there is research showing that NADH supplementation has health benefits. Clinical trials of NADH have found that it can significantly improve conditions such as Parkinson’s disease because it can support the synthesis of dopamine. It was also found to improve dementia in Alzheimer’s disease. NADH’s role in energy production makes it potentially useful for dealing with fatigue. Clinical trials found that NADH was effective against the symptoms of chronic fatigue syndrome. In animal studies, it was found to lower blood pressure, total cholesterol and levels of LDL “bad” cholesterol.

So why does NADH supplementation seem to have a positive effect despite the fact a higher NAD+ to NADH ratio is associated with longer lifespan and mitochondrial function? The fact is that the pharmacokinetics and mechanism of action for NADH supplementation are simply not clearly understood at this time. One proposed explanation that scientists have put forward is that NADH converts back into NAD+, which would explain its positive clinical effects in the face of the emerging NAD+/NADH ratio theory.

Taking this discussion full circle back to caloric restriction, there is a very unique substance called BenaGene that appears to mimic the effect of caloric restriction. BenaGene is thermally stabilized form of oxaloacetate (AKA 3-carboxy-3-oxopropanoic acid), which is a key part of the citric acid cycle that produces energy inside each cell. Increasing oxaloacetate via supplementation promotes a higher NAD+/NADH ratio which is associated with all the beneficial effects of CR we already have discussed. What has scientists and anti-aging enthusiasts so excited is that animal studies have shown that life span was extended by 30% after supplementing with BenaGene. It also promoted a genetic profile similar to calorically restricted animals. While human trials on BenaGene’s effects on life extension have not been conducted, human clinical trials have confirmed both reduction in glucose levels and an improved uptake of glucose without negative side effects. This action alone has a tremendous beneficial effect of numerous disease processes such as diabetes, Alzheimer’s disease, cardiovascular disease and even cancer.

Calorie restriction has numerous health benefits including increased longevity and disease prevention. The mechanism of calorically restricted diet is that it increases the NAD+ to NADH ratio in the mitochondria, optimizing energy production and creating an optimal cellular environment which translates into the expression of beneficial genes. Supplementation with a specific stabilized form of oxaloacetate called BenaGene has shown positive effects that can mimic the effect of a calorically restricted diet. This can translate into clinical applications for almost every chronic disease.



1) Fontana, et al, “Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans, PNAS, April 27, 2004, Vol.101, no. 17, pp 6659-6663

2) Hursting, S et. al. “Calorie Restriction, Aging and Cancer Prevention: Mechanisms of Action and Applicability to Humans”, Annual Review of Medicine, Vol 54: 131-152, February 2003

3) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease, 2003, Current Opinion in Cell Biology, Vol. 15 pp 241-246

4) Lin, S. et al, “Calorie restriction extends yeast life span by lowering the level of NADH”. 2004 Genes & Development Vol. 18 pp 12-16.

5) Lin, S-J. 2006. “Molecular Mechanisms of Longevity Regulation and Calorie Restriction”. In Nutritional Genomics: Discovering the Path to Personalized Nutrition. Kaput, J and Rodriguz, R (eds). Wiley and Sons, Inc. NY. 2006.

6) Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does Oral Coenzyme Q10 Plus NADH Supplementation Improve Fatigue and Biochemical Parameters in Chronic Fatigue Syndrome? Antioxidants & Redox Signaling. 2015;22(8):679-685. doi:10.1089/ars.2014.6181.

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