The Science Behind Signal: Targeting Metabolic Aging by Elevating NAD+ Levels and Activating Mitochondrial Sirtuin 3

Signal combines an NAD+ precursor, nicotinamide mononucleotide (NMN), and a proprietary SIRT3 Activation Complex, to target the effects of aging on metabolism at the cellular level and promote cellular energy production and utilization. Signal’s ingredients are designed to increase levels of NAD+, a key metabolite that declines universally with age, and synergistically activate the mitochondrial sirtuin, SIRT3, to support mitochondrial function and health. 

Targeting Metabolic Aging with NAD+

NAD+ (nicotinamide adenine dinucleotide) is a key metabolite whose levels are closely monitored by the cell in order to tune and balance its metabolic reactions. Regulating the vast number of metabolic reactions to maintain balance or homeostasis between energy production and usage is critical for cell health. During calorie restriction, NAD+ levels increase, triggering a specific network of metabolic reactions that have been shown to provide numerous health benefits. As we age, levels of NAD+ decline. 

Signal provides an immediate precursor to NAD+ called NMN (nicotinamide mononucleotide) which is efficiently converted to NAD+ by cells. Direct supplementation with NAD+ is not practical, as NAD+ cannot enter cells. NMN is one of the most efficient NAD+ precursors, requiring the least number of reaction steps and energy to convert to NAD+. Human clinical studies have demonstrated that dietary supplementation with NMN is safe and efficacious in increasing NAD+ levels [1, 2, 3]. Signal is designed to restore metabolic balance by increasing levels of NAD+ that decline during aging.

A recent study in mice identified an NMN-transporter in the small intestine that facilitates rapid uptake of NMN into the gut and other organs. Furthermore, this transporter was shown to specifically transport NMN but not NR, a different NAD+ precursor molecule. Another preclinical study reported efficient conversion of NR but not NMN into NAD+ in the muscle. Further studies are needed to confirm these results in humans but these preliminary reports suggest there may be potential differences in tissue-preference between NAD+ precursors. Results from human clinical trials also suggest potential differences in the role of these precursors. One study showed that NMN increased insulin sensitivity in prediabetic women whereas a different study showed that NR supplementation failed to affect insulin sensitivity in obese men. Studies directly comparing the different NAD+ precursors, side-by-side, are needed to better understand their potential differences. However, these initial results suggest that there may be potential benefits to combining different NAD+ precursors as part of your daily NAD+ supplementation, to ensure that different tissues in your body are receiving the NAD+ boost they need. 

The SIRT3 Activation Complex: Mitochondrial Protection Using Naturally Occurring Compounds

Signal contains a proprietary SIRT3 Activation Complex which contains two naturally occurring compounds, honokiol and viniferin, and is designed to activate sirtuin 3, or SIRT3. SIRT3 is a member of the sirtuin family of enzymes that depend on NAD+ to function. In 2002, Elysium co-founder and chief scientist Leonard Guarente, Ph.D., showed using preclinical models, that the beneficial effects of caloric restriction on lifespan and healthspan were mediated by sirtuins and NAD+. Published and ongoing clinical studies are validating whether these findings translate to benefits to human health. Since their discovery, sirtuins have emerged as key regulators of the nutrient-sensitive metabolic regulatory circuit. 

Three of the seven sirtuins reside in the mitochondrion which serves as a hub for metabolic reactions and produces ~95% of the cell’s ATP, the energy currency of the cell. Of the mitochondrial sirtuins, SIRT3 is the most studied. SIRT3 plays an essential role in maintaining mitochondrial health and metabolic control: from glucose metabolism, ATP production, fatty acid oxidation, and ketone production during fasting, to amino acid cycling. It has even been implicated in nutrient sensing. Both mitochondrial function and levels of mitochondrial sirtuins decline as we age, contributing extensively to aging through impaired metabolism. 

One of the ingredients in Signal’s SIRT3 Activation complex, is honokiol–a natural biphenolic compound derived from the bark of magnolia trees (Magnolia officinalis) and used in traditional Asian medicine. Honokiol is a potent activator of SIRT3 and has also been shown in preclinical studies to promote mitochondrial function. The second ingredient in the SIRT3 Activation Complex is viniferin, which is derived from grapevine. Viniferin is a derivative of resveratrol (contains two molecules of resveratrol) a naturally occurring polyphenolic compound found in grapes and wine, and extensively studied for its antioxidant, anti-inflammatory, and immunomodulatory properties. Viniferin content is comparable to or greater than resveratrol content, depending on the type of red wine. Viniferin has higher antioxidant activity than resveratrol in some preclinical models and has been shown to increase mitochondrial SIRT3 levels and enhance mitochondrial biogenesis in preclinical models.

Signal combines NMN with the SIRT3 Activation Complex to synergistically activate SIRT3, help maintain overall mitochondrial health, and promote optimal cellular energy production and utilization.

Human Clinical Trials with NMN

A human clinical trial published in the Journal of the International Society of Sports Nutrition studied the effects of NMN supplementation on middle-aged runners’ oxygen utilization capabilities. The results corroborate preclinical studies showing that oral supplementation of NMN improves the body’s ability to absorb and utilize oxygen and may increase athletic endurance. A second clinical study published in the journal Science showed that oral supplementation with NMN provided metabolic benefits to aged women with prediabetes. The study reported improved muscle insulin sensitivity in prediabetic women after NMN supplementation. There are also a number of pilot studies in humans on honokiol demonstrating potential health benefits (see references below). However, these studies used magnolia in combination with other compounds and the results need to be confirmed. As more clinical data becomes available, we look forward to sharing additional information. 

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References for Human Clinical Trials