What is the evidence that B3 vitamins benefit healthspan?
Average lifespan is defined as 73 years for men and 79 years for women. Healthspan, a relatively newer term gaining popularity in the mainstream media, is not yet defined in precise quantitative terms. However, most agree it refers to the number of years that a person enjoys “good” health and is free of chronic disease and disability associated with aging.
Given this definition, extending healthspan is universally appealing, but is it possible, and how?
The first and most tested approach for extending healthspan is, of course, making healthy lifestyle choices. Getting enough physical exercise, eating a nutritious diet, and reducing stress are well-known foundational approaches to promoting health as chronological age increases. In addition to these, a growing body of data is revealing new, evidence-based approaches for extending healthspan.
Although research into human aging is still developing, with many important aspects still undiscovered, there is consensus that health and healthy aging is determined at the cellular level. To have a healthy brain, neuronal cells need to function optimally. To avoid diabetes, the pancreatic islet cells must make and secrete adequate levels of insulin and other hormones. A healthy heart requires healthy heart cells. Altered performance of just one type of cell within an organ can create conditions that alter function of the organ. Altered function of an organ has effects at the organismal level.
The cellular basis of aging is illustrated by the nine hallmarks of aging1: genomic instability, telomere attrition, epigenetics, lost proteostasis, deregulated nutrient sensing, altered intercellular communication, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion—all subcellular phenomena.
While there are undoubtedly many inputs to these cellular functions, one molecule is central to them all. Nicotinamide adenine dinucleotide, or NAD+, is required for essential enzymatic reactions associated with each of the nine hallmarks of aging and is necessary for cells to function properly.
NAD+ is an essential co-enzyme required for cellular function across all orders of life. NAD+ is used as a co-enzyme in oxidation-reduction (redox) reactions, where it functions as an electron carrier and therefore exists in both oxidized (NAD+) and reduced forms (NADH). NAD+ also supports critical cellular functions by serving as a substrate of NAD+-consuming enzymes. These enzymes (sirtuins, CD38, and PARPs) are implicated in key cellular functions associated with aging. Their enzymatic activity breaks a bond in the NAD+ molecule, destroying it, thus making it essential that cells continually synthesize new NAD+ molecules to maintain adequate levels.
Cellular NAD+ levels decline with age—up to 65% between ages 30 to 70. Accordingly, NAD+ depletion is implicated in a variety of age-related diseases and age-related disease phenotypes, including neurodegeneration, diabetes, and progeroid diseases (such as Ataxia Telangiectasia and Werner Syndrome). Research has shown that restoring NAD+ through genetic and molecular means rescues aging and age-associated disease phenotypes in animal models.
In humans, NAD+ is made from precursor molecules, including tryptophan and the B3 family vitamins nicotinamide, nicotinic acid, and nicotinamide riboside (NR). These precursors enter cells and are chemically converted through biosynthetic pathways to NAD+ (See Figure 1). Nicotinamide mononucleotide (NMN) is a nucleotide NAD+ precursor, which needs to be chemically converted to NR to enter most cells (See Figure 1), although a specific transporter may allow direct transport of NMN into some intestinal cells in mice. Studies are needed to determine the physiological relevance of this transporter to disease, the kinetics of NMN uptake, and tissue-specific expression in mammals.
While each of the NAD+ precursors can be found in a healthy varied diet, higher levels may be needed to support cellular health and combat NAD+ decline associated with aging. Among NAD+ precursors, NR and its reduced form NRH are the most orally bioavailable. To date, 24 clinical trials have been published demonstrating the safety and/or activity of NR in humans, and a total of 84 clinical trials of NR are currently listed in the U.S. repository for clinical trials maintained by the National Institutes of Health. Clinical trials of NMN are also ongoing, and several have been published, although the FDA recently withdrew the new dietary ingredient (NDI) status of NMN and issued a statement saying it could not be sold as a supplement.
Clinical trials completed to date showcasing NR as a potential therapeutic strategy for age-related diseases include:
Notably, the Parkinson’s disease trial results were sufficient to justify a phase 2 study, which is being funded by the Norwegian government to further examine the ability of NR to improve scores on the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (UPDRS).
These studies and other completed and ongoing clinical trials warrant the attention of healthcare providers and suggest that NR represents a safe and effective supplement that may help patients maximize health in their later years.
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