Therapeutic potential of NAD-boosting molecules: the in vivo evidence

Luis Rajman,1Karolina Chwalek,1 and David A. Sinclair1,2,#

Summary Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+ sensing enzymes, it controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules. Such molecules hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

Nicotinamide adenine nucleotide (NAD+) has emerged as a key regulator of cellular processes that control the body’s response to stress. Rajman et al. discuss NAD boosters, small molecules that raise NAD+ levels, which are now considered to be highly promising

The rise, fall, and rise of NAD Nicotinamide adenine dinucleotide (NAD) is one of the most important and interesting molecules in the body. It is required for over 500 enzymatic reactions and plays key roles in the regulation of almost all major biological processes (Ansari and Raghava, 2010). Above all, it may allow us to lead healthier and longer lives. NAD was first described in 1906 by Harden and Young as a cell component that enhanced alcohol fermentation (Harden and Young, 1906). Then in 1936, Warburg showed that NAD is required for redox reactions (Warburg and Christian, 1936) and solidified the nomenclature: “NAD” refers to the chemical backbone irrespective of charge, “NAD+” and “NADH” refer to the oxidized and reduced forms respectively.

By 1960, it was assumed that all the exciting work on NAD had been done. In 1963, a breakthrough came with the discovery that NAD+ is a co-substrate for the addition of poly-ADP-ribose to proteins (Chambon et al., 1963). PARylation, as it is now called, is carried out by the poly(ADP-ribose) polymerases (PARPs), a family of 17 proteins involved in a wide variety of cellular functions. Some PARPs are mono-(ADP-ribose) transferases, so a better name for these proteins is MARTs (Bai, 2015; Gupte et al., 2017). PARPs control numerous cellular functions, from DNA repair to gene expression, though multiple members remain poorly characterized. Much of the renewed interest in NAD over the last decade can be attributed to the sirtuins, a family of NAD+-dependent protein deacylases (SIRT1-7). In 1999 Frye discovered that mammalian sirtuins metabolized NAD+ (Frye, 1999), then the Guarente and Sternglanz labs revealed that yeast Sir2 is an NAD+-dependent histone deacetylase (Imai et al., 2000; Landry et al., 2000). Since then, sirtuins have been shown to play a major regulatory role in almost all cellular functions. At the physiological level, sirtuins impact inflammation, cell growth, circadian rhythms, energy metabolism, neuronal function, and stress resistance (Gertler and Cohen, 2013; Imai and Yoshino, 2013). In this article, we review the physiology, pharmacology and potential use of “NAD-boosting molecules” for the treatment of diverse diseases and potentially even aging.

NAD+ synthesis NAD+ is one of the most abundant molecules in the human body, required for approximately 500 different enzymatic reactions and present at about three grams in the average person. Though it was once considered a relatively stable molecule, NAD+ is now known to be in a constant state of synthesis, degradation and recycling, not only in the cytoplasm but also within major organelles including the nucleus, Golgi and peroxisomes (Anderson et al., 2003). Recent advancements in high-resolution, high-sensitivity NAD+ metabolite tracing methods such as mitoPARP, PARAPLAY, and Apollo-NADP+ (Cambronne et al., 2016; Cameron et al., 2016; Dolle et al., 2010) have revealed that the concentration and distribution of NAD+ and its metabolites are different depending on the cell compartment and change in response to physiological stimuli and cellular stress. NAD+ has two main pools, the “free” pool and protein-associated, “bound” pool, and the ratio of these pools varies across different organelles, cell types, tissues and even the age of individuals. There is also evidence that there are rapid, local fluctuations of NAD+ (Zhang et al., 2012). With the exception of neurons, mammalian cells cannot import NAD+, so they must synthesize it either de novo by the kynurenine pathway from tryptophan (trp), or forms of vitamin-B3 such as nicotinamide (NAM) or nicotinic acid (NA) (Figure 1). To maintain NAD+ levels, most NAD+ is recycled via salvage pathways rather than generated de novo. The majority of NAD+ is salvaged from NAM, the product of CD38 and the PARPs (Magni et al., 2004; Magni et al., 1999) or from the various forms of niacin taken up in the diet including NAM, NA, NR and nicotinamide mononucleotide (NMN) (Bogan and Brenner, 2008; Mills et al., 2016; Trammell et al., 2016b; Ummarino et al., 2017). The precursor NR is thought to be directed into the salvage pathway via equilibrative nucleoside transporters (ENTs) (Nikiforov et al., 2011) and converted to NMN by nicotinamide riboside kinases (NRK1/2) (Ratajczak et al., 2016). NR generates unexpectedly high levels of NAAD in mouse liver and heart, as well as in human PBMCs, though the actual mechanism remains to be determined (Trammell et al., 2016a).

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