Nicotinamide adenine dinucleotide (NAD+) is called the “anti-aging molecule” because research has shown that its levels fall with age and that restoring them can extend years of good health and even longevity itself. This molecule plays a key role in several biological processes that help cells get energy and stay healthy, such as metabolism, DNA repair, gene expression, and cell signaling. Scientists class NAD+ as a coenzyme, meaning that it does not act alone but helps the enzymes that drive these vital cell processes. One family of enzymes that NAD+ has an ancient “intimate connection” with is the sirtuins. Studies have shown that as NAD+ declines with age, it reduces sirtuin activity in ways that affect the communication between the cell nucleus and its mitochondria. Besides sirtuins, other enzymes, such as the poly ADP‐ribose polymerase (PARP) protein family and the cyclic ADP‐ribose (cADPR) synthases, such as CD38 and CD157, are currently known to require NAD+ as a cosubstrate to perform their function. The dependence of these important metabolic enzymes on NAD+ levels provides an attractive possibility to modulate their activity and thereby achieve health benefits and has led to an increased interest in NAD+ metabolism over the last decade. The therapeutic potential of NAD+ boosting techniques to activate the sirtuins has now been explored in a large spectrum of preclinical disease models that mimic rare genetic disorders, such as the xeroderma (XPA), as well as pandemic‐like contemporary diseases, such as obesity or non‐alcoholic fatty liver disease (NAFLD).
A new study, which the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland led, features in the journal Nature. It demonstrates two compounds that could restore fallen levels of NAD+ in the liver and kidneys. Cells synthesize NAD+ from scratch using the amino acid tryptophan as the main building block. This “de novo synthesis” requires the presence of certain enzymes, including one called ACMSD (amino-carboxymuconate semialdehyde decarboxylase), which has the effect of limiting the production of NAD+. The team describe the way in which ACMSD controls NAD+ levels in cells as being “evolutionarily conserved.” Their investigation demonstrated that the mechanism was the same in both Caenorhabditis elegans, a type of worm, and mice, and that blocking ACMSD increased both NAD+ and mitochondrial activity. The researchers discovered that blocking ACMSD also raised the activity of one of the sirtuins that NAD+ works with. The combination of elevated sirtuin activity and increased NAD+ synthesis boosted mitochondrial activity.Working with TES Pharma, the team then tested the effect of two selective ACMSD blockers in animal models of nonalcoholic fatty liver disease and kidney damage. Both compounds seemed to “preserve” liver and kidney function. As ACMSD does not occur elsewhere in the body, the finding could pave the way for a protective treatment that boosts NAD+ without affecting other organs.
Multiple studies demonstrated the loss of SIRT1 and SIRT3 activity as a key feature of kidney dysfunction, including kidney abnormalities linked with aging. Acute kidney injury (AKI) is characterized by a reduction in NAD+ content and NAMPRT expression. Promoting NAD+ synthesis via NAM or NMN precursor supplementation was reported to mitigate AKI in ischemia/reperfusion‐induced mouse models of AKI. Furthermore, administration of the nucleotide AICAR, which positively impacts on NAD+ levels, was protective against chemotherapy‐induced AKI in SIRT3‐dependent manner. First study author Elena Katsyuba, of the Interfaculty Institute of Bioengineering at EPFL, comments: “Since the enzyme is mostly found in the kidneys and liver, we wanted to test the capacity of the ACMSD inhibitors to protect these organs from injury. Put simply, the enzyme will not be missed by an organ that does not have it anyway. Although it was thought that the NAD+ biosynthetic pathways were entirely understood, we still continue to discover new actors of NAD+metabolism. Additionally, it is possible that we still ignore some functions that NAD+might accomplish within the cell. For instance, very recently NAD+ was found to be linked to RNA in bacteria. In man, we know that several neurodegenerative diseases (e.g. ALS or SMN) are linked to defects in RNA metabolism. No wondering that we could expect more surprises in this field”.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Pellicciari R et al. J Med Chem. 2018; 61(3):745-759.
Katsyuba E et al., Auwerx J. Nature. 2018 Oct 24.