Increased synthesis of a coenzyme linked to longevity can combat disease

The coenzyme NAD+ can be produced from the amino acid tryptophan. It emerges that inhibiting an enzyme that degrades an intermediate in this pathway can help to combat kidney and liver diseases in mouse models.
Samir M. Parikh is in the Center for Vascular Biology, Department of Medicine and Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

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Throughout the history of life on Earth, there has been a requirement for small molecules called nucleotides. Long chains of nucleotides make up the genetic code, and single nucleotides transduce signals or transfer energy. In addition, a dimeric form of nucleotide called nicotinamide adenine dinucleotide (NAD+) serves at least two pivotal cellular functions. The first is to shuttle high-energy electrons to enzymatic complexes found in organelles called mitochondria, where their energy can be efficiently harvested; the second is as a substrate for enzymes such as sirtuins, which regulate many cellular behaviours. In a paper in Nature, Katsyuba et al.1 shed light on a fundamental mechanism by which the correct levels of NAD+ are maintained in cells, and demonstrate how augmenting this pathway can affect disease.

In simple terms, the available pool of NAD+ in a cell is governed by the balance between its generation and its consumption. The predominant pathway by which NAD+ is generated in rodents relies on the recycling of a molecule called nicotinamide (Nam) that is either ingested or released by enzymes that consume NAD+ (Fig. 1). There are several other routes of NAD+ production, including a de novo synthesis pathway that starts with the essential amino acid tryptophan (Trp)2. Mutations that disrupt the enzymes responsible for converting Trp to NAD+ result in multi-system developmental alterations in humans3, demonstrating the importance of this de novo pathway.

Figure 1 | NAD+ biosynthesis in disease. When the coenzyme nicotinamide adenine dinucleotide (NAD+) is consumed by enzymes, nicotinamide (Nam) is generated as a reaction product. Through a recycling mechanism called the salvage pathway, NAD+ can then be regenerated. Nam salvage is considered the predominant mechanism for NAD+ biosynthesis, but NAD+ can also be generated through multiple other routes. One of these is the de novo pathway, whereby the amino acid tryptophan (Trp) is converted to NAD+ through several intermediates, including α-amino-β-carboxymuconate-ε-semialdehyde (ACMS). This pathway can be depleted by the enzyme ACMS decarboxylase (ACMSD), which degrades ACMS to picolinic acid (Pic). Katsyuba et al.1 report that chemical inhibition of ACMSD raises NAD+ levels in mice and nematode worms, and improves outcomes in mouse models of liver and kidney diseases.

Katsyuba et al. set out to study α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), an unstable and little-studied intermediate of the Trp pathway. ACMS can either spontaneously convert to the next intermediate on the path to NAD+, or can be degraded by a train of enzymes, starting with ACMS decarboxylase (ACMSD). As such, ACMSD would be predicted to limit the amount of NAD+ produced through de novo synthesis. ACMSD is evolutionarily conserved from the nematode worm C. elegans to mice4 — an observation that is striking because, until recently, nematodes were not thought to synthesize NAD+ de novo.

The authors inhibited the acsd-1 gene, which encodes the equivalent of ACMSD in nematodes. This inhibition did increase NAD+ levels. Increasing NAD+ is well known to extend lifespan in worms, and the authors found that lifespan was longer in the worms in which acsd-1 expression was completely blocked. Moreover, preventing acsd-1 expression led to molecular responses that have been linked to defence against ageing5,6: increased activation of the sirtuin enzyme sir-2.1; enhanced mitochondrial function; and a protective mitochondrial stress response.

In mice and humans, ACMSD is most highly expressed in the liver and kidney7, and a recent study indicates that these are the main organs for Trp-dependent NAD+ generation8. Katsyuba et al. found that inhibition of the Acmsd gene increased NAD+ levels and mitochondrial function in cultured mouse liver cells. The authors therefore developed chemical inhibitors of ACMSD, and tested whether these inhibitors could improve outcomes in mouse models of two ageing-related diseases: diet-induced fatty liver disease and acute kidney injury.

Earlier work had already described a beneficial effect of augmenting NAD+ in each of these settings9,10. Katsyuba and colleagues’ data confirmed the potential for therapeutic NAD+ augmentation — treatment with their inhibitors protected against disease in these models. The results also suggest that increases in the de novo NAD+ synthesis pathway alone are sufficiently robust to ameliorate liver and kidney diseases associated with low NAD+ levels. However, proving this will require a demonstration that the benefit of ACMSD inhibition derives from the increase in NAD+, rather than from another mechanism such as depletion of the molecule picolinic acid, which is produced by ACMSD-mediated degradation of ACMS. If proved, this finding would be consistent with a study11 that identified a different enzyme in the Trp pathway, quinolinate phosphoribosyltransferase, as a determinant of susceptibility to acute kidney injury.

Several basic questions merit further consideration. For instance, what evolutionary pressures could have led to the conservation of multiple biosynthetic routes to NAD+? And why is the de novo pathway most active in organs involved in detoxification of the body in mammals? One attractive possibility is that the liver and kidney are more exposed than other organs to toxic stressors that stimulate NAD+ consumption. The fact that these organs export Nam to the rest of the body8 might explain some aspects of inter-organ metabolic relationships in health and disease — for example, why people with chronic liver disease often develop impaired brain and heart function.

The ACMSD inhibitors developed by Katsyuba et al. are indicative of the interest in harnessing NAD+ augmentation in the clinic. It has been nearly 20 years since NAD+ was first proposed to be a determinant of lifespan12. But because ageing is so complex, a clinically testable definition has been lacking. Trials to examine the relationship between NAD+ augmentation and human lifespan would take too long to be financially feasible. If, instead, a definition of ageing incorporated waning resistance to acute stressors such as infections, trauma or surgery, then clinical testing of NAD+ modulators could become more viable. Another study has recently applied this logic, reporting a trial of orally administered Nam among people undergoing cardiac bypass surgery — an invasive procedure often performed on older individuals and associated with post-operative kidney injury11. The beneficial effect of NAD+ augmentation on acute kidney injury observed in that work, although preliminary, illuminates a translational track for NAD+ manipulation.

However, oral consumption of NAD+ precursors might not be an efficient way to increase NAD+ levels8, so there is a need to consider more-targeted pharmacological approaches. The ACMSD inhibitors developed by Katsyuba and colleagues are therefore a valuable proof of concept. Given the enrichment of enzymes of the de novo pathway in the kidney and liver, this particular strategy also raises the intriguing possibility of tissue-specific NAD+ manipulation.

The list of conditions potentially amenable to NAD+ augmentation is varied and growing, from glaucoma13 to neurodegenerative conditions14 and metabolic syndrome15. A confluence of work using distinct approaches — human genetics3, radiochemistry8, comparative phylogeny1 and clinical studies11 — now indicates that the Trp pathway is both a major gatekeeper of NAD+ levels and a target for medical exploration.

Nature 563, 332-333 (2018)

doi: 10.1038/d41586-018-07088-4
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