Anti-aging molecule NAD+ gets a boost from blocking an enzyme

October 24, 2018, Ecole Polytechnique Federale de Lausanne
Histological section of a normal kidney (left) versus a kidney after acute kidney injury (right). Credit: J. Auwerx, EPFL

Nicotinamide adenine dinucleotide (NAD+) is a major player in nutrition today. Studies have shown that NAD+ concentrations decrease during aging and that recovering the body's levels of NAD+ can prolong both health span and even life span, making it the focus of much research in nutritional science, medicine, and even pharmaceutics.

In terms of biology, NAD+ is what is known as a "co-—a necessary molecule that helps an enzyme carry out its respective reaction in the cell. NAD+ is a common co-enzyme for multiple metabolic enzymes across all living cells, meaning that it is heavily involved in producing energy and keeping cells alive and healthy.

Publishing in Nature, scientists led by Johan Auwerx at EPFL's Interfaculty Institute of Bioengineering in collaboration with TES Pharma have found a new way of increasing NAD+ in the kidney and liver by blocking an enzyme competing with its production.

The de novo synthesis of NAD+ in the cell begins with the amino acid tryptophan. One of the key enzymes involved in this process is ACMSD, which limits the amount of NAD+ produced by the de novo synthesis pathway.

The scientists were able to show that ACMSD controls the levels of NAD+ in the cell through a mechanism that doesn't seem to have changed during evolution. The researchers found that in both the earthworm Caenorhabditis elegans and mice, blocking the enzyme resulted in higher NAD+ levels and enhanced mitochondrial function.

The inactivation of ACMSD also increased the activity of Sirtuin 1, an enzyme that NAD+ works with in its role as co-enzyme. Sirtuin 1 is known to play major roles in mitochondrial well-being, and as a result, the boost of NAD+ levels ultimately enhanced .

The team then used two potent and selective inhibitors of ACMSD developed by TES Pharma. "Since the enzyme is mostly found in the kidney and liver, we wanted to test the capacity of the ACMSD inhibitors to protect these organs from injury," explains Elena Katsyuba, first author of the paper.

Both inhibitors were shown to preserve kidney and liver function in animal models of and of disease, offering much promise for their future therapeutic potential in humans. "The fact that ACMSD is exclusively present only in the liver and kidneys reduces the risk of negative repercussions of its loss on other organs," says Katsyuba. "Put simply, the enzyme will not be missed by an organ that does not have it anyway."

"Given the beneficial health effects of boosting NAD+ levels that we have seen in worm and mouse models of disease, we are looking forward to bringing these compounds soon to the clinic to the benefit of patients suffering from and diseases, two areas with a large unmet clinical need," says Johan Auwerx.

Explore further: Nutrients may reduce blood glucose levels

More information: Elena Katsyuba et al, De novo NAD+ synthesis enhances mitochondrial function and improves health, Nature (2018). DOI: 10.1038/s41586-018-0645-6

Related Stories

Nutrients may reduce blood glucose levels

October 10, 2018

Type 2 diabetes is driven by many metabolic pathways, with some pathways driven by amino acids, the molecular building blocks for proteins. Scientists at Joslin Diabetes Center now have shown that one amino acid, alanine, ...

New regulator of liver metabolism discovered

September 29, 2017

Researchers from Charité - Universitätsmedizin Berlin have identified an enzyme that has a major effect on glucose utilization in liver cells. The enzyme, retinol saturase, helps these cells adapt to variations in glucose ...

Recommended for you

Scientists bring polymers into atomic-scale focus

November 12, 2018

From water bottles and food containers to toys and tubing, many modern materials are made of plastics. And while we produce about 110 million tons per year of synthetic polymers like polyethylene and polypropylene worldwide ...

Synthetic molecule invades double-stranded DNA

November 12, 2018

Carnegie Mellon University researchers have developed a synthetic molecule that can recognize and bind to double-stranded DNA or RNA under normal physiological conditions. The molecule could provide a new platform for developing ...

Nitrogen fixation in ambient conditions

November 12, 2018

Abundant in the atmosphere, nitrogen is rarely used in the industrial production of chemicals. The most important process using nitrogen is the synthesis of ammonia used for the preparation of agricultural fertilizers.

New catalyst turns pollutant into fuel

November 12, 2018

Rather than allow power plants and industry to toss carbon dioxide into the atmosphere, incoming Rice University assistant professor Haotian Wang has a plan to convert the greenhouse gas into useful products in a green way.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.