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

EPA adviser is promoting harmful ideas, scientists say

March 22, 2019

The Trump administration's reliance on industry-funded environmental specialists is again coming under fire, this time by researchers who say that Louis Anthony "Tony" Cox Jr., who leads a key Environmental Protection Agency ...

The taming of the light screw

March 22, 2019

DESY and MPSD scientists have created high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might ...

Male fish can thank genes for colourful looks

March 22, 2019

Striking traits seen only in males of some species – such as colourful peacock feathers or butterfly wings – are partly explained by gene behaviour, research suggests.

Coffee-based colloids for direct solar absorption

March 22, 2019

Solar energy is one of the most promising resources to help reduce fossil fuel consumption and mitigate greenhouse gas emissions to power a sustainable future. Devices presently in use to convert solar energy into thermal ...

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.