Study unveils NAD's link to aging and disease development

UiB researchers are behind a new discovery that tells us how associated neurodegenerative diseases might develop.

In the center of this new discovery stands a molecule called NAD, or Nicotinamide Adenine Dinucleotide.

Professor Mathias Ziegler from the Department of Biomedicine, University of Bergen (UiB), led the international team of researchers behind the new study and explains its significance:

The fascinating thing about NAD is that the molecule is essential to life, as it plays critical roles in all cellular processes. Therefore, dysregulated NAD levels are involved in aging processes as well as many pathologies ranging from cancer to diabetes and neurodegenerative diseases. And the reason for this is that it holds a key position in both energy metabolism and the regulation of vital functions."

Professor Mathias Ziegler, Department of Biomedicine, University of Bergen

NAD is like a rechargeable battery

As we all know: All bodily functions depend on energy. Without energy we can neither run, breathe nor think. The energy that our body, or our cells, need to function comes from the food we ingest. Nutrients, such as sugar or fat, are converted to a universal form of energy that our cells can use to maintain all energy-demanding functions.

"NAD is central to these conversions as it functions like a rechargeable battery. It is charged by the energy retrieved from food and passes it on to fuel all cellular activities. An important part of this energy transfer takes place in cellular structures called mitochondria, which are also referred to as the powerhouse of the cell", Ziegler explains.

Crucially, NAD also contributes to many other vital functions throughout the cell. It serves as a chemical signal to regulate key cellular events including gene expression and DNA repair, which take place in the cell nucleus.

"Interestingly, during aging, our DNA may accumulate damage which, in turn, will increase the demand for NAD molecules. Indeed, we see that cellular NAD levels decrease as we age, and it is assumed that increased DNA repair activity is one of the main reasons for this decline" explains Ziegler.

"The problem arises when the mitochondria or their NAD store are affected or tapped over extended periods of time".

But how do cells cope with the increased demand for NAD and do decreased NAD levels necessarily result in pathological conditions?
To answer these questions, Ziegler and his team developed models to study how cells react to reduced NAD levels as they occur during aging.

They had previously developed a method that enabled them to detect cellular NAD molecules and their distribution in living cells. In addition, they now implemented advanced analytical techniques, including high-resolution mass spectrometry, to study the cellular dynamics of NAD-dependent processes. As a result, the researchers discovered a hitherto unrecognized role of mitochondria in the maintenance of cellular NAD levels:

"These organelles serve as an NAD reservoir that is filled when cells function normally, and it supplies the cell with NAD when there is an increased demand", explains Lena Høyland, PhD student and first author of the study.

Employing gene-technological methods such as CRISPR-Cas9 genome editing they were able to establish the molecular mechanisms of how mitochondria counteract cellular NAD decline.

"Decreased cellular NAD levels thus appear to be generally well tolerated by the cells", she says.

"The problem, however, arises when the mitochondria or their NAD store are affected or tapped over extended periods of time. This can have fatal consequences since the cells may no longer have sufficient NAD "battery capacity" to drive vital, energy-dependent processes", Professor Ziegler adds.

NAD supplementation has provided encouraging results

Research over the past years has established that mitochondrial dysfunction and lowered cellular NAD levels represent characteristics of aging, and age-related disorders, such as dementia or neurodegenerative diseases.

Based on their new findings, the team of researchers believes that excessive consumption of mitochondrial NAD might constitute a key factor leading to dysfunctional cellular powerhouses and thus aging-associated diseases.

Indeed, initial clinical trials in Norway and internationally using therapeutic supplementation approaches aiming to increase NAD levels have provided encouraging results.

"We are very excited about having discovered yet another mechanism potentially involved in disease development and progression", says Høyland, and Ziegler concludes:

"Our study also demonstrates the importance of basic research to identify promising targets to slow aging and to treat aging-related diseases".

The results have been published in the renowned journal Nature Metabolism and featured in a News and Views article in the same issue.