Study unveils NAD’s link to aging and disease development

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

At the center of this new discovery is 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 for life, because it plays a crucial role in all cellular processes. Therefore, dysregulated NAD levels are involved in aging processes and in many pathologies ranging from cancer to diabetes and neurodegenerative diseases. And the reason for this is that it occupies 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 cannot run, breathe or 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 into a universal form of energy that our cells can use to maintain all energy-requiring functions.

“NAD plays a central role in these conversions because it functions like a rechargeable battery. It is charged by the energy extracted 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. are also called the powerhouse of the cell,” Ziegler explains.

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

“Interestingly, our DNA can accumulate damage as we age, which will in turn increase the demand for NAD molecules. Indeed, we see that cellular NAD levels decline as we age, and increased DNA repair activity is believed to be one of the main reasons for this decline,” Ziegler explains.

“The problem arises when the mitochondria or their NAD stores are compromised or tapped for extended periods of time.”

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

They had previously developed a method that allowed them to detect cellular NAD molecules and their distribution in living cells. Furthermore, 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 previously unknown role of mitochondria in maintaining cellular NAD levels:

“These organelles serve as a 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.

Using genetic engineering methods such as CRISPR-Cas9 genome editing, they were able to pinpoint the molecular mechanisms of how mitochondria counteract the decline of cellular NAD.

“So reduced cellular NAD levels appear to be generally well tolerated by the cells,” she says.

“However, the problem arises when the mitochondria or their NAD stores are compromised or drained for extended periods of time. This can have fatal consequences, as the cells may no longer have sufficient NAD ‘battery capacity’ to power vital, energy-dependent processes. “, adds Professor Ziegler.

NAD supplementation has shown encouraging results

Research in recent years has shown that mitochondrial dysfunction and reduced cellular NAD levels are hallmarks of aging and of age-related conditions, such as dementia or neurodegenerative diseases.

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

Indeed, the first clinical trials in Norway and internationally using therapeutic supplementation approaches aimed at increasing NAD levels have shown encouraging results.

“We are very excited about the fact that we have discovered yet another mechanism that may be 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 treat aging-related diseases.”

The results were published in the renowned journal Nature Metabolism and included in a News and Views article in the same issue.