Newly discovered mechanism reveals NAD's role in aging and disease

Good news!

"... "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," ...

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. ..."

From the abstract:

"The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption.

To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged.

Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected."

Newly discovered mechanism reveals NAD's role in aging and disease

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+ (no public access)

Proposed model for the cooperation of SLC25A51 and NMNAT3 to buffer cellular NAD+ fluctuations.