Advancements in NAD+ Research

New research on NAD+ metabolism, NMN supplementation, and mitochondrial NAD+ levels was presented at the esteemed longevity conference, the Aging Research and Drug Discovery (ARDD) Meeting.

Key Points

  • CD38 degrades NMN more significantly than NAD+
  • NMN improved leg strength and blood cholesterol levels in adults
  • Mitochondria NAD+ levels may be an important therapeutic target

CD38 Degrades NMN and Regulates NAD+ Levels

The accumulation of the NAD+-degrading enzyme, CD38, plays a key role in the age-related decline of NAD+ levels.

Studies have revealed that CD38 degrades NMN even more than NAD+, and that controlling NMN availability has a significant effect on NAD+ levels.

To investigate the effect of NAD+ levels on aging, Dr. Eduardo Chini and other researchers have developed a mouse model in which young mice have tissue NAD+ levels comparable to those typically observed in older mice.

Initial experiments in the mice yielded important insights:

  • Mice with low NAD+ levels exhibit features of aging similar to older mice (hair discoloration, increased frailty, osteoporosis, eye disease)
  • There are 159 genes that change in the same way with aged mice and with mice that have low NAD+ levels

Studies have shown that giving mice substances that block the enzyme CD38 can improve their health in several ways, including better blood sugar control, stronger hearts, and increased lifespan.

NMN Improved Leg Strength and Blood Cholesterol in Adults

Dr. David Sinclair reported supplementation with 1000 mg of MIB-626 (a form of NMN) for 28 days increased leg strength and improved blood cholesterol levels.

“Lipids and cholesterol went in the right direction for improved health.” (Dr. David Sinclair)

Sinclair also reported on progress in restoring genes to reverse aging. Yamanaka factors (a set of genes important in aging) have shown to be effective in resetting age-related changes to genes related to eye health and restoring eyesight in several models.

Mitochondrial NAD+ Levels May Be an Important Target

A cell is composed of various compartments with different functions. Studies have shown that NAD+ levels and functions differ across these cellular compartments.

“We know there are at least 5 distinct pools of NAD+ in the cell that are membrane bound and separate.” (Dr. Joe Baur)

The identification of a transporter (SLC25A51) responsible for moving NAD+ into the mitochondria, has significantly expanded our understanding of NAD+ metabolism and its functions within the cell.

A mouse model of liver regeneration was chosen to study the effects of mitochondrial NAD+ levels because of observations from previous animal studies:

  • NAD+ levels decrease overall during liver regeneration, but increase in the mitochondria simultaneously.
  • Supplementing with the NAD+ precursor, Nicotinamide Riboside (NR), enhances liver recovery.

Dr. Joe Baur’s laboratory increased the levels of  SLC25A51 (and thus increased the amount of NAD+ in the mitochondria), in the liver regeneration mouse model and found enhanced recovery and regeneration of the liver.

The effect was similar to what was observed after supplementation with NR.

This suggests that modulating mitochondrial NAD+ levels may be a key mechanism through which NAD+ precursors contribute to liver regeneration.

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