Researchers here argue for enhanced levels of NAD+ to boost stem cell function through improved mitochondrial function. This is an area of metabolism that has gained increasing attention of late, a second pass at the whole topic of sirtuins, mitochondrial function, and metabolism in aging. I'd say the jury is still out on whether it is worth pursing aggressively in human medicine. One or two early trials seem promising, in the sense of obtaining benefits that look similar to those derived from exercise, but the magnitude and reliability of those benefits is the important question.
The bone marrow stem cell population responsible for generating blood and immune cells, hematopoietic stem cells, declines in activity with age, as is the case for other stem cell populations. Some of this is due to intrinsic damage, but the evidence to date suggests that, up until very late life, the majority of the loss of activity can be overridden - it is an evolved response to rising levels of damage, possibly arising because it reduces cancer risk, rather than the direct consequence of damage. Thus researchers are in search of ways to safely override this response, via a variety of means.
Mitochondria are generally characterized as the powerhouse of the cell, since this is the site where energy is produced from ATP. In addition to energy production, mitochondria play a key role in several important cellular processes, including growth, signaling, differentiation, reactive oxygen species (ROS) production, apoptosis, and cell cycle control. Interestingly, unlike other cellular organelles, mitochondria have their own DNA, mitochondrial DNA (mtDNA), and several studies have indicated an association between the accumulation of mtDNA mutations and mammalian aging.
Historically, mitochondria have not been considered important in restoring the functions of aged hematopoietic stem cells (HSCs); however, emerging studies on rejuvenating HSCs suggest an association between sirtuins (SIRTs) and mitochondrial activities. In addition, a study on the deregulation of the mitochondrial stress-mediated metabolic system demonstrated that SIRT7 strongly influences the regenerative capacity of HSCs. Although the functions of musculoskeletal stem cells (MuSCs) and HSCs are distinct, alteration of the SIRT1-associated nuclear/mitochondrial axis appears to be a common hallmark of aging in both cell types.
Recent research suggests the possibility of restoring the mitochondrial functions of aged stem cells, including MuSCs, nerve tissue stem cells (NSCs), and melanocyte stem cells (McSCs), by NAD+ supplementation without genetic manipulation. The remedial effect of the NAD+ precursor nicotinamide riboside (NR) enhances mitochondrial functions in stem cells, including respiration, membrane potential, ATP production, and the mitochondrial unfolded protein response (UPR); however, these effects are not observed in stem cells with a SIRT1 deficit. Moreover, NR was found to suppress the process of senescence in adult NSCs and McSCs.
These findings have reinforced the notion that NAD+ precursors can function as a pharmacological tool to enhance SIRT activities. This, in turn, paves the way for clinical translation of NAD+ precursor treatment through further investigations of hematopoietic tissues. We review evidence relating mitochondrial dysfunction to HSC aging, and propose a strategy for mitochondrial-targeted recovery as a potentially safe, effective, and non-invasive method for the control or prevention of aging-related hematopoietic diseases.