Mitochondria are the power plants of the cell. They produce the chemical energy store molecule ATP that is used to power cellular operations. Unfortunately, mitochondrial function falters throughout the body with advancing age, and while this is harmful in all tissues, the effects are particularly problematic in energy-hungry tissues such as the muscle and brain. Research of recent years has implicated the loss of nicotinamide adenine dinucleotide (NAD+) in mitochondria in this process. Evidence suggests that loss of effectiveness in mitophagy, the process that recycles worn and damaged mitochondria, is the important issue connected to NAD+ deficiency. NAD+ is largely produced by recycling its products, rather than by synthesis, but both the recycling and synthesis pathways suffer a loss of effectiveness with advancing age.
Various approaches to boost levels of NAD+ have been assessed in animals and are readily available for application to humans. Delivering NAD+ directly is inefficient in comparison to providing precursors and metabolites used in the synthesis and recycling pathways. Nicotinamide riboside supplementation is at present the only approach to upregulation of NAD+ in mitochondria with human trial data. The results from a small trial show a modest reduction in blood pressure in older hypertensive individuals, comparable with what can be achieved through lifestyle choices, due to improved smooth muscle function in blood vessels. One would expect there to be many more forms of benefit resulting from systemic improvement in mitochondrial function, but it is always hard to predict the size of effect in advance, and thus whether or not a particular approach to aging is actually worth it.
The research here is interesting for suggesting that NAD+ upregulation via nicotinamide riboside will lead to gains in immune function via improving the generation of immune cells in bone marrow. This is something that can be tested and quantified in humans without too much trouble, via examination of immune populations in a blood sample. That sort of effort is well within the reach of the self-experimentation community - though, as ever, it is more likely that the research community will get around to running a formal trial before self-experimenters organize sufficiently to produce robust data. The question at the end of the day is the size of effect: is it actually larger than that produced by exercise, and how does that vary by age?
Hematopoietic stem cells (HSCs) consist of a small cell-population in the bone-marrow (BM) that are responsible for lifelong production of all mature blood cells in an organism. A delicate balance of different HSC fates, namely, quiescence, self-renewal, and differentiation is decisive in maintaining the HSC pool and blood cell homeostasis. Cellular metabolism has emerged as one of the fundamental regulators of HSC fate decision process. HSCs rely primarily on anaerobic glycolysis while downstream progenitors use mitochondrial metabolism to fulfil their energy requirements.
In a recent study we have tested the mitochondrial modulator and NAD+ boosting agent, Nicotinamide Riboside (NR), in the context of regenerative hematopoiesis. One week of NR dietary supplementation to wild type mice resulted in increased BM cellularity and expansion of hematopoietic progenitor cells, this reflected in a significant increase in terminally differentiated circulating blood and immune cells. Importantly, mitochondrial profiling of HSCs derived from mice supplemented with NR revealed significant reduction of mitochondrial membrane potential (an indirect readout on mitochondrial activity), indicating that NR has a direct effect on HSC metabolism when administered systemically.
To understand the molecular mechanisms driving the effect of NR, we performed transcriptome analysis (by RNA sequencing) on ex vivo cultured HSCs. We found upregulation of autophagy (and mitophagy) and of NAD salvage pathway genes upon NR treatment, and a concomitant downregulation of mitochondrial metabolism pathway genes (TCA cycle and Oxidative Phosphorylation). NR-induced mitophagy was confirmed by image analysis of in vitro cultured HSCs and by bone marrow analysis of mitophagy reporter mice (mito-QC). We discovered that mitophagy induction was coupled with activation of mitochondrial unfolded protein response (UPRmt), that has been recently proposed as a conservation mechanism of the HSCs pool during aging. We hypothesize that NR-induced mitochondrial stress leads to the clearance of damaged mitochondria unable to coop with the metabolic stress. This complex mechanism initiates an instruction process where cells are primed toward asymmetric self-renewing cell division via differential distribution of active mitochondria in daughter cells.
Given that previous studies have implicated the importance of mitophagy and autophagy in HSC function and aging, we believe that NAD boosting strategies could be used to improve functionality of the hematopoietic stem cell pool in the elderly, where HSCs lose their capacity to produce a balanced immune system, being strongly primed toward a myeloid fate.