Continued Evolution of a NAD Centered View of Aging
There are researchers who consider declining levels of nicotinamide adenine dinucleotide (NAD) in mitochondria to be important in aging. The inability to produce sizable effects on longevity and age-related disease by upregulating NAD levels (or SIRT1 for that matter) argues against this view. Like very many other measures, NAD reduction is not all that important in and of itself, and fixing it in isolation isn't all that useful. Still, a fair number of researchers continue to explore the biochemistry surrounding the role of NAD in mitochondrial function. As yet, ways to meaningfully influence the progression of aging have yet to emerge from this part of the space. Looking at the decades of work put into IGF-1 signaling with a similar lack of tangible results when it comes to the treatment of aging, we might expect this state of affairs to continue for research into NAD.
The very first attempt to have such a meaningful image for the regulation of aging and longevity resulted in the introduction of a concept named the "NAD World" in 2009. The NAD World is a systemic regulatory network that connects NAD+ metabolism, biological rhythm, and aging and longevity control in mammals. In the original NAD World concept, two critical components were proposed to drive the NAD World: The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+-biosynthetic enzyme NAMPT. While NAMPT generates a circadian oscillation of NAD+ production in multiple tissues, SIRT1 responds to NAD+ availability and regulates many fundamental cellular and physiological processes, including transcription, DNA repair, stress response, metabolism, circadian rhythm, and aging. Through these coordinated functions, SIRT1 and NAMPT control the system dynamics of the NAD World and determine the process of aging and eventually, lifespan. The most important prediction from the concept of the NAD World was that the driving force of aging is the systemic decline in NAD+ levels.
The concept of the NAD World was then reformulated as the NAD World 2.0 in 2016, based on significant progress in the field over seven years. In the NAD World 2.0, three key tissues have been identified: The hypothalamus as the control center of aging, skeletal muscle as a mediator, and adipose tissue as a modulator. The details of the NAD World 2.0 were described previously6. Among several predictions from the NAD World 2.0, the most critical one is that the secretion of extracellular NAMPT (eNAMPT) from adipose tissue is a key inter-tissue communication between the hypothalamus and adipose tissue in mammalian aging and longevity control. A related prediction is the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate and the product of the NAMPT enzymatic reaction, in the maintenance of biological robustness. With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.
I think the NAD thing is best approached via mitochondrial fission/fusion. At least that's what's worked for me.