A great synopsis in regards to not only the importance of NAD+ for systemic health, but also about what drives the well-known depletion of NAD+ (thus lowering the mitochondrial NAD+/NADH ratio) seen in virtually all diseases, both acute and chronic. There is an enzyme known as PARP-1 and it is involved in DNA repair. It is the primary consumer of NAD+ and upregulation of PARP-1 is one of the hallmarks of cancer. There are several drugs on the market that inhibit PARP-1 and they have shown great promise in treating cancer. Recent studies have demonstrated that PARP-1 is also elevated in many chronic conditions aside from cancer, but the reason for this elevation was unknown until now. The article below suggests that any metabolic disturbance (by diet, environment, stress, drugs, etc) is sufficient to activate PARP-1 by raising lactate (increased acidity) and thus deplete NAD+, which then becomes a vicious circle since lower NAD+ means lower oxidative metabolism, higher glycolysis and thus more lactate generation. Conversely, raising NAD+ levels lowers lactate (by stimulating the reverse LDH reaction to create pyruvate from lactate) and activates pyruvate dehydrogenase (PDH), thus increase oxidative metabolism rate, which regenerates even more NAD+. Exactly as Ray said it – i.e. disease promotes disease and health promotes health, with oxidative metabolism (and is surrogate NAD+) sitting at the center of the whole process and thus health/disease.
“…To understand our findings, it is important to define the issue we were initially intending to explore: acidic stress. Acidic stress is a condition in which cells are exposed to a low pH environment. It commonly occurs in inflamed tissues, aging organs, and tumors. This acidity disrupts cellular function and metabolism, potentially further acidifying the local cellular environment. Having said this, the reason acidic stress is so disruptive is that cells require strict pH levels to function properly. Healthy cells require constant and efficient energy production. When that balance shifts, the consequences move quickly through the entire cellular system.”
“…The mechanism behind the metabolomics finding is specific. Acidity activates an enzyme called PARP1, which rapidly consumes NAD+ as part of the cell’s own stress response. At the same time, mitochondria are forced into a backup mode, and cells rely more heavily on glycolysis (splitting glucose for energy), a less efficient way to generate ATP. This metabolic shift can increase lactate production, which further acidifies the environment. The stress accelerates itself. Together, these three datasets do not describe separate problems. They describe one cascade: acidity triggers a NAD+ drain, energy production fails, the immune alarm activates, and the mitochondrial genome destabilizes. Each step follows the last. Surprisingly, supplementation with the NAD⁺ precursor nicotinamide mononucleotide, a molecule widely studied for its potential longevity-promoting effects, restored intracellular NAD⁺ levels and markedly increased cellular resilience to acidic stress.”
“…I believe this research has broader significance than a single study on pH. If acidity is actively driving NAD+ depletion as our research describes, then the implications reach into how we understand the progression of some of the most prevalent and complex health conditions we face today.”
