A cell’s NAD+ pool is determined by its production and consumption. NAD+’s generation must be regularly boosted. Despite this, NAD+ levels declines with age, even if other factors such as food remain constant. The expense of NAD+ decreases is enormous. The loss of NAD+ appears to be linked to metabolic malfunction and age-related illnesses. That’s why researchers are increasingly focused on boosting NAD+ levels.
Determining whether the decline is mediated by changes in its degradation synthesis or both is important to intervening appropriately in the vicious circle of NAD+ levels. The influence of DNA damage, inflammation, and senescence (the age-related freezing of cell replication) on cellular NAD+ metabolism are also essential.
Aging and NAD+ biosynthesis
NAD+ levels decline with aging since the available precursor molecules aren’t synthesized as rapidly. NAMPT, the enzyme that creates most NAD+, declines with age for unknown causes, affecting the activities of NAD+-dependent proteins. The age-related drop in NAMPT levels appears to be complex.
Circadian rhythm changes have been linked to age-related NAMPT decrease. A weak or mistimed circadian rhythm causes insufficient NAMPT production, lowering NAD+ levels. Chronic inflammation is another probable explanation for age-related NAMPT decrease. Internal and external stresses that induce chronic inflammation cause damage to several metabolic tissues, including fat, skeletal muscle, and liver, as we age. Inflammatory signaling molecules called cytokines are generated in damaged tissues, which can worsen cellular damage. These cytokines have been shown to reduce NAMPT levels.
Age-related NAD+ Degradation
Numerous enzymes that utilize NAD+ are known to be involved in a variety of key cellular activities. The PARPs, CD38, and SARM1 are three important enzymes.
- PARPs are significant NAD+ users. PARP1 and PARP2 are important NAD+ consumers, reacting to DNA strand breaks and promoting DNA repair. PARP activation appears to lead to large declines in intracellular NAD+ with age, presumably due to ongoing DNA damage from internal and external stressors such as oxidative stress and UV radiation.
- CD38 is an enzyme that consumes NAD+ and regulates NAD+ levels in mammals. The age-related rise in CD38 protein levels in numerous tissues and organs is linked to the NAD+ decline. Cytokines and bacterial toxins also boost CD38 levels and activity. Thus, persistent inflammation with age may increase CD38 expression and decrease NAD+.
- The enzyme SARM1 uses NAD+ to degrade axons following damage and to initiate numerous neurodegenerative disorders. SARM1-mediated NAD+ depletion causes damaged neurons to die, a critical event in the early stages of age-related neurological diseases such as Parkinson’s, Alzheimer’s, and Amyotrophic Lateral Sclerosis (ALS).
Sirtuins and the age-related NAD+ Decline
NAD+ depletion is exacerbated by reduced NAD+ production and increased NAD+ degradation. Whether inadequate production or excessive consumption contributes to NAD+ deficiency varies by cell type and tissue. Whatever causes NAD+ decline, sirtuins appear to be key downstream mediators. The sirtuin family consists of seven members in humans (SIRT1-SIRT7), each of which is involved in a variety of cellular metabolic processes associated with healthspan and longevity. Sirtuins, in general, deacetylate target proteins to control reactions involved in essential physiological functions such as metabolism, DNA and cellular repair, stress responses, circadian rhythm, and other cellular activities.
Sirtuins are evolutionarily conserved regulators of aging and lifespan in many species due to their ability to mediate such extensive roles. Sirtuins’ NAD+-decline actions make them important regulators of aging and lifespan in many species. For example, mice with more SIRT1 than normal brains live longer. Activating SIRT1 may also help treat neurodegenerative illnesses including Huntington’s and ALS (ALS). Also, mice with more SIRT6 in their bodies live longer.