## 3 Functional Roles of Nicotinamide and Pyridoxine
### Metabolic, Redox, and Immune-Modulatory Functions in Muscle Aging  
#### 3.3.1 Nicotinamide (Vitamin B3)  
Nicotinamide plays a central role in redox biology through its involvement in NAD\({}^{+}\)/NADH and NADP\({}^{+}\)/NADPH systems. NAD\({}^{+}\) is an essential cofactor for dehydrogenase enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, and \(\beta\)-oxidation of fatty acids, supporting energy production in skeletal muscle. NADP\({}^{+}\), meanwhile, is reduced to NADPH, which acts as a reducing agent in antioxidant defenses, particularly in the regeneration of reduced glutathione (GSH) and thioredoxin. NAD\({}^{+}\) is also a substrate for several key regulatory enzymes including sirutins, PARPs, and CD38 [18; 31; 38; 54; 74; 123; 124; 125; 126; 127; 128; 129; 130]. Sirtuins (SIRT1-7) are NAD\({}^{+}\)-dependent deacetylases that modulate gene expression, mitochondrial biogenesis, and oxidative stress responses. In muscle, SIRT1 activation enhances autophagy, protects against oxidative damage, and promotes stem cell maintenance. PARPs are involved in DNA repair, and excessive PARP activity during stress depletes NAD\({}^{+}\) pools. CD38 and CD157 are NAD\({}^{+}\)-glycolrorolases that regulate calcium signaling and immune responses. CD38 expression increases with age, contributing to systemic NAD\({}^{+}\) depletion. During aging, NAD\({}^{+}\) levels decline due to increased consumption by CD38 and decreased activity of NAMPT. This depletion impairs mitochondrial function, disrupts redox homeostasis, and promotes inflammaging, leading to reduced regenerative capacity in muscle stem cells (Figure 4) [18; 31; 38; 54; 74; 123; 124; 125; 126; 127; 128; 129; 130].  
Figure 4: NAD\({}^{+}\)-dependent metabolic and regulatory pathways influenced by nicotinamide in aging skeletal muscle. Nicotinamide supports redox balance, energy metabolism, and gene regulation through its role in NAD\({}^{+}\) homeostasis. NAD\({}^{+}\) fuels dehydrogenase activity in key metabolic pathways, supports antioxidant regeneration via NADPH, and regulates sirtuin- and PARP-mediated cellular processes. Age-related NAD\({}^{+}\) decline, driven by increased CD38 and reduced NAMPT levels, impairs mitochondrial function, increases inflammation, and reduces muscle regeneration.  
Nicotinamide N-methyltransferase transferase (NNMT) is an emerging regulator of NAD\({}^{+}\) homeostasis, particularly relevant in the context of aging and metabolic dysfunction. NNMT catalyzes the methylation of nicotinamide (NAM) to form 1-methylnicotinamide (MNA), using S-adenosylmethionine (SAM) as the methyl donor. This reaction effectively diverts NAM from the NAD\({}^{+}\) salvage pathway, reducing the pool of available substrates for NAD\({}^{+}\) biosynthesis via NAMPT. Elevated NNMT activity has been observed in various pathological conditions, including cancer, obesity, type 2 diabetes, and age-related vascular dysfunction [131; 132]. By limiting NAD\({}^{+}\) availability, NNMT overexpression may suppress the activity of NAD\({}^{+}\)-dependent enzymes such as SIRT1, which plays a key role in autophagy, mitochondrial biogenesis, and anti-inflammatory signaling. Notably, several NNMT inhibitors--including bisubstrate analogs and novel macrocyclic peptides--have been developed and shown to restore intracellular NAD\({}^{+}\) levels and inhibit MNA production in vitro [133; 134; 135]. These findings suggest that targeting NNMT may offer a novel strategy to preserve NAD\({}^{+}\) metabolism, enhance SIRT1 activation, and counteract aging-associated muscle decline.