The Asian Working Group for Sarcopenia defines sarcopenia as an age-related condition marked by a decline in muscle mass, strength, and physical function (Chen et al., 2014). Oxidative stress occurs when an imbalance between oxidants and antioxidants leads to excessive oxidative activity, damaging vital molecules such as sugars, lipids, proteins, and DNA (Sies et al., 2017). Aging is associated with a decrease in the quantity and activity of antioxidant enzymes, fostering an overproduction of reactive oxygen species (ROS), which disrupt cellular redox balance (Sullivan-Gunn and Lewandowski, 2013). Research has conclusively demonstrated that oxidative stress significantly contributes to sarcopenia (Coto-Montes et al., 2017) by accelerating muscle protein degradation through hyperactivation of the ubiquitin-proteasome and autophagy-lysosome pathways, while simultaneously impeding protein synthesis (Jang et al., 2020). Furthermore, oxidative stress impairs mitochondrial biogenesis, diminishes ATP production, and disrupts mitochondrial autophagy, leading to energy metabolism disorders in skeletal muscle fibers and exacerbating muscle wasting (Jang et al., 2010). In addition, oxidative stress stimulates the accumulation of inflammatory cytokines and enhances the phagocytic activity of macrophages and neutrophils, triggering a chronic inflammatory response that intensifies oxidative stress (Bartnik et al., 2000.). This vicious cycle further damages muscle fiber structure and function (Chen et al., 2022). Mitochondrial dysfunction, central to aging (López-Otín et al., 2023), involves the accumulation of mtDNA mutations, imbalances in protein synthesis and degradation, instability of respiratory chain complexes, and altered mitochondrial dynamics. These changes undermine mitochondrial integrity and function, contributing to muscle fiber degeneration. Deterioration in mitochondrial function increases ROS production and mitochondrial membrane permeability, precipitating inflammation and cellular destruction (Hepple, 2014).

In the muscles of aged mice and elderly humans, levels of autophagy markers, including autophagy-related protein7 (ATG7)and Light Chain 3 (LC3) lipidation, are reduced, indicating impaired autophagic function (Carnio et al., 2014). Skeletal muscles in ATG7-specific knockout mice exhibit muscle atrophy, reduced strength, and pathological features characteristic of myopathy, with the decline in muscle strength becoming more pronounced with aging (Masiero et al., 2009). Impaired autophagy disrupts the protein quality control system, leading to increased protein aggregates that further exacerbate sarcopenia (Jiao and Demontis, 2017). Aging is often accompanied by chronic low-grade inflammation, primarily associated with senescent cells and their senescence-associated secretory phenotype (SASP). The SASP increases with age, releasing pro-inflammatory cytokines that contribute to both inflammation and aging (Fulop et al., 2018; Fulop et al., 2021). Previous studies have shown that elevated IL-6 levels can predict disability in the elderly, likely due to the direct effects of IL-6 on muscle atrophy (Ferrucci et al., 1999). Additionally, IL-1β levels are negatively correlated with walking speed, further linking inflammation to the decline in skeletal muscle function (Morawin et al., 2023). Inflammatory cytokines activate protein degradation and inhibit protein synthesis, leading to sarcopenia (Jo et al., 2012).

Age-related structural and functional decline of the neuromuscular junction (NMJ) significantly contributes to muscular dystrophy. Aging leads to the thinning and degradation of motor neuron axons, which exhibit disordered terminal branching (Padilla et al., 2021). Decreased reactivity of terminal Schwann cells and a reduction in the quantity and density of acetylcholine receptors on muscle fibers contribute to neural innervation failure and disrupted muscle contractions (Alice et al., 2016).Skeletal muscle stem cells (MuSCs) are crucial for the regenerative and repair functions of skeletal muscles due to their quantity and functionality (Jiang et al., 2024). In male rats between 15 and 18 months of age, the number of MuSCs declines with advancing age, and they undergo morphological changes, including flattening, enlargement, and a loss of three-dimensional structure. Consequently, these alterations weaken the proliferation and self-renewal potential of MuSCs, causing a shift from a reversible dormant state to a permanently quiescent state, which compromises the regenerative capacity of skeletal muscles (Pedro et al., 2021).

NAD⁺ was one of the most prominent metabolites that decreased in older adults, and this decline was even more pronounced in impaired older adults (Janssens et al., 2022). This outcome is a consequence of both reduced synthesis efficiency and increased consumption. Across various tissues in humans and mice, the level of NAMPT in the NAD⁺ salvage pathway declines with age (De Guia et al., 2019; Stein and Imai, 2014; Xing et al., 2019), resulting in decreased synthesis of NAD⁺. Furthermore, as the aging process progresses, the accumulation of DNA damage, inflammation, and oxidative stress intensifies, leading to an enhancement in the activity of NAD⁺ consuming enzymes such as CD38 and PARPs (Covarrubias et al., 2020; Goody and Henry, 2018; Khaidizar et al., 2021; Schultz and Sinclair, 2016; Silva et al., 2023). Enhancing NAD⁺ metabolism has emerged as a viable therapeutic approach to mitigate age-related conditions and extend lifespan, as supported by numerous studies (Gerdts et al., 2015; Krafczyk and Klotz, 2022; Mouchiroud et al., 2013; Tzameli, 2012). Lifelong overexpression of NAMPT can maintain NAD⁺ content and functionality in the skeletal muscle of aged mice (Frederick et al., 2016). We summarize the mechanisms by which the NAMPT salvage pathway improves aging skeletal muscle, including alleviating oxidative stress, maintaining the stability of the NAD⁺ pool, promoting autophagy, reducing chronic low-grade inflammation, enhancing the quantity and function of MuSCs, and improving the formation of neuromuscular junctions.

Increasing NAD⁺ enhances the function of silent information regulator factor (SIRT1) (Khaidizar et al., 2017), which activates the forkhead box proteins (FoxOs)pathway (Olmos et al., 2013), increases levels of antioxidant enzymes like Superoxide Dismutase 2 (SOD2), strengthens antioxidant defense mechanisms, reduces ROS (Zhang et al., 2023), mitigates oxidative stress damage, and therefore retards the aging process in skeletal muscle. Activated SIRT1 acts as an antioxidant by suppressing NF-κB expression while boosting levels of peroxisome proliferator-activated receptor γ coactivator 1α(PGC-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2), which are key regulators of cellular defense against oxidative stress (Tzameli, 2012). The malate-aspartate shuttle (MAS), essential for the exchange between mitochondrial NAD⁺ and cytoplasmic NADH (Yang et al., 2007), stabilizes mitochondrial NAD⁺ during increased energy demands, facilitated by PGC-1α activation in skeletal muscle (Kang and Li Ji, 2012). The mitochondrial unfolded protein response (UPRmt) is crucial for maintaining mitochondrial function and homeostasis. Enhancing NAD⁺ in skeletal muscle models activates UPRmt, balancing mitochondrial protein systems and improving function (Mouchiroud et al., 2013). The NAD⁺-dependent enzyme SIRT1 deacetylates LC3 at K49 and K51 sites, enabling LC3 to interact with nucleoproteins and translocate to the cytoplasm, where it binds with autophagy factors such as ATG7, thereby promoting autophagy in skeletal muscle (Huang et al., 2015). Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) is a key initiator of autophagy (Ge et al., 2022), and SIRT1 can activate AMPK (Gao et al., 2020; Ruderman et al., 2010). AMPK, in turn, activates Unc-51-like autophagy activating kinase 1 (ULK1) through phosphorylation. ULK1 then activates downstream molecules such as Bcl-2-interacting coiled-coil protein 1 (Beclin1) and ATGs, thereby promoting the autophagy process (Holczer et al., 2020). Studies have also shown that AMPK protects cells from oxidative stress-induced aging by increasing autophagic flux and enhancing NAD⁺ levels (Han et al., 2016). The NLR family pyrin domain containing 3(NLRP3) inflammasome is an intracellular signaling complex that produces pro-inflammatory cytokines, such as IL-1β. Reducing NLRP3 inflammasome expression can enhance muscle fiber size and contractility (McBride et al., 2017). SIRT2 inhibits NLRP3 inflammasome activity by deacetylating NLRP3, thereby reducing aging-associated chronic inflammation (He et al., 2020). Oral administration of nicotinamide riboside (NR) can increase skeletal muscle NAD⁺ levels and reduce circulating inflammatory cytokines in skeletal muscle (Elhassan et al., 2019). The regulation of other inflammatory factors by NAD⁺ to improve skeletal muscle function is discussed in the section on T2DM in this paper.

Research shows that the NAD⁺ salvage pathway enhances neuromuscular junctions (NMJ). Administering NMN to increase NAD⁺ levels improves vesicle count in axons, restores neuronal function, and maintains synaptic connectivity and transmission at NMJs (Oki et al., 2015; Samuel et al., 2020). Supplementing with NAMPT to increase NAD⁺ levels can boost MuSCs counts (Hongbo et al., 2016), as NAD⁺ promotes SIRT1 overexpression, which prevents aging of these cells (Ma et al., 2017), aiding in repair and maintaining the integrity of NMJs (Larouche et al., 2021). The TIR domain of SARM1 can cause axon damage, but overexpressing NAMPT in dorsal root ganglion neurons counters this effect, preventing axon degeneration and cell death (Gerdts et al., 2015). Overexpression of NAMPT also protects against glutamate excitotoxicity and neuronal apoptosis due to oxygen-glucose deprivation, thereby enhancing neuroprotection (Wang et al., 2016). Restoring the number and function of quiescent muscle stem cells in aging skeletal muscle helps improve sarcopenia. The NAD⁺-dependent SIRT1 deacetylates substrates such as histone H4K16ac, regulating gene expression and maintaining the quiescent state of stem cells (Ryall et al., 2015). NR supplementation can increase the number of MuSCs and enhance their self-renewal capacity (Hongbo et al., 2016). Paired Box 7(PAX7)is essential for maintaining the regenerative function of adult muscle stem cells (Sambasivan et al., 2011). SIRT2 deacetylates PAX7, promoting muscle stem cell self-renewal, inhibiting differentiation, and maintaining the undifferentiated state of MuSCs (Sincennes et al., 2021). Studies in twins have shown that NR promotes the activation of MuSCs from differentiation and fusion to formation of muscle fibers (Lapatto et al., 2023). In conclusion, the NAD⁺ salvage pathway holds therapeutic potential for treating sarcopenia by reversing pathogenic processes, as depicted in Figure 2.

Current epidemiological data shows approximately 387 million adults worldwide are affected by diabetes, with projections suggesting this number will increase to 693 million by 2045 (Cole and Florez, 2020). Type 2 diabetes (T2DM) is characterized by elevated blood sugar levels, primarily due to impaired β-cell function, leading to inadequate insulin secretion or reduced insulin sensitivity. T2DM affects skeletal muscles through insulin resistance, chronic inflammation, advanced glycation end products, and increased oxidative stress, all of which undermine muscle structure, function, and mass (Chen et al., 2023). This results in muscle loss, decreased quality of life, and a higher risk of disability or death (Kawada, 2021), with diabetics having a 1.5–2 times greater risk of muscle loss than non-diabetics (Izzo et al., 2021). GLUT4, a glucose transporter, manages about 80% of glucose uptake, mainly in skeletal muscles (Son et al., 2017). In T2DM, impaired insulin signaling prevents GLUT4 from effectively transporting glucose, reducing muscle glycogen synthesis and contributing to insulin resistance in muscle tissues. High glucose levels lead to fat accumulation in skeletal muscles, activating protein kinase C-epsilon (PKCε) and worsening insulin resistance (Meex et al., 2019). Increased fat in muscles also releases fatty and inflammatory molecules (Donath and Shoelson, 2011), promoting chronic inflammation, which impairs muscle formation, accelerates muscle breakdown, and causes muscle wasting (Cole and Florez, 2020). Hyperglycemia affects neurons by decreasing their responsiveness to electrical stimuli and altering action potential conduction at the neuromuscular junctions. Additionally, it reduces sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) levels (Bayley et al., 2016), impairing skeletal muscle contraction.

Nicotinamide phosphoribosyltransferase (NAMPT), an adipokine resembling insulin, plays a vital role in the NAD⁺ salvage pathway, which is crucial for the function of pancreatic islet β-cells and is closely linked to glucose and insulin metabolism (Revollo et al., 2007; Yoshino et al., 2011). Research indicates that NMN supplementation can enhance insulin secretion and sensitivity in diabetic mice by improving the NAD⁺ synthesis pathway (Yoshino et al., 2011). Additionally, elevating SIRT1 specifically in the pancreatic islet β-cells of C57BL/6 mice enhances insulin secretion, improves glucose tolerance, and increases insulin sensitivity (Moynihan et al., 2005).NMN supplementation significantly enhances muscle insulin signaling in prediabetic women, improving skeletal muscle insulin sensitivity and increasing glucose uptake and metabolism in skeletal muscle (Yoshino et al., 2021). NR ameliorates insulin resistance in the skeletal muscle of high-fat diet (HFD) mice by activating the AMPK signaling pathway, which inhibits oxidative stress and enhances mitochondrial function (Li et al., 2023). The NAD⁺-dependent enzyme SIRT1 regulates AMPK activity (Imi et al., 2023; Liu and Chang, 2018), which phosphorylates Histone Deacetylase 5 (HDAC5) at Ser259 and Ser498, reducing HDAC5 binding to the GLUT4 gene promoter. This increases GLUT4 gene expression and improves skeletal muscle insulin sensitivity (McGee et al., 2008). AMPK also reduces inflammation and insulin resistance in the skeletal muscle of HFD-fed mice, thereby improving skeletal muscle function in T2DM (Zhao et al., 2018). In the skeletal muscle-specific NAMPT knockout mouse model, k-means clustering analysis was conducted on all detected genes, revealing a distinct cluster associated with inflammation and immune response-related genes (Frederick et al., 2016). The activation of the nuclear factor kappa-B (NF-κB) pathway, a key player in inflammation (van der Heiden et al., 2010), triggers the upregulation of muscle-specific E3 ubiquitin ligase (MuRF1) and cytokines such as TNF, IL-6, and IL-1β. This increases muscle protein breakdown and inhibits protein synthesis, disrupting protein balance and leading to muscle atrophy (Cai et al., 2004). The activity of NF-κB in skeletal muscle of T2DM patients is 2.7 times higher than that of normal glucose tolerant subjects (Tantiwong et al., 2010). Inhibiting NF-κB can significantly reduce muscle loss. Supplementation with NAMPT enhances NAD⁺ synthesis, thereby increasing SIRT1 activity (Stein and Imai, 2012). This activity includes the deacetylation of RelA AcK310 by SIRT1, which inhibits NF-κB transcriptional activity (Yeung et al., 2004), decreases inflammation in skeletal muscles, and improves muscle function in diabetes.

Patients with type 2 diabetes and obesity typically exhibit increased fat accumulation around organs, especially in skeletal muscles and liver. Fat accumulation in the skeletal muscle of T2DM patients leads to decreased muscle strength and function (Almurdhi et al., 2016). Adiponectin, a key gene in glucose metabolism (Banks et al., 2015), acts as an insulin sensitizer, increasing insulin sensitivity in skeletal muscle, thereby enhancing glucose uptake and metabolism (Ceddia et al., 2005; Liu et al., 2009). Targeted deletion of NAMPT in mouse adipocytes results in systemic insulin resistance, reduced fat metabolism, lower adiponectin levels, and decreased metabolic efficiency (Stromsdorfer et al., 2016). PPARγ is crucial for fat synthesis, and its complete deletion in mice leads to the loss of both white and brown adipose tissues, causing severe metabolic issues (Gilardi et al., 2019). Additionally, PPARγ suppresses NF-κB activation, which otherwise enhances muscle inflammation (Huang and Glass, 2010). Supplementing PPARγ helps maintain insulin responsiveness in peripheral tissues, increases glucose uptake and utilization in muscles, improves lipid metabolism, and lowers triglyceride levels (Ji et al., 2022). Specific overexpression of NAM in adipose tissue results in a 32-fold increase in NAD⁺ (Luo et al., 2022), levels and a corresponding rise in carnitine content. This enhancement promotes the transport of fatty acids to mitochondria for oxidative breakdown (Rebouche and Seim, 1998). Reduced NAD⁺ levels cause phosphorylation of PPARγ at Ser273 in adipose tissue, which disrupts PPARγ's role in lipid metabolism and inhibits adiponectin function, thereby affecting glucose metabolism (Stromsdorfer et al., 2016). Deacetylating PPARγ at K268 and K293 promotes the recruitment of coactivators that facilitate the browning of white adipose tissue, thereby increasing insulin sensitivity, enhancing energy expenditure, and reducing obesity (Ji et al., 2022). P7C3, an orally active neuroprotective agent, targets the NAMPT enzyme, enhancing the NAD⁺ salvage pathway. This increases insulin sensitivity, boosts mitochondrial fatty acid β-oxidation in skeletal muscle, and improves energy metabolism in T2DM mice (Ravikumar et al., 2022) which is depicted in Figure 3.

NAMPT agonists can enhance the efficiency of the body’s salvage synthesis pathway to produce NMN, and even with small or intermittent supplementation of NMN or NR, they can maintain high levels of NAD⁺ in the long term. Therefore, many studies have attempted to explore the types and potential roles of NAMPT agonists. P7C3 is the first discovered activator of NAMPT. The active variants of P7C3 can enhance the activity of purified NAMPT, and their promotion of NMN production is dose-dependent (Wang et al., 2014). Research has shown that P7C3-mediated NAMPT activation improves insulin sensitivity and muscle function in obese mice, reducing diabetic symptoms (Ravikumar et al., 2022). The exact mechanisms of how P7C3 activates NAMPT or competes with its inhibitors are still under investigation. The synthesis of SBI-797812, an NAMPT activator, involved modifying the GNI-50 molecule by moving the pyridine group from the third to the fourth position. This change enhances NAMPT’s catalytic efficiency, increasing NMN synthesis by 2.1 times (Gardell et al., 2019). SBI-797812 also counteracts the inhibitory effects of NAD⁺ on NAMPT by binding to its rear channel, boosting NAMPT activity and increasing NAD⁺ levels (Ratia et al., 2023). NAT and its active variant NAT-5r, potent NAMPT activators, interact through a hydrogen bond with NAMPT’s K189 residue, enhancing its catalysis and countering FK866-induced cell death (Hong et al., 2022). High-throughput screening has identified several compounds that enhance NAMPT function, including NAMPT positive allosteric modulators A1 (NP-A1) (Zhengnan et al., 2023). These modulators increase NAMPT activity by 1.6–2.6 times, binding to its back channel (Ratia et al., 2023). N-PAMs reduce NAD⁺'s inhibitory effect on NAMPT, enhancing its function. Natural activators like notoginseng leaf triterpenes (PNGL) also stimulate NAMPT (Xie et al., 2020), activating NAMPT-NAD⁺-SIRT1/2/3-Foxo3a-MnSOD/PGC-1α pathways that improve mitochondrial function and prevent mitochondrial damage. The hypertension peptide IRW increases muscle cell NAMPT content significantly (Bhullar et al., 2021). Additionally, substances like low-dose nicotine enhance NAMPT activity by facilitating its interaction with SIRT1, boosting NAD⁺ and β-NMN levels, and improving metabolic function in aging tissues (Liang et al., 2023).

Although NAMPT agonists have shown therapeutic potential in laboratory studies, they have revealed certain safety concerns in clinical trials, their therapeutic effects do not yet meet clinical needs, and the progress of clinical trials has been slow (Wen et al., 2024). Moreover, NAMPT regulates macrophage survival and pro-inflammatory activity, contributing to the modulation of the tumor inflammatory microenvironment and promoting tumor cell metastasis (Lucena-Cacace et al., 2018; Piacente et al., 2017). NAMPT activity appears to be tightly controlled by NMN and NAD⁺ through strict feedback regulation (Burgos and Schramm, 2008; Takahashi et al., 2010). Developing NAMPT agonists that can specifically enhance NAD⁺ production without affecting other functions, such as immune response regulation and cancer cell metabolism, remains a significant challenge.

NAD⁺ precursors, such as NA, NMN, NR, and NAM, have gained significant attention for NAD⁺ supplementation and have been shown in both animal and human studies to extend lifespan, enhance muscle regeneration, improve mitochondrial and stem cell function, boost glucose metabolism, and enhance cardiovascular function. The specific effects of these precursors on the body are detailed in several excellent reviews (Iqbal and Nakagawa, 2024; Keisuke and Takashi, 2023; Lautrup et al., 2024; Montllor-Albalate et al., 2021; Reiten et al., 2021). However, different NAD⁺ precursors exhibit varying effects depending on the experimental subjects. For instance, postmenopausal overweight or obese women with prediabetes who took NMN(250 mg/day) for 10 weeks showed significant improvements in muscle insulin sensitivity (Yoshino et al., 2021). In contrast, healthy, obese, sedentary men aged 40–70 who received NR (2000 mg/day) for 12 weeks did not experience improvements in insulin sensitivity, endogenous glucose production, glucose handling, or oxidation (Dollerup et al., 2018). Older men with diabetes and impaired physical function did not see improvements in muscle strength after taking NMN 250 (mg/day) for 24 weeks (Akasaka et al., 2023). Patients with mitochondrial myopathy who took NA 750–1,000 (mg/day) for four months showed improvements in muscle NAD⁺ levels, disease symptoms, and muscle metabolism (Pirinen et al., 2020). These variations in outcomes may be associated with factors such as gut microbiota, dose dependency, and individual differences. Currently, NAD⁺ precursors such as NA, NAM, NR, and NMN are used clinically and have demonstrated certain levels of safety and bioavailability (Reiten et al., 2021). However, more comprehensive research is needed to evaluate their potential side effects and therapeutic efficacy. The interactions of gut microbiota with NAD⁺ precursors add complexity to NAD⁺ metabolism. Optimizing precursor formulations and administration methods could enhance their stability and conversion efficiency in the body. Furthermore, exploring targeted delivery methods of NAD⁺ precursors to specific organs or tissues could improve clinical trial outcomes.

NAD⁺ boosters also include inhibitors of NAD⁺-consuming enzymes. CD38 inhibitors improve age-related metabolic disorders by reversing tissue NAD⁺ decline, increasing muscle fiber size, and reducing fibrosis (Tarragó et al., 2018). CD38-deficient mice prevent high-fat diet-induced obesity by activating the SIRT-PGC1α axis through elevated NAD⁺ levels (Barbosa et al., 2007). The deletion of the PARP gene increases NAD⁺ content and SIRT1 activity in brown adipose tissue and muscle, enhancing mitochondrial content and oxidative metabolism (Bai et al., 2011). However, using PARP inhibitors could have adverse effects, as PARP is involved in essential cellular processes, and its inhibition may lead to genomic instability (Beneke et al., 2004). The development of NAD⁺ consumption enzyme inhibitors requires comprehensive consideration of drug safety, its impact on tumor development, the role of inflammation and metabolic regulation, biological rhythms and adaptive responses, individual differences, and optimization of supplementation strategies. These challenges need to be fully addressed in future research.

NAMPT agonists accelerate NAD⁺ synthesis, NAD⁺ precursors provide direct supplementation, and consumption inhibitors reduce NAD⁺ degradation, forming a multifaceted synthesis and protection network that significantly enhances intracellular NAD⁺ levels. This synergistic approach holds promise as a target for treating diseases and disorders associated with disrupted NAD⁺ homeostasis.