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1 NAD+ may be a potential target for anti-aging
Studies have confirmed that there is a decrease in NAD+ that occurs with aging in different tissues of multiple species. This decrease is considered to be an important factor leading to a variety of aging-related diseases. Therefore, maintaining the level of NAD+ plays a vital role in the aging process. Studies have confirmed that NAD+ precursor substance Nicotinamide Mononucleotide (NMN) significantly reverses the aging process at the cellular and overall level. Similarly, supplementing another NAD+ precursor substance, Nicotinamide Riboside (NR) can increase the level of NAD+ and reverse the aging process of worms and mice.
Sirtuins are a group of NAD+-dependent deacetylases. There are 7 different subtypes (SIRT1-SIRT7) in mammals. They play an important role in oxidative stress, energy metabolism, apoptosis, and aging. Recent studies have shown that the beneficial effects of NAD+ may be related to the activation of Sirtuins and related pathways, suggesting that the reactivation of NAD+-dependent enzymes may be one of the targets for improving metabolism and delaying aging.
2 The mechanism of supplementing NAD+ and its precursor substances to delay aging
2.1 Promote DNA repair
The accumulation of DNA damage often occurs during aging, which may be related to damage to the DNA repair mechanism. Therefore, maintaining an effective DNA repair mechanism may delay the occurrence and development of aging and related diseases. Studies have found that NAD+ metabolism affects the key DNA repair process. Supplementation of NAD+ precursor substances has been shown to have a positive effect on DNA repair in aging-related diseases. For example, NAD+ deficiency is related to skin aging and cancer. NAM prevents UV-induced
ATP depletion enhances cell energy and DNA repair activity; topical use of NAM can reduce skin aging7. In addition, NAD+ supplementation can also improve the aging phenotypes of certain DNA repair-deficient diseases, such as xeroderma pigmentosum, ataxia telangiectasia, and Cockain syndrome, by promoting DNA repair and mitochondrial autophagy. . DNA homologous recombination repair is the main method of Double-Strand Break Repair (DSBR) caused by ionizing radiation. In human patients’ fibroblasts and DSBR protein ataxia-telangiectasia mutation (Ataxia-Telangiectasia Mutated, ATM)-deficient mouse brain tissue, DNA damage has occurred in the nucleus and mitochondrial genome, and NR supplementation can be partially passed SIRT1/SIRT6-dependent DSBR improves the genomic stability of ATM-deficient neurons and enhances the tolerance to ionizing radiation.
2.2 Improve mitochondrial function
Many studies have shown that mitochondrial dysfunction exists in a series of aging-related diseases. Improving mitochondrial function is one of the important mechanisms for supplementing NAD + and its precursors to delay aging. Directly regulating cellular NAD+ levels through drugs can inhibit inflammation and oxidative stress, maintain mitochondrial function and promote mitochondrial biogenesis, and prevent ARHL and its accompanying harmful effects. Mitochondrial dysfunction is a biomarker of muscle aging, and NR prevents muscle aging by improving mitochondrial function. In the PD model, by supplementing NAD+precursor NR, up-regulation of NAD+ significantly improved the mitochondrial function of the patient’s neurons. The activation of Sirtuins is believed to be beneficial to metabolism and aging-related diseases (such as obesity induced by a high-fat diet, neurodegenerative diseases, etc.). This is partly because Sirtuins regulate mitochondrial activity by deacetylating mitochondrial-related proteins.
2.3 Induction of autophagy
Autophagy is an important mechanism for cells to purify their own redundant or damaged organelles, maintain protein metabolism balance, remove waste from cells and rebuild structures. During aging, the autophagy ability of cells is significantly reduced, leading to slow renewal of mitochondria and other organelles, triggering inflammation and cell death, and accelerating aging. Many studies have shown that the occurrence of aging and related diseases is closely related to the decline of autophagy. NAD+ supplementation has a positive effect on senile diseases by inducing autophagy, thereby delaying aging. The use of NAD+ precursors (such as NMN and NR) to supplement NAD+ can inhibit cardiac senescence by activating Sirtuins (including SIRT1 and SIRT3), increasing protein deacetylation in the nucleus and mitochondria, and activating autophagy. Oxidative stress is an important pathological change of Age-related Macular Degeneration (AMD). Exogenous NAD+ inhibits H2O2-induced oxidative stress through up-regulation of autophagy and protects retinal pigment epithelial cells from polyadenosine The necrotizing death mediated by ribose diphosphate polymerase-1 suggests that exogenous NAD+ may have potential value in the treatment of AMD. NAD+ can activate autophagy through SIRT1. First, the NAD+/SIRT1 pathway may deacetylate autophagy proteins and up-regulate the expression of autophagy-related proteins ; secondly, NAD+ may also activate AMP protein kinase (Adenosine 5'- Monophosphate-Activated Protein Kinase, AMPK) induces autophagy. NAD+/SIRT1 can activate rat primary cortical neurons AMPK, and then phosphorylate the Ser387 site of tuberous sclerosis complex 2, thereby activating autophagy by inhibiting the target protein of rapamycin  remote NR, NAM, and other NAD+ The precursor substances can also induce autophagy/mitochondrial autophagy in human fibroblasts, murine cortical neurons, and 3xTg AD mice.
3 Exercise's Regulation of NAD+ Levels in the Body
Intracellular NAD+ levels are not only affected by many cell activities but also regulated by exercise. For example, in a mouse model of obesity-induced by a high-fat diet (HFD), 6 weeks of exercise training can improve glucose tolerance and increase muscle NAD+ levels. Caldwell et al. divided the 13-15-month-old CAG140 knock-in mice into an exercise group and sedentary group and found that the NAD+ value of the exercise group was 6 times higher than that of the sedentary group. Studies on mice and humans also show that exercise can change the NAD+ in the circulation in a biphasic manner, that is, moderate-intensity exercise increases the level of NAD+, while vigorous exercise reduces the level of NAD+°This indicates that exercise intensity affects the human body’s NAD+ level and An important factor in the NAD+/NADH ratio.
4 Exercise's regulation of NAD+-dependent enzyme Sirtuins
In recent years, the relationship between exercise and Sirtuins has also attracted much attention, among which SIRT1 and SIRT3 have been studied more. Activating SIRT1 and SIRT3 can avoid aging-related sarcopenia and further help individuals exercise, while physical activity can increase the expression levels of SIRT1 and SIRT3, thereby triggering a beneficial cycle that can fight aging and related diseases. The effect of exercise on human skeletal muscle SIRT1 and SIRT3 largely depends on the type of exercise. Acute exercise activates SIRT1, which in turn activates mitochondrial oxidation capacity. After several aerobic pieces of training, SIRT3 and PGC-la of sedentary individuals increase. Although exercise activates the Sirtuins pathway in different ways, they can all improve mitochondrial health. The role of. A previous study by Vargas-Ortiz et al. also confirmed, that SIRT3 participates in regulating mitochondrial energy homeostasis by activating PGC-la, and remote aerobic training increases the expression level of SIRT3 and PGC-la in sedentary, overweight, or obese adolescents. Pingyao Radak et al. It is mentioned that regular exercise will restore the level of SIRT1 in the kidney, liver, and brain of patients with neurodegenerative diseases to a system-adapted state, thereby normalizing cell metabolism and improving neurodegenerative diseases. In addition, studies on Drosophila suggest that exercise training can activate the NAD +/dSIR2/PGC-1a pathway and improve the fat-toxic cardiomyopathy caused by HFD or cardiac dSIR2 knockout in elderly Drosophila.If you want to know more, please contact us: firstname.lastname@example.org