With time there are many natural aging mosaics in the human body and skin aging is one of them, which is perceptible with time and expedites variations in different cells, tissues, and organs. While aging signs are perceivable by the skin with time, it is difficult to observe aging inside the organs. Skin aging has many factors influencing it which include a combination of extrinsic factors such as pollution, ionizing radiation, chemicals, toxins, and intrinsic elements including genetics, cellular metabolism, hormone, and metabolic processes. A combination of these factors causes skin alternation eventually leading to changes in skin impression majorly in sun-exposed regions. With the increase in human expectancy around the globe, there has been observed an increased number of people seeking aid for their aging-related issues.
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Role of NAD+ in anti-aging
Nicotinamide mononucleotide (NMN) is an antecedent of nicotinamide adenine dinucleotide (NAD+ ), an essential enzyme required for important cell processes which include DNA repair, metabolism, and cell functions. An enormous multi-million dollar market has gained momentum after the positive results in the clinical trials and outstanding results in animal and cell studies.
NAD+ is required in processes such as the addition of deacetylating activity of sirtuin enzymes. It helps in the conversion of poly-ADP ribose to protein both of which are critically important in energy metabolism, and stress resistance, and regulating cell growth.
Availability
NAD+ can be found in cell cytoplasm as well as the cell nucleus and mitochondria. NMN, tryptophan, nicotinic acid, nicotinamide riboside, and nicotinamide are used for the synthesis of NAD+. Natural foods such as cow's milk, meat, and vegetables contain a small amount of antecedent of NAD+. These antecedents use various ways to enter cells: Nicotinamide riboside enters cells via nicotinamide riboside transporters, nicotinamide diffuses into cells due to its small size, and NMN is probably transported across cell membranes by the Slc12a8 transporter3.
Changes with aging
Across many tissues, a decline of NAD+ can be observed with age whereas acceptance of NAD+ depends from tissue to tissue. In humans, newborns have a significantly higher concentration of NAD+ than an average adult. Reduced synthesis and boosted concentration have been observed as a result of these fallen levels of NAD+ with boosted concentration including degradation by poly(ADP-ribose) polymerase (PARP) and NADase CD38. Through its role as a substrate for sirtuins, CD38s, and PARPs, NAD + regulates various cellular processes such as energy metabolism, repair of DNA damage, gene expression, and response to oxidative stress. The pathways for NAD+ generation are of two types:
Pathways and how to take their advantages
a.Sirtuin pathway
Sirtuins are evolutionarily conserved NAD + -dependent deacetylases. Increased sirtuin expression has been shown to affect the longevity of various species. Sirtuins have received a great deal of attention since the discovery of Sirtuin Silence Information Regulator 2 (Sir2) that can extend yeast lifespan. The closest mammalian homology to this regulator is SIRT1, which is predominantly present in the nucleus but also in the cytosol. Its nuclear transport signal allows a shuttle to the cytosol under certain circumstances. NAD + SIRT1 signaling has been shown in vivo to promote mitochondrial activity. Previous studies have shown that increasing SIRT1 in the brain, especially the dorsomedial and lateral hypothalamic nuclei, can delay aging and prolong lifespan in mice. Recently, it has been found that over-pression of Sirt1, which is specific to the heart, delays aging and protects against oxidative stress in the heart. NRSIRT1 signaling can suppress cardiac stem cell aging by enhancing mitochondrial and muscular stem cell function, thereby prolonging mouse lifespan. Further studies are needed to determine if increased NAD + levels in vivo enhance SIRT1 activity and thereby delay aging.
b.The PARPs Pathway
PARP is expressed in most eukaryotic cells and is involved in the recognition and repair of DNA damage, cell death pathways, etc. Aging is associated with the accumulation of DNA damage. Degradation of NAD + is involved in cell death by PARP1. Although this enzyme plays an important role in cells, overactivation of PARP1 can lead to NAD + depletion, decreased ATP, decreased SIRT1 activity, loss of mitochondrial function, and even cell death. Raising NAD + levels when SIRT1 is intact can reduce cell death caused by the activation of PARP1 in cardiomyocytes.
c.CD38 and NAD+
CD38 is a multifunctional protein. Studies have shown that CD38 is a NADase in mammalian tissue. This is thought to contribute to the age-related decline in NAD + levels. CD38 also functions as an antigen for lymphocyte activation and as an external enzyme in endothelial and inflammatory cells. Aging cells are known to express small molecules, including secreted cytokines, growth factors, and extracellular matrix modifiers, to promote chronic aseptic inflammation and fibrosis. This reaction process, known as the senescence-related secretory phenotype, involves the secretion of factors that induce the expression of CD38 in non-senescent cells by senescent cells. This increased CD38 activity can upset the delicate balance between intracellular NAD + and its reduced NADH. Recently, the small molecule CD38 inhibitor 78c has been shown to reverse age-related loss of NAD +.
Conclusion
NAD + is a cofactor for many important enzymes. Decreased NAD + levels are associated with aging. There is evidence that NAD + precursor supplementation or inhibition of NAD + degradation may improve metabolic function. NAD + precursor supplementation has been shown to delay aging in mice, but the anti-aging effect of NAD + in human subjects has not yet been demonstrated. The use of more accurate aging biomarkers, such as DNA methylation clocks takes the field significantly forward. Recently, several human clinical trials have been started and hopefully it will open the gateway to new anti-aging supplements.
