Mechanism underlying the anti-aging activity of NMN
Aging, as a natural process is identified by downregulation of energy production in mitochondria of various organs such as brain, adipose tissue, skin, liver, skeletal muscle and pancreas due to the depletion of NAD +. NAD + levels in the body decrease as a con-sequence of increasing NAD + consuming enzymes when aging. These NAD + consuming enzymes include NADase (CD38/CD157), poly (ADP-ribose) polymerase (PARP), NAD + dependent acetylase (sirtuins), BST and tankyrase (TNKS). Sirtuins consume NAD + in order to execute a variety of functions such as deacetylation, deglutarylase, lipoamidase, demalonylase and desuccinylase activities. Regulation of longevity, aging and age-associated physiologi-cal changes is one of the substantial aspects of sirtuin biology, while CD38 utilises NAD + to produce cyclic ADP-ribose and nicoti-
namide. Apart from that, PARP expends NAD + to form branched ADP-ribose polymers which assists in DNA repairing. This depleted NAD + level by NAD + consuming enzymes can be compensated by administration of NMN to the body since NMN is an inter-mediate compound of the NAD + biosynthesis.
There are three different biosynthesis pathways to produce NAD + in mammalian cells including de novo synthesis from trypto-phan, salvage and Preiss-Handler pathways. Among these three pathways, NMN is an intermediate by-product in salvage pathway, and it is involved in NAD + biosynthesis through salvage and Preiss-Handler pathways as illustrated in Fig. 3. The salvage pathway is the most efficient and the main route for the NAD + biosynthesis, in which nicotinamide and 5-phosphoribosyl-1-pyrophosphate are converted to NMN with the enzyme action of NAMPT followed by conjugation to ATP and conversion to NAD by NMNAT. Fur-thermore, NAD + consuming enzymes are responsible for degradation of NAD + and consequent formation of nicotinamide as a by-product. In the Preiss-Handler pathway, initially, nicotinic acid is converted to nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyl-transferase enzyme (NAPRT) activity followed by biosynthesis of nicotinic acid adenine dinucleotide (NAAD + ) from NAMN using nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT 1/2/3). Subsequently, NAAD + is trans-formed to NAD + by NAD + synthetase (NADS) using ATP and ammonia.
Chronic inflammation and oxidative stress, which come along with aging, are the causes for reduction and inhibition of NAMPT-mediated NAD + biosynthesis. The depletion of NAD +contents along with aging, which particularly of nuclear origin, is associated with interruption of mitochondrial regulation of PCG-1 a /b-independent pathway of oxidative-phosphorylation as well, causing pseudohypoxia. This incident can be overturned by raising the NAD + content.
Apart from reducing the functions of mitochondria, biological changes such as cognitive impairments, DNA damage and sirtulin gene inactivation, are brought about by aging which can be evaded by enhancing NAD + count in the body. Apart from NMN supplementation, NAD + levels in the body can be increased as a response to conditions related to lower energy intake , calorie restriction, fasting, lack of glucose content in the body and exercise. Nevertheless, NAD + levels decrease as a consequence of intake of high-fat diets and aging.
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