Aging by definition is a “cascade of robustness breakdown triggered by a decrease in systemic NAD+ biosynthesis and the resultant functional defects in susceptible organs and tissues.”Until recently, aging was a process inherent to the life cycle, but in 2018 the World Health Organization (WHO) released the 11th edition of its International Classification of Diseases. For the first time, it added aging. 

Indeed, classifying aging as a disease means that we can reverse age-related diseases using novel therapies. Furthermore, nutrients and their interplay with different pathways have been the main focus of new investigations. For instance, the mammalian target of the rapamycin (mTOR) pathway regulates protein synthesis and cell growth. Also, the activated protein kinase (AMPK) senses intracellular adenosine nucleotide levels and promotes ATP generation. Furthermore, sirtuins are also a crucial part of these investigations. 

SIRT and NAD+

Sirtuins consist of 7 different proteins dependent on nicotinamide adenine dinucleotide (NAD+) that modulate DNA by expression and aging. In addition, sirtuins regulate a wide variety of processes including, cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development, and aging. Therefore, these mediators are critical for the development of age-related diseases like cancer.

NAD+ is a critical mediator of energy production and promoter of cellular repair. However, several reports affirm that the intracellular levels of NAD+decrease as we hit our middle-age years. On the other hand, increasing our levels of NAD+ has resulted in better insulin sensitivity, an improvement of mitochondrial function, and lifespan extension. 

How can we improve NAD+ production?

Vitamin B3 is crucial to synthesize NAD+, but also enhancing the enzymatic conversion of NAD+ is fundamental to increase its levels. Indeed, the inhibition of the CD38 enzyme is associated with increased levels of NAD+. Besides these actions, supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside(NR), which are rapidly absorbed and converted into NAD+. Furthermore, an increase in NAD+ biosynthesis and robustness comes with beneficial results:

• Decreased age-related adipose tissue inflammation.
• Modulated insulin secretion and better insulin sensitivity.
• A marked improvement in neuronal function.
• An increased mitochondrial function resulting in better metabolic health and enhanced muscle mass.

Nicotinamide mononucleotide (NMN)

This NAD+ precursor can be found in small amounts in vegetables like cucumber, avocados, broccoli, cabbage, and edamame. Nevertheless, its conversion to NAD+ depends on rate-limiting enzymes like nicotinamide phosphoribosyltransferase (NAMPT). Furthermore, NAMPT can be found inside the cell as iNAMPT and on the outer part of the cells as eNAMPT. 

eNAMPT has a higher enzymatic activity of these two enzymatic forms and is found in many cells like hepatocytes, adipocytes, monocytes, cardiomyocytes, and glia cells. Recent research shows that white and brown adipocytes actively secrete eNAMPT reflecting a crucial role of adipose tissue on NAD+ biosynthesis.

The increased synthesis of NAD+ is fundamental to keep intracellular levels of energy on the proper level. However, as we age, NAD+ levels start to drop, and age-related issues arise. New research has found that NMN supplementation can increase NAD+ levels, which results in better insulin secretion and sensitivity, improved mitochondrial function, and may reverse age-related issues.- Ana Paola Rodríguez Arciniega, MS.

References:

Shade C. (2020). The Science Behind NMN-A Stable, Reliable NAD+Activator and Anti-Aging Molecule. Integrative medicine (Encinitas, Calif.), 19(1), 12–14.

Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in cell biology, 24(8), 464–471. doi.org/10.1016/j.tcb.2014.04.002

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