N1-Methylnicotinamide: The Mysterious Anti-aging Actor in Renal Transplantation

The fast global aging of people worldwide is a crucial demographic trend. According to evidence, Americans aged 65 and above will compose 21.6% of the population by 2040. During the aging process, the kidney undergoes gradual functional decrease, which turned out to be a forthcoming problem in clinical practice. Age-related decrease in renal function, evaluated by total glomerular filtration rate (GFR), which has been shown to drop by approximately 5-10% per decade after the age of 35. The sustaining extended period renal homeostasis is the main purpose of any therapeutic options intended for delaying or even reversing the aging kidney. The renal transplant has been regarded as the common alternative for kidney replacement therapy for elderly patients with end-stage renal disease (ESRD). In the last few years, considerable progress has been made to find novel therapeutic options for alleviating renal aging, in particular, calorie restriction and pharmacologic therapy. Nicotinamide N-methyltransferase is an enzyme responsible for generating N1-Methylnicotinamide (MNAM), notorious for its anti-diabetic, anti-thrombotic, and anti-inflammatory activity. MNAM is one of the important factors regarded as in vivo probes for evaluating the activity of some renal drug transporters. Furthermore, it has been shown to have therapeutic potential in the pathogenesis of proximal tubular cell damage and tubulointerstitial fibrosis. In this article, in addition to addressing the role of MNAM in renal function, we also explained its anti-aging effects. We conducted an in-depth investigation of the urinary excretion of MNAM and its metabolites, especially N1-methyl-2-pyridone-5- carboxamide (2py) in RTR. The excretion of MNAM and its metabolite, 2py, was inversely correlated with the risk of all-cause mortality in renal transplant recipients (RTR), independent of possible confounders. Therefore, we have shown that the reason for the lower mortality rate in RTR who had higher urinary excretion of MNAM and 2py may be related to the anti- aging effects of MNAM through transiently generating low levels of reactive oxygen species, stress resistance and the activation of antioxidant defense pathways.