LONGECITY

Abstract

 

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD⁺-dependence of sirtuin activity, adequate hypothalamic NAD⁺ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD⁺-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD⁺ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.

 

 

Concluding Remarks

 

Research data obtained from the genetic manipulation of enzymes involved in NAD+ biosynthesis or consumption have indicated that impaired NAD+ biology in hypothalamic neurons significantly contributes to diet- and aging-induced metabolic disorders and circadian disruption. Moreover, trials targeting hypothalamic NAD+ biology have revealed therapeutic benefits in terms of reversing the hypothalamic dysfunction that occurs during the progression of aging and dietinduced obesity, as well as in promoting healthy aging. It should be noted that the exogenous supplementation of the NAD+ precursors NMN and NR, and NAD+ itself, effectively recover the NAD+ deficiency in the hypothalamus in rodents. Future studies are warranted to reveal the metabolic pathways and transport mechanisms for exogenous NAD+ precursors and NAD+ in the hypothalamus. Moreover, the therapeutic potential of NAD+ biology-targeting drugs should be precisely tested in humans undergoing aging and also in obese subjects.

https://www.mdpi.com...3X/10/3/396/pdf