NAD+ Deficits in Age-Related Diseases and Cancer

Garrido, Amanda; Djouder, Nabil

doi:10.1016/j.trecan.2017.06.001

Cited by 44 publications

(26 citation statements)

References 152 publications

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“…This substrate-dependent, allosteric activation of SIRT1 exerted by the vast majority of STACs cannot compensate for the reduction in NAD + levels. Accordingly, a variety of physiological and pharmacological strategies aimed to boost NAD + levels or inhibit NAD + consumption is being rapidly pursued for nutraceutical and pharmaceutical development to control SIRT1 activity and thereby achieve healthy benefits ( 44 – 46 , 49 ). Given the valuable physiological effects of improving the catalytic efficiency of SIRT1 under NAD + depletion in a substrate-independent manner, a preferred general strategy for activation of sirtuins including SIRT1 would be to lower the K m for NAD + .…”

Section: Discussionmentioning

confidence: 99%

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

et al. 2018

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Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.

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Section: Discussionmentioning

confidence: 99%

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

et al. 2018

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“…Tryptophan, through the kynurenine pathway, is involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD + ) [ 94 ], which has a key role in human health as it is an essential coenzyme for the cellular processes of energy metabolism, cell protection and biosynthesis. Moreover, decreased cellular NAD + concentrations occur during aging and supplementation with NAD + precursors can prolong both life span and health span [ 95 , 96 ]. NAD + is indeed an important co-substrate of sirtuins.…”

Section: Gut Microbiota Age-related Changes Brain Functions and Neurmentioning

confidence: 99%

Gut microbiota changes in the extreme decades of human life: a focus on centenarians

Santoro

Ostan

Candela

et al. 2017

Cell. Mol. Life Sci.

191

103

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The gut microbiota (GM) is a complex, evolutionarily molded ecological system, which contributes to a variety of physiological functions. The GM is highly dynamic, being sensitive to environmental stimuli, and its composition changes over the host’s entire lifespan. However, the basic question of how much these changes may be ascribed to variables such as population, diet, genetics and gender, and/or to the aging process per se is still largely unanswered. We argue that comparison among studies on centenarians—the best model of healthy aging and longevity—recruited from different geographical areas/populations (different genetics and dietary habits) can help to disentangle the contribution of aging and non-aging-related variables to GM remodeling with age. The current review focuses on the role of population, gender and host genetics as possible drivers of GM modification along the human aging process. The feedback impact of age-associated GM variation on the GM–brain axis and GM metabolomics is also discussed. We likewise address the role of GM in neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and its possible therapeutic use, taking advantage of the fact that centenarians are characterized by an extreme (healthy) phenotype versus patients suffering from age-related pathologies. Finally, it is argued that longitudinal studies combining metagenomics sequencing and in-depth phylogenetic analysis with a comprehensive phenotypic characterization of centenarians and patients using up-to-date omics (metabolomics, transcriptomics and meta-transcriptomics) are urgently needed.

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“…Disrupted NAD synthesis may cause NAD deficiency [ 25 ]. Lower NAD levels relate to aging, mitochondrial dysfunction, cancer and other age-related diseases [ 26 , 27 ]. Altered expression of sirtuin 1 (SIRT1) has been described in bipolar patients [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Acid Long-Term Effectiveness in a Patient with Bipolar Type II Disorder: A Case of Vitamin Dependency

Jonsson

2018

Nutrients

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Nicotinic acid (NA), often called niacin, a form of vitamin B3, is a water-soluble nutrient found in animal and vegetarian foods. Vitamin B3 for healthy people is considered to be needed in doses of less than 20 mg daily. In higher doses, NA has been described to be beneficial in some patients with psychiatric disorders. This report describes a male patient with bipolar type II disorder who for many years had been treated with lithium and other medications applied in affective disorders. These pharmacological drugs had beneficial effects but were at times insufficient. When the patient was prescribed NA, he experienced a comparatively strong effect. Slowly it was discovered that the patient could lower and cease all medications except NA. For over 11 years he has been stable and calm with NA and currently takes 1 g three times daily. When not taking NA, he consistently became anxious and depressed within 2–3 days. The resumption of NA resulted in a normal state usually within 1 day. This finding has been described as a vitamin dependency. The paper discusses possible mechanisms for the effect of NA in this patient. Further studies are needed to investigate the prevalence of vitamin B3 dependency and the biochemical explanations for this phenomenon.

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NAD+ Deficits in Age-Related Diseases and Cancer

Cited by 44 publications

References 152 publications

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

Gut microbiota changes in the extreme decades of human life: a focus on centenarians

Nicotinic Acid Long-Term Effectiveness in a Patient with Bipolar Type II Disorder: A Case of Vitamin Dependency

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