NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Yoshino, Jun; Baur, Joseph A.; Imai, Shoichi

doi:10.1016/j.cmet.2017.11.002

Cited by 665 publications

(695 citation statements)

References 124 publications

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“…NAD concentration decreases in muscle over the course of natural aging and increasing NAD synthesis has been suggested to delay some age-related degenerative processes [42]. Our data showed that mid-age muscles had significantly higher NADH than young muscles.…”

Section: Discussionmentioning

confidence: 51%

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information

Zhao

Chellappa

et al. 2019

Mol Imaging Biol

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Purpose: Optical redox imaging (ORI) technique images cellular autofluorescence of nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp containing FAD, i.e., flavin adenine dinucleotide). ORI has found wide applications in the study of cellular energetics and metabolism and may potentially assist in disease diagnosis and prognosis. Fixed tissues have been reported to exhibit autofluorescence with similar spectral characteristics to those of NADH and Fp. However, few studies report on quantitative ORI of formalin-fixed paraffin-embedded (FFPE) unstained tissue slides for disease biomarkers. We investigate whether ORI of FFPE unstained skeletal muscle slides may provide relevant quantitative biological information. Procedures: Living mouse muscle fibers and frozen and FFPE mouse muscle slides were subjected to ORI. Living mouse muscle fibers were imaged ex vivo before and after paraformaldehyde fixation. FFPE muscle slides of three mouse groups (young, mid-age, and muscle-specific overexpression of nicotinamide phosphoribosyltransferase (Nampt) transgenic mid-age) were imaged and compared to detect age-related redox differences. Results: We observed that living muscle fiber and frozen and FFPE slides all had strong autofluorescence signals in the NADH and Fp channels. Paraformaldehyde fixation resulted in a significant increase in the redox ratio Fp/(NADH + Fp) of muscle fibers. Quantitative image analysis on FFPE unstained slides showed that mid-age gastrocnemius muscles had stronger NADH and Fp signals than young muscles. Gastrocnemius muscles from mid-age Nampt mice had lower NADH compared to age-matched controls, but had higher Fp than young controls. Soleus muscles had the same trend of change and appeared to be more oxidative than gastrocnemius muscles. Differential NADH and Fp signals were found between gastrocnemius and soleus muscles within both mid-aged control and Nampt groups. Conclusion: Aging effect on redox status quantified by ORI of FFPE unstained muscle slides was reported for the first time. Quantitative information from ORI of FFPE unstained slides may be useful for biomedical applications.

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Section: Discussionmentioning

confidence: 51%

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information

Zhao

Chellappa

et al. 2019

Mol Imaging Biol

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“…They participate in reactions such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. In addition, it serves as a substrate for several enzymes involved in DNA damage repair, such as the sirtuins and poly (ADP-ribose) polymerases (PARPs) (Imai and Guarente, 2014; Verdin, 2015; Yoshino et al , 2018). …”

Section: [Background]mentioning

confidence: 99%

Two Different Methods of Quantification of Oxidized Nicotinamide Adenine Dinucleotide (NAD+) and Reduced Nicotinamide Adenine Dinucleotide (NADH) Intracellular Levels: Enzymatic Coupled Cycling Assay and Ultra-performance Liquid Chromatography (UPLC)-Mass Spectrometry

Kanamori¹,

Oliveira²,

Auxiliadora‐Martins³

et al. 2018

BIO-PROTOCOL

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Current studies on the age-related development of metabolic dysfunction and frailty are each day in more evidence. It is known, as aging progresses, nicotinamide adenine dinucleotide (NAD+) levels decrease in an expected physiological process. Recent studies have shown that a reduction in NAD+ is a key factor for the development of age-associated metabolic decline. Increased NAD+ levels in vivo results in activation of pro-longevity and health span-related factors. Also, it improves several physiological and metabolic parameters of aging, including muscle function, exercise capacity, glucose tolerance, and cardiac function in mouse models of natural and accelerated aging. Given the importance of monitoring cellular NAD+ and NADH levels, it is crucial to have a trustful method to do so. This protocol has the purpose of describing the NAD+ and NADH extraction from tissues and cells in an efficient and widely applicable assay as well as its graphic and quantitative analysis.

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“…Several studies have shown that obesity causes declines in skeletal muscle NAD levels (Yoshino et al., 2017). Thus, we investigated whether Nmnat3 overexpression can compensate for NAD deficiencies in skeletal muscle due to diet‐induced obesity.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, dietary interventions with the NAD precursors NMN and NR have been shown to increase NAD levels and ameliorate diet‐induced obesity and diabetes (Canto et al., 2012; Yoshino et al., 2017). In these models, increased NAD levels induced deacetylation of PGC1α and subsequently stimulated mitochondrial biogenesis and activity.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, NAD is considered a nexus for metabolism and aging. Numbers of studies show that NAD levels decrease with aging in multiple organs and that declines in intracellular NAD concentrations are related to various aging‐associated phenotypes (Canto et al., 2015; Rajman, Chwalek, & Sinclair, 2018; Yoshino, Baur, & Imai, 2017). Therefore, increases in intracellular NAD levels may combat with aging‐associated diseases.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

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SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

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NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Cited by 665 publications

References 124 publications

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information

Two Different Methods of Quantification of Oxidized Nicotinamide Adenine Dinucleotide (NAD+) and Reduced Nicotinamide Adenine Dinucleotide (NADH) Intracellular Levels: Enzymatic Coupled Cycling Assay and Ultra-performance Liquid Chromatography (UPLC)-Mass Spectrometry

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

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