NAD Abstracts 7

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Rejuvenating stem cells to restore muscle regeneration in aging.
            (Bengal et al., 2017) Download
Adult muscle stem cells, originally called satellite cells, are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of satellite cell dysfunction in aging animals, with the ultimate goal of rejuvenating old satellite cells and improving muscle function in elderly people. This review focuses on the recently identified network of cell-intrinsic and -extrinsic factors and processes contributing to the decline of satellite cells in old animals. Some studies suggest that aging-related satellite-cell decay is mostly caused by age-associated extrinsic environmental changes that could be reversed by a "youthful environment". Others propose a central role for cell-intrinsic mechanisms, some of which are not reversed by environmental changes. We believe that these proposals, far from being antagonistic, are complementary and that both extrinsic and intrinsic factors contribute to muscle stem cell dysfunction during aging-related regenerative decline. The low regenerative potential of old satellite cells may reflect the accumulation of deleterious changes during the life of the cell; some of these changes may be inherent (intrinsic) while others result from the systemic and local environment (extrinsic). The present challenge is to rejuvenate aged satellite cells that have undergone reversible changes to provide a possible approach to improving muscle repair in the elderly.

Biosensor reveals multiple sources for mitochondrial NAD⁺.
            (Cambronne et al., 2016) Download
Nicotinamide adenine dinucleotide (NAD(+)) is an essential substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases (PARPs), which are NAD(+)-consuming enzymes localized in the nucleus, cytosol, and mitochondria. Fluctuations in NAD(+) concentrations within these subcellular compartments are thought to regulate the activity of NAD(+)-consuming enzymes; however, the challenge in measuring compartmentalized NAD(+) in cells has precluded direct evidence for this type of regulation. We describe the development of a genetically encoded fluorescent biosensor for directly monitoring free NAD(+) concentrations in subcellular compartments. We found that the concentrations of free NAD(+) in the nucleus, cytoplasm, and mitochondria approximate the Michaelis constants for sirtuins and PARPs in their respective compartments. Systematic depletion of enzymes that catalyze the final step of NAD(+) biosynthesis revealed cell-specific mechanisms for maintaining mitochondrial NAD(+) concentrations.

CELL METABOLISM. The resurgence of NAD⁺.
            (Guarente, 2016) Download
Interventions that can slow mammalian aging have been rare. On pages 1436 and 1474 of this issue, Zhang et al. (1) and Cambronne et al. (2), respectively, highlight nicotinamide adenine dinucleotide (NAD) as a major intervention point to slow or ameliorate phenotypes of aging.

The Circadian NAD(+) Metabolism: Impact on Chromatin Remodeling and Aging.
            (Nakahata and Bessho, 2016) Download
Gene expression is known to be a stochastic phenomenon. The stochastic gene expression rate is thought to be altered by topological change of chromosome and/or by chromatin modifications such as acetylation and methylation. Changes in mechanical properties of chromosome/chromatin by soluble factors, mechanical stresses from the environment, or metabolites determine cell fate, regulate cellular functions, or maintain cellular homeostasis. Circadian clock, which drives the expression of thousands of genes with 24-hour rhythmicity, has been known to be indispensable for maintaining cellular functions/homeostasis. During the last decade, it has been demonstrated that chromatin also undergoes modifications with 24-hour rhythmicity and facilitates the fine-tuning of circadian gene expression patterns. In this review, we cover data which suggests that chromatin structure changes in a circadian manner and that NAD(+) is the key metabolite for circadian chromatin remodeling. Furthermore, we discuss the relationship among circadian clock, NAD(+) metabolism, and aging/age-related diseases. In addition, the interventions of NAD(+) metabolism for the prevention and treatment of aging and age-related diseases are also discussed.

Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders.
            (Srivastava, 2016) Download
Nicotinamide adenine dinucleotide (NAD(+)) is a central metabolic cofactor in eukaryotic cells that plays a critical role in regulating cellular metabolism and energy homeostasis. NAD(+) in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The NAD(+)/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb's cycle, and fatty acid oxidation. Intracellular NAD(+) is synthesized de novo from L-tryptophan, although its main source of synthesis is through salvage pathways from dietary niacin as precursors. NAD(+) is utilized by various proteins including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD(+) pool is thus set by a critical balance between NAD(+) biosynthetic and NAD(+) consuming pathways. Raising cellular NAD(+) content by inducing its biosynthesis or inhibiting the activity of PARP and cADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD(+) directly links the cellular redox state with signaling and transcriptional events. NAD(+) levels decline with mitochondrial dysfunction and reduced NAD(+)/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as during aging. Here, I will provide an overview of the current knowledge on NAD(+) metabolism including its biosynthesis, utilization, compartmentalization and role in the regulation of metabolic homoeostasis. I will further discuss how augmenting intracellular NAD(+) content increases oxidative metabolism to prevent bioenergetic and functional decline in multiple models of mitochondrial diseases and age-related disorders, and how this knowledge could be translated to the clinic for human relevance.

NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.
            (Yang and Sauve, 2016) Download
We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD(+) and NADP(+) which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD(+) has become reinvigorated by new understandings that dynamics within NAD(+) metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD(+) as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD(+), including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD(+) biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD(+) homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD(+) can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD(+) concentrations can provide ameliorative or curative benefits. Thus NAD(+) metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.


 

NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.
            (Zhang et al., 2016) Download
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals.

 


References

Bengal, E, et al. (2017), ‘Rejuvenating stem cells to restore muscle regeneration in aging.’, F1000Res, 6 76. PubMed: 28163911
Cambronne, XA, et al. (2016), ‘Biosensor reveals multiple sources for mitochondrial NAD⁺.’, Science, 352 (6292), 1474-77. PubMed: 27313049
Guarente, L (2016), ‘CELL METABOLISM. The resurgence of NAD⁺.’, Science, 352 (6292), 1396-97. PubMed: 27313027
Nakahata, Y and Y Bessho (2016), ‘The Circadian NAD(+) Metabolism: Impact on Chromatin Remodeling and Aging.’, Biomed Res Int, 2016 3208429. PubMed: 28050554
Srivastava, S (2016), ‘Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders.’, Clin Transl Med, 5 (1), 25. PubMed: 27465020
Yang, Y and AA Sauve (2016), ‘NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.’, Biochim Biophys Acta, 1864 (12), 1787-800. PubMed: 27374990
Zhang, H, et al. (2016), ‘NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.’, Science, 352 (6292), 1436-43. PubMed: 27127236