The NAD+/PARP1/SIRT1 Axis in Aging

Mendelsohn, Andrew R; Larrick, James W.

doi:10.1089/rej.2017.1980

Cited by 72 publications

(57 citation statements)

References 24 publications

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“…Interestingly, inhibition of PARP-1 can enhance mitochondrial metabolism and activate Sirt1 enzyme (Bai et al, 2011). Thus our data reinforce the existence of cross-talk between Sirt1 and PARP-1 (Cantó et al, 2013), possibly triggered by KD treatment, and modulated by NAD + levels (Fouquerel and Sobol, 2014; Hegedűs and Virág, 2014; Mendelsohn and Larrick, 2017). …”

Section: Discussionsupporting

confidence: 86%

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

Elamin

Ruskin

Masino

et al. 2018

Front. Cell. Neurosci.

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The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 (PARP-1). As a result, activation of NAD+-dependent enzymes’ downstream pathways could be the origin of KD’s broad beneficial effects. Here rats were fed ad libitum regular chow or KD for 2 days or 3 weeks and the levels of hippocampal sirtuins, PARP-1, and the oxidative DNA damage marker 8-hydroxy-2’-deoxyguanosine were quantified. We found a significant immediate and persistent increase in the collective activity of nuclear sirtuin enzymes, and a significant augmentation of Sirt1 mRNA at 2 days. Levels of PARP-1 and 8-hydroxy-2’-deoxyguanosine decreased after 2 days of treatment and further declined at 3 weeks. Our data show that a KD can rapidly modulate energy metabolism by acting on NAD+-dependent enzymes and their downstream pathways. Thus, therapy with a KD can potentially enhance brain health and increase overall healthspan via NAD+-related mechanisms that render cells more resilient against DNA damage and a host of metabolic, epileptic, neurodegenerative, or neurodevelopmental insults.

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Section: Discussionsupporting

confidence: 86%

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

Elamin

Ruskin

Masino

et al. 2018

Front. Cell. Neurosci.

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“…). PARP‐1 consumes NAD + to recruit repair enzymes to single‐stranded DNA breaks . PARP‐1 activation in response to simulated hypoxia–reperfusion injury can deplete NAD + and ATP, as well as blunt mitochondrial function .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells

et al. 2019

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Senescence-associated dysfunction deleteriously affects biological activities of human c-Kit + cardiac progenitor cells (hCPCs), particularly under conditions of in vitro culture. In comparison, preservation of self-renewal and decreases in mitochondrial reactive oxygen species (ROS) are characteristics of murine CPCs in vivo that reside within hypoxic niches. Recapitulating hypoxic niche oxygen tension conditions of $1% O 2 in vitro for expansion of hCPCs rather than typical normoxic cell culture conditions (21% O 2 ) could provide significant improvement of functional and biological activities of hCPCs. hCPCs were isolated and expanded under permanent hypoxic (hCPC-1%) or normoxic (hCPC-21%) conditions from left ventricular tissue explants collected during left ventricular assist device implantation. hCPC-1% exhibit increased self-renewal and suppression of senescence characteristics relative to hCPC-21%. Oxidative stress contributed to higher susceptibility to apoptosis, as well as decreased mitochondrial function in hCPC-21%. Hypoxia prevented accumulation of dysfunctional mitochondria, supporting higher oxygen consumption rates and mitochondrial membrane potential. Mitochondrial ROS was an upstream mediator of senescence since treatment of hCPC-1% with mitochondrial inhibitor antimycin A recapitulated mitochondrial dysfunction and senescence observed in hCPC-21%. NAD + /NADH ratio and autophagic flux, which are key factors for mitochondrial function, were higher in hCPC-1%, but hCPC-21% were highly dependent on BNIP3/NIX-mediated mitophagy to maintain mitochondrial function. Overall, results demonstrate that supraphysiological oxygen tension during in vitro expansion initiates a downward spiral of oxidative stress, mitochondrial dysfunction, and cellular energy imbalance culminating in early proliferation arrest of hCPCs. Senescence is inhibited by preventing ROS through hypoxic culture of hCPCs. STEM CELLS 2019;37:555-567 SIGNIFICANCE STATEMENTHuman c-Kit + cardiac progenitor cell (hCPC) biological function is hampered by limited expansion potential and early replicative senescence. Permanent hypoxia (1% O 2 ) preserved clonogenicity and mitochondrial function of hCPCs derived from heart failure patients while maintaining high levels of intracellular NAD + /NADH ratio and suppressing reactive oxygen species and oxidative stress. Figure 7. Long-term hypoxic culture preserves human c-Kit + cardiac progenitor cell (hCPC) mitochondrial function and inhibits senescence. (A): Schematic of feed-forward cycle of oxidative damage on hCPC-21% that leads to mitochondrial dysfunction and senescence in normoxic culture. The cycle is rescued by hypoxic culture of hCPCs. (B): Illustration of hypoxic and normoxic isolation and expansion strategies and respective outcomes on either hCPC-1% or hCPC-21%.

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“…CD38 activity is necessary for functions such as memory, amnesia, and autism: single nucleotide polymorphisms of CD38 alter the availability of cADPR, regulating brain oxytocin secretion. CD38 levels increase during aging, exerting a high NADase activity [52][53][54]. Mitochondrial depletion of NAD + has been linked to ageing and various human diseases [8,[55][56][57][58][59][60][61].…”

Section: Nicotinic Acid Adenine Dinucleotide Phosphate (Naadp) and Cymentioning

confidence: 99%

Roles of Nicotinamide Adenine Dinucleotide (NAD+) in Biological Systems

Poltronieri

Čerekovic

2018

Challenges

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NAD + has emerged as a crucial element in both bioenergetic and signaling pathways since it acts as a key regulator of cellular and organism homeostasis. NAD + is a coenzyme in redox reactions, a donor of adenosine diphosphate-ribose (ADPr) moieties in ADP-ribosylation reactions, a substrate for sirtuins, a group of histone deacetylase enzymes that use NAD + to remove acetyl groups from proteins; NAD + is also a precursor of cyclic ADP-ribose, a second messenger in Ca ++ release and signaling, and of diadenosine tetraphosphate (Ap4A) and oligoadenylates (oligo2 -5 A), two immune response activating compounds. In the biological systems considered in this review, NAD + is mostly consumed in ADP-ribose (ADPr) transfer reactions. In this review the roles of these chemical products are discussed in biological systems, such as in animals, plants, fungi and bacteria. In the review, two types of ADP-ribosylating enzymes are introduced as well as the pathways to restore the NAD + pools in these systems.

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The NAD+/PARP1/SIRT1 Axis in Aging

Cited by 72 publications

References 24 publications

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells

Roles of Nicotinamide Adenine Dinucleotide (NAD+) in Biological Systems

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