Nicotinamide Adenine Dinucleotide (NAD)

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    Nicotinamide Adenine Dinucleotide (NAD) is a vital coenzyme found in every cell of our bodies and has become a focal point in the field of longevity and aging research. NAD+ plays a central role in energy metabolism and is essential for the function of several enzymes that are associated with aging and DNA repair.

    NAD exists in two main forms: NAD+ and NADH. NAD+ is the oxidized form of the compound and is essential for various cellular processes, including DNA repair, gene expression, and calcium signaling. When NAD+ accepts electrons during metabolic reactions, it becomes reduced and transforms into NADH. NADH, the reduced form, primarily functions in the production of ATP, the cell's primary energy currency, through the electron transport chain. The dynamic interconversion between these two forms, NAD+ and NADH, is fundamental to the cell's energy production and overall function.

    The Role of NAD+ in the Cell

    NAD+ is involved in several crucial biological processes:

    1. Energy Production: NAD+ helps in converting nutrients into energy within the mitochondria, the powerhouse of cells.
    2. DNA Repair: It's essential for the function of enzymes like PARPs and sirtuins, which are involved in DNA repair and have links to longevity.
    3. Cell Signaling: As a substrate for various enzymes, it plays a role in cellular communication and adaptations to stress.
    CD38/NADase increases during aging, and causes NAD decline and subsequent mitochondrial dysfunction.

    NAD+ Decline with Age

    A significant finding in the field of aging research is that NAD+ levels naturally decline as we age. This reduction has been associated with:

    • A decrease in mitochondrial function, leading to reduced energy output.
    • Reduced activity of sirtuins, proteins linked to lifespan extension in various organisms.
    • Enhanced vulnerability of DNA to damage.
    • Increased susceptibility to age-related diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases.

    A gradual increase in CD38 has been implicated in the decline of NAD+ with age.[1][2] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.[3] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,[4] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).[5] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction.[4]

    Boosting NAD+ Levels

    Given the importance of NAD+ in various cellular functions and its decline with age, researchers have been exploring ways to replenish or boost NAD+ levels in the body. Several methods are under investigation:

    1. Nicotinamide Mononucleotide (NMN): A precursor to NAD+ that, when supplemented, has shown potential in increasing NAD+ levels in various studies, mainly in animals.
    2. Nicotinamide Riboside (NR): Another NAD+ precursor that can elevate NAD+ levels in the body.
    3. Caloric Restriction: It has been observed to enhance NAD+ levels and activate sirtuins.
    4. NAD+ Infusions: Direct infusion of NAD+ is being explored as a method, although it's still in the early stages of research.

    ⇒ see NAD+ Booster

    Safety and Implications for Longevity

    While initial studies, primarily on animal models, have shown promise in boosting NAD+ levels for promoting health and extending lifespan, it's essential to approach the findings with caution. Comprehensive human trials are needed to understand:

    • The long-term effects of boosting NAD+.
    • The effective dosages and potential side effects.
    • The real impact on human longevity.

    NAD+, Sirtuins and Longevity-Promoting Pathway

    The CD38/NAD+/SIRT1 Axis. NAD+ levels in the body can be influenced by the supplementation of precursors nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD+ levels decrease with age and are further metabolized by the activation of SIRT1, PARP1, SARM1, and CD38. Restoring NAD+ levels allows for an increase in SIRT1 activity due to increased substrate availability, resulting in the inhibition of age-promoting pathways and activation of adaptive and protective transcription factors and processes. The central lineage may be described as the CD38/NAD+/SIRT1 axis, and targeting this access with nutraceutical interventions may prevent the age-related decline of NAD+ levels in the body. Black lines indicate conversion or activation. Red lines indicate inhibitors or destroyers of the indicated target.[6]

    Disruption of proper NAD+ levels and the loss of protective sirtuin activity have emerged as prime targets for NAD+-based interventions[7]. Administration of NAD+ precursors, such as Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN), has shown potential in alleviating age-related NAD+ decline and associated pathologies, particularly in the context of age-related diseases[8][9][10]. Aging is associated with a decreased NAD+/NADH ratio in human plasma, mainly due to the deterioration of NAD+ stores, rather than an increase in NADH[11]. Replenishing NAD+ has been shown to rescue mitochondrial regulatory function from NAD+ induced pseudohypoxic mitochondrial stress during aging[12].

    SIRT1, a member of the sirtuin protein family involved in cellular response to stress, has been implicated in longevity, although results are mixed and context-dependent. High-level athletes, for instance, exhibit higher telomere length and reduced insulin resistance, correlating with higher levels of SIRT1 expression[13]. SIRT1's beneficial activity may depend on the deacetylation and activation of Forkhead transcription factors like FoxO and PGC1α[14][15]. FoxOs are involved in stress resistance, cell cycle arrest, apoptosis, and tumor suppression, and their activation has been linked with longevity in worms and flies[16][17]. The insulin/insulin-like growth factor signaling (IIS) pathway, which regulates growth, development, metabolism, reproduction, and longevity, extends neuronal activity and longevity under low IIS conditions through FoxO activity[18][19]. PGC1α, influencing mitochondrial biogenesis, is important in metabolic diseases, and its overexpression has been linked to improved insulin sensitivity in muscle[20][21][22]. Additionally, AMPK, involved in energy expenditure, exhibits a bidirectional interplay with SIRT1 and inhibits mTOR, a process linked to longevity; it also activates SIRT1 by increasing available NAD+ stores[23]. Furthermore, nuclear factor κB (NF-κB) signaling, involved in innate immunity, can be inhibited by SIRT1 activity to reduce prolonged inflammatory signaling[24]. The availability of NAD+ in the body makes SIRT1 an interesting target in manipulating age-related pathways to promote longevity[9][25][26][27]. Maintaining adequate NAD+ levels for optimal SIRT1 activity during aging may be a key factor in regulating longevity.

    See also

    Todo

    • 2021, NAD+ metabolism and its roles in cellular processes during ageing [28]
    • 2022, Efficient Assay and Marker Significance of NAD+ in Human Blood [29]
    • 2021, Age-Dependent Decline of NAD+-Universal Truth or Confounded Consensus? [30]

    References

    1. ↑ Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (June 2016). "CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism". Cell Metabolism. 23 (6): 1127–1139. doi:10.1016/j.cmet.2016.05.006. PMC 4911708. PMID 27304511.
    2. ↑ Schultz MB, Sinclair DA (June 2016). "Why NAD(+) Declines during Aging: It's Destroyed". Cell Metabolism. 23 (6): 965–966. doi:10.1016/j.cmet.2016.05.022. PMC 5088772. PMID 27304496.
    3. ↑ Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN (May 2018). "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline". Cell Metabolism. 27 (5): 1081–1095.e10. doi:10.1016/j.cmet.2018.03.016. PMC 5935140. PMID 29719225.
    4. ↑ 4.0 4.1 Cambronne XA, Kraus WL (2020). "Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences. 45 (10): 858–873. doi:10.1016/j.tibs.2020.05.010. PMC 7502477. PMID 32595066.
    5. ↑ Kang BE, Choi J, Stein S, Ryu D (2020). "Implications of NAD + boosters in translational medicine". European Journal of Clinical Investigation. 50 (10): e13334. doi:10.1111/eci.13334. PMID 32594513. S2CID 220254270.
    6. ↑ Sharma A et al.: Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients 2023. (PMID 36678315) [PubMed] [DOI] [Full text] Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.
    7. ↑ Mendelsohn AR & Larrick JW: The NAD+/PARP1/SIRT1 Axis in Aging. Rejuvenation Res 2017. (PMID 28537485) [PubMed] [DOI] NAD+ levels decline with age in diverse animals from Caenorhabditis elegans to mice. Raising NAD+ levels by dietary supplementation with NAD+ precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial function and muscle and neural and melanocyte stem cell function in mice, as well as increases murine life span. Decreased NAD+ levels with age reduce SIRT1 function and reduce the mitochondrial unfolded protein response, which can be overcome by NR supplementation. Decreased NAD+ levels cause NAD+-binding protein DBC1 to form a complex with PARP1, inhibiting poly(adenosine diphosphate-ribose) polymerase (PARP) catalytic activity. Old mice have increased amounts of DBC1-PARP1 complexes, lower PARP activity, increased DNA damage, and reduced nonhomologous end joining and homologous recombination repair. DBC1-PARP1 complexes in old mice can be broken by increasing NAD+ levels through treatment with NMN, reducing DNA damage and restoring PARP activity to youthful levels. The mechanism of declining NAD+ levels and its fundamental importance to aging are yet to be elucidated. There is a correlation of PARP activity with mammalian life span that suggests that NAD+/SIRT1/PARP1 may be more significant than the modest effects on life span observed for NR supplementation in old mice. The NAD+/PARP1/SIRT1 axis may link NAD+ levels and DNA damage with the apparent epigenomic DNA methylation clocks that have been described.
    8. ↑ Fang EF et al.: NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med 2017. (PMID 28899755) [PubMed] [DOI] [Full text] The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demands and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD+ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD+ biosynthesis, together with putative mechanisms of NAD+ action against aging, including recent preclinical and clinical trials.
    9. ↑ 9.0 9.1 Yaku K et al.: NAD metabolism: Implications in aging and longevity. Ageing Res Rev 2018. (PMID 29883761) [PubMed] [DOI] Nicotinamide adenine dinucleotide (NAD) is an important co-factor involved in numerous physiological processes, including metabolism, post-translational protein modification, and DNA repair. In living organisms, a careful balance between NAD production and degradation serves to regulate NAD levels. Recently, a number of studies have demonstrated that NAD levels decrease with age, and the deterioration of NAD metabolism promotes several aging-associated diseases, including metabolic and neurodegenerative diseases and various cancers. Conversely, the upregulation of NAD metabolism, including dietary supplementation with NAD precursors, has been shown to prevent the decline of NAD and exhibits beneficial effects against aging and aging-associated diseases. In addition, many studies have demonstrated that genetic and/or nutritional activation of NAD metabolism can extend the lifespan of diverse organisms. Collectively, it is clear that NAD metabolism plays important roles in aging and longevity. In this review, we summarize the basic functions of the enzymes involved in NAD synthesis and degradation, as well as the outcomes of their dysregulation in various aging processes. In addition, a particular focus is given on the role of NAD metabolism in the longevity of various organisms, with a discussion of the remaining obstacles in this research field.
    10. ↑ Chini CCS et al.: NAD and the aging process: Role in life, death and everything in between. Mol Cell Endocrinol 2017. (PMID 27825999) [PubMed] [DOI] [Full text] Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD). From the simplest organism, such as bacteria, to the most complex multicellular organisms, NAD is a key cellular component. NAD is extremely abundant in most living cells and has traditionally been described to be a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD has also been shown to play a key role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin. Thus, NAD is a molecule that provides an important link between signaling and metabolism, and serves as a key molecule in cellular metabolic sensoring pathways. Importantly, it has now been clearly demonstrated that cellular NAD levels decline during chronological aging. This decline appears to play a crucial role in the development of metabolic dysfunction and age-related diseases. In this review we will discuss the molecular mechanisms responsible for the decrease in NAD levels during aging. Since other reviews on this subject have been recently published, we will concentrate on presenting a critical appraisal of the current status of the literature and will highlight some controversial topics in the field. In particular, we will discuss the potential role of the NADase CD38 as a driver of age-related NAD decline.
    11. ↑ Clement J et al.: The Plasma NAD+ Metabolome Is Dysregulated in "Normal" Aging. Rejuvenation Res 2019. (PMID 30124109) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an electron carrier in cellular metabolism and plays a crucial role in the maintenance of balanced redox homeostasis. Quantification of NAD+:NADH and NADP+:NADPH ratios are pivotal to a wide variety of cellular processes, including intracellular secondary messenger signaling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase (PARP), epigenetic regulation of gene expression by NAD-dependent histone deacetylase enzymes known as sirtuins, and regulation of the oxidative pentose phosphate pathway. We quantified changes in the NAD+ metabolome in plasma samples collected from consenting healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. However, an age-related increase in the reduced form of NAD+ and NADP+-NADH and NADPH-and nicotinamide (NAM), N-methyl-nicotinamide (MeNAM), and the products of adenosine diphosphoribosylation, including adenosine diphosphate ribose (ADPR) was also reported. Whereas, plasma levels of nicotinic acid (NA), nicotinamide mononucleotide (NMN), and nicotinic acid mononucleotide (NAMN) showed no statistically significant changes across age groups. Taken together, our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome. Our future research will seek to elucidate the role of modulating NAD+ metabolites in the treatment and prevention of age-related diseases.
    12. ↑ Gomes AP et al.: Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013. (PMID 24360282) [PubMed] [DOI] [Full text] Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
    13. ↑ Aguiar SS et al.: Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?. Int J Sports Med 2022. (PMID 34256387) [PubMed] [DOI] Lower SIRT1 and insulin resistance are associated with accelerated telomere shortening. This study investigated whether the lifestyle of master athletes can attenuate these age-related changes and thereby slow aging. We compared insulin, SIRT1, and telomere length in highly trained male master athletes (n=52; aged 49.9±7.2 yrs) and age-matched non-athletes (n=19; aged 47.3±8.9 yrs). This is a cross-sectional study, in which all data were collected in one visit. Overnight fasted SIRT1 and insulin levels in whole blood were assessed using commercial kits. Relative telomere length was determined in leukocytes through qPCR analyses. Master athletes had higher SIRT1, lower insulin, and longer telomere length than age-matched non-athletes (p<0.05 for all). Insulin was inversely associated with SIRT1 (r=-0.38; p=0.001). Telomere length correlated positively with SIRT1 (r=0.65; p=0.001), whereas telomere length and insulin were not correlated (r=0.03; p=0.87). In conclusion, master athletes have higher SIRT1, lower insulin, and longer telomeres than age-matched non-athletes. Furthermore, SIRT1 was negatively associated with insulin and positively associated with telomere length. These findings suggest that in this sample of middle-aged participants reduced insulin, increased SIRT1 activity, and attenuation of biological aging are connected.
    14. ↑ Tang BL: Sirt1 and the Mitochondria. Mol Cells 2016. (PMID 26831453) [PubMed] [DOI] [Full text] Sirt1 is the most prominent and extensively studied member of sirtuins, the family of mammalian class III histone deacetylases heavily implicated in health span and longevity. Although primarily a nuclear protein, Sirt1's deacetylation of Peroxisome proliferator-activated receptor Gamma Coactivator-1α (PGC-1α) has been extensively implicated in metabolic control and mitochondrial biogenesis, which was proposed to partially underlie Sirt1's role in caloric restriction and impacts on longevity. The notion of Sirt1's regulation of PGC-1α activity and its role in mitochondrial biogenesis has, however, been controversial. Interestingly, Sirt1 also appears to be important for the turnover of defective mitochondria by mitophagy. I discuss here evidences for Sirt1's regulation of mitochondrial biogenesis and turnover, in relation to PGC-1α deacetylation and various aspects of cellular physiology and disease.
    15. ↑ Brunet A et al.: Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004. (PMID 14976264) [PubMed] [DOI] The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
    16. ↑ Greer EL & Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005. (PMID 16288288) [PubMed] [DOI] A wide range of human diseases, including cancer, has a striking age-dependent onset. However, the molecular mechanisms that connect aging and cancer are just beginning to be unraveled. FOXO transcription factors are promising candidates to serve as molecular links between longevity and tumor suppression. These factors are major substrates of the protein kinase Akt. In the presence of insulin and growth factors, FOXO proteins are relocalized from the nucleus to the cytoplasm and degraded via the ubiquitin-proteasome pathway. In the absence of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest, stress resistance, or apoptosis. Stress stimuli also trigger the relocalization of FOXO factors into the nucleus, thus allowing an adaptive response to stress stimuli. Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression.
    17. ↑ Zhao Y & Liu YS: Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases. Front Cardiovasc Med 2021. (PMID 35004893) [PubMed] [DOI] [Full text] Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people. Emerging evidence indicates that FOXO3 plays a critical role in vascular aging. FOXO3 inactivation is implicated in several aging-related vascular diseases. In experimental studies, FOXO3-engineered human ESC-derived vascular cells improve vascular homeostasis and delay vascular aging. The purpose of this review is to explore how FOXO3 regulates vascular aging and its crucial role in aging-related vascular diseases.
    18. ↑ Kaletsky R et al.: The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Nature 2016. (PMID 26675724) [PubMed] [DOI] [Full text] Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism's most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory and axon regeneration with age, in both mammals and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.
    19. ↑ Slack C et al.: dFOXO-independent effects of reduced insulin-like signaling in Drosophila. Aging Cell 2011. (PMID 21443682) [PubMed] [DOI] [Full text] The insulin/insulin-like growth factor-like signaling (IIS) pathway in metazoans has evolutionarily conserved roles in growth control, metabolic homeostasis, stress responses, reproduction, and lifespan. Genetic manipulations that reduce IIS in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse have been shown not only to produce substantial increases in lifespan but also to ameliorate several age-related diseases. In C. elegans, the multitude of phenotypes produced by the reduction in IIS are all suppressed in the absence of the worm FOXO transcription factor, DAF-16, suggesting that they are all under common regulation. It is not yet clear in other animal models whether the activity of FOXOs mediate all of the physiological effects of reduced IIS, especially increased lifespan. We have addressed this issue by examining the effects of reduced IIS in the absence of dFOXO in Drosophila, using a newly generated null allele of dfoxo. We found that the removal of dFOXO almost completely blocks IIS-dependent lifespan extension. However, unlike in C. elegans, removal of dFOXO does not suppress the body size, fecundity, or oxidative stress resistance phenotypes of IIS-compromised flies. In contrast, IIS-dependent xenobiotic resistance is fully dependent on dFOXO activity. Our results therefore suggest that there is evolutionary divergence in the downstream mechanisms that mediate the effects of IIS. They also imply that in Drosophila, additional factors act alongside dFOXO to produce IIS-dependent responses in body size, fecundity, and oxidative stress resistance and that these phenotypes are not causal in IIS-mediated extension of lifespan.
    20. ↑ Brenmoehl J & Hoeflich A: Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion 2013. (PMID 23583953) [PubMed] [DOI] In this review, we discuss the dual control of mitochondrial biogenesis and energy metabolism by silent information regulator-1 and -3 (SIRT1 and SIRT3). SIRT1 activates the peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α)-mediated transcription of nuclear and mitochondrial genes encoding for proteins promoting mitochondria proliferation, oxidative phosphorylation and energy production, whereas SIRT3 directly acts as an activator of proteins important for oxidative phosphorylation, tricarboxylic acid (TCA) cycle and fatty-acid oxidation and indirectly of PGC-1α and AMP-activated protein kinase (AMPK). The complex network involves different cellular compartments, transcriptional activation, post-translational modification and a plethora of secondary effectors. Overall, the mode of interaction between both sirtuin family members may be considered as a prominent case of molecular job-sharing.
    21. ↑ Chan MC & Arany Z: The many roles of PGC-1α in muscle--recent developments. Metabolism 2014. (PMID 24559845) [PubMed] [DOI] [Full text] Skeletal muscle is the largest organ in the body and contributes to innumerable aspects of organismal biology. Muscle dysfunction engenders numerous diseases, including diabetes, cachexia, and sarcopenia. At the same time, skeletal muscle is also the main engine of exercise, one of the most efficacious interventions for prevention and treatment of a wide variety of diseases. The transcriptional coactivator PGC-1α has emerged as a key driver of metabolic programming in skeletal muscle, both in health and in disease. We review here the many aspects of PGC-1α function in skeletal muscle, with a focus on recent developments.
    22. ↑ Summermatter S et al.: PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes 2013. (PMID 23086035) [PubMed] [DOI] [Full text] Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders.
    23. ↑ Cantó C et al.: AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009. (PMID 19262508) [PubMed] [DOI] [Full text] AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
    24. ↑ Kauppinen A et al.: Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013. (PMID 23770291) [PubMed] [DOI] Recent studies have indicated that the regulation of innate immunity and energy metabolism are connected together through an antagonistic crosstalk between NF-κB and SIRT1 signaling pathways. NF-κB signaling has a major role in innate immunity defense while SIRT1 regulates the oxidative respiration and cellular survival. However, NF-κB signaling can stimulate glycolytic energy flux during acute inflammation, whereas SIRT1 activation inhibits NF-κB signaling and enhances oxidative metabolism and the resolution of inflammation. SIRT1 inhibits NF-κB signaling directly by deacetylating the p65 subunit of NF-κB complex. SIRT1 stimulates oxidative energy production via the activation of AMPK, PPARα and PGC-1α and simultaneously, these factors inhibit NF-κB signaling and suppress inflammation. On the other hand, NF-κB signaling down-regulates SIRT1 activity through the expression of miR-34a, IFNγ, and reactive oxygen species. The inhibition of SIRT1 disrupts oxidative energy metabolism and stimulates the NF-κB-induced inflammatory responses present in many chronic metabolic and age-related diseases. We will examine the molecular mechanisms of the antagonistic signaling between NF-κB and SIRT1 and describe how this crosstalk controls inflammatory process and energy metabolism. In addition, we will discuss how disturbances in this signaling crosstalk induce the appearance of chronic inflammation in metabolic diseases.
    25. ↑ Mao K & Zhang G: The role of PARP1 in neurodegenerative diseases and aging. FEBS J 2022. (PMID 33460497) [PubMed] [DOI] Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive memory loss and motor impairment. Aging is a major risk factor for neurodegenerative diseases. Neurodegenerative diseases and aging often develop in an irreversible manner and cause a significant socioeconomic burden. When considering their pathogenesis, many studies usually focus on mitochondrial dysfunction and DNA damage. More recently, neuroinflammation, autophagy dysregulation, and SIRT1 inactivation were shown to be involved in the pathogenesis of neurodegenerative diseases and aging. In addition, studies uncovered the role of poly (ADP-ribose)-polymerase-1 (PARP1) in neurodegenerative diseases and aging. PARP1 links to a cluster of stress signals, including those originated by inflammation and autophagy dysregulation. In this review, we summarized the recent research progresses on PARP1 in neurodegenerative diseases and aging, with an emphasis on the relationship among PARP1, neuroinflammation, mitochondria, and autophagy. We discussed the possibilities of treating neurodegenerative diseases and aging through targeting PARP1.
    26. ↑ Amjad S et al.: Role of NAD+ in regulating cellular and metabolic signaling pathways. Mol Metab 2021. (PMID 33609766) [PubMed] [DOI] [Full text] BACKGROUND: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. SCOPE OF REVIEW: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. MAJOR CONCLUSIONS: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation.
    27. ↑ Sedlackova L & Korolchuk VI: The crosstalk of NAD, ROS and autophagy in cellular health and ageing. Biogerontology 2020. (PMID 32124104) [PubMed] [DOI] [Full text] Cellular adaptation to various types of stress requires a complex network of steps that altogether lead to reconstitution of redox balance, degradation of damaged macromolecules and restoration of cellular metabolism. Advances in our understanding of the interplay between cellular signalling and signal translation paint a complex picture of multi-layered paths of regulation. In this review we explore the link between cellular adaptation to metabolic and oxidative stresses by activation of autophagy, a crucial cellular catabolic pathway. Metabolic stress can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a co-factor in a variety of enzymatic reactions and thus trigger autophagy that acts to sequester intracellular components for recycling to support cellular growth. Likewise, autophagy is activated by oxidative stress to selectively recycle damaged macromolecules and organelles and thus maintain cellular viability. Multiple proteins that help regulate or execute autophagy are targets of post-translational modifications (PTMs) that have an effect on their localization, binding affinity or enzymatic activity. These PTMs include acetylation, a reversible enzymatic modification of a protein's lysine residues, and oxidation, a set of reversible and irreversible modifications by free radicals. Here we highlight the latest findings and outstanding questions on the interplay of autophagy with metabolic stress, presenting as changes in NAD levels, and oxidative stress, with a focus on autophagy proteins that are regulated by both, oxidation and acetylation. We further explore the relevance of this multi-layered signalling to healthy human ageing and their potential role in human disease.
    28. ↑ Covarrubias AJ et al.: NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021. (PMID 33353981) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
    29. ↑ Balashova NV et al.: Efficient Assay and Marker Significance of NAD+ in Human Blood. Front Med (Lausanne) 2022. (PMID 35665345) [PubMed] [DOI] [Full text] Oxidized nicotinamide adenine dinucleotide (NAD+) is a biological molecule of systemic importance. Essential role of NAD+ in cellular metabolism relies on the substrate action in various redox reactions and cellular signaling. This work introduces an efficient enzymatic assay of NAD+ content in human blood using recombinant formate dehydrogenase (FDH, EC 1.2.1.2), and demonstrates its diagnostic potential, comparing NAD+ content in the whole blood of control subjects and patients with cardiac or neurological pathologies. In the control group (n = 22, 25-70 years old), our quantification of the blood concentration of NAD+ (18 μM, minimum 15, max 23) corresponds well to NAD+ quantifications reported in literature. In patients with demyelinating neurological diseases (n = 10, 18-55 years old), the NAD+ levels significantly (p < 0.0001) decrease (to 14 μM, min 13, max 16), compared to the control group. In cardiac patients with the heart failure of stage II and III according to the New York Heart Association (NYHA) functional classification (n = 24, 42-83 years old), the blood levels of NAD+ (13 μM, min 9, max 18) are lower than those in the control subjects (p < 0.0001) or neurological patients (p = 0.1). A better discrimination of the cardiac and neurological patients is achieved when the ratios of NAD+ to the blood creatinine levels, mean corpuscular volume or potassium ions are compared. The proposed NAD+ assay provides an easy and robust tool for clinical analyses of an important metabolic indicator in the human blood.
    30. ↑ Peluso A et al.: Age-Dependent Decline of NAD+-Universal Truth or Confounded Consensus?. Nutrients 2021. (PMID 35010977) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.
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