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    [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75]

    1. ↑ 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.
    2. ↑ Tomé-Carneiro J et al.: Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 2013. (PMID 23448440) [PubMed] [DOI] [Full text] Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol- based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of 'potential' benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called 'Resveratrol Paradox', i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol's effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.
    3. ↑ Riche DM et al.: Analysis of safety from a human clinical trial with pterostilbene. J Toxicol 2013. (PMID 23431291) [PubMed] [DOI] [Full text] Objectives. The purpose of this trial was to evaluate the safety of long-term pterostilbene administration in humans. Methodology. The trial was a prospective, randomized, double-blind placebo-controlled intervention trial enrolling patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200 mg/dL and/or baseline low-density lipoprotein cholesterol ≥100 mg/dL). Eighty subjects were divided equally into one of four groups: (1) pterostilbene 125 mg twice daily, (2) pterostilbene 50 mg twice daily, (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, and (4) matching placebo twice daily for 6-8 weeks. Safety markers included biochemical and subjective measures. Linear mixed models were used to estimate primary safety measure treatment effects. Results. The majority of patients completed the trial (91.3%). The average age was 54 years. The majority of patients were females (71%) and Caucasians (70%). There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs. Conclusion. Pterostilbene is generally safe for use in humans up to 250 mg/day.
    4. ↑ Ramírez-Garza SL et al.: Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients 2018. (PMID 30513922) [PubMed] [DOI] [Full text] The effect of resveratrol (RV) intake has been reviewed in several studies performed in humans with different health status. The purpose of this review is to summarize the results of clinical trials of the last decade, in which RV was determined in biological samples such as human plasma, urine, and feces. The topics covered include RV bioavailability, pharmacokinetics, effects on cardiovascular diseases, cognitive diseases, cancer, type 2 diabetes (T2D), oxidative stress, and inflammation states. The overview of the recent research reveals a clear tendency to identify RV in plasma, showing that its supplementation is safe. Furthermore, RV bioavailability depends on several factors such as dose, associated food matrix, or time of ingestion. Notably, enterohepatic recirculation of RV has been observed, and RV is largely excreted in the urine within the first four hours after consumption. Much of the research on RV in the last 10 years has focused on its effects on pathologies related to oxidative stress, inflammatory biomarkers, T2D, cardiovascular diseases, and neurological diseases.
    5. ↑ Li YR et al.: Effect of resveratrol and pterostilbene on aging and longevity. Biofactors 2018. (PMID 29210129) [PubMed] [DOI] Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms. © 2017 BioFactors, 44(1):69-82, 2018.
    6. ↑ McCormack D & McFadden D: A review of pterostilbene antioxidant activity and disease modification. Oxid Med Cell Longev 2013. (PMID 23691264) [PubMed] [DOI] [Full text] Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.
    7. ↑ Knutson MD & Leeuwenburgh C: Resveratrol and novel potent activators of SIRT1: effects on aging and age-related diseases. Nutr Rev 2008. (PMID 18826454) [PubMed] [DOI] Studies show that the plant polyphenol resveratrol can extend the life span of yeast, worms, flies, and fish. It also mitigates the metabolic dysfunction of mice fed high-fat diets. Resveratrol appears to mediate these effects partly by activating SIRT1, a deacetylase enzyme that regulates the activity of several transcriptional factors and enzymes responsive to nutrient availability. However, few foods contain resveratrol and humans metabolize it extensively, resulting in very low systemic bioavailability. Substantial research effort now focuses on identifying and testing more bioavailable and potent activators of SIRT1 for use as pharmacologic interventions in aging and age-related disorders.
    8. ↑ Kasiotis KM et al.: Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties. Food Chem Toxicol 2013. (PMID 23567244) [PubMed] [DOI] Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest. Among them, their antioxidant, anti-aging and anti-angiogenesic properties are well established and subjects of numerous research endeavors. This mini-review aspires to account and present the literature reports published on research concerning various natural and synthetic stilbenes, such as trans-resveratrol. Special focus was given to most recent research findings, while the mechanisms underlying their anti-aging and anti-angiogenic effects as well as the respective signaling pathways involved were also presented and discussed.
    9. ↑ Hecker A et al.: The impact of resveratrol on skin wound healing, scarring, and aging. Int Wound J 2022. (PMID 33949795) [PubMed] [DOI] [Full text] Resveratrol is a well-known antioxidant that harbours many health beneficial properties. Multiple studies associated the antioxidant, anti-inflammatory, and cell protective effects of resveratrol. These diverse effects of resveratrol are also potentially involved in cutaneous wound healing, scarring, and (photo-)aging of the skin. Hence, this review highlighted the most relevant studies involving resveratrol in wound healing, scarring, and photo-aging of the skin. A systematic review was performed and the database PubMed was searched for suitable publications. Only original articles in English that investigated the effects of resveratrol in wound healing, scarring, and (photo-)aging of the skin were analysed. The literature search yielded a total of 826 studies, but only 41 studies met the inclusion criteria. The included studies showed promising results that resveratrol might be a feasible treatment approach to support wound healing, counteract excessive scarring, and even prevent photo-aging of the skin. Resveratrol represents an interesting and promising novel therapy regime but to confirm resveratrol-associated effects, more evidence based in vitro and in vivo studies are needed.
    10. ↑ Yabluchanskiy A et al.: Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology (Bethesda) 2013. (PMID 24186934) [PubMed] [DOI] [Full text] Matrix metalloproteinase (MMP)-9, one of the most widely investigated MMPs, regulates pathological remodeling processes that involve inflammation and fibrosis in cardiovascular disease. MMP-9 directly degrades extracellular matrix (ECM) proteins and activates cytokines and chemokines to regulate tissue remodeling. MMP-9 deletion or inhibition has proven overall beneficial in multiple animal models of cardiovascular disease. As such, MMP-9 expression and activity is a common end point measured. MMP-9 cell-specific overexpression, however, has also proven beneficial and highlights the fact that little information is available on the underlying mechanisms of MMP-9 function. In this review, we summarize our current understanding of MMP-9 physiology, including structure, regulation, activation, and downstream effects of increased MMP-9. We discuss MMP-9 roles during inflammation and fibrosis in cardiovascular disease. By concentrating on the substrates of MMP-9 and their roles in cardiovascular disease, we explore the overall function and discuss future directions on the translational potential of MMP-9 based therapies.
    11. ↑ Moens U et al.: The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation. Genes (Basel) 2013. (PMID 24705157) [PubMed] [DOI] [Full text] Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase, and a MAPK. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed.
    12. ↑ de la Lastra CA & Villegas I: Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 2005. (PMID 15832402) [PubMed] [DOI] Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.
    13. ↑ Teng WL et al.: Pterostilbene Attenuates Particulate Matter-Induced Oxidative Stress, Inflammation and Aging in Keratinocytes. Antioxidants (Basel) 2021. (PMID 34679686) [PubMed] [DOI] [Full text] Particulate matter (PM) is the main indicator of air pollutants, and it may increase the level of reactive oxygen species (ROS) in keratinocytes, leading to skin inflammation, aging, and decreased moisturizing ability. Pterostilbene (PTS) is a dimethylated analog of resveratrol that has antioxidant effects. However, the molecular mechanisms of PTS in preventing PM-induced keratinocyte inflammation and aging have not been investigated yet. Therefore, we used PM-induced human keratinocytes to investigate the protective mechanisms of PTS. The results showed that 20 μM PTS had no toxicity to HaCaT keratinocytes and significantly reduced PM-induced intracellular ROS production. In addition, nuclear translocation of the aryl hydrocarbon receptor (AHR) was inhibited by PTS, leading to reduced expression of its downstream CYP1A1. PTS further inhibited PM-induced MAPKs, inflammation (COX-2), and aging (MMP-9) protein cascades, and rescued moisturizing (AQP-3) protein expression. We analyzed the PTS content in cells at different time points and compared the concentration required for PTS to inhibit the target proteins. Finally, we used the skin penetration assay to show that the PTS essence mainly exists in the epidermal layer and did not enter the system circulation. In conclusion, PTS could protect HaCaT keratinocytes from PM-induced damage and has the potential to become a cosmetic ingredient.
    14. ↑ Fernández AF & Fraga MF: The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan. Epigenetics 2011. (PMID 21613817) [PubMed] [DOI] The physiological effects of the dietary polyphenol resveratrol are being extensively studied. Resveratrol has been proposed to promote healthy aging and to increase lifespan primarily through the activation of the class III histone deacetylases (sirtuins). Although its positive effects are evident in yeast and mice they still have to be confirmed in humans. The molecular mechanisms involved in the processes are not fully understood because resveratrol may have other targets than sirtuins and the direct activation of sirtuins by resveratrol is under debate.
    15. ↑ Hu Y et al.: The controversial links among calorie restriction, SIRT1, and resveratrol. Free Radic Biol Med 2011. (PMID 21569839) [PubMed] [DOI] It has been widely known that slow metabolism induced by calorie restriction (CR) can extend the life span of model organisms though the underlying mechanism remains poorly understood. Accumulated evidence suggests that SIRT1 may be actively involved in CR-induced signaling pathways. As a putative activator of SIRT1, resveratrol, known for the French paradox, can partially mimic the physiological effects of CR. While the deacetylase activity of SIRT1 is important for the beneficial effects of resveratrol, resveratrol-induced SIRT1 activation has recently been challenged by the observations that resveratrol could not induce SIRT1-mediated deacetylation of native substrates in vitro. To resolve the discrepancy of resveratrol-induced activation of SIRT1 deacetylase activity between the in vitro and in vivo assays, a model of indirect SIRT1 activation by resveratrol is proposed. In this review, we will discuss the emerging roles of SIRT1 and resveratrol in CR and focus on debate over the links between SIRT1 and resveratrol.
    16. ↑ Bonkowski MS & Sinclair DA: Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 2016. (PMID 27552971) [PubMed] [DOI] [Full text] The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.
    17. ↑ Bai LB et al.: Improvement of tissue-specific distribution and biotransformation potential of nicotinamide mononucleotide in combination with ginsenosides or resveratrol. Pharmacol Res Perspect 2022. (PMID 35844164) [PubMed] [DOI] [Full text] Decreased Nicotinamide adenine dinucleotide (NAD+ ) level has received increasing attention in recent years since it plays a critical role in many diseases and aging. Although some research has proved that supplementing nicotinamide mononucleotide (NMN) could improve the level of NAD+ , it is still uncertain whether the NAD+ level in specific tissues could be improved in combination with other nutrients. So far, a variety of nutritional supplements have flooded the market, which contains the compositions of NMN coupled with natural products. However, the synergy and transformation process of NMN has not been fully elucidated. In this study, oral administration of NMN (500 mg/kg) combined with resveratrol (50 mg/kg) or ginsenoside Rh2&Rg3 (50 mg/kg) was used to validate the efficacy of appropriate drug combinations in mice. Compared with NMN alone, NMN combined with resveratrol could increase the levels of NAD+ in the heart and muscle by about 1.6 times and 1.7 times, respectively, whereas NMN coupled with ginsenoside Rh2&Rg3 could effectively improve the level of NAD+ in lung tissue for approximately 2.0 times. Our study may provide new treatment ideas for aging or diseases in cardiopulmonary caused by decreased NAD+ levels.
    18. ↑ Simic P et al.: Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC Nephrol 2020. (PMID 32791973) [PubMed] [DOI] [Full text] BACKGROUND: Preclinical studies have identified both NAD+ and sirtuin augmentation as potential strategies for the prevention and treatment of AKI. Nicotinamide riboside (NR) is a NAD+ precursor vitamin and pterostilbene (PT) is potent sirtuin activator found in blueberries. Here, we tested the effect of combined NR and PT (NRPT) on whole blood NAD+ levels and safety parameters in patients with AKI. METHODS: We conducted a randomized, double-blind, placebo-controlled study of escalating doses of NRPT in 24 hospitalized patients with AKI. The study was comprised of four Steps during which NRPT (5 subjects) or placebo (1 subject) was given twice a day for 2 days. NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD+ levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. RESULTS: AKI resulted in a 50% reduction in whole blood NAD+ levels at 48 h compared to 0 h in patients receiving placebo (p = 0.05). There was a trend for increase in NAD+ levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD+ response to treatment. Considering all Steps together, NRPT treatment increased NAD+ levels by 37% at 48 h compared to 0 h (p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. CONCLUSION: NRPT increases whole blood NAD+ levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. TRIAL REGISTRATION: NCT03176628 , date of registration June 5th, 2017.
    19. ↑ Dellinger RW et al.: Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis 2017. (PMID 29184669) [PubMed] [DOI] [Full text] NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD+ in whole blood demonstrated that NRPT significantly increases the concentration of NAD+ in a dose-dependent manner. NAD+ levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD+ levels was sustained throughout the entire 8-week trial. NAD+ levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD+ levels sustainably.
    20. ↑ Garrido-Maraver J et al.: Coenzyme q10 therapy. Mol Syndromol 2014. (PMID 25126052) [PubMed] [DOI] [Full text] For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These 2 functions constitute the basis for supporting the clinical use of CoQ10. Also, at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory cofactor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects the expression of genes involved in human cell signaling, metabolism and transport, and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, aging-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer, and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral administration of CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
    21. ↑ Garrido-Maraver J et al.: Clinical applications of coenzyme Q10. Front Biosci (Landmark Ed) 2014. (PMID 24389208) [PubMed] [DOI] Coenzyme Q10 (CoQ10) or ubiquinone was known for its key role in mitochondrial bioenergetics as electron and proton carrier; later studies demonstrated its presence in other cellular membranes and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical indication of CoQ10. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, metabolism and transport and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also a secondary effect of statin treatment. Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscular and cardiovascular diseases have been associated with low CoQ10 levels. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral CoQ10 treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
    22. ↑ Martelli A et al.: Coenzyme Q10: Clinical Applications in Cardiovascular Diseases. Antioxidants (Basel) 2020. (PMID 32331285) [PubMed] [DOI] [Full text] Coenzyme Q10 (CoQ10) is a ubiquitous factor present in cell membranes and mitochondria, both in its reduced (ubiquinol) and oxidized (ubiquinone) forms. Its levels are high in organs with high metabolism such as the heart, kidneys, and liver because it acts as an energy transfer molecule but could be reduced by aging, genetic factors, drugs (e.g., statins), cardiovascular (CV) diseases, degenerative muscle disorders, and neurodegenerative diseases. As CoQ10 is endowed with significant antioxidant and anti-inflammatory features, useful to prevent free radical-induced damage and inflammatory signaling pathway activation, its depletion results in exacerbation of inflammatory processes. Therefore, exogenous CoQ10 supplementation might be useful as an adjuvant in the treatment of cardiovascular diseases such as heart failure, atrial fibrillation, and myocardial infarction and in associated risk factors such as hypertension, insulin resistance, dyslipidemias, and obesity. This review aims to summarize the current evidences on the use of CoQ10 supplementation as a therapeutic approach in cardiovascular diseases through the analysis of its clinical impact on patients' health and quality of life. A substantial reduction of inflammatory and oxidative stress markers has been observed in several randomized clinical trials (RCTs) focused on several of the abovementioned diseases, even if more RCTs, involving a larger number of patients, will be necessary to strengthen these interesting findings.
    23. ↑ Hernández-Camacho JD et al.: Coenzyme Q10 Supplementation in Aging and Disease. Front Physiol 2018. (PMID 29459830) [PubMed] [DOI] [Full text] Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
    24. ↑ Gutierrez-Mariscal FM et al.: Coenzyme Q10: From bench to clinic in aging diseases, a translational review. Crit Rev Food Sci Nutr 2019. (PMID 29451807) [PubMed] [DOI] Coenzyme Q10 (CoQ10) is a ubiquitous molecule present in all eukaryotic organisms whose principal role in the cell is related to its participation in the electron transport chain in the inner mitochondrial membrane. CoQ10 plays a major role in the control of cell redox status, and both the amount and functionality of this molecule have been related to the regulation of reactive oxygen species generation. Numerous reports can be found discussing the implications of CoQ10 supplementation in human studies and clinical trials related to aging. However, few reviews have made an updating through the translational point of view to integrate both basic and clinical aspects. The aim of this paper is to review our current knowledge from CoQ10 implications at biochemical and physiological level, in order to unravel the molecular mechanisms involved in its application in clinical practice. Although the importance of CoQ10 has been mainly attributed to its role as an agent for energy transduction in mitochondria, new functions for CoQ10 have been described in the recent past years, including anti-inflammatory effects, gene expression regulation and lipid bilayer membranes stabilization, which explain its involvement in aging and age-related diseases such as cardiovascular diseases, renal failure and neurodegenerative diseases.
    25. ↑ Díaz-Casado ME et al.: The Paradox of Coenzyme Q10 in Aging. Nutrients 2019. (PMID 31540029) [PubMed] [DOI] [Full text] Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q10 (CoQ10) supplementation has shown benefits as an anti-aging agent, especially under certain conditions associated with increased oxidative stress. Also, CoQ10 has shown therapeutic benefits in aging-related disorders, particularly in cardiovascular and metabolic diseases. Thus, we discuss the paradox of health benefits due to a defect in the CoQ biosynthetic pathway or exogenous supplementation of CoQ10.
    26. ↑ González-Guardia L et al.: Effects of the Mediterranean diet supplemented with coenzyme q10 on metabolomic profiles in elderly men and women. J Gerontol A Biol Sci Med Sci 2015. (PMID 24986061) [PubMed] [DOI] BACKGROUND: Characterization of the variations in the metabolomic profiles of elderly people is a necessary step to understand changes associated with aging. This study assessed whether diets with different fat quality and supplementation with coenzyme Q10 (CoQ) affect the metabolomic profile in urine analyzed by proton nuclear magnetic resonance spectroscopy from elderly people. METHODS: Ten participants received, in a cross-over design, four isocaloric diets for 4-week periods each: Mediterranean diet supplemented with CoQ (Med + CoQ diet); Mediterranean diet; Western diet rich in saturated fat diet; low-fat, high-carbohydrate diet enriched in n-3 polyunsaturated fat. RESULTS: Multivariate analysis showed differences between diets when comparing Med + CoQ diet and saturated fat diet, with greater hippurate urine levels after Med + CoQ diet and higher phenylacetylglycine levels after saturated fat diet in women. Following consumption of Med + CoQ, hippurate excretion was positively correlated with CoQ and β-carotene plasma levels and inversely related to Nrf2, thioredoxin, superoxide dismutase 1, and gp91(phox) subunit of NADPH oxidase gene expression. After saturated fat diet consumption, phenylacetylglycine excretion was inversely related to CoQ plasma level and positively correlated with isoprostanes urinary level. CONCLUSIONS: The association between hippurate excretion and antioxidant biomarkers along with the relationship between phenylacetylglycine excretion and oxidant biomarkers suggests that the long-term consumption of a Med + CoQ diet could be beneficial for healthy aging and a promising challenge in the prevention of processes related to chronic oxidative stress, such as cardiovascular and neurodegenerative disease.
    27. ↑ Castro-Marrero J et al.: Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr 2016. (PMID 26212172) [PubMed] [DOI] BACKGROUND & AIMS: Chronic Fatigue Syndrome (CFS) is a complex condition, characterized by severe disabling fatigue with no known cause, no established diagnostic tests, and no universally effective treatment. Several studies have proposed symptomatic treatment with coenzyme Q10 (CoQ10) and nicotinamide adenine dinucleotide (NADH) supplementation. The primary endpoint was to assess the effect of CoQ10 plus NADH supplementation on age-predicted maximum heart rate (max HR) during a cycle ergometer test. Secondary measures included fatigue, pain and sleep. METHODS: A proof-of-concept, 8-week, randomized, controlled, double-blind trial was conducted in 80 CFS patients assigned to receive either CoQ10 plus NADH supplementation or matching placebo twice daily. Maximum HR was evaluated at baseline and at end of the run-in period using an exercise test. Fatigue, pain and sleep were evaluated at baseline, and then reassessed at 4- and 8-weeks through self-reported questionnaires. RESULTS: The CoQ10 plus NADH group showed a significant reduction in max HR during a cycle ergometer test at week 8 versus baseline (P = 0.022). Perception of fatigue also showed a decrease through all follow-up visits in active group versus placebo (P = 0.03). However, pain and sleep did not improve in the active group. Coenzyme Q10 plus NADH was generally safe and well tolerated. CONCLUSIONS: Our results suggest that CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max HR during a cycle ergometer test and also on fatigue in CFS. Further additional larger controlled trials are needed to confirm these findings. Clinical trial registrationThis trial was registered at clinicaltrials.gov as NCT02063126.
    28. ↑ Castro-Marrero J et al.: Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome?. Antioxid Redox Signal 2015. (PMID 25386668) [PubMed] [DOI] [Full text] Chronic fatigue syndrome (CFS) is a chronic and extremely debilitating illness characterized by prolonged fatigue and multiple symptoms with unknown cause, diagnostic test, or universally effective treatment. Inflammation, oxidative stress, mitochondrial dysfunction, and CoQ10 deficiency have been well documented in CFS. We conducted an 8-week, randomized, double-blind placebo-controlled trial to evaluate the benefits of oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation on fatigue and biochemical parameters in 73 Spanish CFS patients. This study was registered in ClinicalTrials.gov (NCT02063126). A significant improvement of fatigue showing a reduction in fatigue impact scale total score (p<0.05) was reported in treated group versus placebo. In addition, a recovery of the biochemical parameters was also reported. NAD+/NADH (p<0.001), CoQ10 (p<0.05), ATP (p<0.05), and citrate synthase (p<0.05) were significantly higher, and lipoperoxides (p<0.05) were significantly lower in blood mononuclear cells of the treated group. These observations lead to the hypothesis that the oral CoQ10 plus NADH supplementation could confer potential therapeutic benefits on fatigue and biochemical parameters in CFS. Larger sample trials are warranted to confirm these findings.
    29. ↑ Zeisel S: Choline, Other Methyl-Donors and Epigenetics. Nutrients 2017. (PMID 28468239) [PubMed] [DOI] [Full text] Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms that modify gene expression without modifying the genetic code depend on the methylation of DNA or of histones; and diet availability of choline and other methyl-group donors influences both of these methylations. Examples of methyl-donor mediated epigenetic effects include the changes in coat color and body weight in offspring when pregnant agouti mice are fed high choline, high methyl diets; the changes in tail kinking in offspring when pregnant Axin(Fu) mice are fed high choline, high methyl diets; the changes in Cdkn3 methylation and altered brain development that occurs in offspring when pregnant rodents are fed low choline diets. When choline metabolism is disrupted by deleting the gene Bhmt, DNA methylation is affected (especially in a region of chromosome 13), expression of specific genes is suppressed, and liver cancers develop. Better understanding of how nutrients such as choline and methyl-donors influence epigenetic programs has importance for our understanding of not only developmental abnormalities but also for understanding the origins of chronic diseases.
    30. ↑ Go EK et al.: Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol A Biol Sci Med Sci 2005. (PMID 16282556) [PubMed] [DOI] Betaine is an important human nutrient obtained from various foods. In the present study, we assessed the anti-inflammatory effect of betaine on nuclear factor-kappaB (NF-kappaB) during aging. Sprague-Dawley (SD) rats, ages 7 and 21 months, were used in this study. The older rats were fed betaine. To elucidate the effect of betaine on oxidative stress-induced NF-kappaB and its signaling pathway at molecular levels, YPEN-1 cells were used. Results showed that betaine suppressed NF-kappaB and its related gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), and intracellular cell adhesion molecule-1 (ICAM-1) in aged kidney. Furthermore, betaine attenuated oxidative stress-induced NF-kappaB via nuclear factor-inducing kinase/IkappaB kinase (NIK/IKK) and mitogen-activated protein kinases (MAPKs) in the YPEN-1 cells. On the basis of these results, we concluded that betaine suppressed the age-related NF-kappaB activities associated with upregulated NIK/IKK and MAPKs that were induced by oxidative stress. Thus, betaine might be useful as a preventive agent against the activation of NF-kappaB induced during inflammation and aging.
    31. ↑ Zhao G et al.: Betaine in Inflammation: Mechanistic Aspects and Applications. Front Immunol 2018. (PMID 29881379) [PubMed] [DOI] [Full text] Betaine is known as trimethylglycine and is widely distributed in animals, plants, and microorganisms. Betaine is known to function physiologically as an important osmoprotectant and methyl group donor. Accumulating evidence has shown that betaine has anti-inflammatory functions in numerous diseases. Mechanistically, betaine ameliorates sulfur amino acid metabolism against oxidative stress, inhibits nuclear factor-κB activity and NLRP3 inflammasome activation, regulates energy metabolism, and mitigates endoplasmic reticulum stress and apoptosis. Consequently, betaine has beneficial actions in several human diseases, such as obesity, diabetes, cancer, and Alzheimer's disease.
    32. ↑ Sun WP et al.: Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr 2017. (PMID 27567458) [PubMed] [DOI] AIM: The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine. METHODS: Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N1-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N1-methyl-2-pyridone-5-carboxamide during the test period were examined. RESULTS: The level of 3-h plasma nicotinamide, N1-methylnicotinamide, homocysteine, the urinary excretion of N1-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N1-methylnicotinamide (1.90 ± 0.20 μmol/l vs. 3.62 ± 0.27 μmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 μmol/l vs. 18.08 ± 1.02 μmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 μmol/l vs. 23.52 ± 0.61 μmol/l, P < 0.05) than that of the NM group. CONCLUSION: The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification.
    33. ↑ Li D et al.: Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats. Br J Nutr 2013. (PMID 23768418) [PubMed] [DOI] Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine-homocysteine S-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.
    34. ↑ Kashyap D et al.: Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules 2019. (PMID 31064104) [PubMed] [DOI] [Full text] Despite advancements in healthcare facilities for diagnosis and treatment, cancer remains the leading cause of death worldwide. As prevention is always better than cure, efficient strategies are needed in order to deal with the menace of cancer. The use of phytochemicals as adjuvant chemotherapeutic agents in heterogeneous human carcinomas like breast, colon, lung, ovary, and prostate cancers has shown an upward trend during the last decade or so. Flavonoids are well-known products of plant derivatives that are reportedly documented to be therapeutically active phytochemicals against many diseases encompassing malignancies, inflammatory disorders (cardiovascular disease, neurodegenerative disorder), and oxidative stress. The current review focuses on two key flavonols, fisetin and quercetin, known for their potential pharmacological relevance. Also, efforts have been made to bring together most of the concrete studies pertaining to the bioactive potential of fisetin and quercetin, especially in the modulation of a range of cancer signaling pathways. Further emphasis has also been made to highlight the molecular action of quercetin and fisetin so that one could explore cancer initiation pathways and progression, which could be helpful in designing effective treatment strategies.
    35. ↑ Yousefzadeh MJ et al.: Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 2018. (PMID 30279143) [PubMed] [DOI] [Full text] BACKGROUND: Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity. METHODS: A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated. FINDINGS: Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. INTERPRETATION: The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies. FUND: NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401-1 (JLK, EAA).
    36. ↑ Jang SY et al.: Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem 2012. (PMID 22493485) [PubMed] [DOI] [Full text] Active autophagy coupled with rapid mitochondrial fusion and fission constitutes an important mitochondrial quality control mechanism and is critical to cellular health. In our previous studies, we found that exposure of cells to nicotinamide causes a decrease in mitochondrial content and an increase in mitochondrial membrane potential (MMP) by activating autophagy and inducing mitochondrial fragmentation. Here, we present evidence to show that the effect of nicotinamide is mediated through an increase of the [NAD(+)]/[NADH] ratio and the activation of SIRT1, an NAD(+)-dependent deacetylase that plays a role in autophagy flux. The [NAD(+)]/[NADH] ratio was inversely correlated with the mitochondrial content, and an increase in the ratio by the mobilization of the malate-aspartate shuttle resulted in autophagy activation and mitochondrial transformation from lengthy filaments to short dots. Furthermore, treatment of cells with SIRT1 activators, fisetin or SRT1720, induced similar changes in the mitochondrial content. Importantly, the activators induced mitochondrial fragmentation only when SIRT1 expression was intact. Meanwhile, MMP did not increase when the cells were treated with the activators, suggesting that the change in MMP is not induced by the mitochondrial turnover per se and that elevation of the [NAD(+)]/[NADH] ratio may activate additional mechanisms that cause MMP augmentation. Together, our results indicate that a metabolic state resulting in an elevated [NAD(+)]/[NADH] ratio can modulate mitochondrial quantity and quality via pathways that may include SIRT1-mediated mitochondrial autophagy.
    37. ↑ Deepika PK & Maurya: Health Benefits of Quercetin in Age-Related Diseases. Molecules 2022. (PMID 35458696) [PubMed] [DOI] [Full text] Polyphenols are the known group of phytochemicals that essentially consists of phenolic rings. These are the plant product present in varied fruits and vegetables. These secondary metabolites perform a protective function in plants from environmental and biological stress. When consumed as a human diet these are also known to prevent various age-associated diseases. Polyphenols are known to possess antioxidant properties and protect against oxidative stress. The literature survey was carried out using databases such as PubMed, Science direct and Springer. The research articles from last 10-12 years were selected for this review based on its relevancy with the topic. The articles selected was mainly focused on quercetin and its health benefits. The present review highlights the main functions of a flavonoid, quercetin. Quercetin is among the widely occurring polyphenol, found abundantly in nature. It is commonly present in different plant products. Onion is known to have the highest quantity of quercetin. This plant compound is possessed antioxidant properties and is considered to have a protective function against aging. It is known to be present in both free and conjugated forms. Quercetin has anti-oxidative, anti-inflammatory, anti-proliferative, anti-carcinogenic, anti-diabetic, and anti-viral properties. The molecule is lipophilic and can easily cross the BBB (Blood-Brain Barrier) and hence protects from neurodegenerative diseases. Various in vivo and in vitro studies have demonstrated the role of quercetin and here a detailed review of quercetin as a curative agent in neurodegeneration, diabetes, cancer, and inflammation has been carried out. Studies have proved that quercetin plays a crucial role in the prevention of age-related disorders. Quercetin is a potent antioxidant which is currently being used in various pharmaceuticals. Properties of quercetin can be further explored in various other disorders. Nanoformulations and liposomal formulations of quercetin can be made to treat other age associated diseases.
    38. ↑ Geng L et al.: Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell 2019. (PMID 30069858) [PubMed] [DOI] [Full text] Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
    39. ↑ Escande C et al.: Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 2013. (PMID 23172919) [PubMed] [DOI] [Full text] Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD(+)ase in mammals. Moreover, CD38 knockout mice have higher NAD(+) levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD(+) levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD(+) levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD(+) levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.
    40. ↑ Zhang F et al.: Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp Ther Med 2020. (PMID 33200005) [PubMed] [DOI] [Full text] Inflammation and oxidative stress serve interrelated roles in the development of atherosclerosis and other vascular diseases. Quercetin has been previously reported to exhibit numerous beneficial properties towards several metabolic conditions and cardiovascular disease. The present study aimed to evaluate the effects of quercetin on the 5'adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NF-κB signaling pathway and inflammatory/oxidative stress response in diabetic-induced atherosclerosis in the carotid artery of rats. Male Wistar rats were used to create a diabetes-induced atherosclerosis model by the administration of high fat diet (HFD) with streptozotocin, which lasted for 8 weeks. Control and diabetic rats received quercetin (30 mg/kg/day; orally) for the last 2 weeks of the diabetic period. Plasma lipid profile and vascular levels of oxidative stress markers, inflammatory cytokines, NF-κB signaling proteins and SIRT1 expression were evaluated using ELISA and western blotting. Quercetin treatment in HFD diabetic rats was reported to improve the lipid profile and reduce the number of atherosclerotic lesions, atherogenic index and malondialdehyde levels, whilst increasing the activity of enzymatic antioxidants in the carotid artery. Additionally, the inflammatory response was suppressed by quercetin administration, as indicated by the reduced NF-κB and IL-1β levels, and increased IL-10 levels. Furthermore, SIRT1 expression was revealed to be significantly increased in response to quercetin treatment compared with non-treated HFD rats. However, these effects of quercetin were abolished or reversed by the administration of compound-C (0.2 mg/kg), a specific AMPK blocker, in HFD rats. Therefore, quercetin may have promising potential in ameliorating atherosclerotic pathophysiology in the rat carotid artery by inhibiting oxidative stress and inflammatory responses mechanistically by modulating the AMPK/SIRT1/NF-κB signaling pathway.
    41. ↑ Buss GD et al.: The action of quercetin on the mitochondrial NADH to NAD(+) ratio in the isolated perfused rat liver. Planta Med 2005. (PMID 16395647) [PubMed] [DOI] It has been suggested that active forms of quercetin ( o-semiquinones) are able to oxidize NADH in mammalian cells. The purpose of this study was to investigate this proposition by measuring the beta-hydroxybutyrate to acetoacetate ratio as an indicator of the mitochondrial NADH/NAD (+) redox ratio in the isolated perfused rat liver. The NADH to NAD (+) ratio was reduced by quercetin; half-maximal reduction occurred at a concentration of 32.6 microM. Additionally, quercetin (25 to 300 microM) stimulated the Krebs cycle ( (14)CO (2) production) and inhibited oxygen uptake (50 to 300 microM). Low quercetin concentrations (25 microM) stimulated oxygen uptake. The results of the present work confirm the hypothesis that quercetin is able to participate in the oxidation of NADH in mammalian cells, shifting the cellular conditions to a more oxidized state (prooxidant activity). Stimulation of the Krebs cycle was probably caused by the increased NAD (+) availability whereas the decreased NADH availability and the inhibition of mitochondrial energy transduction could be the main causes for oxygen uptake inhibition.
    42. ↑ Gendrisch F et al.: Luteolin as a modulator of skin aging and inflammation. Biofactors 2021. (PMID 33368702) [PubMed] [DOI] Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense. Furthermore, anti-oxidative and anti-inflammatory activities of luteolin were described on keratinocytes and fibroblasts as well as on several immune cells (e.g., macrophages, mast cell, neutrophils, dendritic cells and T cells). Luteolin can suppress proinflammatory mediators (e.g., IL-1β, IL-6, IL-8, IL-17, IL-22, TNF-α and COX-2) and regulate various signaling pathway (e.g., the NF-κB, JAK-STAT as well as TLR signaling pathway). In this way, luteolin modulates many inflammatory processes of the skin. The present review summarizes the recent in vitro and in vivo research on luteolin in the field of skin aging and skin cancer, wound healing as well as inflammatory skin diseases, including psoriasis, contact dermatitis and atopic dermatitis. In conclusion, luteolin might be a promising molecule for the development of topic formulations and systemic agents against inflammatory skin diseases.
    43. ↑ Kellenberger E et al.: Flavonoids as inhibitors of human CD38. Bioorg Med Chem Lett 2011. (PMID 21641214) [PubMed] [DOI] CD38 is a multifunctional enzyme which is ubiquitously distributed in mammalian tissues. It is involved in the conversion of NAD(P)(+) into cyclic ADP-ribose, NAADP(+) and ADP-ribose and the role of these metabolites in multiple Ca(2+) signaling pathways makes CD38 a novel potential pharmacological target. The dire paucity of CD38 inhibitors, however, renders the search for new molecular tools highly desirable. We report that human CD38 is inhibited at low micromolar concentrations by flavonoids such as luteolinidin, kuromanin and luteolin (IC(50) <10 μM). Docking studies provide some clues on the mode of interaction of these molecules with the active site of CD38.
    44. ↑ Boslett J et al.: Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H). J Pharmacol Exp Ther 2017. (PMID 28108596) [PubMed] [DOI] [Full text] We recently showed that ischemia/reperfusion (I/R) of the heart causes CD38 activation with resultant depletion of the cardiac NADP(H) pool, which is most marked in the endothelium. This NADP(H) depletion was shown to limit the production of nitric oxide by endothelial nitric oxide synthase (eNOS), which requires NADPH for nitric oxide production, resulting in greatly altered endothelial function. Therefore, intervention with CD38 inhibitors could reverse postischemic eNOS-mediated endothelial dysfunction. Here, we evaluated the potency of the CD38 inhibitor luteolinidin, an anthocyanidin, at blocking CD38 activity and preserving endothelial and myocardial function in the postischemic heart. Initially, we characterized luteolinidin as a CD38 inhibitor in vitro to determine its potency and mechanism of inhibition. We then tested luteolinidin in the ex vivo isolated heart model, where we determined luteolinidin uptake with aqueous and liposomal delivery methods. Optimal delivery methods were then further tested to determine the effect of luteolinidin on postischemic NAD(P)(H) and tetrahydrobiopterin levels. Finally, through nitric oxide synthase-dependent coronary flow and left ventricular functional measurements, we evaluated the efficacy of luteolinidin to protect vascular and contractile function, respectively, after I/R. With enhanced postischemic preservation of NADPH and tetrahydrobiopterin, there was a dose-dependent effect of luteolinidin on increasing recovery of endothelium-dependent vasodilatory function, as well as enhancing the recovery of left ventricular contractile function with increased myocardial salvage. Thus, luteolinidin is a potent CD38 inhibitor that protects the heart against I/R injury with preservation of eNOS function and prevention of endothelial dysfunction.
    45. ↑ Wissler Gerdes EO et al.: Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev 2021. (PMID 34699859) [PubMed] [DOI] [Full text] Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
    46. ↑ Farkas O et al.: Polymethoxyflavone Apigenin-Trimethylether Suppresses LPS-Induced Inflammatory Response in Nontransformed Porcine Intestinal Cell Line IPEC-J2. Oxid Med Cell Longev 2015. (PMID 26180592) [PubMed] [DOI] [Full text] The in vitro anti-inflammatory effect of apigenin and its trimethylated analogue (apigenin-trimethylether) has been investigated in order to evaluate whether these flavonoids could attenuate LPS-induced inflammation in IPEC-J2 non-transformed intestinal epithelial cells. Levels of IL-6, IL-8, TNF-α, and COX-2 mRNA were measured as a marker of inflammatory response. The extracellular H2O2 level in IPEC-J2 cells was also monitored by Amplex Red assay. Our data revealed that both compounds had significant lowering effect on the inflammatory response. Apigenin (at 25 μM) significantly decreased gene expression of IL-6 in LPS-treated cells, while apigenin-trimethylether in the same concentration did not influence IL-6 mRNA level. Both apigenin and apigenin-trimethylether reduced IL-8 gene expression significantly. TNF-α mRNA level was decreased by apigenin-trimethylether, which was not influenced by apigenin. Treatment with both flavonoids caused significant reduction in the mRNA level of COX-2, but the anti-inflammatory effect of the methylated analogue was more effective than the unmethylated one. Furthermore, both flavonoids reduced significantly the level of extracellular H2O2 compared to the control cells. In conclusion, the methylated apigenin analogue could avoid LPS-induced intestinal inflammation and it could be applied in the future as an effective anti-inflammatory compound.
    47. ↑ Ahmed SA et al.: Rationalizing the therapeutic potential of apigenin against cancer. Life Sci 2021. (PMID 33333052) [PubMed] [DOI] BACKGROUND: Despite the remarkable advances made in the diagnosis and treatment of cancer during the past couple of decades, it remains the second largest cause of mortality in the world, killing approximately 9.6 million people annually. The major challenges in the treatment of the advanced stage of this disease are the development of chemoresistance, severe adverse effects of the drugs, and high treatment cost. Therefore, the development of drugs that are safe, efficacious, and cost-effective remains a 'Holy Grail' in cancer research. However, the research over the past four decades shed light on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action. Apigenin is one such compound, which is known to be safe and has significant potential in the prevention and therapy of this disease. AIM: To assess the literature available on the potential of apigenin and its analogs in modulating the key molecular targets leading to the prevention and treatment of different types of cancer. METHOD: A comprehensive literature search has been carried out on PubMed for obtaining information related to the sources and analogs, chemistry and biosynthesis, physicochemical properties, biological activities, bioavailability and toxicity of apigenin. KEY FINDINGS: The literature search resulted in many in vitro, in vivo and a few cohort studies that evidenced the effectiveness of apigenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK/ERK, Wnt/β-catenin, etc., which play a crucial role in the development and progression of cancer. In addition, apigenin was also shown to inhibit chemoresistance and radioresistance and make cancer cells sensitive to these agents. Reports have further revealed the safety of the compound and the adaptation of nanotechnological approaches for improving its bioavailability. SIGNIFICANCE: Hence, the present review recapitulates the properties of apigenin and its pharmacological activities against different types of cancer, which warrant further investigation in clinical settings.
    48. ↑ Alam W et al.: Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction. Antioxidants (Basel) 2021. (PMID 34679777) [PubMed] [DOI] [Full text] Metabolic syndrome and its associated disorders such as obesity, insulin resistance, atherosclerosis and type 2 diabetes mellitus are globally prevalent. Different molecules showing therapeutic potential are currently available for the management of metabolic syndrome, although their efficacy has often been compromised by their poor bioavailability and side effects. Studies have been carried out on medicinal plant extracts for the treatment and prevention of metabolic syndrome. In this regard, isolated pure compounds have shown promising efficacy for the management of metabolic syndrome, both in preclinical and clinical settings. Apigenin, a natural bioactive flavonoid widely present in medicinal plants, functional foods, vegetables and fruits, exerts protective effects in models of neurological disorders and cardiovascular diseases and most of these effects are attributed to its antioxidant action. Various preclinical and clinical studies carried out so far show a protective effect of apigenin against metabolic syndrome. Herein, we provide a comprehensive review on both in vitro and in vivo evidence related to the promising antioxidant role of apigenin in cardioprotection, neuroprotection and renoprotection, and to its beneficial action in metabolic-syndrome-dependent organ dysfunction. We also provide evidence on the potential of apigenin in the prevention and/or treatment of metabolic syndrome, analysing the potential and limitation of its therapeutic use.
    49. ↑ Choi WH et al.: Apigenin Ameliorates the Obesity-Induced Skeletal Muscle Atrophy by Attenuating Mitochondrial Dysfunction in the Muscle of Obese Mice. Mol Nutr Food Res 2017. (PMID 28971573) [PubMed] [DOI] SCOPE: It was investigated whether apigenin (AP) protected against skeletal muscle atrophy induced by obesity. METHODS AND RESULTS: Mice were fed a high-fat diet (HFD) for 9 weeks to induce obesity, and then were assigned to two groups; the HFD group received a high-fat diet, and the HFD+AP group received a 0.1% AP-containing HFD. After additional feeding of the experimental diet for 8 weeks, mice in the HFD group were highly obese compared with the mice in the standard diet fed mice group. The mice in the AP-treated group showed less fat pad accumulation and less inflammatory cytokines without body weight reduction. The weight of skeletal muscle in the AP group tended to increase as compared with that of the HFD group. Furthermore, AP reduced the expression of atrophic genes, including MuRF1 and Atrogin-1, but increased the exercise capacity. The mitochondrial function and mitochondrial biogenesis were enhanced by AP. In cultured C2C12 cells, AP also suppressed palmitic acid-induced muscle atrophy and mitochondrial dysfunction. In addition, AP activated AMP-activated protein kinase (AMPK) in the C2C12 and the muscle of HFD-induced obese mice. CONCLUSION: The results suggested that AP ameliorated the obesity-induced skeletal muscle atrophy by attenuating mitochondrial dysfunction.
    50. ↑ Su T et al.: Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity. Pharmacol Res 2020. (PMID 31877350) [PubMed] [DOI] Visceral obesity is the excess deposition of visceral fat within the abdominal cavity that surrounds vital organs. Visceral obesity is directly associated with metabolic syndrome, breast cancer and endometrial cancer. In visceral obese subjects, signal transducer and activator of the transcription 3 (STAT3) in adipocytes is constitutively active. In this study, we aimed to screen for dietary herbal compounds that possess anti-visceral obesity effect. Apigenin is abundant in fruits and vegetables. Our data show that apigenin significantly reduces body weight and visceral adipose tissue (VAT), but not subcutaneous (SAT) and epididymal adipose tissues (EAT), of the high fat diet (HFD)-induced obese mice. Mechanistic studies show that HFD increases STAT3 phosphorylation in VAT, but not in SAT and EAT. Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPAR-γ expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.
    51. ↑ Clayton ZS et al.: Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. Am J Physiol Heart Circ Physiol 2021. (PMID 34114892) [PubMed] [DOI] [Full text] We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 mo) and old (27 mo) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young and 7 old) or apigenin (0.5 mg/mL in vehicle; 10 young and 9 old) for 6 wk. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old versus young (70% ± 9% vs. 92% ± 1%, P < 0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of Tempol (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434 ± 9 vs. 346 ± 5 cm/s, P < 0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end products (AGEs), and proinflammatory cytokine abundance. In old mice, apigenin restored EDD (96% ± 2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress, and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373 ± 5 cm/s) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.NEW & NOTEWORTHY Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.
    52. ↑ Li BS et al.: Apigenin Alleviates Oxidative Stress-Induced Cellular Senescence via Modulation of the SIRT1-NAD[Formula: see text]-CD38 Axis. Am J Chin Med 2021. (PMID 34049472) [PubMed] [DOI] Oxidative stress-induced cellular senescence is now regarded as an important driving mechanism in chronic lung diseases-particularly chronic obstructive pulmonary disease (COPD). 4[Formula: see text],5,7-trihydroxyflavone (Apigenin) is a natural flavonoid product abundantly present in fruits, vegetables, and Chinese medicinal herbs. It has been known that apigenin has anti-oxidant, anti-inflammatory and liver-protecting effects. The efficacy of apigenin for lung aging, however, has not been reported. In this study, we selected the hydrogen peroxide (H2O[Formula: see text]- or doxorubicin (DOXO)-induced senescence model in WI-38 human embryonic lung fibroblast cells to determine the potential anti-aging effects of apigenin in vitro and associated molecular mechanisms. We found that apigenin reduced senescence-associated [Formula: see text]-galactosidase (SA-[Formula: see text]-gal) activity and promoted cell growth, concomitant with a decrease in levels of Acetyl (ac)-p53, p21[Formula: see text], and p16[Formula: see text] and an increase in phospho (p)-Rb. Apigenin also increased the activation ratio of silent information regulator 1 (SIRT1), nicotinamide adenine dinucleotide (NAD[Formula: see text], and NAD[Formula: see text]/NADH and inhibited cluster of differentiation 38 (CD38) activity in a concentration-dependent manner. SIRT1 inhibition by SIRT1 siRNA abolished the anti-aging effect of apigenin. In addition, CD38 inhibition by CD38 siRNA or apigenin increased the SIRT1 level and reduced H2O2-induced senescence. Our findings suggest that apigenin is a promising phytochemical for reducing the impact of senescent cells in age-related lung diseases such as COPD.
    53. ↑ Ogura Y et al.: CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD+/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats. Aging (Albany NY) 2020. (PMID 32507768) [PubMed] [DOI] [Full text] Mitochondrial oxidative stress is a significant contributor to the pathogenesis of diabetic kidney disease (DKD). We previously showed that mitochondrial oxidative stress in the kidneys of Zucker diabetic fatty rats is associated with a decreased intracellular NAD+/NADH ratio and NAD+-dependent deacetylase Sirt3 activity, and increased expression of the NAD+-degrading enzyme CD38. In this study, we used a CD38 inhibitor, apigenin, to investigate the role of CD38 in DKD. Apigenin significantly reduced renal injuries, including tubulointerstitial fibrosis, tubular cell damage, and pro-inflammatory gene expression in diabetic rats. In addition, apigenin down-regulated CD38 expression, and increased the intracellular NAD+/NADH ratio and Sirt3-mediated mitochondrial antioxidative enzyme activity in the kidneys of diabetic rats. In vitro, inhibition of CD38 activity by apigenin or CD38 knockdown increased the NAD+/NADH ratio and Sirt3 activity in renal proximal tubular HK-2 cells cultured under high-glucose conditions. Together, these results demonstrate that by inhibiting the Sirt3 activity and increasing mitochondrial oxidative stress in renal tubular cells, CD38 plays a crucial role in the pathogenesis of DKD.
    54. ↑ Sztretye M et al.: Astaxanthin: A Potential Mitochondrial-Targeted Antioxidant Treatment in Diseases and with Aging. Oxid Med Cell Longev 2019. (PMID 31814873) [PubMed] [DOI] [Full text] Oxidative stress is characterized by an imbalance between prooxidant and antioxidant species, leading to macromolecular damage and disruption of redox signaling and cellular control. It is a hallmark of various diseases including metabolic syndrome, chronic fatigue syndrome, neurodegenerative, cardiovascular, inflammatory, and age-related diseases. Several mitochondrial defects have been considered to contribute to the development of oxidative stress and known as the major mediators of the aging process and subsequent age-associated diseases. Thus, mitochondrial-targeted antioxidants should prevent or slow down these processes and prolong longevity. This is the reason why antioxidant treatments are extensively studied and newer and newer compounds with such an effect appear. Astaxanthin, a xanthophyll carotenoid, is the most abundant carotenoid in marine organisms and is one of the most powerful natural compounds with remarkable antioxidant activity. Here, we summarize its antioxidant targets, effects, and benefits in diseases and with aging.
    55. ↑ Zhang XS et al.: Astaxanthin ameliorates oxidative stress and neuronal apoptosis via SIRT1/NRF2/Prx2/ASK1/p38 after traumatic brain injury in mice. Br J Pharmacol 2021. (PMID 33326114) [PubMed] [DOI] BACKGROUND AND PURPOSE: Oxidative stress and neuronal apoptosis play key roles in traumatic brain injury. We investigated the protective effects of astaxanthin against traumatic brain injury and its underlying mechanisms of action. EXPERIMENTAL APPROACH: A weight-drop model of traumatic brain injury in vivo and hydrogen peroxide exposure in vitro model were established. Brain oedema, behaviour tests, western blot, biochemical analysis, lesion volume, histopathological study and cell viability were performed. KEY RESULTS: Astaxanthin significantly reduced oxidative insults on Days 1, 3 and 7 after traumatic brain injury. Neuronal apoptosis was also ameliorated on Day 3. Additionally, astaxanthin improved neurological functions up to 3 weeks after traumatic brain injury. Astaxanthin treatment dramatically enhanced the expression of peroxiredoxin 2 (Prx2), nuclear factor-erythroid 2-related factor 2 (NRF2/Nrf2) and sirtuin 1 (SIRT1), while it down-regulated the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and p38. Inhibition of Prx2 by siRNA injection reversed the beneficial effects of astaxanthin against traumatic brain injury. Additionally, Nrf2 knockout prevented the neuroprotective effects of astaxanthin in traumatic brain injury. In contrast, overexpression of Prx2 in Nrf2 knockout mice attenuated the secondary brain injury after traumatic brain injury. Moreover, inhibiting SIRT1 by EX527 dramatically inhibited the neuroprotective effects of astaxanthin and suppressed SIRT1/Nrf2/Prx2/ASK1/p38 pathway both in vivo and in vitro. CONCLUSION AND IMPLICATIONS: Astaxanthin improved the neurological functions and protected the brain from injury after traumatic brain injury, primarily by reducing oxidative stress and neuronal death via SIRT1/Nrf2/Prx2/ASK1/p38 signalling pathway and might be a new candidate to ameliorate traumatic brain injury.
    56. ↑ Zhang J et al.: Astaxanthin attenuated pressure overload-induced cardiac dysfunction and myocardial fibrosis: Partially by activating SIRT1. Biochim Biophys Acta Gen Subj 2017. (PMID 28300638) [PubMed] [DOI] BACKGROUND: Myocardial fibrosis contributes to cardiac dysfunction. Astaxanthin (AST), a member of the carotenoid family, is a well-known antioxidant, but its effect on and underlying mechanisms in myocardial fibrosis are poorly understood. METHODS: In vivo, myocardial fibrosis and cardiac dysfunction were induced using transverse aortic constriction (TAC). AST was administered to mice for 12weeks post-surgery. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate human cardiac fibroblasts (HCFs). EX-527 (6-chloro-2, 3, 4, 9-tetrahydro-1H-carbazole-1-carboxamide) and SIRT1 siRNA were used to inhibit SIRT1 in vivo and in vitro, respectively. The effects of AST on cardiac function and fibrosis were determined. SIRT1 expression and activity were measured to explore the mechanisms underlying its effects. RESULTS: AST improved cardiac function and attenuated fibrosis. Receptor activated-SMADs (R-SMADs), including SMAD2 and SMAD3, played important roles in these processes. The TAC surgery-induced increases in the expression of phosphorylated and acetylated R-SMADs were attenuated by treatment with AST, the translocation and transcriptional activity of R-SMADs were also restrained. These effects were accompanied by an increase in the expression and activity of SIRT1. Inhibiting SIRT1 attenuated the acetylation and transcriptional activity of R-SMADs, but not their phosphorylation and translocation. CONCLUSIONS: Our data demonstrate that AST improves cardiac function and attenuates fibrosis by decreasing phosphorylation and deacetylation of R-SMADs. SIRT1 contributes to AST's protective function by reducing acetylation of R-SMADs. GENERAL SIGNIFICANCE: These data suggest that AST may be useful as a preventive/therapeutic agent for cardiac dysfunction and myocardial fibrosis.
    57. ↑ Shatoor AS & Al Humayed S: Astaxanthin Ameliorates high-fat diet-induced cardiac damage and fibrosis by upregulating and activating SIRT1. Saudi J Biol Sci 2021. (PMID 34867002) [PubMed] [DOI] [Full text] This study evaluated the protective effect of astaxanthin (ASX) against high-fat diet (HFD)-induced cardiac damage and fibrosis in rats and examined if the mechanism of protection involves modulating SIRT1. Rat were divided into 5 groups (n = 10/group) as: 1) control: fed normal diet (3.82 kcal/g), 2) control + ASX (200 mg/kg/orally), 3) HFD: fed HFD (4.7 kcal/g), 4) HFD + ASX (200 mg/kg/orally), and HFD + ASX + EX-527 (1 mg/kg/i.p) (a selective SIRT1 inhibitor). All treatments were conducted for 14 weeks. Administration of ASX reduced cardiomyocyte damage, inhibited inflammatory cell infiltration, preserved cardiac fibers structure, prevented collagen deposition and protein levels of TGF-β 1 in the left ventricles (LVs) of HFD-fed rats. In the LVs of both the control and HFD-fed rat, ASX significantly reduced levels of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and p-smad2/3 (Lys19) but increased the levels of glutathione (GSH), catalase, and manganese superoxide dismutase (MnSOD). Concomitantly, it increased the nuclear activity of Nrf2 and reduced that of NF-κB p65. Furthermore, administration of ASX to both the control and HFD-fed rats increased total and nuclear levels of SIRT1, stimulated the nuclear activity of SIRT1, and reduced the acetylation of Nrf2, NF-κB p65, and Smad3. All these cardiac beneficial effects of ASX in the HFD-fed rats were abolished by co-administration of EX-527. In conclusion, ASX stimulates antioxidants and inhibits markers of inflammation under basal and HFD conditions. The mechanism of protection involves, at least, activation SIRT1 signaling.
    58. ↑ Gao D et al.: Protective effect of astaxanthin against contrast-induced acute kidney injury via SIRT1-p53 pathway in rats. Int Urol Nephrol 2019. (PMID 30456546) [PubMed] [DOI] PURPOSE: The present study was designed to further investigate the protective effect of astaxanthin (AST) on contrast-induced acute kidney injury (CI-AKI) in rats and the relationship between SIRT1-p53 pathway and astaxanthin. METHODS: 40 adult male Sprague Dawley (SD) rats were randomly divided into five groups (n = 8/group): control (CON), normal rats treated with AST (AST), CM-treated (CM), CM rats treated with isoform of nitric oxide synthase (iNOS) inhibitor (iNOS + CM), and CM rats treated with AST (AST + CM). Serum creatinine (Scr) and blood urea nitrogen (BUN) values were measured at 72 h following the procedure. Hematoxylin and eosin (H-E) staining was used to observe the pathologic changes of kidney. Tunel staining was used to test apoptosis of kidney tubules. Oxidative stress, SIRT1 activity, nitric oxide (NO), and 3-nitrotyrosine (3-NT) content were individually measured with the commercial available kits. RESULTS: Compared with the CON group, Scr and BUN levels significantly increased in the CM group (P < 0.05), and the values in two pre-treatment groups (iNOS + CM and AST + CM) had significantly decreased (P < 0.05). H-E and Tunel staining had shown that renal tubular injury was severe in CM group. The renal injury score and apoptosis index in the two pre-treatment groups also decreased (P < 0.05). The present study showed that in CM group the levels of oxidative stress indicators significantly increased, and the activities of antioxidant stress indicators significantly decreased. These indicators in two pre-treatment groups significantly improved (P < 0.05). In the CM group the expression levels of SITR1 significantly increased, and the ac-p53/p53 significantly increased (P < 0.05). Compared with the CM group, in AST + CM group the expression levels of SIRT1 increased, the expression levels of p53 and ac-p53/p53 decreased (P < 0.05).The levels of NO and 3-NT in CM group significantly increased (P < 0.05). Compared the CM group, the levels in the two pre-treatment groups significantly decreased (P < 0.05). CONCLUSIONS: Astaxanthin has a protective effect on CI-AKI, the mechanism may be related to the SIRT1-p53 pathway. Astaxanthin can reduce the content of NO and 3-NT in renal tissue of CI-AKI, and alleviate the renal injury induced by contrast agents.
    59. ↑ Petyaev IM: Lycopene Deficiency in Ageing and Cardiovascular Disease. Oxid Med Cell Longev 2016. (PMID 26881023) [PubMed] [DOI] [Full text] Lycopene is a hydrocarbon phytochemical belonging to the tetraterpene carotenoid family and is found in red fruit and vegetables. Eleven conjugated double bonds predetermine the antioxidant properties of lycopene and its ability to scavenge lipid peroxyl radicals, reactive oxygen species, and nitric oxide. Lycopene has a low bioavailability rate and appears in the blood circulation incorporated into chylomicrons and other apo-B containing lipoproteins. The recent body of evidence suggests that plasma concentration of lycopene is not only a function of intestinal absorption rate but also lycopene breakdown via enzymatic and oxidative pathways in blood and tissues. Oxidative stress and the accumulation of reactive oxygen species and nitric oxide may represent a major cause of lycopene depletion in ageing, cardiovascular disease, and type 2 diabetes mellitus. It has been shown recently that low carotenoid levels, and especially decreased serum lycopene levels, are strongly predictive of all-cause mortality and poor outcomes of cardiovascular disease. However, there is a poor statistical association between dietary and serum lycopene levels which occurs due to limited bioavailability of lycopene from dietary sources. Hence, it is very unlikely that nutritional intervention alone could be instrumental in the correction of lycopene and carotenoid deficiency. Therefore, new nutraceutical formulations of carotenoids with enhanced bioavailability are urgently needed.
    60. ↑ Li J et al.: Lycopene ameliorates insulin resistance and increases muscle capillary density in aging via activation of SIRT1. J Nutr Biochem 2022. (PMID 34530111) [PubMed] [DOI] Lycopene (Ly) is a kind of hydrocarbon, which belongs to the family of tetraterpene carotene and exists in red fruits and vegetables. The decrease of capillary density and blood flow with age is a significant reason for the increase of mortality and morbidity. Herein, our study aims to explore the effects of Ly (a bioactive food compound) on vascular aging in vitro and in vivo and its potential mechanisms. The cytological results showed that Ly could promote the proliferation of human umbilical vein endothelial cell (HUVECs) and enhance the ability of HUVECs to form capillary-like structures. Furthermore, the expression of SIRT1 in aged HUVECs was up-regulated. In vivo, aging rats showed signs of insulin resistance and blood vessel damage. Additionally, the capillary density and blood flow were reduced during the vascular aging process in both D-gal-induced and naturally aging muscle. However, when Ly was given, these conditions could be reversed. Simultaneously, the contents of ATP, lactic acid and pyruvic acid were determined, and it was found that Ly could promote angiogenesis by increasing the utilization rate of glucose and promoting energy metabolism. Finally, in the insulin resistance cell model, we knocked down the SIRT1 and administrated with Ly, and found that it couldn't restore insulin transdution. In conclusion, all the data in this study demonstrate that Ly could reactivate SIRT1 and improve insulin resistance, which was a reversible cause of vascular aging.
    61. ↑ Liu X et al.: The combination of nicotinamide mononucleotide and lycopene prevents cognitive impairment and attenuates oxidative damage in D-galactose induced aging models via Keap1-Nrf2 signaling. Gene 2022. (PMID 35183682) [PubMed] [DOI] Aging is referred to progressive dysfunction of body organs, including the brain. This study aims to explore the anti-aging effect of combing nicotinamide mononucleotide (NMN) and lycopene (Lyco) (NMN + Lyco) on aging rats and senescent PC12 cells. Both in vivo and in vitro aging models were established using D-galactose (D-gal). The combination showed a trend to superiority over monotherapy in preventing aging in vivo and in vitro. Morris water maze test showed that NMN + Lyco effectively improved the ability of spatial location learning and memory of aging model rats. NMN + Lyco mitigated the oxidative stress of rat brains, livers, and PC12 cells by elevating the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), GSH, as well as total antioxidant capacity (T-AOC), and reducing malondialdehyde (MDA) content. CCK-8 assay, senescence-associated β-galactosidase staining, and flow cytometer confirmed the cellular senescence of PC12 cells after exposing D-gal, and indicated the anti-senescence effect of NMN + Lyco in vitro. Moreover, NMN + Lyco effectively down-regulated the expressions of p53, p21, and p16 (senescence-related genes), and activated Keap1-Nrf2 signaling in both in vivo and in vitro aging models. In total, NMN + Lyco protected rats and PC12 cells from cognitive impairment and cellular senescence induced by D-gal, of which effects might be linked to the reduction of oxidative stress and the activation of Keap1-Nrf2 signaling.
    62. ↑ Bielak-Zmijewska A et al.: The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci 2019. (PMID 30871021) [PubMed] [DOI] [Full text] It is believed that postponing ageing is more effective and less expensive than the treatment of particular age-related diseases. Compounds which could delay symptoms of ageing, especially natural products present in a daily diet, are intensively studied. One of them is curcumin. It causes the elongation of the lifespan of model organisms, alleviates ageing symptoms and postpones the progression of age-related diseases in which cellular senescence is directly involved. It has been demonstrated that the elimination of senescent cells significantly improves the quality of life of mice. There is a continuous search for compounds, named senolytic drugs, that selectively eliminate senescent cells from organisms. In this paper, we endeavor to review the current knowledge about the anti-ageing role of curcumin and discuss its senolytic potential.
    63. ↑ Zendedel E et al.: Impact of curcumin on sirtuins: A review. J Cell Biochem 2018. (PMID 30145851) [PubMed] [DOI] Curcumin is a bioactive phytochemical that modulates several physiological and cellular processes leading to therapeutic effects against different diseases. Sirtuins are highly conserved nicotine adenine dinucleotide-dependent proteins that regulate the activity of target enzymes and transcription factors by deacetylation. Curcumin possesses both antioxidant and anti-inflammatory properties and has been shown to increase sirtuin-1 (SIRT1) by activating small molecules. Upregulation of SIRT1 by curcumin has been reported to confer protective effects against a range of neurological disorders including glutamate excitotoxicity, β-amyloid-induced cell death in cortical neurons, cerebral ischemic damage, and stroke. Activation of AMPK and SIRT1 by curcumin has also been noted to mediate the protective effects of curcumin against ischemia/reperfusion injury, cardiac fibrosis, diabetes, and lipid metabolism abnormalities. These protective effects of SIRT1 activation are partly mediated by the deacetylation of p53 and reduction of apoptosis. In this review, we summarize the role of SIRT1 in mediating the pharmacological effects of curcumin in several diseases.
    64. ↑ Hu A et al.: Curcumin as therapeutics for the treatment of head and neck squamous cell carcinoma by activating SIRT1. Sci Rep 2015. (PMID 26299580) [PubMed] [DOI] [Full text] SIRT1 is one of seven mammalian homologs of Sir2 that catalyzes NAD(+)-dependent protein deacetylation. The aim of the present study is to explore the effect of SIRT1 small molecule activator on the anticancer activity and the underlying mechanism. We examined the anticancer activity of a novel oral agent, curcumin, which is the principal active ingredient of the traditional Chinese herb Curcuma Longa. Treatment of FaDu and Cal27 cells with curcumin inhibited growth and induced apoptosis. Mechanistic studies showed that anticancer activity of curcumin is associated with decrease in migration of HNSCC and associated angiogenesis through activating of intrinsic apoptotic pathway (caspase-9) and extrinsic apoptotic pathway (caspase-8). Our data demonstrating that anticancer activity of curcumin is linked to the activation of the ATM/CHK2 pathway and the inhibition of nuclear factor-κB. Finally, increasing SIRT1 through small molecule activator curcumin has shown beneficial effects in xenograft mouse model, indicating that SIRT1 may represent an attractive therapeutic target. Our studies provide the preclinical rationale for novel therapeutics targeting SIRT1 in HNSCC.
    65. ↑ Bańkowski S et al.: Effect of 6-week curcumin supplementation on aerobic capacity, antioxidant status and sirtuin 3 level in middle-aged amateur long-distance runners. Redox Rep 2022. (PMID 36125053) [PubMed] [DOI] [Full text] BACKGROUND: The study was undertaken to evaluate the effect of 6-week supplementation with a daily dose of 2g of curcumin on VO2max and prooxidant/antioxidant homeostasis in middle-aged amateur long-distance runners during the preparatory period of the macrocycle. METHODS: Thirty runners were randomly assigned to a placebo group (PL) and a curcumin-supplemented group (CU). Their VO2max was assessed before supplementation and after 6 weeks of supplementation. Venous blood samples were collected from the participants at rest, immediately after exercise, and after 1h of recovery to evaluate the activity of antioxidant enzymes (SOD, CAT, GPx), non-enzymatic antioxidants (GSH, UA) and sirtuin 3 level (SIRT 3), as well as the levels of oxidative stress markers (TOS/TOC, MDA, and 8-OHdG) and muscle damage markers (CK, LDH, and Mb). RESULTS: VO2max, the activity of enzymatic antioxidants, the concentrations of non-enzymatic antioxidants, the levels of oxidative stress markers, and the levels of muscle damage markers did not change significantly in the CU group over 6 weeks of supplementation with curcumin. However, the resting concentration of SIRT 3 was found to be significantly higher (p ≤ 0.05) compared with pre-supplementation. CONCLUSION: Curcumin supplementation does not have a significant effect on VO2max and prooxidant/antioxidant homeostasis in runners.
    66. ↑ Rhoads TW & Anderson RM: Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice. Cell Metab 2020. (PMID 32877686) [PubMed] [DOI] [Full text] In this issue of Cell Metabolism, Asadi Shahmirzadi et al. (2020) demonstrate that late-onset dietary supplementation with calcium alpha-ketoglutarate results in increased survival, compressed morbidity, and reduced frailty in mice. The study provides further evidence for critical links between metabolism, inflammation, and aging.
    67. ↑ Chin RM et al.: The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 2014. (PMID 24828042) [PubMed] [DOI] [Full text] Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
    68. ↑ Bayliak MM & Lushchak VI: Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent. Ageing Res Rev 2021. (PMID 33340716) [PubMed] [DOI] An intermediate of tricarboxylic acid cycle alpha-ketoglutarate (AKG) is involved in pleiotropic metabolic and regulatory pathways in the cell, including energy production, biosynthesis of certain amino acids, collagen biosynthesis, epigenetic regulation of gene expression, regulation of redox homeostasis, and detoxification of hazardous substances. Recently, AKG supplement was found to extend lifespan and delay the onset of age-associated decline in experimental models such as nematodes, fruit flies, yeasts, and mice. This review summarizes current knowledge on metabolic and regulatory functions of AKG and its potential anti-ageing effects. Impact on epigenetic regulation of ageing via being an obligate substrate of DNA and histone demethylases, direct antioxidant properties, and function as mimetic of caloric restriction and hormesis-induced agent are among proposed mechanisms of AKG geroprotective action. Due to influence on mitochondrial respiration, AKG can stimulate production of reactive oxygen species (ROS) by mitochondria. According to hormesis hypothesis, moderate stimulation of ROS production could have rather beneficial biological effects, than detrimental ones, because of the induction of defensive mechanisms that improve resistance to stressors and age-related diseases and slow down functional senescence. Discrepancies found in different models and limitations of AKG as a geroprotective drug are discussed.
    69. ↑ Demidenko O et al.: Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test. Aging (Albany NY) 2021. (PMID 34847066) [PubMed] [DOI] [Full text] The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10-12). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.
    70. ↑ Asadi Shahmirzadi A et al.: Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab 2020. (PMID 32877690) [PubMed] [DOI] [Full text] Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.
    71. ↑ Payne A et al.: Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives for Neuroprotection, Aging, and Neuroinflammation for the Modern Age. Biomolecules 2022. (PMID 35327563) [PubMed] [DOI] [Full text] Alzheimer's and Parkinson's diseases are the two most common forms of neurodegenerative diseases. The exact etiology of these disorders is not well known; however, environmental, molecular, and genetic influences play a major role in the pathogenesis of these diseases. Using Alzheimer's disease (AD) as the archetype, the pathological findings include the aggregation of Amyloid Beta (Aβ) peptides, mitochondrial dysfunction, synaptic degradation caused by inflammation, elevated reactive oxygen species (ROS), and cerebrovascular dysregulation. This review highlights the neuroinflammatory and neuroprotective role of epigallocatechin-3-gallate (EGCG): the medicinal component of green tea, a known nutraceutical that has shown promise in modulating AD progression due to its antioxidant, anti-inflammatory, and anti-aging abilities. This report also re-examines the current literature and provides innovative approaches for EGCG to be used as a preventive measure to alleviate AD and other neurodegenerative disorders.
    72. ↑ Niu Y et al.: The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats. Aging Cell 2013. (PMID 23834676) [PubMed] [DOI] It is known that phytochemicals have many potential health benefits in humans. The aim of this study was to investigate the effects of long-term consumption of the phytochemical, epigallocatechin gallate (EGCG), on body growth, disease protection, and lifespan in healthy rats. 68 male weaning Wistar rats were randomly divided into the control and EGCG groups. Variables influencing lifespan such as blood pressure, serum glucose and lipids, inflammation, and oxidative stress were dynamically determined from weaning to death. The median lifespan of controls was 92.5 weeks. EGCG increased median lifespan to 105.0 weeks and delayed death by approximately 8-12 weeks. Blood pressure and serum glucose and lipids significantly increased with age in both groups compared with the levels at 0 week. However, there were no differences in these variables between the two groups during the whole lifespan. Inflammation and oxidative stress significantly increased with age in both groups compared with 0 week and were significantly lower in serum and liver and kidney tissues in the EGCG group. Damage to liver and kidney function was significantly alleviated in the EGCG group. In addition, EGCG decreased the mRNA and protein expressions of transcription factor NF-κB and increased the upstream protein expressions of silent mating type information regulation two homolog one (SIRT1) and forkhead box class O 3a (FOXO3a). In conclusion, EGCG extends lifespan in healthy rats by reducing liver and kidney damage and improving age-associated inflammation and oxidative stress through the inhibition of NF-κB signaling by activating the longevity factors FoxO3a and SIRT1.
    73. ↑ Pai PY et al.: Epigallocatechin Gallate Reduces Homocysteine-Caused Oxidative Damages through Modulation SIRT1/AMPK Pathway in Endothelial Cells. Am J Chin Med 2021. (PMID 33371812) [PubMed] [DOI] Elevated plasma concentration of total homocysteine is a pathological condition that causes vascular endothelial injury and subsequently leads to the progression of endothelial apoptosis in atherosclerosis. Epigallocatechin gallate (EGCG), a well-known anti-oxidant in green tea, has been reported with benefits on metabolic and cardiovascular diseases. This study aimed to explore that EGCG ameliorates homocysteine-induced endothelial cell apoptosis through enhancing the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) survival signaling pathway. Human umbilical endothelial cells were treated with homocysteine in the presence or absence of EGCG. We found that EGCG significantly increased the activities of SIRT1 and AMPK. EGCG diminished homocysteine-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation by inhibiting protein kinase C activation as well as reactive oxygen species (ROS) generation and recovered the activity of the endogenous antioxidant enzyme, superoxidase dismutase (SOD). Besides, EGCG also restores homocysteine-mediated dephosphorylation of Akt and decreases endothelial NO synthase (eNOS) expression. Furthermore, EGCG ameliorates homocysteine-activated pro-apoptotic events. The present study shows that EGCG prevents homocysteine-induced endothelial cell apoptosis via enhancing SIRT1/AMPK as well as Akt/eNOS signaling pathways. Results from this study indicated that EGCG might have some benefits for hyperhomocysteinemia.
    74. ↑ Ayissi VB et al.: Epigenetic effects of natural polyphenols: a focus on SIRT1-mediated mechanisms. Mol Nutr Food Res 2014. (PMID 23881751) [PubMed] [DOI] Polyphenols are a class of natural compounds widely distributed in fruits, vegetables, and plants. They have been reported to possess a wide range of activities in prevention and alleviation of various diseases like cancer, neuroinflammation, diabetes, and aging. Polyphenols are effective against chronic diseases and recent reports indicated strong epigenetic effects of polyphenols. Most of the studies investigating epigenetic effects of natural polyphenols have focused on their beneficial effects in cancer treatment. However, epigenetic defects have been demonstrated in many other diseases as well, and application of polyphenols to modulate the epigenome is becoming an interesting field of research. This review summarizes the effects of natural polyphenols in modulating epigenetic-related enzymes as well as their effect in prevention and treatment of chronic diseases with a focus on SIRT1 modulation. We have also discussed the relation between the structure and function of epigenetic-modifying polyphenols.
    75. ↑ Jiang S et al.: EGCG Inhibits Proliferation and Induces Apoptosis Through Downregulation of SIRT1 in Nasopharyngeal Carcinoma Cells. Front Nutr 2022. (PMID 35548580) [PubMed] [DOI] [Full text] Epigallocatechin-3-gallate (EGCG), a frequently studied catechin in green tea, has been shown involved in the anti-proliferation and apoptosis of human nasopharyngeal carcinoma (NPC) cells. However, the underlying molecular mechanism of the apoptotic effects of EGCG has not been fully investigated. Recent literature emphasized the importance of Sirtuin 1 (SIRT1), an NAD+-dependent protein deacetylase, in regulating cellular stress responses, survival, and organismal lifespan. Herein, the study showed that EGCG could significantly inhibit cell proliferation and promote apoptosis of 2 NPC (CNE-2 and 5-8F) cell lines. Moreover, it was also found that SIRT1 is down-regulated by EGCG, and the SIRT1-p53 signaling pathway participates in the effects of EGCG on CNE-2 and 5-8 F cells. Taken together, the findings of this study provided evidence that EGCG could inhibit the growth of NPC cell lines and is linked with the inhibition of the SIRT1-p53 signaling pathway, suggesting the therapeutic potential of EGCG in human NPC.
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