The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation.

The molecule NAD+ is a coenzyme for enzymes catalyzing cellular redox reactions in several metabolic pathways, encompassing glycolysis, TCA cycle, and oxidative phosphorylation, and is a substrate for NAD+-dependent enzymes. In addition to a hydride and electron transfer in redox reactions, NAD+ is a substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases and even moderate decreases in its cellular concentrations modify signaling of NAD+-consuming enzymes. Age-related reduction in cellular NAD+ concentrations results in metabolic and aging-associated disorders, while the consequences of increased NAD+ production or decreased degradation seem beneficial. This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.

Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies.

Precursors of nicotinamide adenine dinucleotide (NAD+), modulators of enzymes of the NAD+ biosynthesis pathways and inhibitors of NAD+ consuming enzymes, are the main boosters of NAD+. Increasing public awareness and interest in anti-ageing strategies and health-promoting lifestyles have grown the interest in the use of NAD+ boosters as dietary supplements, both in scientific circles and among the general population. Here, we discuss the current trends in NAD+ precursor usage as well as the uncertainties in dosage, timing, safety, and side effects. There are many unknowns regarding pharmacokinetics and pharmacodynamics, particularly bioavailability, metabolism, and tissue specificity of NAD+ boosters. Given the lack of long-term safety studies, there is a need for more clinical trials to determine the proper dose of NAD+ boosters and treatment duration for aging prevention and as disease therapy. Further research will also need to address the long-term consequences of increased NAD+ and the best approaches and combinations to increase NAD+ levels. The answers to the above questions will contribute to the more efficient and safer use of NAD+ boosters.

Risk Assessment of Oxidative Stress Induced by Metal Ions Released from Fixed Orthodontic Appliances during Treatment and Indications for Supportive Antioxidant Therapy: A Narrative Review.

The treatment with fixed orthodontic appliances could have an important role in the induction of oxidative stress and associated negative consequences. Because of the simultaneous effects of corrosion, deformation, friction, and mechanical stress on fixed orthodontic appliances during treatment, degradation of orthodontic brackets and archwires occurs, causing higher concentrations of metal ions in the oral cavity. Corroded appliances cause the release of metal ions, which may lead to the increased values of reactive oxygen species (ROS) due to metal-catalyzed free radical reactions. Chromium, iron, nickel, cobalt, titanium, and molybdenum all belong to the group of transition metals that can be subjected to redox reactions to form ROS. The estimation of health risk due to the amount of heavy metals released and the level of selected parameters of oxidative stress generated for the time of treatment with fixed orthodontic appliances is presented. Approaches to avoid oxidative stress and recommendations for the preventive use of topical or systemic antioxidants during orthodontic treatment are discussed.

Antioxidants, Food Processing and Health.

The loss and/or modification of natural antioxidants during various food processing techniques and storage methods, like heat/thermal, UV, pulsed electric field treatment, drying, blanching and irradiation is well described. Antioxidants in their reduced form are modified mainly by oxidation, and less by pyrolysis and hydrolysis. Thus, they are chemically converted from the reduced to an oxidized form. Here we describe the neglected role of the oxidized forms of antioxidants produced during food processing and their effect on health. While natural antioxidants in their reduced forms have many well studied health-promoting characteristics, much less is known about the effects of their oxidized forms and other metabolites, which may have some health benefits as well. The oxidized forms of natural antioxidants affect cell signaling, the regulation of transcription factor activities and other determinants of gene expression. Very low doses may trigger hormesis, resulting in specific health benefits by the activation of damage repair processes and antioxidative defense systems. Functional studies determining the antioxidants' effects on the organisms are important, especially as reduced or oxidized antioxidants and their metabolites may have additional or synergistic effects.

Nature Versus Nurture: What Can be Learned from the Oldest-Old's Claims About Longevity?

Beneficial genetic or environmental factors that influence the length and quality of life can be evaluated while studying supercentenarians. The oldest-old can withstand serious/fatal illnesses more than their peers and/or their aging rate is decreased. Supercentenarians are an interesting group of individuals whose lifestyle is not particularly healthy according to the common guidelines, namely some of them seem to have similar harmful behaviors, but still manage to stay healthier for longer, and while eventually dying from the same degenerative diseases as the general population, they develop symptoms 20-30 years later. As there are not many supercentenarians by definition, it is worthwhile to diligently collect their data to enable future meta-analyses on larger samples; much can be learned from supercentenarians' habits and lifestyle choices about the aging process. Contributions of genetics, lifestyle choices, and epigenetics to their extended life span are discussed here.

Causation of Oxidative Stress and Defense Response of a Yeast Cell Model after Treatment with Orthodontic Alloys Consisting of Metal Ions.

Misaligned teeth have a tremendous impact on oral and dental health, and the most efficient method of correcting the problem is orthodontic treatment with orthodontic appliances. The study was conducted to investigate the metal composition of selected orthodontic alloys, the release of metal ions, and the oxidative consequences that the metal ions may cause in the cell. Different sets of archwires, stainless steel brackets, and molar bands were incubated in artificial saliva for 90 days. The composition of each orthodontic material and quantification of the concentration of metal ions released were evaluated. Metal ion mixtures were prepared to determine the occurrence of oxidative stress, antioxidant enzyme defense system, and oxidative damage to proteins. The beta titanium alloy released the fewest metal ions and did not cause oxidative stress or protein damage. The metal ions from stainless steel and the cobalt-chromium alloy can cause oxidative stress and protein damage only at high concentrations. All metal ions from orthodontic alloys alter the activity of antioxidant enzymes in some way. The determined amounts of metal ions released from orthodontic appliances in a simulated oral environment are still below the maximum tolerated dose, and the concentrations of released metal ions are not capable of inducing oxidative stress, although some changes in antioxidant enzyme activity were observed at these concentrations.

Are Metal Ions That Make up Orthodontic Alloys Cytotoxic, and Do They Induce Oxidative Stress in a Yeast Cell Model?

Compositions of stainless steel, nickel-titanium, cobalt-chromium and ß-titanium orthodontic alloys were simulated with mixtures of Fe, Ni, Cr, Co, Ti and Mo metal ions as potential oxidative stress-triggering agents. Wild-type yeast Saccharomyces cerevisiae and two mutants ΔSod1 and ΔCtt1 were used as model organisms to assess the cytotoxicity and oxidative stress occurrence. Metal mixtures at concentrations of 1, 10, 100 and 1000 µM were prepared out of metal chlorides and used to treat yeast cells for 24 h. Every simulated orthodontic alloy at 1000 µM was cytotoxic, and, in the case of cobalt-chromium alloy, even 100 µM was cytotoxic. Reactive oxygen species and oxidative damage were detected for stainless steel and both cobalt-chromium alloys at 1000 µM in wild-type yeast and 100 µM in the ΔSod1 and ΔCtt1 mutants. Simulated nickel-titanium and ß-titanium alloy did not induce oxidative stress in any of the tested strains.

Healthy Lifestyle Recommendations: Do the Beneficial Effects Originate from NAD+ Amount at the Cellular Level?

In this review, we describe the role of oxidized forms of nicotinamide adenine dinucleotide (NAD+) as a molecule central to health benefits as the result from observing selected healthy lifestyle recommendations. Namely, NAD+ level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity, low glucose availability, and heat shocks. NAD+ is reduced with age at a cellular, tissue, and organismal level due to inflammation, defect in NAMPT-mediated NAD+ biosynthesis, and the PARP-mediated NAD+ depletion. This leads to a decrease in cellular energy production and DNA repair and modifies genomic signalling leading to an increased incidence of chronic diseases and ageing. By implementing healthy lifestyle approaches, endogenous intracellular NAD+ levels can be increased, which explains the molecular mechanisms underlying health benefits at the organismal level. Namely, adherence to here presented healthy lifestyle approaches is correlated with an extended life expectancy free of major chronic diseases.

Systemic Level of Oxidative Stress during Orthodontic Treatment with Fixed Appliances.

The aim of the study was to assess the level of selected systemic oxidative stress parameters during the first week of orthodontic treatment with fixed appliances. Fifty-four males with malocclusion and having a similar lifestyle were randomized using a computer based procedure and allocated to either the treatment group (TG; n=27;24.6 ± 1.7 years) or control group (CG; n=27;24.7 ± 1.7 years). Capillary blood was collected at baseline and 6 hours, 24 hours, and 7 days after archwire insertion. At the same time points, capillary blood was retrieved in the CG. In order to determine the oxidative stress, both the reactive oxygen species (ROS) formation and the antioxidative defense (AD) potential were measured using the ROS testing and oxygen free radicals defense (equivalent to antioxidant defense) testing, respectively, by a blinded operator. The ratio between ROS and AD (ROS/AD) was calculated and data were analyzed using nonparametric tests. No drop-outs or harms were detected. At baseline, neither ROS (1.54 [1.22; 2.12] and 1.74 [1.40; 2.01] for the TG and CG, respectively), AD (1.19 [0.66; 1.50] and 1.19 [0.57; 1.42] for the TG and CG, respectively), nor ROS/AD levels were significantly different (p>0.05). After 24 hours, the ROS level significantly increased in the TG (2.05 [1.71; 2.26]) and was higher compared to the CG ROS level (1.67 [1.29; 1.95]; p=0.025), while for the AD level, no marked between and within group differences were detected. A notable change of ROS/AD ratio was observed over time only within the TG (p=0.026). Moreover, a significantly higher ROS/AD ratio was detected 24 hours after archwire insertion in the TG compared to the CG (2.69 [1.44; 3.89] and 1.79 [1.45; 2.35], respectively), followed by a decrease. Orthodontic treatment with fixed appliances might induce systemic oxidative stress in the short-term, since ROS levels and ROS/AD levels are normalized within 7 days after archwire insertion.