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Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures

1
Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy
2
Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, CIBERER, E-46010 Valencia, Spain
3
Vall d’Hebron Institut de Recerca, E-08035 Barcelona, Catalunya, Spain
4
Institute of Molecular Biology and Biophysics of the “Federal Research Center of Fundamental and Translational Medicine”, Novosibirsk 630117, Russia
5
Department of Life and Environmental Sciences, Polytechnical University of Marche, I-60100 Ancona, Italy
6
Internal Medicine Unit, San Francesco d’Assisi Hospital, I-84020 Oliveto Citra (SA), Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7060; https://doi.org/10.3390/ijms21197060
Received: 28 August 2020 / Revised: 20 September 2020 / Accepted: 22 September 2020 / Published: 25 September 2020
(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases: Partie Deux)

Abstract

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential–and distinct—roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.
Keywords: aging-related disorders; oxidative stress; mitochondria; mitochondrial dysfunction; mitochondrial nutrients; optic neuropathies; microbiome aging-related disorders; oxidative stress; mitochondria; mitochondrial dysfunction; mitochondrial nutrients; optic neuropathies; microbiome

1. Introduction

The multiple phases of mitochondrial function and the combined relationships of mitochondrial machineries with OS have been established since early studies in the mid-20th century and the ensuing studies are still a major subject of up-to-date reports [1,2,3]. Thus, mitochondria are commonly recognized as the main cell’s powerplant and the first victims of their energy-producing and prooxidant functions. These organelles also display strong antioxidant properties, and this is the case for ALA, involved in the citric acid cycle, for CoQ10, involved in the electron transport chain (ETC), and for CARN, the main carrier of acyl groups across the mitochondrial membrane. This background knowledge has led to the awareness of the key roles of mitochondrial cofactors in aging and in ARD. Further studies were focused on an extensive number of dysmetabolic and inborn disorders [4,5,6,7,8,9,10,11,12], also including the group of mitochondrial diseases dating back to the initial definition of “mitochondrial medicine” by Luft (1994) [6]. In turn, this awareness has generated a body of experimental and clinical studies targeted to the potential use of these mitochondrial cofactors, termed as “mitochondrial nutrients” (MNs) [13,14,15,16,17]. These mitoprotective strategies in counteracting ARD progression have been applied in a thriving body of in vitro and animal investigations, as well as in recent and current clinical trials, which are highlighted in the present review. The use of individual MNs in most of the published reports is critically discussed, in view of the as yet scanty reports using combinations of two MNs in clinical studies [18,19] or in experimental ARD models [20,21,22], in view of our suggested use of a MN “triad” (ALA + CoQ10 + CARN) in prospect study design.

2. Biochemical Principles and Prospects for the Use of Mitochondrial Nutrients in ARD

ALA is an organosulfur compound derived from octanoic acid, whose main chemical feature is the presence of two sulfur atoms bound by a disulfide bond. ALA is an essential cofactor in many enzyme complexes. It is especially important in the Krebs cycle for energy production by mitochondria and for pyruvate dehydrogenase activity [23].
ALA is metabolized in different ways when administered to mammals as a dietary supplement in various combinations; the safety of ALA has been demonstrated in numerous clinical studies [24,25,26]. A recent review by Dos Santos et al. [27] on the role of ALA in Alzheimer’s disease (AD) assessed the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs that demonstrate the mitochondrial mechanisms of ALA involved in AD protection.
Coenzyme Q identifies a family of lipophilic cofactors that are ubiquitous in many organisms [28]. The most abundant form in humans is CoQ10, which has a side chain of ten isoprenoid units. As the other MNs considered, it is an endogenous molecule, but it is also taken with food, and as such it is considered a dietary supplement. The main chemical characteristic of CoQ10 is its capability to act as an electron carrier. It plays a central role in the mitochondrial ETC, which is responsible for the transport of electrons from the respiratory complexes I (NADH dehydrogenase) and II (succinate dehydrogenase), to complex III (coenzyme Q: cytochrome c–oxidoreductase). In its reduced state, ubiquinol, it is also a free radical scavenger, so it can be considered as a physiological antioxidant. Ubiquinol protects biological membranes from oxidation, inhibits lipid peroxidation, and participates in α-tocopherol recycling.
CoQ10 levels were found decreased in patients affected by cerebellar multiple system atrophy (MSA) [29,30]. The authors suggested that CoQ10 deficiency may contribute to the pathogenesis of MSA, and that increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients. Analogous conclusions were provided by Shimizu et al. [31], and by Hargreaves and Mantle [32] that focused on the potential role of CoQ10 supplementation in the treatment of tissue fibrosis and cardiovascular risk, by improving cardiovascular function and reducing the risk of cardiovascular-associated mortality.
Besides the content, the oxidative status of CoQ10 is also noteworthy. CoQ10 can be present in oxidized (ubiquinone) or reduced (ubiquinol) forms. As mentioned, It should be noted that ubiquinol is the active antioxidant form of CoQ10 [33,34]; therefore, unlike ubiquinone, which requires activation of reductase activity to be chemically activated as an antioxidant, it provides direct efficacy, improved bioavailability, and, therefore, greater potential for treatment.
Moreover, a CoQ10 derivative, ubiquinone and ubiquinonyl-decyl-triphenylphosphonium (MitoQ) [35], exhibits the property of directly penetrating across the mitochondrial membrane. MitoQ has a recognized use as a CoQ10-based dietary supplement, as evaluated in experimental and clinical studies [36].
Carnitine (CARN, β-hydroxy-γ-N-trimethylaminobutyric acid, 3-hydroxy-4-N,N,N-trimethylaminobutyrate) is a quaternary ammonium compound associated with the transport of fatty acids in the mitochondrial membrane through CARN palmitoyltransferase I and CARN palmitoyltransferase II [37]. This process is of paramount importance for the delivery of free fatty acids released from different tissues, especially adipose tissue, to the mitochondria. These fatty acids will be used for ATP production after β oxidation. The CARN-mediated mitochondrial entry process is a rate-limiting factor for fatty acid oxidation and hence the production of cellular ATP.

3. Basic Research Studies

A body of literature has focused on the effects of MNs in aged animals, and in vivo as well as in vitro ARD models. As shown in Table 1, ALA has been tested in aged or ARD rat and canine models [21,22,38,39] such as AD and diabetic neuropathy, with beneficial effects on a number of endpoints. With one exception to these effects, ALA—unlike CoQ10—failed to improve nerve conductivity [21]. Three studies tested ALA and CoQ10 alone [21,22] or in combination [20], and two studies tested ALA with multiple antioxidant supplements [40,41]. Among these studies, Sadeghiyan Galeshkalami et al. [20] reported that the combination of ALA + CoQ10 successfully ameliorated the conditions of diabetic rats by preventing apoptosis and neuronal degeneration, regulating caspase 3 expression and inducing ATP production.
Several in vitro studies have reported the effects of ALA in rat cell cultures [41,42] and CoQ10 in human cells [43,44], consistently showing decreased ROS production and inflammation, as well as an increase in thiol production and an improvement in ETC. Polyphenols can exert antioxidant or prooxidant effects depending on the oxygen and glucose levels used in the cell culture. In addition, high concentrations of glucose in the cultured cell medium sometimes result in a glycolitic switch (Warburg effect).
Altogether, it can be assumed that most of the literature on animal and in vitro models can predict analogous beneficial effects of ALA and CoQ10—or a combination of both [19,20]—in people with ARD.

4. Mitochondrial Nutrient-Based Clinical Trials in Aging-Related Disorders

An extensive body of literature has been devoted to clinical trials testing MNs in ARD patients, focused on CVD, T2D, and other ARD, as shown in Table 2.
Among trials conducted in patients with CVD, CoQ10 was tested alone or with antioxidant supplements [45,46,47,48,49] and beneficial effects included decreased fibrosis, morbidity, and mortality, as well as decreased levels of pro-inflammatory cytokines, with improved left ventricular function and quality of life. A clinical trial conducted in CVD patients by McMackin et al. [18], testing a combination of ALA and acetyl-CARN, reported a significant improvement of blood pressure and vascular tone. Two other clinical trials [50,51] were conducted on acyl-CARN in CVD patients, which also reported positive effects on CVD endpoints, as well as OS parameters such as decreased concentrations of malondialdehyde and 4-hydroxynonenal. Altogether, one may recognize that CVD patients may benefit from adjuvant treatments with CoQ10, ALA, and acyl-CARN [18,45,46,47,48,49,50,51].
An extensive body of research evidence from the 1960s to the 1990s established a protective role for ALA in relation to diabetic complications and progression [24,52,53,54,61,62,63,64], up to recognition by the German Drug Agency in 1994 [65] as a prescription agent in treating diabetic patients.
Several clinical trials were carried out in patients affected by other ARD. Shinto et al. [55] tested the effects of ALA + ω-3 fatty acids in patients with AD, and reported an improvement in neurological conditions. Galasko et al. [66] found improvement in cerebrospinal fluid biomarkers in AD patients receiving ALA, CoQ10, and antioxidant vitamins. Improvement in inflammatory markers was found by Sanoobar et al. [67] in patients with multiple sclerosis following treatment with CoQ10. A report by Pistone et al. [68], testing CARN in elderly subjects with rapid muscle fatigue, found favorable effects on fatigue and serum lipids, as well as a decrease in total fat mass and an increase in total muscle mass. Administration of acetyl-CARN or propionyl-CARN reduced mental fatigue [69], while CoQ10 deficiency was found in patients with chronic fatigue syndrome (CFS) [70]. An early study reported on 30 patients with CFS to compare CARN and amantadine, showing a statistically significant clinical improvement in 12 out of the 18 CSF parameters after eight weeks of treatment [57]. A randomized, double-blind placebo-controlled trial on 73 CFS patients showed that administration of CoQ10 (200 mg/day) plus NADH (20 mg/day) conferred benefits on fatigue and biochemical parameters [58]. The on-going trial by Stough et al. [59] is investigating the effects of CoQ10 administration on cognitive and cardiovascular function, and on OS in elderly subjects.
Apart from the successful clinical trials of MNs in patients with ARD, other studies have focused on disorders of a different nature, yet variously related to mitochondrial anomalies. This was the case for the studies of MNs in Down syndrome [71,72], an example of an accelerated aging disease, fibromyalgia [60], and mitochondrial disorders [73,74], which reported suggestive evidence for MN-induced beneficial effects. Other clinical trials failed to report clear positive effects of MN administration in patients with some ARD, such as rheumatoid arthritis [75] or Parkinson’ disease [76], or of acetyl-CARN in T2D patients [77].
Another example of age-related changes that implies medical relevance in dermatology is given by skin aging and measures to reduce the progression of wrinkles. In this area, a pre-existing—and current—literature has focused on the role of mitochondria in creating a prooxidant state since the early studies [78,79]. Hence, a line of studies has pursued MN-containing preparations [80,81], and a body of literature has reported the favorable effects of topical MN administration using ALA [82,83] or CoQ10 [84,85] or CARN [86], as evaluated in clinical trials. In several studies, MN administration was accompanied by other ingredients.

5. The Case of Progerias

Progerias, also termed progeroid syndromes (PGS), are a set of genetic disorders with various gene defects, yet exhibiting phenotypes characterized by symptoms of early aging, along with the involvement of a prooxidant state and MDF. The most investigated PGS are Hutchinson–Gilford progeria syndrome (HGPS), Cockayne syndrome (CS), Werner syndrome (WS), and Down syndrome (DS), altogether resulting in a number of signs of early aging [87,88,89].
Rivera-Torres et al. [90] studied fibroblasts from healthy subjects and patients with HGPS, as well as a mouse HGPS model, and found a marked downregulation of mitochondrial oxidative phosphorylation proteins, accompanied by MDF in HGPS cells. MDF has also been found in fibroblasts of adult progeroid mice expressing progerin or prelamin A. Tissue analysis of these mouse models has shown that the damaging effect of these proteins on mitochondrial function is time- and dose-dependent.
WS is recognized as a model of human aging. WS-affected patients display late onset (adolescence) with some of the characteristics of normal aging such as cataracts, hair graying, skin aging, and cancer propension [91]. In addition, WS individuals have a high incidence of inflammatory diseases such as atherosclerosis and T2D. The in vivo phenotype of WS is associated with significantly increased prooxidant endpoints in circulating leukocytes compared to other genetic diseases. These parameters included: (a) leukocyte and urinary 8-hydroxy-2′-deoxyguanosine; (b) blood glutathione; (c) plasma glyoxal and methylglyoxal; and (d) some plasma antioxidants (uric acid and ascorbic acid) [92]. The WRN mouse model was investigated by Lebel et al. [93], who found ascorbate-induced improvement in metabolic abnormalities in WRN mutant mice, such as reduced OS in liver and heart tissues and reversal of hypertriglyceridemia, hyperglycemia, and insulin resistance.
CS is an autosomal recessive segmental PGS with a complex series of pathological features. There are five genes responsible for this syndrome: CSA, CSB, XPB, XPD, and XPG, in which various mutations have been found [94]. The phenotypic effects of these mutations include a defective DNA oxidative damage repair system.
The consequences of OS and MDF in DS have been investigated from early studies and to the present. Ultrastructural abnormalities in cultured cerebellar neurons from trisomy 16 (Ts16) mice, a model of DS, have been reported by Bersu et al. [95]. The abnormalities included, among others, irregular-shaped mitochondria and decreased microtubule levels, which were not observed in any of the control neurons. Druzhyna et al. [96] reported defective repair of mitochondrial DNA (mtDNA) oxidative damage in fibroblasts from DS patients, while Schuchmann and Heinemann [97] found mitochondria-associated anomalies in neurons of Ts16 mice. A selective decrease in respiration was detected with the Complex I substrates, malate and glutamate, but not with the succinate of the Complex II substrate, in isolated cortex mitochondria of the Ts16 mice [98]. Conti et al. [99] investigated the gene expression profile of chromosome 21 (Hsa21) using oligonucleotide microarrays in the hearts of human fetuses with and without Hsa21 trisomy, and found that Hsa21 gene expression in trisomic samples was increased by 1.5 times. Evaluation of functional classes and analysis of the enrichment of a set of 473 genes revealed a downregulation of genes encoding mitochondrial enzymes and an upregulation of genes encoding extracellular matrix proteins. The authors concluded that the dose-dependent upregulation of Hsa21 genes causes dysregulation of genes responsible for mitochondrial function and organization of the extracellular matrix in the fetal heart of trisomic subjects [99]. Overall, the body of evidence in PGS and in DS points to a central role of OS and MDF in these disorders, prompting the design of mitoprotective clinical strategies to mitigate the adverse phenotypic effects of PGS [100].

6. The Case of Optic Neuropathies

Although MNs have been studied for their ability to decelerate the aging of various organisms, the effectiveness in preventing ARD must be weighed against the optimal dose and number of drugs. Therefore, the search for a suitable disease model that allows obtaining an unbiased readout and monitoring clinical outcomes can greatly strengthen the applicability of MNs. Since aging likely contributes to the vulnerability of the optic nerve over time, progressive optic neuropathy in the form of glaucoma may become such a disease. Indeed, treatment of glaucoma with MNs may provide some clear data for monitoring clinical improvements. The rationale and efficacy of CoQ10 in protecting from retinal diseases and neuroretinal degeneration were reviewed by Zhang et al. [101,102]. CoQ10 can ameliorate OS-mediated alterations in mitochondria of the optic nerve head astrocytes [103]. Intraocular administration of CoQ10 prevents retinal damage in rats [104,105], inhibits glutamate excitotoxicity and OS-mediated changes in mitochondria of a mouse model of glaucoma [106], and demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension [107]. In a study of 43 patients with open-angle glaucoma associated with CoQ10 and vitamin E supplementation, Parisi et al. [56] found improvement in retinal function followed by an increase in visual cortical responses. The first randomized, double-blind controlled-fashion study in 612 individuals with glaucoma is currently underway to investigate the neuroprotective effects of CoQ10 and Vit E [108]. For another MN, CARN, Calandrella et al. [109] reported its neuroprotective, antiapoptotic, and antioxidant effects in a glaucoma rat model. In a randomized double-blind pilot study of 40 patients with ocular discomfort syndrome secondary to glaucoma, treatment for 15 days with eye drop solutions containing eledoisin and CARN showed a 50% reduction in symptom severity [110]. Finally, ALA treatment limits glaucoma-related retinal ganglion cell death and dysfunction [111] and exerts a neuroprotective effect against OS in retinal neurons in vitro and in vivo [112]. In addition, topical administration of ALA to rabbit eyes prevents and/or reduces fibrosis by inhibiting the pathways of inflammation, revascularization, and accumulation of the extracellular matrix [113]. However, it should be taken into account that the etiology of glaucoma is extensive, and the use of MNs can be recommended for those glaucoma-related processes where mitochondria are involved in the physiopathological process.

7. MNs in the Content of Microbiome and Aging

Given the recent advances in metabolomics, the gut microbiome is currently viewed as an endocrine organ that produces a wide range of metabolites in response to foods. In this regard, all mitochondrial supplements and the gut microbiome constitute the food metabolome, obtained as a result of the digestion and biotransformation of food [114,115]. Changes in the gut microbiome are associated with a variety of diseases, including neurological disorders, CVD [116], and metabolic diseases such as obesity and T2D [117]. The aging process also affects the food metabolome and its interaction with the immune system [118]. In this regard, the MNs produced by the microbiome can be exchanged between kingdoms with mammalian cells, thus altering or enhancing the need for energy production in some mitochondrial disorders. For instance, in a murine cell culture model of the central nervous system, the structural analogs of CARN produced by anaerobic commensal bacteria in the intestine can colocalize with CARN in the brain and interfere with CARN-mediated fatty acid oxidation [119].
CARN transports long-chain fatty acids across the mitochondrial membrane for energy production and promotes the excretion of toxic organic acids in urine [120]. Some age-related metabolites (creatinine, creatine, glycine, betaine/trimethylamine N-oxide, citrate, succinate, and acetone) can be cleared from the body over a long period of time, which suggests their use in patients with mitochondrial disorders [121,122]. The role of CoQ10 in the metabolome is still unclear, since it is difficult to separate ubiquinone synthesized in eukaryotic cells from intestinal menaquinone in bacterial cells [123]. However, recent reports provided evidence that CoQ10 supplementation affects the metabolomic profile in the urine of elderly people and may be beneficial for healthy aging [124].
It is noteworthy that four alternative forms of quinone biosynthetic enzymes have been identified in the human intestinal microbiome [123]. Disruption of quinone biosynthesis can lead to metabolic disorders, since all these quinones are growth factors for the human intestinal microbiota [124]. Hence, substitution with an MN mix can compensate for the altered microbiome, leading to clinical improvement of the whole organism. In turn, ALA has a direct effect on lipid metabolism and the liver, modulating mitochondrial function [125], and can reinforce the redox state in mice, which leads to modulation of intestinal microbiota and improved metabolic health [126].
Although data on the metabolism and pharmacokinetics of MNs in humans are limited, several studies have shown that withdrawal of MN (CoQ10) supplementation returns levels to normal within a few days [25]. Therefore, novel MN formulations should be developed to increase or prolong the bioavailability of MNs. Given the importance of the MN in maintaining the intermetabolic pathways of the microbiome, serious consideration should be given to the maladjustment of the intestinal and host microbiota to correct age-related dysbiosis.

8. Aging, Antioxidants, and Possible Advantages of the MN “Triad”

In view of the concept of ROS-mediated ARD, a number of antioxidants have been proposed as a front line treatment for aging. Without diminishing the benefits of the role of antioxidants as anti-aging compounds, it should be emphasized that there is still no evidence base for the use of such compounds in medical practice. Furthermore, no evidence for the accumulation of commonly used gerontoprotectors (e.g., tert-butylhydroxylamin) or vitamin E in mitochondria has been reported so far. In this regard, the concept of preventing an age-related increase in the level of mitochondrial ROS should prompt ad hoc investigations [127]. These may lead to search for and to use substances aimed not at the general elimination of any ROS in cells and tissues, but at maintaining a low ROS content in the intramitochondrial space. Although an excess of mitochondrial ROS is detrimental for any organism, ROS are required both for the immune system against pathogens and for redox signaling [128]. Recently, mild depolarization of the inner mitochondrial membrane was shown as a major component of an anti-aging program [129]. ROS perform a physiological function as messenger molecules, but they also constitute reactive molecules potentially harmful for the cellular system. In particular, mitochondria are an important source and target of ROS and are critical modulators of the cellular metabolic process and programmed cell death.
In this context, the proposed MNs may be the safest triad for mild mitochondrial effects. Lipoic acid can directly scavenge superoxide and improve mitochondrial function [130], CoQ10 is an important endogenous lipid-soluble antioxidant [131], and CARN reduces OS in many biological systems [132,133]. Despite the fact that the components of the MN triad are safe for use in clinical trials and have been studied for their ability to decelerate the aging of different organisms, their effectiveness will most likely depend on the selection of the optimal doses and on the time of their administration.

9. Concluding Remarks

Beyond the above-cited experimental and clinical reports, the extensive literature discusses the potential benefits of treating ARD and mitochondria-defective diseases using MNs [14,25,134,135,136,137,138,139,140,141,142,143,144]. Consistent with the available database from pre-clinical and clinical investigations, the available MDF-related reviews mainly focus on the potential advantages of using individual MNs in the treatment of mitochondria-defective disorders, with the exception of the “mitochondrial cocktail” perspective proposed by Tarnopolsky [136] and as discussed in our previous review [137].
One might argue that an approach based on individual MNs may contradict basic, well-established knowledge about mitochondrial function based on the combined synergism of different metabolic systems, as was built by Palade in 1964 [2] and in an extensive body of basic research over sixty years. It is postulated that the regulation of mitochondrial homeostasis by any of the MN components during aging affects age-related declines. Thus, the choice of treatment for MDF disorders such as ARD, CVD, and T2D or neurodegenerative diseases with only one MN may be justified in the case of precise information about a deficiency in one specific MN. An alternative approach may consist of pharmaco-epidemiological studies aimed at addressing the potential impact of MNs on the course of ARD. This research might both provide an important contribution to the evidence-based need for rational decision making in medicine and reduce the financial burden of full-scale clinical trials. The knowledge gained from such research will significantly expand the therapeutic strategies available for treating ARD and help reduce the enormous public health burden of these diseases world-wide. It can be assumed that a line of investigations may be warranted in an attempt to recognize a specific deficiency in a given MN that would justify treatment with this defective MN. In the absence of this individual MN deficit, a temporary solution in study design could be based on the following steps:
(1)
Preclinical studies (lifelong treatments and/or experimental diabetes) comparing the protective effects of CoQ10 vs. ALA vs. (acyl-)CARN and combinations thereof;
(2)
Clinical trials (morbidity, mortality, and cognitive decline; T2D compensation), which may be conducted following the results of pre-clinical investigations.
The physiological roles of the three MNs, along with the outcomes of several reports, suggest the expected safety of treatments with MN combinations, thereby safeguarding ethical issues in research proposals.
Preclinical studies are recognized to feature year-long durations, similar to investigations to test chronic toxicity or carcinogenesis in rodents, with a life expectancy of 2 years. Potential results from animal investigations could lay the groundwork for the design of clinical trials that can be multi-year- or 10-year-long in accordance with, for example, the guidelines of the National Social Life, Health and Aging Project [145]
Expecting broader and more targeted studies, we can at least recommend the long-term management of elderly patients and patients with ARD through chronic treatment with appropriate dosages and combinations of MNs and physical exercise, not excluding specific treatment methods aimed at the disease.

Author Contributions

G.P., M.T. (Marco Trifuoggi): conceptualization; G.P.: writing—original draft; F.V.P., A.L., L.T., M.R.F., M.T. (Maria Toscanesi): writing-review and editing; L.T., M.T. (Marco Trifuoggi): supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. Harman, D. Aging: A theory based on free radical and radiation. J. Gerontol. 1956, 11, 298–300. [Google Scholar] [CrossRef] [PubMed]
  2. Palade, G.E. The organization of living matter. Proc. Natl. Acad. Sci. USA 1964, 52, 613–634. [Google Scholar] [CrossRef]
  3. Haas, R.H. Mitochondrial dysfunction in aging and diseases of aging. Biology (Basel) 2019, 8, 48. [Google Scholar] [CrossRef] [PubMed]
  4. Richter, C.; Kass, G.E. Oxidative stress in mitochondria: Its relationship to cellular Ca2+ homeostasis, cell death, proliferation and differentiation. Chem. Biol. Interact. 1991, 77, 1–23. [Google Scholar] [CrossRef]
  5. Sohal, R.S.; Brunk, U.T. Mitochondrial production of pro-oxidants and cellular senescence. Mutat. Res. 1992, 275, 295–304. [Google Scholar] [CrossRef]
  6. Luft, R. The development of mitochondrial medicine. Proc. Natl. Acad. Sci. USA 1994, 91, 8731–8738. [Google Scholar] [CrossRef]
  7. Quintanilla, R.A.; Johnson, G.V. Role of mitochondrial dysfunction in the pathogenesis of Huntington’s disease. Brain Res. Bull. 2009, 80, 242–247. [Google Scholar] [CrossRef]
  8. Pagano, G.; Talamanca, A.A.; Castello, G.; Cordero, M.D.; d’Ischia, M.; Gadaleta, M.N.; Pallardó, F.V.; Petrović, S.; Tiano, L.; Zatterale, A. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: Toward a rational design of chemoprevention strategies by means of mitochondrial nutrients. Oxidative Med. Cell. Longev. 2014, 2014, 541230. [Google Scholar] [CrossRef]
  9. Phillipson, O.T. Management of the aging risk factor for Parkinson’s disease. Neurobiol. Aging 2014, 35, 847–857. [Google Scholar] [CrossRef]
  10. Al Shahrani, M.; Heales, S.; Hargreaves, I.; Orford, M. Oxidative stress: Mechanistic insights into inherited mitochondrial disorders and Parkinson’s disease. J. Clin. Med. 2017, 6, 100. [Google Scholar] [CrossRef]
  11. Barcelos, I.P.; Haas, R.H. CoQ10 and Aging. Biology (Basel) 2019, 8, 28. [Google Scholar] [CrossRef]
  12. Cenini, G.; Lloret, A.; Cascella, R. Oxidative stress in neurodegenerative diseases: From a mitochondrial point of view. Oxidative Med. Cell. Longev. 2019, 2019, 2105607. [Google Scholar] [CrossRef]
  13. Liu, J.; Ames, B.N. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer’s disease, and Parkinson’s disease. Nutr. Neurosci. 2005, 8, 67–89. [Google Scholar] [CrossRef] [PubMed]
  14. Liu, J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: An overview. Neurochem. Res. 2008, 33, 194–203. [Google Scholar] [CrossRef] [PubMed]
  15. Smith, R.A.; Murphey, M.P. Mitochondria-targeted antioxidants as therapies. Discov. Med. 2011, 11, 106–114. [Google Scholar]
  16. Ajith, T.A.; Padmajanair, G. Mitochondrial pharmaceutics: A new therapeutic strategy to ameliorate oxidative stress in Alzheimer’s disease. Curr. Aging Sci. 2015, 8, 235–240. [Google Scholar] [CrossRef]
  17. Akbari, M.; Ostadmohammadi, V.; Lankarani, K.B.; Tabrizi, R.; Kolahdooz, F.; Khatibi, S.R.; Asemi, Z. The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials. Metabolism 2018, 87, 56–69. [Google Scholar] [CrossRef]
  18. McMackin, C.J.; Widlansky, M.E.; Hamburg, N.M. Effect of combined treatment with alpha-lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J. Clin. Hypertens. 2007, 9, 249–255. [Google Scholar] [CrossRef] [PubMed]
  19. Palacka, P.; Kucharska, J.; Murin, J.; Dostalova, K.; Okkelova, A.; Cizova, M.; Waczulikova, I.; Moricova, S.; Gvozdjakova, A. Complementary therapy in diabetic patients with chronic complications: A pilot study. Bratisl. Lek. Listy 2010, 111, 205–211. [Google Scholar]
  20. Sadeghiyan Galeshkalami, N.; Abdollahi, M.; Najafi, R.; Baeeri, M.; Jamshidzade, A.; Falak, R.; Gholami, M.D.; Gholamreza Hassanzadeh, G.; Mokhtari, T.; Hassani, S.; et al. Alpha-lipoic acid and coenzyme Q10 combination ameliorates experimental diabetic neuropathy by modulating oxidative stress and apoptosis. Life Sci. 2019, 216, 101–110. [Google Scholar] [CrossRef]
  21. Ayaz, M.; Tuncer, S.; Okudan, N.; Gokbel, H. Coenzyme Q(10) and alpha-lipoic acid supplementation in diabetic rats: Conduction velocity distributions. Methods Find. Exp. Clin. Pharmacol. 2008, 30, 367–374. [Google Scholar] [CrossRef] [PubMed]
  22. Snigdha, S.; de Rivera, C.; Milgram, N.W.; Cotman, C.W. Effect of mitochondrial cofactors and antioxidants supplementation on the aged canine. Neurobiol. Aging 2016, 37, 171–178. [Google Scholar] [CrossRef]
  23. Solmonson, A.; DeBerardinis, R.J. Lipoic acid metabolism and mitochondrial redox regulation. J. Biol. Chem. 2018, 293, 7522–7530. [Google Scholar] [CrossRef] [PubMed]
  24. Ziegler, D.; Low, P.A.; Litchy, W.J.; Boulton, A.J.; Vinik, A.I.; Freeman, R.; Samigull, R.; Tritschler, H.; Munzel, U.; Maus, J.; et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 trial. Diabetes Care 2011, 34, 2054–2060. [Google Scholar] [CrossRef] [PubMed]
  25. Xiang, G.D.; Sun, H.L.; Zhao, L.S.; Hou, J.; Yue, L.; Xu, L. The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance. Clin. Endocrinol. (Oxf.) 2008, 68, 716–723. [Google Scholar] [CrossRef] [PubMed]
  26. Heinisch, B.B.; Francesconi, M.; Mittermayer, F.; Schaller, G.; Gouya, G.; Wolzt, M.; Pleiner, J. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: A placebo-controlled randomized trial. Eur. J. Clin. Investig. 2010, 40, 148–154. [Google Scholar] [CrossRef]
  27. Dos Santos, S.M.; Romeiro, C.F.R.; Rodrigues, C.A.; Cerqueira, A.R.L.; Monteiro, M.C. Mitochondrial dysfunction and alpha-lipoic acid: Beneficial or harmful in Alzheimer’s disease? Oxidative Med. Cell. Longev. 2019, 2019, 8409329. [Google Scholar] [CrossRef]
  28. Bhagavan, H.N.; Chopra, R.K. Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics. Free. Radic. Res. 2000, 40, 445–453. [Google Scholar] [CrossRef]
  29. Barca, E.; Kleiner, G.; Tang, G.; Ziosi, M.; Tadesse, S.; Masliah, E.; Louis, E.D.; Faust, P.; Kang, U.J.; Torres, J.; et al. Decreased coenzyme Q10 levels in multiple system atrophy cerebellum. J. Neuropathol. Exp. Neurol. 2016, 75, 663–672. [Google Scholar] [CrossRef]
  30. Schottlaender, L.V.; Bettencourt, C.; Kiely, A.P.; Chalasani, A.; Neergheen, V.; Holton, J.L.; Hargreaves, I.; Houlden, H. Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients. PLoS ONE 2016, 11, e0149557. [Google Scholar] [CrossRef]
  31. Shimizu, M.; Miyazaki, T.; Takagi, A.; Sugita, Y.; Yatsu, S.; Murata, A.; Kato, T.; Suda, S.; Ouchi, S.; Aikawa, T.; et al. Low circulating coenzyme Q10 during acute phase is associated with inflammation, malnutrition, and in-hospital mortality in patients admitted to the coronary care unit. Heart Vessel. 2017, 32, 668–673. [Google Scholar] [CrossRef] [PubMed]
  32. Hargreaves, I.P.; Mantle, D. Coenzyme Q10 supplementation in fibrosis and aging. Adv. Exp. Med. Biol. 2019, 1178, 103–112. [Google Scholar] [CrossRef] [PubMed]
  33. Ernster, L.; Forsmark-Andrée, P. Ubiquinol: An endogenous antioxidant in aerobic organisms. Cin. Investig. 1993, 71, S60–S65. [Google Scholar] [CrossRef] [PubMed]
  34. Sies, H. Oxidative stress: Oxidants and antioxidants. Exp. Physiol. 1997, 82, 291–295. [Google Scholar] [CrossRef] [PubMed]
  35. Skulachev, V.P. A biochemical approach to the problem of aging: “Megaproject”on membrane-penetrating ions. The first results and prospects. Biochemistry (Moscow) 2007, 72, 1385–1396. [Google Scholar] [CrossRef]
  36. Braakhuis, A.J.; Nagulan, R.; Somerville, V. The effect of MitoQ on aging-related biomarkers: A systematic review and meta-analysis. Oxidative Med. Cell. Longev. 2018, 2018, 8575263. [Google Scholar] [CrossRef]
  37. Zammit, V.A.; Ramsay, R.R.; Bonomini, M.; Arduini, A. Carnitine, mitochondrial function and therapy. Adv. Drug Deliv. Rev. 2009, 61, 1353–1362. [Google Scholar] [CrossRef]
  38. Finlay, L.A.; Michels, A.J.; Butler, J.A.; Smith, E.J.; Monette, J.S.; Moreau, R.F.; Petersen, S.K.; Frei, B.; Hagen, T.M. R-α-lipoic acid does not reverse hepatic inflammation of aging, but lowers lipid anabolism, while accentuating circadian rhythm transcript profiles. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 302, R587–R597. [Google Scholar] [CrossRef]
  39. Thakurta, I.G.; Chattopadhyay, M.; Ghosh, A.; Chakrabarti, S. Dietary supplementation with N-acetyl cysteine, α-tocopherol and α-lipoic acid reduces the extent of oxidative stress and proinflammatory state in aged rat brain. Biogerontology 2012, 13, 479–488. [Google Scholar] [CrossRef]
  40. Head, E.; Murphey, H.L.; Dowling, A.L.; McCarty, K.L.; Bethel, S.R.; Nitz, J.A.; Pleiss, M.; Vanrooyen, J.; Grossheim, M.; Smiley, J.R.; et al. A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer’s disease. J. Alzheimers Dis. 2012, 32, 1029–1042. [Google Scholar] [CrossRef]
  41. Nobakht-Haghighi, N.; Rahimifard, M.; Baeeri, M.; Rezvanfar, M.A.; Moini Nodeh, S.; Haghi-Aminjan, H.; Hamurtekin, E.; Abdollahi, M. Regulation of aging and oxidative stress pathways in aged pancreatic islets using alpha-lipoic acid. Mol. Cell. Biochem. 2018, 449, 267–276. [Google Scholar] [CrossRef]
  42. Baeeri, M.; Bahadar, H.; Rahimifard, M.; Navaei-Nigjeh, M.; Khorasani, R.; Rezvanfar, M.A.; Gholami, M.; Abdollah, M. α-Lipoic acid prevents senescence, cell cycle arrest, and inflammatory cues in fibroblasts by inhibiting oxidative stress. Pharmacol. Res. 2019, 141, 214–223. [Google Scholar] [CrossRef] [PubMed]
  43. Schniertshauer, D.; Gebhard, D.; Bergemann, J. Age-dependent loss of mitochondrial function in epithelial tissue can be reversed by coenzyme Q10. J. Aging Res. 2018, 2018, 6354680. [Google Scholar] [CrossRef] [PubMed]
  44. Marcheggiani, F.; Cirilli, I.; Orlando, P.; Silvestri, S.; Vogelsang, A.; Knott, A.; Blatt, T.; Weise, J.M.; Tiano, L. Modulation of coenzyme Q10 content and oxidative status in human dermal fibroblasts using HMG-CoA reductase inhibitor over a broad range of concentrations. From mitohormesis to mitochondrial dysfunction and accelerated aging. Aging (Albany NY) 2019, 11, 2565–2582. [Google Scholar] [CrossRef]
  45. Alehagen, U.; Aaseth, J.; Alexander, J.; Svensson, E.; Johansson, P.; Larsson, A. Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality? Biofactors 2018, 44, 137–147. [Google Scholar] [CrossRef]
  46. Mortensen, S.A.; Rosenfeldt, F.; Kumar, A.; Dolliner, P.; Filipiak, K.J.; Pella, D.; Alehagen, U.; Steurer, G.; Littarru, G.P.; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial. JACC Fail. 2014, 2, 641–649. [Google Scholar] [CrossRef] [PubMed]
  47. Fumagalli, S.; Fattirolli, F.; Guarducci, L.; Cellai, T.; Baldasseroni, S.; Tarantini, F.; di Bari, M.; Masotti, G.; Marchionni, N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: A randomized, placebo-controlled, double-blind study. Clin. Cardiol. 2011, 34, 211–217. [Google Scholar] [CrossRef]
  48. Witte, K.K.; Nikitin, N.P.; Parker, A.C.; von Haehling, S.; Volk, H.D.; Anker, S.D.; Clark, A.L.; Cleland, J.G. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur. Heart J. 2005, 26, 2238–2244. [Google Scholar] [CrossRef]
  49. Lee, B.J.; Huang, Y.C.; Chen, S.J.; Lin, P.T. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition 2012, 28, 250–255. [Google Scholar] [CrossRef] [PubMed]
  50. Ruggenenti, P.; Cattaneo, D.; Loriga, G.; Ledda, F.; Motterlini, N.; Gherardi, G.; Orisio, S.; Remuzzi, G. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: Effects of acetyl-L-carnitine therapy. Hypertension 2009, 54, 567–574. [Google Scholar] [CrossRef] [PubMed]
  51. Signorelli, S.S.; Fatuzzo, P.; Rapisarda, F.; Neri, S.; Ferrante, M.; Oliveri Conti, G.; Fallico, R.; Di Pino, L.; Pennisi, G.; Celotta, G.; et al. A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis. Drugs Aging 2006, 23, 263–270. [Google Scholar] [CrossRef] [PubMed]
  52. Porasuphatana, S.; Suddee, S.; Nartnampong, A.; Konsil, J.; Harnwong, B.; Santaweesuk, A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: A randomized double-blinded placebo-controlled study. Asia Pac. J. Clin. Nutr. 2012, 21, 12–21. [Google Scholar] [PubMed]
  53. Zhao, L.; Hu, F.X. α-Lipoic acid treatment of aged type 2 diabetes mellitus complicated with acute cerebral infarction. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 3715–3719. [Google Scholar] [PubMed]
  54. Saboori, S.; Falahi, E.; Eslampour, E.; Zeinali Khosroshahi, M.; Yousefi Rad, E. Effects of alpha-lipoic acid supplementation on C-reactive protein level: A systematic review and meta-analysis of randomized controlled clinical trials. Nutr. Metab. Cardiovasc. Dis. 2018, 28, 779–786. [Google Scholar] [CrossRef]
  55. Shinto, L.; Quinn, J.; Montine, T.; Dodge, H.H.; Woodward, W.; Baldauf-Wagner, S.; Waichunas, D.; Bumgarner, L.; Bourdette, D.; Silbert, L.; et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J. Alzheimers Dis. 2014, 38, 111–120. [Google Scholar] [CrossRef]
  56. Parisi, V.; Centofanti, M.; Gandolfi, S.; Marangoni, D.; Rossetti, L.; Tanga, L.; Tardini, M.; Traina, S.; Ungaro, N.; Vetrugno, M. Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma. J. Glaucoma 2014, 23, 391–404. [Google Scholar] [CrossRef]
  57. Plioplys, A.V.; Plioplys, A. Amantadine and L-carnitine treatment of chronic fatigue syndrome. Neuropsychobiology 1997, 35, 16–23. [Google Scholar] [CrossRef]
  58. Castro-Marrero, J.; Cordero, M.D.; Segundo, M.J.; Sáez-Francàs, N.; Calvo, N.; Román-Malo, L.; Aliste, L.; Fernández de Sevilla, T.; Alegre, J. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid. Redox Signal. 2015, 22, 679–685. [Google Scholar] [CrossRef]
  59. Stough, C.; Nankivell, M.; Camfield, D.A.; Perry, N.L.; Pipingas, A.; Macpherson, H.; Wesnes, K.; Ou, R.; Hare, D.; de Haan, J.Y.; et al. CoQ10 and cognition: A review and study protocol for a 90-day randomized controlled trial investigating the cognitive effects of ubiquinol in the healthy elderly. Front. Aging Neurosci. 2019, 11, 103. [Google Scholar] [CrossRef]
  60. Cordero, M.D.; Cano-García, F.J.; Alcocer-Gómez, E.; de Miguel, M.; Sánchez-Alcázar, J.A. Oxidative stress correlates with headache symptoms in fibromyalgia: Coenzyme Q10 effect on clinical improvement. PLoS ONE 2012, 7, e35677. [Google Scholar] [CrossRef]
  61. Bock, E.; Schneeweiss, J. A contribution to the therapy of neuropathia diabetica. Munch. Med. Wochenschr. 1959, 101, 1911–1912. [Google Scholar]
  62. Packer, L. Antioxidant properties of lipoic acid and its therapeutic effects in prevention of diabetes complications and cataracts. Ann. N. Y. Acad. Sci. 1994, 738, 257–264. [Google Scholar] [CrossRef] [PubMed]
  63. Packer, L.; Cadenas, E. Lipoic acid: Energy metabolism and redox regulation of transcription and cell signaling. J. Clin. Biochem. Nutr. 2011, 48, 26–32. [Google Scholar] [CrossRef] [PubMed]
  64. Hosseini, A.; Abdollahi, M. Diabetic neuropathy and oxidative stress: Therapeutic perspectives. Oxid. Med. Cell. Longev. 2013, 2013, 168039. [Google Scholar] [CrossRef] [PubMed]
  65. German Drug Index. 1994. Available online: http://www.gbe-bund.de (accessed on 20 August 2020).
  66. Galasko, D.R.; Peskind, E.; Clark, C.M.; Quinn, J.F.; Ringman, J.M.; Jicha, G.A.; Cotman, C.; Cottrell, B.; Montine, T.J.; Thomas, R.G.; et al. Antioxidants for Alzheimer disease: A randomized clinical trial with cerebrospinal fluid biomarker measures. Arch. Neurol. 2012, 69, 836–841. [Google Scholar] [CrossRef] [PubMed]
  67. Sanoobar, M.; Eghtesadi, S.; Azimi, A.; Khalili, M.; Khodadadi, B.; Jazayeri, S.; Gohari, M.R.; Aryaeian, N. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: A double blind, placebo, controlled randomized clinical trial. Nutr. Neurosci. 2014, 18, 169–176. [Google Scholar] [CrossRef] [PubMed]
  68. Pistone, G.; Marino, A.; Leotta, C.; dell’Arte, S.; Finocchiaro, G.; Malaguarnera, M. Levocarnitine administration in elderly subjects with rapid muscle fatigue: Effect on body composition, lipid profile and fatigue. Drugs Aging 2003, 20, 761–767. [Google Scholar] [CrossRef]
  69. Kuratsune, H.; Yamaguti, K.; Lindh, G.; Evengård, B.; Hagberg, G.; Matsumura, K.; Iwase, M.; Onoe, H.; Takahashi, M.; Machii, T.; et al. Brain regions involved in fatigue sensation: Reduced acetylcarnitine uptake into the brain. Neuroimage 2002, 17, 1256–1265. [Google Scholar] [CrossRef]
  70. Maes, M.; Mihaylova, I.; Kubera, M.; Uytterhoeven, M.; Vrydags, N.; Bosmans, E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol. Lett. 2009, 30, 470–476. [Google Scholar]
  71. Tiano, L.; Padella, L.; Santoro, L.; Carnevali, P.; Principi, F.; Brugè, F.; Gabrielli, O.; Littarru, G.P. Prolonged coenzyme Q10 treatment in Down syndrome patients: Effect on DNA oxidation. Neurobiol. Aging 2012, 33, 626.e1–626.e8. [Google Scholar] [CrossRef]
  72. Larsen, E.L.; Padella, L.; Bergholdt, H.K.M.; Henriksen, T.; Santoro, L.; Gabrielli, O.; Enghusen Poulsen, H.; Littarru, G.P.; Orlando, P.; Tiano, L. The effect of long-term treatment with coenzyme Q10 on nucleic acid modifications by oxidation in children with Down syndrome. Neurobiol. Aging 2018, 67, 159–161. [Google Scholar] [CrossRef] [PubMed]
  73. Rodriguez, M.C.; MacDonald, J.R.; Mahoney, D.J.; Parise, G.; Beal, M.F.; Tarnopolsky, M.A. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 2007, 35, 235–242. [Google Scholar] [CrossRef] [PubMed]
  74. Glover, E.I.; Martin, J.; Maher, A.; Thornhill, R.E.; Moran, G.R.; Tarnopolsky, M.A. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve 2010, 42, 739–748. [Google Scholar] [CrossRef] [PubMed]
  75. Bae, S.C.; Jung, W.J.; Lee, E.J.; Yu, R.; Sung, M.K. Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients. J. Am. Coll. Nutr. 2009, 28, 56–62. [Google Scholar] [CrossRef]
  76. Storch, A.; Jost, W.H.; Vieregge, P.; Spiegel, J.; Greulich, W.; Durner, J.; Müller, T.; Kupsch, A.; Henningsen, H.; Oertel, W.H.; et al. German Coenzyme Q(10) Study Group. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Arch. Neurol. 2007, 64, 938–944. [Google Scholar] [CrossRef]
  77. Parvanova, A.; Trillini, M.; Podestà, M.A.; Iliev, I.P.; Aparicio, C.; Perna, A.; Peraro, F.; Rubis, N.; Gaspari, F.; Cannata, A.; et al. Blood pressure and metabolic effects of acetyl-l-carnitine in Type 2 Diabetes: DIABASI randomized controlled trial. J. Endocr. Soc. 2018, 2, 420–436. [Google Scholar] [CrossRef]
  78. Hoppe, U.; Bergemann, J.; Diembeck, W.; Ennen, J.; Gohla, S.; Harris, I.; Jacob, J.; Kielholz, J.; Mei, W.; Pollet, D.; et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 1999, 9, 371–378. [Google Scholar] [CrossRef]
  79. Ames, B.N. A role for supplements in optimizing health: The metabolic tune-up. Arch. Biochem. Biophys. 2004, 423, 227–234. [Google Scholar] [CrossRef]
  80. Zhou, Z.; Liu, C.; Wan, X.; Fang, L. Development of a w/o emulsion using ionic liquid strategy for transdermal delivery of anti-aging component α-lipoic acid: Mechanism of different ionic liquids on skin retention and efficacy evaluation. Eur. J. Pharm. Sci. 2020, 141, 105042. [Google Scholar] [CrossRef]
  81. El-Leithy, E.S.; Makky, A.M.; Khattab, A.M.; Hussein, D.G. Optimization of nutraceutical coenzyme Q10 nanoemulsion with improved skin permeability and anti-wrinkle efficiency. Drug Dev. Ind. Pharm. 2018, 44, 316–328. [Google Scholar] [CrossRef]
  82. Thom, E. A randomized, double-blind, placebo-controlled study on the clinical efficacy of oral treatment with DermaVite on ageing symptoms of the skin. J. Int. Med. Res. 2005, 33, 267–272. [Google Scholar] [CrossRef] [PubMed]
  83. Beitner, H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin. Br. J. Dermatol. 2003, 149, 841–849. [Google Scholar] [CrossRef] [PubMed]
  84. Žmitek, K.; Pogačnik, T.; Mervic, L.; Žmitek, J.; Pravst, I. The effect of dietary intake of coenzyme Q10 on skin parameters and condition: Results of a randomised, placebo-controlled, double-blind study. Biofactors 2017, 43, 132–140. [Google Scholar] [CrossRef] [PubMed]
  85. Knott, A.; Achterberg, V.; Smuda, C.; Mielke, H.; Sperling, G.; Dunckelmann, K.; Vogelsang, A.; Krüger, A.; Schwengler, H.; Behtash, M.; et al. Topical treatment with coenzyme Q10-containing formulas improves skin’s Q10 level and provides antioxidative effects. Biofactors 2015, 41, 383–390. [Google Scholar] [CrossRef] [PubMed]
  86. Czajka, A.; Kania, E.M.; Genovese, L.; Corbo, A.; Merone, G.; Luci, C.; Sibilla, S. Daily oral supplementation with collagen peptides combined with vitamins and other bioactive compounds improves skin elasticity and has a beneficial effect on joint and general wellbeing. Nutr. Res. 2018, 57, 97–108. [Google Scholar] [CrossRef]
  87. Kamenisch, Y.; Berneburg, M. Progeroid syndromes and UV-induced oxidative DNA damage. J. Investig. Dermatol. Symp. Proc. 2009, 14, 8–14. [Google Scholar] [CrossRef]
  88. Davis, T.; Wyllie, F.S.; Rokicki, M.J.; Bagley, M.C.; Kipling, D. The role of cellular senescence in Werner syndrome: Toward therapeutic intervention in human premature aging. Ann. N. Y. Acad. Sci. 2007, 1100, 455–469. [Google Scholar] [CrossRef]
  89. Isaev, N.K.; Genrikhs, E.E.; Oborina, M.V.; Stelmashook, E.V. Accelerated aging and aging process in the brain. Rev. Neurosci. 2018, 29, 233–240. [Google Scholar] [CrossRef]
  90. Rivera-Torres, J.; Acín-Perez, R.; Cabezas-Sánchez, P.; Osorio, F.G.; Gonzalez-Gómez, C.; Megias, D.; Cámara, C.; López-Otín, C.; Enríquez, J.A.; Luque-García, J.L.; et al. Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. J. Proteom. 2013, 91, 466–477. [Google Scholar] [CrossRef]
  91. Li, B.; Iglesias-Pedraz, J.M.; Chen, L.Y.; Yin, F.; Cadenas, E.; Reddy, S.; Comai, L. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging Cell 2014, 13, 367–378. [Google Scholar] [CrossRef]
  92. Lloret, A.; Calzone, R.; Dunster, C.; Manini, P.; d’Ischia, M.; Degan, P.; Kelly, F.J.; Pallardó, F.V.; Zatterale, A.; Pagano, G. Different patterns of in vivo prooxidant states in a set of cancer- or ageing-related genetic diseases. Free. Radic. Biol. Med. 2008, 44, 495–503. [Google Scholar] [CrossRef] [PubMed]
  93. Lebel, M.; Massip, L.; Garand, C.; Thorin, E. Ascorbate improves metabolic abnormalities in Wrn mutant mice but not the free radical scavenger catechin. Ann. N. Y. Acad. Sci. 2010, 1197, 40–44. [Google Scholar] [CrossRef]
  94. Flores-Alvarado, L.J.; Ramirez-Garcia, S.A.; Núñez-Reveles, N.Y. The metabolic and molecular bases of Cockayne syndrome. Rev. Investig. Clin. 2010, 62, 480–490. [Google Scholar]
  95. Bersu, E.T.; Ahmad, F.J.; Schwei, M.J.; Baas, P.W. Cytoplasmic abnormalities in cultured cerebellar neurons from the trisomy 16 mouse. Brain Res. Dev. Brain Res. 1998, 109, 115–120. [Google Scholar] [CrossRef]
  96. Druzhyna, N.; Nair, R.G.; LeDoux, S.P.; Wilson, G.L. Defective repair of oxidative damage in mitochondrial DNA in Down’s syndrome. Mutat. Res. 1998, 409, 81–89. [Google Scholar] [CrossRef] [PubMed]
  97. Schuchmann, S.; Heinemann, U. Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: A model of Down’s syndrome. Free. Radic. Biol. Med. 2000, 28, 235–250. [Google Scholar] [CrossRef]
  98. Bambrick, L.L.; Fiskum, G. Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res. 2008, 1188, 9–16. [Google Scholar] [CrossRef]
  99. Conti, A.; Fabbrini, F.; D’Agostino, P.; Negri, R.; Greco, D.; Genesio, R.; D’Armiento, M.; Olla, C.; Paladini, D.; Zannini, M.; et al. Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genom. 2007, 8, 268. [Google Scholar] [CrossRef]
  100. Valenti, D.; Braidy, N.; De Rasmo, D.; Signorile, A.; Rossi, L.; Atanasov, A.G.; Volpicella, M.; Henrion-Caude, A.; Nabavi, S.M.; Vacca, R.A. Mitochondria as pharmacological targets in Down syndrome. Free. Radic. Biol. Med. 2018, 114, 69–83. [Google Scholar] [CrossRef]
  101. Zhang, X.; Biswas, L.; Tohari, A.M.; Reilly, J.; Tiano, L.; Shu, X. Coenzyme Q10 as a therapeutic candidate for treating inherited photoreceptor degeneration. Neural Regen. Res. 2017, 12, 1979–1981. [Google Scholar] [CrossRef]
  102. Zhang, X.; Tohari, A.M.; Marcheggiani, F.; Zhou, X.; Reilly, J.; Tiano, L.; Shu, X. Therapeutic potential of co-enzyme Q10 in retinal diseases. Curr. Med. Chem. 2017, 24, 4329–4339. [Google Scholar] [CrossRef]
  103. Noh, Y.H.; Kim, K.Y.; Shim, M.S.; Choi, S.H.; Choi, S.; Ellisman, M.H.; Weinreb, R.N.; Perkins, G.A.; Ju, W.K. Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell. Death Dis. 2013, 4, e820. [Google Scholar] [CrossRef]
  104. Nucci, C.; Tartaglione, R.; Cerulli, A.; Mancino, R.; Spanò, A.; Cavaliere, F.; Rombolà, L.; Bagetta, G.; Corasaniti, M.T.; Morrone, L.A. Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int. Rev. Neurobiol. 2007, 82, 397–406. [Google Scholar] [CrossRef] [PubMed]
  105. Russo, R.; Cavaliere, F.; Rombolà, L.; Gliozzi, M.; Cerulli, A.; Nucci, C.; Fazzi, E.; Bagetta, G.; Corasaniti, M.T.; Morrone, L.A. Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection. Prog. Brain Res. 2008, 173, 575–582. [Google Scholar] [CrossRef] [PubMed]
  106. Lee, D.; Shim, M.S.; Kim, K.Y.; Noh, Y.H.; Kim, H.; Kim, S.Y.; Weinreb, R.N.; Ju, W.K. Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Investig. Ophthalmol. Vis. Sci. 2014, 55, 993–1005. [Google Scholar] [CrossRef] [PubMed]
  107. Davis, B.M.; Tian, K.; Pahlitzsch, M.; Brenton, J.; Ravindran, N.; Butt, G.; Malaguarnera, G.; Normando, E.M.; Guom, L.; Cordeiro, M.F. Topical Coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion 2017, 36, 114–123. [Google Scholar] [CrossRef]
  108. Quaranta, L.; Riva, I.; Biagioli, E.; Rulli, E.; Rulli, E.; Poli, D.; Legramandi, L.; The CoQun® Study Group. Evaluating the effects of an ophthalmic solution of coenzyme Q10 and vitamin E in open-angle glaucoma patients: A study protocol. Adv. Ther. 2019, 36, 2506–2514. [Google Scholar] [CrossRef]
  109. Calandrella, N.; De Seta, C.; Scarsella, G.; Risuleo, G. Carnitine reduces the lipoperoxidative damage of the membrane and apoptosis after induction of cell stress in experimental glaucoma. Cell Death Dis. 2010, 1, 62. [Google Scholar] [CrossRef]
  110. Nebbioso, M.; Evangelista, M.; Librando, A.; Plateroti, A.M.; Pescosolido, N. Iatrogenic dry eye disease: An eledoisin/carnitine and osmolyte drops study. Biomed. Pharmacother. 2013, 67, 659–663. [Google Scholar] [CrossRef]
  111. Inman, D.M.; Lambert, W.S.; Calkins, D.J.; Horner, P.J. α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction. PLoS ONE 2013, 8, e65389. [Google Scholar] [CrossRef]
  112. Koriyama, Y.; Nakayama, Y.; Matsugo, S.; Kato, S. Protective effect of lipoic acid against oxidative stress is mediated by Keap1/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cell line. Brain Res. 2013, 1499, 145–157. [Google Scholar] [CrossRef] [PubMed]
  113. Ekinci, M.; Cagatay, H.H.; Ceylan, E.; Keles, S.; Koban, Y.; Gokce, G.; Huseyinoğlu, U.; Ozcan, E.; Oba, M.E. Reduction of conjunctival fibrosis after trabeculectomy using topical α-lipoic acid in rabbit eyes. J. Glaucoma 2014, 23, 372–379. [Google Scholar] [CrossRef]
  114. Scalbert, A.; Brennan, L.; Manach, C.; Andres-Lacueva, C.; Dragsted, L.O.; Draper, J.; Rappaport, S.M.; van der Hooft, J.J.J.; Wishart, D.S. The food metabolome: A window over dietary exposure. Am. J. Clin. Nutr. 2014, 99, 1286–1308. [Google Scholar] [CrossRef] [PubMed]
  115. Tang, W.H.; Hazen, S.L. The contributory role of gut microbiota in cardiovascular disease. J. Clin. Investig. 2014, 124, 4204–4211. [Google Scholar] [CrossRef] [PubMed]
  116. Griffin, J.L.; Wang, X.; Stanley, E. Does our gut microbiome predict cardiovascular risk? A review of the evidence from metabolomics. Circ. Cardiovasc. Genet. 2015, 8, 187–191. [Google Scholar] [CrossRef] [PubMed]
  117. Johnson, E.L.; Heaver, S.L.; Walters, W.A.; Ley, R.E. Microbiome and metabolic disease: Revisiting the bacterial phylum Bacteroidetes. J. Mol. Med. (Berl.) 2017, 95, 1–8. [Google Scholar] [CrossRef]
  118. Biagi, E.; Candela, M.; Turroni, S.; Garagnani, P.; Franceschi, C.; Brigidi, P. Ageing and gut microbes: Perspectives for health maintenance and longevity. Pharmacol. Res. 2013, 69, 11–20. [Google Scholar] [CrossRef]
  119. Hulme, H.; Meikle, L.M.; Strittmatter, N.; van der Hooft, J.J.J.; Swales, J.; Bragg, R.A.; Villar, V.H.; Ormsby, M.J.; Barnes, S.; Brown, S.L.; et al. Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication. Sci. Adv. 2020, 6, eaax6328. [Google Scholar] [CrossRef] [PubMed]
  120. Mamedov, I.; Zolkina, I.; Nikolaeva, E.; Glagovsky, P.; Sukhorukov, V. Carnitine insufficiency in children with inborn errors of metabolism: Prevalence and treatment efficacy. J. Pediatr. Endocrinol. Metab. 2015, 28, 1299–1304. [Google Scholar] [CrossRef]
  121. Vallance, H.D.; Koochin, A.; Branov, J.; Rosen-Heath, A.; Bosdet, T.; Wang, Z.; Hazen, S.L.; Horvath, G. Marked elevation in plasma trimethylamine-N-oxide (TMAO) in patients with mitochondrial disorders treated with oral l-carnitine. Mol. Genet. Metabol. Rep. 2018, 15, 130–133. [Google Scholar] [CrossRef]
  122. Miller, M.J.; Bostwick, B.L.; Kennedy, A.D.; Donti, T.R.; Sun, Q.; Sutton, V.R.; Elsea, S.H. Chronic oral L-carnitine supplementation drives marked plasma TMAO elevations in patients with organic acidemias despite dietary meat restrictions. JIMD Rep. 2016, 30, 39–44. [Google Scholar] [CrossRef] [PubMed]
  123. Ravcheev, D.A.; Thiele, I. Genomic analysis of the human gut microbiome suggests novel enzymes involved in quinone biosynthesis. Front. Microbiol. 2016, 7, 128. [Google Scholar] [CrossRef] [PubMed]
  124. Hernández-Camacho, J.D.; Bernier, M.; López-Lluch, G.; Navas, P. Coenzyme Q10 supplementation in aging and disease. Front. Physiol. 2018, 9, 44. [Google Scholar] [CrossRef] [PubMed]
  125. Fenn, K.; Strandwitz, P.; Stewart, E.J.; Dimise, E.; Rubin, S.; Gurubacharya, S.; Clardy, J.; Lewis, K. Quinones are growth factors for the human gut microbiota. Microbiome 2017, 5, 161. [Google Scholar] [CrossRef]
  126. Valdecantos, M.P.; Pérez-Matute, P.; Prieto-Hontoria, P.; Moreno-Aliaga, M.J.; Martínez, J.A. Impact of dietary lipoic acid supplementation on liver mitochondrial bioenergetics and oxidative status on normally fed Wistar rats. Int. J. Food Sci. Nutr. 2019, 70, 834–844. [Google Scholar] [CrossRef]
  127. Qiao, Y.; Sun, J.; Ding, Y.; Le, G.; Shi, Y. Alterations of the gut microbiota in high-fat diet mice is strongly linked to oxidative stress. Appl. Microbiol. Biotechnol. 2013, 97, 1689–1697. [Google Scholar] [CrossRef]
  128. Skulachev, V.P.; Anisimov, V.N.; Antonenko, Y.N.; Bakeeva, L.E.; Chernyak, B.V.; Erichev, V.P.; Filenko, O.F.; Kalinina, N.I.; Kapelko, V.I.; Kolosova, N.G.; et al. An attempt to prevent senescence: A mitochondrial approach. Biochim. Biophys. Acta (BBA)-Bioenerg. 2009, 1787, 437–461. [Google Scholar] [CrossRef]
  129. Lyakhovich, A.; Graifer, D. Mitochondria-mediated oxidative stress: Old target for new drugs. Curr. Med. Chem. 2015, 22, 3040–3053. [Google Scholar] [CrossRef]
  130. Vyssokikh, M.Y.; Holtze, S.; Averina, O.A.; Lyamzaev, K.G.; Panteleeva, A.A.; Marey, M.V.; Zinovkin, R.A.; Severin, F.F.; Skulachev, M.V.; Fasel, N.; et al. Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program. Proc. Natl. Acad. Sci. USA 2020, 117, 6491–6501. [Google Scholar] [CrossRef]
  131. Packer, L.; Kraemer, K.; Rimbach, G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 2001, 17, 888–895. [Google Scholar] [CrossRef]
  132. Kaikkonen, J.; Nyyssönen, K.; Porkkala-Sarataho, E.; Poulsen, H.E.; Metsä-Keteläc, T.; Hayn, M.; Salonen, R.; Salonen, J.T. Effect of oral coenzyme Q10 supplementation on the oxidation resistance of human VLDL+LDL fraction: Absorption and antioxidative properties of oil and granule-based preparations. Free Radic. Biol. Med. 1997, 22, 1195–1202. [Google Scholar] [CrossRef] [PubMed]
  133. Terruzzi, I.; Montesano, A.; Senesi, P.; Villa, I.; Ferraretto, A.; Bottani, M.; Vacante, F.; Spinello, A.; Bolamperti, S.; Luzi, L.; et al. L-Carnitine reduces oxidative stress and promotes cells differentiation and bone matrix proteins expression in human osteoblast-like cells. BioMed Res. Int. 2019, 2019, 5678548. [Google Scholar] [CrossRef] [PubMed]
  134. Nicassio, L.; Fracasso, F.; Sirago, G.; Musicco, C.; Picca, A.; Marzetti, E.; Calvani, R.; Cantatore, P.; Gadaleta, M.N.; Pesce, V. Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats. Exp. Gerontol. 2017, 98, 99–109. [Google Scholar] [CrossRef] [PubMed]
  135. Nilsson, M.I.; Tarnopolsky, M.A. Mitochondria and aging—The role of exercise as a countermeasure. Biology (Basel) 2019, 8, 40. [Google Scholar] [CrossRef]
  136. Tarnopolsky, M.A. The mitochondrial cocktail: Rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv. Drug Deliv. Rev. 2008, 60, 1561–1567. [Google Scholar] [CrossRef]
  137. Pagano, G.; Talamanca, A.A.; Castello, G.; Cordero, M.D.; d’Ischia, M.; Gadaleta, M.N.; Pallardó, F.V.; Petrović, S.; Tiano, L.; Zatterale, A. Current experience in testing mitochondrial nutrients in disorders featuring oxidative stress and mitochondrial dysfunction: Rational design of chemoprevention trials. Int. J. Mol. Sci. 2014, 15, 20169–20208. [Google Scholar] [CrossRef]
  138. Moura, F.A.; de Andrade, K.Q.; dos Santos, J.C.; Goulart, M.O. Lipoic Acid: Its antioxidant and anti-inflammatory role and clinical applications. Curr. Top. Med. Chem. 2015, 15, 458–483. [Google Scholar] [CrossRef]
  139. Moura, F.A.; de Andrade, K.Q.; de Araújo, O.R.; Nunes-Souza, V.; Santos, J.C.; Rabelo, L.A.; Goulart, M.O. Colonic and hepatic modulation by lipoic acid and/or n-acetylcysteine supplementation in mild ulcerative colitis induced by dextran sodium sulfate in rats. Oxidative Med. Cell. Longev. 2016, 2016, 4047362. [Google Scholar] [CrossRef]
  140. Molinari, C.; Morsanuto, V.; Polli, S.; Uberti, F. Cooperative effects of Q10, vitamin D3, and L-arginine on cardiac and endothelial cells. J. Vasc. Res. 2018, 55, 47–60. [Google Scholar] [CrossRef]
  141. Molinari, C.; Morsanuto, V.; Ghirlanda, S.; Ruga, S.; Notte, F.; Gaetano, L.; Uberti, F. Role of combined lipoic acid and vitamin D3 on astrocytes as a way to prevent brain ageing by induced oxidative stress and iron accumulation. Oxidative Med. Cell. Longev. 2019, 2019, 2843121. [Google Scholar] [CrossRef]
  142. Pérez-Sánchez, C.; Aguirre, M.Á.; Ruiz-Limón, P.; Ábalos-Aguilera, M.C.; Jiménez-Gómez, Y.; Arias-de la Rosa, I.; Rodriguez-Ariza, A.; Fernández-Del Río, L.; González-Reyes, J.A.; Segui, P.; et al. Ubiquinol effects on antiphospholipid syndrome prothrombotic profile: A randomized, placebo-controlled trial. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 1923–1932. [Google Scholar] [CrossRef] [PubMed]
  143. Gutierrez-Mariscal, F.M.; Yubero-Serrano, E.M.; Villalba, J.M.; Lopez-Miranda, J. Coenzyme Q: From bench to clinic in aging diseases, a translational review. Crit. Rev. Food. Sci. Nutr. 2019, 59, 2240–2257. [Google Scholar] [CrossRef] [PubMed]
  144. Niklowitz, P.; Onur, S.; Fischer, A.; Laudes, M.; Palussen, M.; Menke, T.; Döring, F. Coenzyme Q10 serum concentration and redox status in European adults: Influence of age, sex, and lipoprotein concentration. J. Clin. Biochem. Nutr. 2016, 58, 240–245. [Google Scholar] [CrossRef] [PubMed]
  145. Vasilopoulos, T.; Kotwal, A.; Huisingh-Scheetz, M.J.; Waite, L.J.; McClintock, M.K.; Dale, W. Comorbidity and chronic conditions in the National Social Life, Health and Aging Project (NSHAP), Wave 2. J. Gerontol. B Psychol. Sci. Soc. Sci. 2014, 69 (Suppl. 2), S154–S165. [Google Scholar] [CrossRef]
Table 1. Main effects of mitochondrial cofactors (ALA, CoQ10, and CARN) in aging-related animal and in vitro models.
Table 1. Main effects of mitochondrial cofactors (ALA, CoQ10, and CARN) in aging-related animal and in vitro models.
ModelsCofactorReported EffectsReferences
Aged and young ratsALAregulation of hepatic genes associated with lipid and energy metabolism and circadian rhythm [38]
Aged and young ratsALA + other supplementsdecreased IL-1β, IL-6, and TNF-α levels[39]
Canine model of humanALA + otherimprovement in spatial attention[40]
Rat diabetic neuropathyALA + CoQ10prevented apoptosis and neuron degeneration regulated expression of caspase 3 and induced ATP[20]
Rat diabetic neuropathyALA or CoQ10CoQ10, not ALA, improved nerve conductivity[21]
Aged dogsALA + CARNimproved social, cognitive, and physical activity[22]
Rat pancreatic cellsALAsuppressed p38 and p53 genes, reducing ROS formation and enhancing thiol levels[41]
Rat embryonic fibroblastsALAdecreased ROS formation and inflammation, and affected cell division[42]
Human cells from skin biopsiesCoQ10improved electron transport chain and its antioxidant potential[43]
Human dermal fibroblastsCoQ10CoQ10 decrease lowers mitochondrial permeability and results in bioenergetic dysfunction[44]
Table 2. Selected clinical studies testing the effects of ALA, CoQ10, or (acyl-) CARN in aging-related disorders.
Table 2. Selected clinical studies testing the effects of ALA, CoQ10, or (acyl-) CARN in aging-related disorders.
DiseasesCofactorReported EffectsReferences
1.Cardiovascular Mortality
Cardiovascular mortalityCoQ10 + SeDecreased fibrosis[45]
Chronic heart failureCoQ10Decreased morbidity and mortality[46]
Chronic heart failureCoQ10 + creatineIncreased peak oxygen consumption[47]
CoQ10 + supplementsImproved left ventricular function, levels of pro-inflammatory cytokines, and quality-of-life[48]
Coronary artery diseaseCoQ10Increases antioxidant enzyme activity [49]
ALA + acetyl-CARNImproved regulation of blood pressure and vascular tone[18]
Increased cardiovascular riskacetyl-CARNAmeliorating hypertension and insulin resistance[50]
Peripheral artery diseasepropionyl-CARNDecreased plasma malondialdehyde and 4-hydroxynonenal concentrations, and the plasma nitrite/nitrate ratio[51]
2. Type 2 Diabetes Mellitus
polarized light +Decreased lactate dehydrogenase activity[19]
ALA + CoQ10 +Decreased plasma lipid peroxides
α-tocopherol
ALAImproved glycemic status and lipid peroxidation[52]
ALADecreased oxidative stress, blood glucose, and lipid levels[53]
ALAImproved diabetic polyneuropathy[54]
3. Miscellaneous Disorders
Alzheimer diseaseALA + ω-3 fatty acidsImproved mental and cognitive state[55]
GlaucomaALADecreased retinal ganglion cell death and dysfunction[56]
Multiple sclerosisCoQ10Improved inflammatory markers[57]
Elderly rapid muscle fatigueCARNReduction in total fat mass, increase in total muscle mass, and favorable effects on fatigue and serum lipids[58]
Age-related cognitive declineCoQ10On-going study of cardiovascular function, oxidative stress, liver function, and mood[59]
FibromyalgiaCoQ10Significant improvement in clinical and headache symptoms[60]
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