Alessandra Caracciolo, Chiara Baroni
INTRODUCTION
Mitochondrial dysfunction and oxidative stress are recognized as fundamental driving mechanisms of aging. The aging process results in an accelerated decline of functional performance including a decline in physiological function and reduced physical activity. The exact mechanisms that cause this functional decline are not fully understood; however, the mitochondrial free radical theory of aging has gained strong support.
As an irreversible physiological process affecting all living organisms, aging is a rather complex physiological phenomenon with several theories being elaborated to help understand its origin. Among such theories, the “evolutionary theory of aging” envisions that human longevity is at the cost of impaired reproductive success.
An advanced vision of this theory, namely “antagonistic pleiotropic theory of aging” favours genes conferring short-term benefits at the expense of quality of later life.
The “free radical theory of aging”, which favours accumulation of oxidant insult leading to ultimate senescence, paved the way to the modern “mitochondrial theory of aging” , or the newly revised concept of “mitochondrial lisosomal axis theory of aging” . Age related increases in oxidative stress could account for aging-induced organ damage.
The “mitochondrial theory of aging” , has gained convincing support on the concept of accumulation of somatic mutations of mitochondrial DNA that may lead to loss of mitochondrial function.
The Emerging Role of Coenzyme Q-10 in Aging, Neurodegeneration, Cardiovascular Disease, Cancer and Diabetes Mellitus
With advancing age, oxidative damage accumulates in individual cells; eventually some cells reach the point at which the mitochondrial energy generation system is seriously impaired.
When the impairment of mitochondrial bioenergetics occurs in a significant number of cells within a tissue, the function of the tissue is compromised and consequently contributes to age-related pathologies .
Since mitochondrial dysfunction and aging are mediated by a number of biochemical pathways, interventions that target multiple pathways through combination therapies may be more efficacious than therapies that only target one pathway. Nutritional based interventions are becoming more popular among consumers and specific combinations of nutritional interventions may effectively bypass electron transport chain defects, provide alternative energy sources, and act as antioxidants as well . Thus, specific nutritional mixtures may have the potential to reduce oxidative stress, prevent mitochondrial functional decline, and preserve performance .
It was studied the potential anti-aging benefits of a Q-ter® based nutritional mixture (commercially known as Eufortyn®) mainly containing the following compounds: terclatred coenzyme Q10 (Qter®), creatine and a standardized ginseng extract. These compounds may act in a synergistic manner when combined.
Beneficial Effects of a Q-ter® Based Nutritional Mixture on Functional Performance, Mitochondrial Function, and Oxidative Stress in Rats
Components of EUFORTYN®
COENZYME Q10
Structure and functions :
Coenzyme Q, also known as ubiquinone, ubidecarenone, is ubiquitous in nature and is widely distributed in plants, animals and microorganism. Coenzyme Q homologs are classified based on their isoprenoid units (Q-n). Q refers to the quinine chemical group; the number, <>Q-n, refers to the amount of isoprenoid units attached to the 6-positions on the benzoquinone ring of the coenzyme Q moiety.
The image below has three isoprenoid units and would be called Q3.
Coenzyme Q10 is a 1,4-benzoquinone .
CoQ10 is found in the membranes of many organelles. Since its primary function in cells is in generating energy, the highest concentration is found on the inner membrane of the mitochondrion . Some other organelles that contain CoQ10 include endoplasmic reticulum, peroxisomes, lysosomes, and vesicles.
CoQ10 is fat-soluble and is therefore mobile in cellular membranes; it plays a unique role in the electron transport chain (ETC). In the inner mitochondrial membrane, electrons from NADH and succinate pass through the ETC to the oxygen, which is then reduced to water. The transfer of electrons through ETC results in the pumping of H+ across the membrane, creating a proton gradient across the membrane, which is used by ATP synthase (located on the membrane) to generate ATP. CoQ10 functions as an electron carrier from enzyme complex I and enzyme complex II to complex III in this process. This is crucial in the process, since no other molecule can perform this function. Thus, CoQ10 functions in every cell of the body to synthesize energy .
The antioxidant nature of CoQ10 derives from its energy carrier function. As an energy carrier, the CoQ10 molecule is continually going through an oxidation-reduction cycle. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced form, the CoQ10 molecule holds electrons rather loosely, so this CoQ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant.
CoQ10 inhibits lipid peroxidation by preventing the production of lipid peroxyl radicals (LOO).
Moreover, CoQ10 reduces the initial perferryl radical and singlet oxygen , with concomitant formation of ubisemiquinone and H2O2. This quenching of the initiating perferryl radicals, which prevent propagation of lipid peroxidation, protects not only lipids, but also proteins from oxidation.
In addition, the reduced form of CoQ effectively regenerates vitamin E from the a-tocopheroxyl radical, thereby interfering with the propagation step.
Furthermore, during oxidative stress, interaction of H2O2 with metal ions bound to DNA generates hydroxyl radicals and CoQ efficiently prevents the oxidation of bases, in particular, in mitochondrial DNA. In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation .
The Emerging Role of Coenzyme Q-10 in Aging, Neurodegeneration, Cardiovascular Disease, Cancer and Diabetes Mellitus
Wikipedia, Coenzima Q
Wikipedia, Coenzyme CoQ10 .
Also CoQ10 is recognized as a modulator of mitochondrial permeability transition, which is associated with the mitochondria mediated apoptosis and cell death. The opening of permeability transition pores (PTP) in the inner mitochondrial membrane can lead to mitochondrial swelling and dysfunction, causing cell death. CoQ10 appears to exert its protective effect by inhibiting the mitochondrial PTP opening.
Protective effects of CoQ10 against oxidative stress and mitochondrial dysfunction have been demonstrated in several in vitro and in vivo models. The capability of CoQ10 to trigger mitochondrial function is thus grounded on sound biochemical evidence. However, its use in humans as a therapeutic agent proved unsatisfactory, most likely because of its poor solubility in water, its limited solubility in lipids, and its relatively high molecular weight (863 g/mol), all result in poor oral bioavailability .
Recently, a mechano-physical procedure called terclatration was developed, whereby CoQ10 is rendered highly water soluble without chemical modification of the moiety. The resultant multicomposite, Q-ter®, can be shown to be 3 to 5 fold more bioavailable in humans, as compared to native CoQ10. In the terclatrate, Q-ter®, CoQ10 stands in a 1:9 ratio with a pharmaceutically inactive matrix.
CREATINE
Creatine supplementation was initially used as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. It has been also reported to act as an antioxidant against reactive species ions, e.g. superoxide anions (ON22) and peroxynitrite (OONO2) , and enhance expression of myogenin and other myogenic regulatory factors that regulate myosin heavy chain expression as well. However, creatine supplementation has recently been recognized as a potential intervention to various neurodegenerative disorders targeting bioenergetic failure observed in these conditions.
For example, creatine has been found to be useful in buffering intracellular energy stores and reducing the cellular energy deficit by improving mitochondrial function and to be effective in attenuating the age-related decline in mitochondrial function . Creatine has also been shown to inhibit mitochondrial permeability transition and enhance mitochondrial function in stimulating mitochondrial energy production via creatine-stimulated respiration and the adenine nucleotide translocase .
GINSENG
Ginseng is a potent antioxidant and has been extensively used to reduce oxidative damage and prevent age-related diseases . Ginsenosides, the major active ingredients of ginseng, are steroidal saponins with different sugar moieties. To date more than 30 types of ginsenosides have been isolated and identified. In particular, ginsenoside Rb1 and Rg1 are considered to be the most effective compounds in ginseng extracts. Various studies provide compelling evidence that ginseng extracts possess mitochondria protective capacity by inhibiting mitochondrial swelling and preserving mitochondrial membrane integrity in rodents .
Beneficial Effects of a Q-ter® Based Nutritional Mixture on Functional Performance, Mitochondrial Function, and Oxidative Stress in Rats
THE STUDY
In the study of Beneficial Effects of a Q-ter® Based Nutritional Mixture on Functional Performance, Mitochondrial Function, and Oxidative Stress in Rats, the potential effects of a nutritional mixture mainly containing Q-terH, creatine and a Rg1 titrated ginseng extract (the mixture is commercially known as EufortynH) is evaluated, using Fischer 344 x Brown Norway rats on health span .
Specifically, it’s examined muscle mitochondrial permeability transition pore opening and protein carbonylation as well as muscle cellular nucleic acid oxidation and functional outcome to explore the effectiveness of EufortynH on anti-aging aspects.
Animals and experimental procedures
Forty-seven Fischer 344 x Brown Norway male rats were housed individually in a temperature and light-controlled environment. The treatment started after acclimation by adding Eufortyn® compounded in a highly palletable food pellet for four weeks. The main ingredients of the commercially available nutritional mixture are CoQ10 (5.3 mg/g of dry powder), creatine (56.7 mg/g) and ginseng (21.7 mg/g) . CoQ10 in the mixture is present as the terclatrate, Q-ter®.
Each rat received approximately one supplementation pellet (Eufortyn® or control) every day and pellet size was adjusted daily according to the body weight of individual animal to ensure that the rat received proper dose of Eufortyn®.
The following daily dosage: 10mg/kg of terclatrated CoQ10, 106.25 mg/kg of creatine, and 40.63 mg/kg of ginseng extract were administered for six weeks.
Parameters measured and evaluated
- Grip strength
- Food intake (Food intake increased with age)
- Body weight
- Muscle mass
- Mitochondrial calcium retention capacity in muscle SSM and IFM (two distinct populations of mitochondria exist. Subsarcolemmal mitochondria (SSM) are located beneath the plasma membrane, while interfibrillar mitochondria (IFM) are found in parallel rows between the myofibrils. The calcium retention capacity of the SSM decreased significantly with age, while there are no age-associated changes in the IFM).
- Protein carbonyl levels in muscle SSM and IFM (The levels of protein carbonyls significantly increased in SSM during the aging process)
- Nucleic acid oxidative damage in gastrocnemius muscle
- Total urine antioxidant power
- Ferric reducing antioxidant power in plasma and muscle tissue
Discussion
The purpose of this study was to assess the effects of Eufortyn® supplementation on oxidative stress, mitochondrial function and physical performance . It's demonstrated that Eufortyn® significantly attenuates declining physical performance and improves Ca2+ retention capacity of SSM in 21 -month-old rats. Moreover, the age-related increase in cellular RNA oxidation and protein oxidation in SSM was significantly ameliorated by Eufortyn®. These findings suggest that Eufortyn® may improve homeostatic regulation of cellular and mitochondrial oxidative stress, mitochondrial function and physical performance if initiated at early middle age .
Functional aging and grip strength : the consequences of the aging process in skeletal muscles are characterized by a decline in physiological function and a loss of muscle strength, a condition incapable of performing strenuous physical work.
The primary outcome variable of this study was grip strength. In both humans and rodents, grip strength is one of most representative measurements in functional aging. It was studied that aged rats with advanced muscle atrophy exhibited reduced grip strength. In the present study, muscle mass and grip strength decreased significantly with age in control groups.
Eufortyn® supplementation significantly ameliorated the decline in grip strength in 21-month- old rats, however, did not have a significant effect when initiated in 29-month-old rats . This suggests there may be a critical time period during which this nutritional combination is effective and they may no longer be beneficial after a threshold is reached . (Another possibility is that the time period of Eufortyn® supplementation and the dosage used were not sufficient to achieve this goal in late middle aged animals).
Mitochondrial PTP opening in the gastrocnemius muscle : Mitochondrial oxidative stress and apoptotic cell death are being increasingly recognized as fundamental driving mechanisms of aging, especially in post-mitotic tissues. The switch to a cell death process can be mediated by opening of the mitochondrial PTP, causing collapse of the membrane potential and swelling. Therefore, inhibition of pore opening is an effective and promising strategy to modulate the aging process.
This study showed that Eufortyn® efficiently mitigated the susceptibility of SSM to Ca2+ induced mitochondrial PTP opening and improved SSM function in 21-month-old rats. It is remarkable that both grip strength and mitochondrial Ca2+ handling capacity increased by Eufortyn® supplementation in 21-month-old rats.
There was also a significant age-associated decrease in mitochondrial Ca2+ retention capacity in SSM, but not in IFM, where the IFM Ca2+ retention capacity remained fairly constant within all age cohorts. The two subpopulations differ in function measurements.
Oxidative stress in the gastrocnemius muscle : Protein carbonyl content is one of the most widely used oxidative markers and increased levels of protein carbonyls have been reported in patients with aging. Carbonyl levels in skeletal muscles are associated with reactive oxygen species produced in mitochondria. Infact, the results of this study indicate that the SSM protein carbonyl levels was significantly elevated in 29-month-old rat gastrocnemius muscles and Eufortyn® supplementation remarkably ameliorated the increase in SSM protein carbonyl levels.
Accordingly, oxidative damage to DNA and RNA in the gastrocnemius muscle was assessed as their oxidation products simultaneously. Muscle RNA oxidative damage product has the tendency to increase at 29 month of age. The functional consequences of increased RNA oxidative damage in skeletal muscles could be serious and even causative to muscle contraction and atrophy. Therefore, the decline in grip force in 29-month-old control rats may be related to the increased SSM protein and RNA oxidation levels in the gastrocnemius muscle.
Total urine antioxidant power and plasma ferric reducing antioxidant power : The decrease in total antioxidant power in plasma or body fluids has been implicated in the aging process and a number of diseases . There was a significant decrease in total urine antioxidant power in late middle aged rats; however, the decrease was completely reserved by Eufortyn®; so Eufortyn® is effective in exerting its antioxidant capacity and modulating in vivo redox status, not only in the skeletal muscle, but also in the metabolic system. Moreover, the changes in total urine antioxidant power as well as in plasma and muscle FRAP after supplementation may provide information on the absorption and bioavailability of nutritional compounds, suggesting that Eufortyn® can be effectively absorbed and its metabolites excreted in the urine.
Conclusion
The current study provides striking results concerning the potential benefits of Eufortyn® used to combat age-related mitochondrial dysfunction. Gastrocnemius muscle mitochondrial function and grip strength were improved in 21-month-old rats fed Eufortyn® compared with their age-matched counterparts. In addition, muscle mitochondrial protein oxidation (carbonyl formation), oxidative stress to RNA, and the age-associated decline of total urine antioxidant power were remarkably attenuated by Eufortyn® supplementation in 29-month-old rats. The study suggests that Eufortyn® is a potent antioxidant and has the potential to improve health span .
Future clinical studies should explore the potential benefits of Eufortyn® on physical function, clinical outcomes, as well as its ability to reduce oxidative stress levels, in middle-aged and older adults.
