Featuring the research of over 55 experts in the area, Understanding the Process of Aging covers the functions of nitric oxide and peroxynitrite in mitochondria integrates several views on the role of mitochondria in the development of apoptosis gives a quantitative analysis of mutations of mitochondrial DNA during human aging highlights mitochondrial free radical production introduces new roles of ubiquinone in mitochondrial functions offers new antioxidant-based complementary therapeutic strategies details aspects of intact cells and whole organisms in health and disease and more!
Featuring over references, tables, drawings, and photographs, Understanding the Process of Aging benefits nutritionists and dieticians, geriatricians, cell and molecular biologists, chemists and biochemists, pharmacologists, biotechnologists, neurologists, cardiologists, oncologists, dermatologists, and graduate and medical school students in these disciplines. Get A Copy. Hardcover , pages. More Details Original Title. Friend Reviews. To see what your friends thought of this book, please sign up. To ask other readers questions about Understanding the Process of Aging , please sign up.
Be the first to ask a question about Understanding the Process of Aging. Lists with This Book. This book is not yet featured on Listopia. Community Reviews. Showing The accumulation of damaged mitochondria in the brain is usually explained as a consequence of the increased ROS production of brain mitochondria during aging [ 14 , 47 , 61 , 62 ].
However, the opposite could be also true, that the increase in mtROS is in fact a consequence of the reduced activity of mitochondria. However, no increase in mtROS levels [ 64 ] or oxidative damage [ 65 ] is observed, which does not support the idea that reduction in mitochondrial electron flow increases ROS levels and oxidative damage.
Reactive oxygen species can cause damage through two different mechanisms Fig. For example, superoxide can attack iron—sulfur clusters synthetized in the mitochondria and present in many mitochondrial enzymes including aconitase, CI, and CII. This causes the release of free iron and hydrogen peroxide leading to the production of hydroxyl radicals, oxidative damage, and cell death [ 70 ].
Accordingly, levels of oxidative damage in the brain correlate with performance in different cognitive and activity tests in rodents [ 54 ] suggesting that this type of damage has an impact at a physiological level. Finally, both processes are probably interconnected since deregulation of ROS signaling triggers oxidative stress [ 74 ] and oxidative stress causes alterations in ROS signaling [ 75 ]. Neuronal death is considered the main driver of aging in the brain and the most important initiator of several neurodegenerative diseases [ 76 ].
Historically glia have not received the same attention as neurons, recently, however, it has become evident that they are as important, if not more, as neurons in the aging process [ 77 ]. Interestingly, changes in gene expression were higher in areas such as the hippocampus and substantia nigra, with higher levels of ROS and oxidative damage as we have discussed previously ROS production in different regions of the brain.
Similarly, high levels of mtROS can cause cell death via apoptosis or necrosis [ 80 ]. Senescent cells are characterized by the secretion of proinflammatory factors that contribute to the transformation or induction of senescence in neighboring cells [ 82 ].
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Subsequently, p21 induces mitochondrial dysfunction and more ROS that are required to maintain DNA damage and senescence [ 84 ]. The existence of such a mechanism indicates that mtROS act as redox messengers and not by indiscriminately increasing oxidative damage. Cellular senescence has been considered a mechanism which affects only mitotic cells and therefore would be restricted to glia in the brain.
Mutations in ETC subunits will result in the assembly of defective respiratory complexes that will produce more ROS [ 87 ]. Although, this hypothesis has a strong internal logic, it is not fully supported by experimental data. Firstly, mutations found in old individuals particularly deletions are more likely caused by errors produced during replication or repair of the mitochondrial DNA than directly by the action of free radicals [ 88 , 89 ].
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Damaged mitochondria, whole organelles or components, are turned over with the help of quality control mechanisms like autophagy and the proteasome. Supporting this hypothesis, boosting autophagy or increasing the activity of the proteasome extends lifespan in model organisms, including mouse models [ 93 - 96 ]. Moreover, specifically boosting mitophagy, that is, the specialized autophagy process that recycles damaged mitochondria, is enough to extend lifespan in worms and flies [ 97 , 98 ].
Damaged mitochondria that produce higher levels of ROS can contribute to the collapse of quality control mechanisms in old individuals. Different reports have shown that the efficiency of cellular quality control is regulated by redox changes in key components such as the 20S proteasome [ 99 ] or the cysteine protease ATG4 [ ]. Very high levels of ROS can cause irreversible oxidation of cysteine residues that are redox regulated impeding the proteins carrying them from executing their normal function.
If this mechanism is true, the question to answer is why mechanisms of quality control fail in the first place and the answer is probably in the genome. Recent publications have shown that changes in mitochondrial function are instrumental for cellular differentiation [ ]. For example, neuronal differentiation requires a switch from glycolysis to oxidative phosphorylation [ ]. Conversely, cellular reprogramming of mouse embryonic fibroblasts into pluripotent cells requires repression of oxidative phosphorylation and activation of glycolysis [ ].
As we mentioned previously, mitochondrial morphology and composition depends on the amount of ATP and accessory functions mitochondria are required to perform mtROS production at the cellular level: mtROS generation in neurons vs glia. These characteristics determine how much the mitochondria respire and how many ROS are generated.
A very clear example of this is the obvious differences between mitochondria in differentiated and undifferentiated cells. Pluripotent cells have mitochondria with lower rates of respiration, fewer cristae, and a rounder morphology [ ] when compared to differentiated cells. In parallel with increased oxidative phosphorylation, cell differentiation occurs after a boost in ROS levels [ ].
As mentioned previously the information to build both types of mitochondria is encoded in the genome. Aging is characterized by the accumulation of genetic and epigenetic changes that affect both the information encoded in the DNA as well as how this information is interpreted, that is, how it is transcribed and translated [ 5 ].
Therefore, it is plausible that genetic and epigenetic changes occurring during aging will impact on the nature of the mitochondria present in aged tissues. Chronically high levels of ROS could potentially trigger oxidative stress and contribute to the saturation of quality control mechanisms, which would spread the damage [ 33 ].
Mutations in proteins involved in DNA repair or maintenance cause DNA damage, underlie progeria and have a strong effect on mitochondrial function [ ]. This could be partially responsible for the increase in damaged mitochondria that produce more ROS. Several papers have described the connection between different ROS generators [ ]. Particularly significant is the connection between NOXs enzymes and mtROS levels that seems to work in both directions.
You would expect that there is coordination between specific ROS generators that are part of ROS signaling to make it efficient. Therefore, one of the caveats of using ROS as a signaling system would be the need to increase the intensity of the signal during aging as a result of the accumulation of other types of damage e. Increasing the intensity of the signal would increase the noise and the possibility of triggering oxidative damage.
In order to find effective antiaging therapies, it is imperative that we understand the exact nature of the ROS which type, where, when, and in which amount as well as in which cell types and brain regions intervention is required. As we have seen, COQ7 mutations in mice cause a decrease in mitochondrial respiration and strongly reduce lifespan without increasing mtROS levels [ 92 ]. These results contradict the mitochondrial theory of aging [ ] that postulates that loss of mitochondrial function is caused by mutations in mtDNA and independent of ROS levels causes aging.
These data indicate that mitochondrial dysfunction is probably more a cause than a consequence of aging. These experiments require replication in other mitochondrial mutants and model organisms but indicate that preventing the accumulation of damaged mitochondria may not be enough to extend lifespan if other hallmarks of aging e. Of course, and since mitochondria from COQ7 mutant mice do not produce more ROS it could be argued that higher levels of mtROS generation are required to cause irreversible damage.
In fact, we have cited many reports demonstrating an increase in mtROS and an accompanying accumulation of oxidative damage in the brain of old individuals Damaged mitochondria that produce more ROS accumulate during aging.
Understanding the Process of Aging
However, it remains to be elucidated whether this is a cause or consequence of aging. Data in lower organisms do not support that increasing ROS accelerates aging. In fact many different reports mainly in worms and flies show that boosting ROS levels can in fact extend lifespan [ 8 ]. This phenomenon has been explained as a specific type of hormesis, called mitohormesis [ ].
For example, overexpression or feeding of antioxidants prevents the positive effect of mitohormesis on lifespan [ 14 , , ]. Moreover, overexpression or feeding of antioxidants, without boosting ROS do not extend lifespan [ 7 ]. These results do not support a major role of antioxidant systems in the lifespan extension conferred by mitohormesis, but other repair or protective systems such as autophagy and the proteasome cannot be discarded.
ROS can become problematic in old individuals due to the failure in quality control mechanisms that occur during aging [ 5 ]. On the other hand, the increase in mtROS could be a signal for the activation of protection mechanisms in middle age. The continuous use of this strategy could cause oxidative stress in later life. Although a consequence and not a cause of aging, this oxidative stress would be still an important contributor to the development of neurodegenerative disorders such as Alzheimer's or Parkinson's disease, decreasing the quality of life and shortening healthy aging.
The present consensus states that low levels of ROS are beneficial, participating in cellular signaling and contributing to homeostasis, while higher levels are deleterious, causing oxidative damage. It is also currently accepted that accumulation of defective mitochondria during aging is a consequence of increased oxidative stress. Unfortunately, this model does not explain a lot of the published observations, for example, the failure of antioxidant therapies to attenuate aging or that increasing ROS levels can extend lifespan. During aging, these signaling pathways, like many others, would be dysregulated, resulting in production of unspecific ROS causing oxidative stress.
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Open access. Review Article Free Access. Alberto Sanz Corresponding Author E-mail address: alberto. Evidence via monitoring biomarkers such as the presence of ROS and RNS as well as antioxidant defense has indicated oxidative damage may be implicated in the pathogenesis of these diseases [ 29 ]. Oxidative stress also contributes to tissue injury following hyperoxia and irradiation. Evidence from studies have shown oxidative stress to play an important role in the pathogenesis and development of metabolic syndrome related disorders such as obesity, hypertension, diabetes, dyslipidemia etc.
Cancer is another disease associated with ROS as ROS have been suggested to stimulate oncogenes such as Jun and Fos whose overexpression is directly associated with lung cancer [ 36 ]. In lung cancers, p53 can be mutated by ROS thereby losing its function of apoptosis and functioning as an oncogene [ 37 ].
Also, the development of gastric cancer has been thought to be due to increase production of ROS and RNS by Helicobacter pylori infection in human stomach [ 29 ]. Excess ROS in human kidney leads to urolithiasis [ 29 ]. ROS have also been reported to damage cellular components in cartilage leading to osteoarthritis [ 38 ] and has been shown to be involved in damaging the islets cells of the pancreas [ 39 ].
More so, hyperglycemia triggers ROS production in both tubular and mesangial cells of human kidney, making functional and structural changes in glomeruli causing diabetic nephropathy [ 40 ]. In response to the prevailing level of free radicals both from exogenous and endogenous sources, the human body developed a defense mechanism for protection against cellular damages. These may involve direct and indirect mechanisms put in place by the body. Firstly, the indirect mechanisms are those mechanisms that do not directly act on the free radicals to eliminate them or convert them to less reactive forms.
Rather this indirect system can act in several ways. Certain regulatory mechanisms can control and regulate processes that lead to the endogenous production of ROS [ 41 ]. This may be transcriptional control of the enzymes that are involved in the generation of endogenous ROS. Another indirect approach consists of certain molecules and enzymes that are transported to oxidative-damage sites for repair of macromolecules.
This may include repair of damage DNA, protein or lipids. For examples damage oxidized adducts of DNA such as 8-hydroxydeoxyguanosine, thiamine glycol, and apurinic can be removed from a nucleotide sequence and replaced by a normal nucleotide base [ 42 ]. Also, certain molecules that can donate hydrogen atoms to damaged molecules are also considered as repair compounds. Molecules such as ascorbate or tocopherol can donate hydrogen atom to a fatty acid radical on cell membrane thereby repairing the membrane.
Certain natural cellular or surface barriers such as the skin or cell membranes act as indirect defense system against ROS by preventing exogenous ROS from entering the body or preventing certain endogenous ROS from reaching the target macromolecules. Though these indirect defense mechanisms are helpful against ROS, they are usually non-specific and do not act directly on the ROS. This category of defense system which constitutes the antioxidant system is the most important because they directly act on free radicals either by decomposing, scavenging or converting free radicals to less reactive forms.
This defense mechanism constitute two groups; the enzymatic and non-enzymatic antioxidants. Superoxide dismutase SOD : SOD is an enzymatic antioxidant that exists in three forms in mammalian tissues and differs on their cofactor, subcellular location and tissue distribution. Copper zinc superoxide dismutase CuZnSOD is present in the cytoplasm and organelles of almost all mammalian cells [ 43 ]. It consists of four protein subunits, each containing a single manganese atom. It is synthesized only in fibroblasts and endothelial cells and expressed on the cell surface where it binds to heparan sulfates.
Following its release from heparin, it is secreted into extracellular fluids and enters into the circulation. Superoxide dismutase catalyzes the dismutation of superoxide to hydrogen peroxide:. Catalase: Catalase was the first antioxidant enzyme to be characterized. It is located mostly within the peroxisomes of cells which contain most of the enzymes capable of generating hydrogen peroxide. Catalase is mostly present in liver and erythrocytes showing the greatest activities but is found in other tissues.
Glutathione peroxidases GPx : Glutathione peroxidase is an enzyme which is synthesized mainly in the kidney and found in almost all tissues although it is highly found in the liver [ 47 ].
Its subcellular location is usually the cytosol and mitochondria. Selenium serves as its cofactor located at the active site of the enzyme and deficiency of selenium greatly affects the activity of the enzyme [ 48 ].
Glutathione peroxidases catalyze the oxidation of reduced glutathione GSH decomposing hydrogen peroxide or another species such as a lipid hydroperoxide:. The fact that GPx also acts on lipid hydroperoxides suggest it may be involved in repairing cellular damages due lipid peroxidation [ 49 ]. The activity of GPx is dependent on the constant availability of reduced glutathione which is regenerated from oxidized glutathione GSSG.
Glutathione reductase GRx : GRx is a flavine nucleotide dependent enzyme and has a similar tissue distribution to glutathione peroxidase [ 49 ]. The NADPH required by this enzyme to replenish the supply of reduced glutathione is provided by Glucosephosphate dehydrogenase GPD in the pentose phosphate pathway. Competing pathway that utilizes NADPH such as the aldose reductase pathway may lead to a deficiency of reduced glutathione thereby limiting the action of glutathione peroxidase.
The non-enzymatic antioxidants are usually low-molecular-weight antioxidant LMWA compounds capable of preventing oxidative damage either by directly interacting with ROS or indirectly by chelating metals [ 50 ]. Transition metals are directly chelated by some of this LMWA thereby preventing them from participating in metal-mediated Haber-Weiss reaction [ 51 ]. Other direct acting LMWA molecules scavenge free radicals by donating electrons to free radicals to make them stable thereby preventing attacks of biological targets. These LMWA molecules also called scavengers may be advantageous over enzymatic antioxidants as they can penetrate cellular membranes and be localized in close proximity to the biological target due to their small size.
More so, these non-enzymatic antioxidants can interact together to scavenge free radicals and their scavenging activity may be synergic. Most scavengers originate from endogenous sources, such as biosynthetic processes and waste-product generation by the cell. However, the number of LMWA synthesized by the living cell or generated as waste products such as histidine dipeptides, glutathione, uric acid, lipoic acid and bilirubin is limited [ 52 ].
More so, the concentration of scavenger must be sufficiently high to compete with the biological target on the deleterious species [ 50 ]. As such, exogenous sources of non-enzymatic antioxidants especially from plant diet and phytochemicals are needed to supplement the endogenous non-enzymatic antioxidants. The oxidative stress defense mechanism in humans is summarized in Figure 2.
Plants have long been consumed as food which is rich in vitamins and other nutrients that are useful for the body. Also, various plants were used in folk medicine for various therapeutic purposes. Though these uses, the notion of plant as a source of antioxidant became more evident in recent time as oxidative stress was considered a major attribute to most diseases in humans and the antioxidant defense system in human was usually not sufficient to overcome the free radical level in the body.
As such, plants have gained considerable interest as a source of antioxidants and so much research has been done to identify plants substances with antioxidant activities. Like other humans, plants do have enzymatic and non-enzymatic antioxidant defense systems to protect them against free radicals. The enzymatic system includes catalase, SOD, glutathione peroxidase GPx , and glutathione reductase GRx [ 7 ], while non-enzymatic systems consist of low molecular weight antioxidants LMWA such as ascorbic acid, proline, glutathione, carotenoids, flavonoids, phenolic acids, etc.
The possible reason for the presence of these antioxidants in plants is that plants lack an immune system unlike animals thus, utilize the antioxidant defense system to protect them against microbial pathogens and animal herbivores. Also, these phytochemicals serve as a defense system against environmental stress.
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Though plants have enzymatic antioxidants, it is usually difficult to isolate these enzymes for therapeutic uses in humans. Also, they are usually denatured during food processing, preparation and not sufficiently present in diets such as fruits and vegetables. On the contrary, non-enzymatic antioxidants are readily present in plants leaves, fruits and food in sufficient amounts and can easily be extracted from plants. For these reasons, this section will focus on the non-enzymatic plant antioxidants. Glutathione: Glutathione is a low-molecular-weight, tripeptide of glutamic acid-cysteine-glycine containing a thiol.
GSH generally acts as a cofactor for glutathione peroxidase, thus serving as an indirect antioxidant by donating the necessary electrons for the decomposition of H 2 O 2. Glutathione also has other cellular functions such metabolism of ascorbic acid [ 55 ]. Also, glutathione prevents the oxidation of SH protein groups and acts as a chelating agent for copper preventing its participation in the Haber-Weiss reaction [ 54 ]. The resultant tocopheroxyl radical in these reactions can be recycled to its active form but this radical is relatively stable in normal circumstances and insufficiently reactive to initiate lipid peroxidation itself, which makes it a good antioxidant [ 58 ].
Ascorbic acid Vitamin C : Ascorbic acid is a water-soluble antioxidant. It also functions as a chain breaker to terminate the lipid peroxidation chain reaction. Two molecules of ascorbate radicals can react rapidly to produce a molecule of ascorbate and a molecule of dehydroascorbate which do not have any scavenging activity. Dehydroascorbate can be reconverted to ascorbate by the addition of two electrons catalyzed by oxidoreductase. More so, ascorbate can react with GSH to regenerate vitamin E in cell membranes [ 59 ].
Vitamin A: Though not fully understood, vitamin A is considered as a vital antioxidant that prevents humans LDL against copper stimulated oxidation [ 60 ]. The antioxidant potential of vitamin A was first revealed by Monaghan and Schmitt who showed that vitamin A can protect lipids against rancidity [ 61 ]. They are the most abundant polyphenols found to possess strong antioxidant activities in scavenging free radicals.