**2. Oxidative stress and aging**

DNA damage. This epigenetic regulation may be responsible for the effects associated with

**Figure 5.** AGEs. The activation of inflammatory genes is triggered by the formation of AGEs. AGEs activate NF-kB

through a cascade of reactions. This image is a modification of QIAGEN's original [Torres-Sánchez ED].

To test this theory, a research reprogrammed human fibroblast cell lines derived from the young and from the old to a state similar to that of embryonic stem cells. Then, they returned these cells back to their fibroblast form, and their mitochondrial respiratory function was examined; the researchers looked for genes that could be controlled epigenetically causing these mitochondrial defects associated with age and found two that regulate the production of glycine in the mitochondria, CGAT, and SHMT2 and showed that by changing the regulation of these genes, they can produce defects or restore mitochondrial function in fibroblast cell lines. The addition of glycine for 10 days in the culture medium of the fibroblast cell line of the 97-year-old people restored its respiratory function. This suggests that glycine treatment can reverse the breathing defects associated with aging in elderly human fibroblasts.

age that is seen in mitochondria [7, 41, 42].

162 Mitochondrial DNA - New Insights

Mitochondria are the easiest target for damage by free radicals due to two reasons:


There is strong evidence that the accumulated DNA damage of mitochondria is directly related to aging metabolic disorders and diseases [45]. The difference between mitochondria and other intracellular compartments is that the mitochondria have their own DNA. The production of free radicals (including superoxide anions and hydrogen peroxide) in mitochondria is a corollary to energy production (**Figure 6**). The accumulation of these by-products inside mitochondria damages their structure and their DNA. This damage is similar to that produced by ionizing radiation, and today there is an important scientific consensus that considers it as one of the main factors of aging [46]; so much so, that mitochondrial dysfunction caused by oxidative damage due to free radicals is already a marker of aging and the pathologies associated with aging, like in Alzheimer's disease, Parkinson's disease, and cancer [47–49].

The energy metabolism intrinsic to the maintenance of the organism and environmental factors (pollution, smoking) determine the continuous generation of oxygen radicals. These radicals produce oxidative damage to lipids, proteins, and DNA, and damaged molecules accumulate during aging [44, 46]. The deterioration secondary to aging is observed more clearly in postmitotic cells, which, when damaged, cannot be replaced by new cells, as is the case of the neuron. Although it has not been possible to demonstrate with certainty what is the role of this damage in senescence, oxidative stress would be one of the mechanisms possibly involved in neurodegenerative diseases [50].

Oxidative stress can increase with aging, both due to increased generation of oxygen radicals and by the decrease in the ability to eliminate these radicals (antioxidant mechanisms) [51]. There is still discussion regarding the apparent decrease in antioxidant mechanisms during aging [51, 52]. However, the available evidence, with respect to the maximum lifespan of individuals, suggests that the mechanisms of defense against oxidation would not be very relevant [52, 53]. The levels of antioxidant enzymes and the low molecular weight antioxidants show an inverse correlation with the maximum longevity of the animals, which indicates that pro-oxidative activity as such is the most relevant one [54]. Nor has it been found that supplementation with antioxidants (or the opposite effect, the elimination of antioxidant mechanisms) significantly modifies the maximum lifespan of an animal. In contrast, studies

**Figure 6.** Mitochondrial dysfunction. The mitochondria are the main endogenous generator of free radicals. This production acts in a vicious circle that damages the mitochondria and therefore the mitochondrial primordial functions as shown in the figure. This image is a modification of QIAGEN's original [Torres-Sánchez ED].

of average survival suggest that in animals treated with antioxidant therapy these can effectively, nonspecifically protect against various causes of early mortality [55, 56]. These protective effects can have great importance for the human population given that due to their living conditions humans live in an adverse environment and are subjected, for example, to radiation and toxic compounds, so they are exposed to damage by oxidative stress of exogenous origin [57–59].

The animals would have regulatory mechanisms active during development that would monitor mitochondrial activity and, in response, establish the rates of respiration, behavior, and aging that persist during adult life [15, 60]. Although many of these studies have been carried out in experimental models, the results are relevant since they suggest that at least some of the interventions aimed at reducing the effects of aging should be considered in the early stages and not during the adult life of the individual [61]. Also, mitochondria that have suffered oxidative damage also contribute to the aging process [62–64]. Based on the studies that associate the increase of oxidative stress with aging, a line of research has been strengthened which proposes that the decrease in caloric intake is associated with an increase in the resistance of the central nervous system to suffer the neurodegenerative disorders of aging (**Figure 7**) [65]. The neuroprotective effect would depend on the decrease in the generation of oxygen radicals and an increase in the production of neurotrophic factors and protein chaperones [66, 67].

**3. DNA mitochondria and disease**

[Torres-Sánchez ED].

Mitochondrial diseases are a group of disorders whose common feature is a defect in the production of ATP. However, this term is frequently applied to disorders caused by damage to the

**Figure 7.** Aging and mitochondrial DNA. DNA damage is important for aging; reactive oxygen species (ROS) generated damage mtDNA and therefor mutations and other alterations. This image is a modification of QIAGEN's original

Mitochondrial Aging and Metabolism: The Importance of a Good Relationship in the Central…

http://dx.doi.org/10.5772/intechopen.76652

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Mitochondrial Aging and Metabolism: The Importance of a Good Relationship in the Central… http://dx.doi.org/10.5772/intechopen.76652 165

**Figure 7.** Aging and mitochondrial DNA. DNA damage is important for aging; reactive oxygen species (ROS) generated damage mtDNA and therefor mutations and other alterations. This image is a modification of QIAGEN's original [Torres-Sánchez ED].
