**16. Features of fatty acids metabolism that increase MetS symptoms and accelerate aging**

Among mammalians the human females have a unique duration of postreproductive longevity [140], which is probably to a large degree associated with the metabolic "protection" that caused slower rate of aging at the reproductive period [122]. There are several reasons to argue that both the accelerated rate of aging of men and the relatively slow aging of women, as well as other sex differences in metabolism and physical performance, are based on the sex differences in fatty acids metabolism. Regardless of age and gender, fats are the major source of energy, carbon and hydrogen for the anaplerotic reactions. **Table 1** shows the relative amounts and times of consumption of the three main sources of mitochondrial substrates for obtaining energy and intermediary metabolites for the growth and maintenance of the body.

**Table 1** shows that carbohydrates stores are small and must be constantly replenished by gluconeogenesis in the liver. Amino acids reserves are practically absent and they are constantly formed due to the digestion of food proteins, as well as in anaplerotic reactions in mitochondria. Carbohydrates are too precious to be used for obtaining energy. Much of glucose, particularly at young age, is used for the synthesis of RNA and DNA, purine and pyrimidine nucleotides. Only erythrocytes, which have no mitochondria utilize glucose for obtaining ATP by glycolysis and NADPH for reducing glutathione. There is an old myth that brain consumes only glucose for supporting its energy needs. However, most of the lactate and neuromediators glutamate and γ-aminobutyric acid, which are also used by synaptic mitochondria as energy substrates, are synthesized by the astrocytes from the carbon atoms of fatty acids and for the expense of energy derived during


#### **Table 1.**

*It is shown that carbohydrates stores are small and must be constantly replenished by gluconeogenesis in the liver. Amino acids reserves are practically absent and they are constantly formed due to the digestion of food proteins, as well as in anaplerotic reactions in mitochondria. Carbohydrates are too precious to be used for obtaining energy. Much of glucose, particularly at young age, is used for the synthesis of RNA and DNA, purine and pyrimidine nucleotides. Only erythrocytes, which have no mitochondria utilize glucose for obtaining ATP by glycolysis and NADPH for reducing glutathione. There is an old myth that brain consumes only glucose for supporting its energy needs. However, most of the lactate and neuromediators glutamate and* γ*-aminobutyric acid, which are also used by synaptic mitochondria as energy substrates, are synthesized by the astrocytes from the carbon atoms of fatty acids and for expense of energy derived during* β*-oxidation of fatty acids. Synaptic mitochondria also gladly oxidize fatty acids in the presence of supporting substrates [85, 87].*

#### *Metabolic Syndrome as the First Stage of Eldership; the Beginning of Real Aging DOI: http://dx.doi.org/10.5772/intechopen.95464*

β-oxidation of fatty acids. Synaptic mitochondria also gladly oxidize fatty acids in the presence of supporting substrates [85, 87].

The energetic efficiency of β-oxidation of fatty acids in the presence of supporting substrates is the only combination of substrates capable to support the highest rates of oxidative phosphorylation in the heart during maximal physical loads. The efficiency is achieved by the reduction of not only NADH/NAD<sup>+</sup> system in mitochondria, but also by reduction of the membrane pool of ubiquinol/ubiquinone. Therefore, during β-oxidation of fatty acids, electrons enter the respiratory chain not only from Complex I, but mainly through complexes II and III. However, when the energy demands by the organ's functions diminish, the excess of energy in mitochondria may redirect electrons for production of the superoxide radicals, and thus HO2 • [66, 88]. Oxidation by mitochondria of the NAD-dependent substrates cannot provide high rates of ATP and ROS production because NADH-dehydrogenase activity of Complex I is the rate limiting step [141].

Brandt [21] observed that the rate of ROS production may be increased, when mitochondria have abundant supply of substrates and low level of ATP consumption (low functional load), and diminish when consumption of energy is high, or the substrate supply is limiting. This explains why the symptoms of MetS strongly depend on the life style. This is probably the main reason why men start aging faster and earlier then women. At the age of 45–50, many men reduce physical activity, eat too much and abuse alcohol, which dramatically accelerates ROS production.

After menopause, the women's hormonal status becomes closer to that of men, and therefore they also must utilize fatty acids as the main substrates for energy production. At the post-reproductive stage of ontogenesis, we can assume that both men and women have metabolic pattern similar to their distant ancestors, who did not consume a lot of carbohydrates. This may explain the origin of the insulin resistance at MetS. This is not a pathology rather than a new physiological reality due to metabolic reprogramming at the post-reproductive stage. With low insulin sensitivity, most consumed carbohydrates are directed to the synthesis of lipids, which accelerates obesity, first of all visceral obesity. Excessive food consumption plus lower physical and mental activities accelerate production of superoxide radicals, and, thus, perhydroxyl radicals. This accelerates IPLP yielding harmful products, which have proinflammatory activities, cause damages to proteins, cardiolipin and PEA resulting in mitochondrial dysfunctions and accelerating aging.

For a long time, these gradually accumulating various functional disorders and structural damages are not accompanied by specific clinical manifestations. In people predisposed to an earlier aging, the clinical symptoms may be unspecific and look like frailty. With time, the accumulated wear and tear will cause development of clinical symptoms, like acute heart failure, Alzheimer's disease, or something else, and finally death.

Literature show diminished fatty acids oxidation and developments of MetS symptoms in the females without estrogen that can be normalized by administration of estrogen [142, 143]. We do not think that those publications contradict to our conclusions presented in this Chapter, because those experiments have been done on young animals 7–8 weeks old.

#### **17. Conclusions**

In this Chapter we have presented evidence that activation of IPLP by hydroperoxyl radical, protonated form of superoxide radical, provides explanation to the slow and inevitable mechanism of aging and resolves many objections against MFRTA in the current paradigms. We also have shown that focusing only on the

**Figure 4.**

*A schematic presentation of approximate differences between men and women in ROS production during ontogeny. The figure was created based on the data presented in Refs. [111, 112, 116–118, 122, 138].*

damages, which accompany aging, is not very helpful, because it gives no answers on why and when aging actually starts, and why women age slower and live longer than men. We have explained the idea that aging is, first of all, the process of development in time, when men and women go through a number of genetically predetermined stages. Because men and women have different biological roles, they also have different metabolic strategies. Fatty acids at all stages of ontogeny are the main substrates for provision of energy and intermediate metabolites for the growth and maintenance. The energetic efficiency of β-oxidation of fatty acids is controlled by the type of mitochondrial metabolites that oxidize simultaneously with fatty acids. However, this results in a significant increase in oxidative stress. We suggest that sex hormones determine the type and quantity of supporting substrates, which result in different rates of energy production and oxidative stress. Women consume more fatty acids with lower efficiency, and thus age at a slower pace. When men and women enter the post-reproductive stage of the ontogeny, the type of metabolism also changes because this last stage of ontogeny is controlled by ancient genes of our distant predecessors. In **Figure 4** we summarized the available information as a scheme, which shows the approximate differences between men and women in ROS production during ontogeny. The metabolic syndrome, which usually begin developing after the age of 45 in men and 55 in women, reflects two main events: the transition to the post-reproductive stage of ontogeny, and the new type of metabolism. Because fatty acids become the major substrates for the energy production in all organs, the rate of ROS production, and, consequently, the rate of aging may increase dramatically. The specific symptoms of the MetS prevailing in particular individuals will depend on the genetic background of their ancestors and the life style.

#### **Acknowledgements**

This work was supported by funding from National Institute of Health (R01HL144943).

*Metabolic Syndrome as the First Stage of Eldership; the Beginning of Real Aging DOI: http://dx.doi.org/10.5772/intechopen.95464*
