59 - Redox timer of aging: from free radical chemistry to systems theory of reliability

Abstract

Similarly to technical devices, biological systems are not perfectly reliable in operation. Namely, for each and every device normal acts of operations alternate with stochastic malfunctions or failures. The field of systems biology, in dealing with the problem of reliability, incorporates theoretical and experimental investigations of quantitative characteristics and mechanisms of failures and renewal processes in biological systems. Regular conferences, starting from 1975 in Kyiv, Ukraine, have given the strong impetus to research in this direction (Grodzinskiy et al., 1987). It has also spurred the similar studies under the style of “robustness” (Kitano, 2004). On the basis of the mathematical theory of reliability, the universal features of aging such as the exponential growth of mortality rate with time and the correlation of longevity with the species-specific resting metabolism are naturally explained. Stochastic malfunctions of the mitochondrial electron transport nanoreactors, which produce anion-radicals of oxygen (O2•‒) as the by-products of oxidative phosphorylation, are of first importance. This radical, as the reducing agent, affects NAD(P)H/NAD(P)+ ratio, thereby impacting on the epigenetic sirtuin regulators of the metabolic repair and renewal processes. As the consequence, oxidative-stress products and other metabolic slag accumulate with the resulting impetus to autophagic or apoptotic cell death accompanied with age-associated clinical disorders. Basing on the theory of reliability, one can estimate that longevity of human brain could reach 250 years should the antioxidant enzyme defense against the O2•‒ failures be perfect. Thus, the free-radical redox timer, located presumably in the special cells of the suprachiasmatic nucleus of hypothalamus, serves as the effective stochastic mechanism of realization of the genetically preset deficiency in reliability (“robustness”) of the system taken in its entirety. Besides, the systems reliability approach provides heuristic methodology in searching the realistic mechanisms of the antioxidant therapy.