Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the "cell aging regulation system”

Abstract

The updated mitochondrial free radical theory of aging (MFRTA) is reviewed as part of the cell aging regulatory system (CARS). Any valid theory of aging should explain why different animal species age at so different rates. Only two known parameters correlate with species longevity in the right sense: the mitochondrial rate of reactive oxygen species production (mitROSp) and the degree of fatty acid unsaturation of tissue membranes calculated as the double bond index (DBI). Both are low in long-lived animals. Dietary restriction (DR), which increases longevity, also decreases mitROSp and % free radical leak (FRL) at complex I and oxidative damage to mtDNA. This can increase longevity by decreasing mtDNA fragments accumulation inside nuclear DNA which revitalizes MFRTA. Lowered mitROSp and FRL at complex I also occurs during protein or methionine restriction, and rapamycin treatment (which also increases longevity). The decrease in mitROSp during DR (dietary restriction) is due to restriction of a single substance, methionine, and occurs at the matrix domain of complex I. This updated MFRTA focuses on low mitROSp and low sensitivity of membranes to oxidation in long-lived animals. The three best known aging effectors of the genetic Aging Program of aerobic tissues are mitROSp, membrane fatty acid unsaturation, and autophagy. This program reacts to cytoplasmic signaling proteins, influenced by nutrients, drugs and hormones, varying the activity of the mitROSp and macroautophagy aging effectors. An analogous program, although with additional gene clusters of aging involved, and different output activity, can determine longevity in different animal species.