Moderate exercise in a treadmill (10, 15, and 20 cm/s, for 5 min each, weekly) from 28 to 78 wk of age extended male and female mice life span by 19 and 9% accompanied by 36 and 13% and 13 and 9% increased performance in behavioral assays (tightrope and T-maze tests) at 52 wk of age. Moderate exercise significantly decreased the aging-associated development of oxidative stress by preventing 1) the increase in protein carbonyls and thiobarbituric acid-reactive substances contents of submitochondrial membranes; 2) the decrease in antioxidant enzyme activities (Mn- and Cu,Zn-superoxide dismutase and catalase); and 3) the decrease in mitochondrial NADH-cytochrome-c reductase and cytochrome oxidase activities observed at 52 wk of mice age in brain, heart, liver, and kidney. These effects were no longer significant at 78 wk of age in mice. Moderate exercise, started at young age in mice, increased life span, decreased oxidative stress, and prevented the decline of cytochrome oxidase activity and behavioral performance at middle age but not at old age.

Navarro A, Ló pez-Cepero JM, Bá ndez MJ, Sá nchez-Pino M-J, Gó mez C, Cadenas E, Boveris A. Hippocampal mitochondrial dysfunction in rat aging. Am J Physiol Regul Integr Comp Physiol 294: R501-R509, 2008. First published December 12, 2007 doi:10.1152/ajpregu.00492.2007.-Hippocampus mitochondrial dysfunction with impaired electron transfer and increased oxidative damage was observed upon rat aging. Hippocampal mitochondria of aged (12 mo) and senescent (20 mo) rats showed, compared with young (4 mo) rats, marked decreases in the rate of state 3 respiration with NAD-dependent substrates (32-51%) and in the activities of mitochondrial complexes I (57-73%) and IV (33-54%). The activity of mitochondrial nitric oxide synthase was also decreased, 53-66%, with age. These losses in enzymatic activity were more marked in the hippocampus than in brain cortex or in whole brain. The histochemical assay of mitochondrial complex IV in the hippocampus showed decreased staining upon aging. Oxidative damage, determined as the mitochondrial content of thiobarbituric-acid reactive substances (TBARS) and protein carbonyls, increased in aged and senescent hippocampus (66 -74% in TBARS and 48 -96% in carbonyls). A significant statistical correlation was observed between mitochondrial oxidative damage and enzymatic activity. Mitochondrial dysfunction with shortage of energy supply is considered a likely cause of dysfunction in aged hippocampus. mitochondrial nitric oxide synthase; reduced nicotinamide adenide dinucleotide dehydrogenase; cytochrome oxidase; oxidative damage MAMMALIAN AGING is characterized by a gradual and continuous loss, starting at full adulthood, of the quality of physiological functions and responses. The losses are more marked in the functions that depend on the integrated response of the central nervous system (19) than in the functions of the renal or cardiovascular systems. Mitochondria were brought to attention in mammalian aging biology because of the central role of mitochondria in producing biochemical energy (ATP) to meet cellular requirements in aerobic cells and to the decline of basal metabolic rate and of physical performance that are characteristic of aging (32).The free radical theory of aging, based on the pioneer works of Gerschman et al. (18) and Harman (20), considers that aging is caused by the continuous inactivation of biologically essential macromolecules and subcellular structures due to chemical modifications produced by reactions mediated by oxygen free radicals. When the free radical theory of aging is focused in mitochondria, it emerges as the mitochondrial theory of aging (6,21,32,47). Mitochondria are considered likely pacemakers of tissue aging because of their continuous production of superoxide radical (O 2•Ϫ ) and of nitric oxide (NO) and to the mitochondrial sensitivity to free radical-mediated oxidative damage (32).Aged mammalian brain shows a decreased capacity to produce ATP by oxidative phosphorylation, and it is considered that this decreased capacity for energy production ...

-Female rats were treated with FSH (40 IU/kg) on the first and second diestrus days (D1 and D2) and with LH (40 IU/kg) on the proestrus (P) day to synchronize and maximize ovarian changes. Follicle area increased by 50% from D1 to P, and the estrus (E) phase showed multiple corpora lutea and massive apoptosis. Increased oxygen uptakes (42-102%) were determined in ovary slices and in isolated mitochondria in active state 3 along the proliferation phase (D1-D2-P) that returned to initial values in the E phase. Mitochondrial content and the electron transfer activities of complexes I and IV were also maximal in the P phase (20 -79% higher than in D1). Production of NO by mitochondrial nitric oxide synthase (mtNOS), biochemically determined, and the mtNOS functional activity in regulating state 3 oxygen uptake were also maximal at P and 79 -88% higher than at D1. The moderately increased rate of NO in the proliferative phase is associated with mitochondrial biogenesis, whereas the high rate of NO generation by mtNOS at phase P appears to trigger mitochondria-dependent apoptosis. The calculated fraction of ovary mitochondria in state 3 was at a minimal value at the P phase. Mitochondrial oxidative damage, with increased thiobarbituric acid-reactive substances and protein carbonyls, indicates progressive mitochondrial dysfunction between phases P and E. The roles of mitochondria as ATP provider, as a source of NO to signal for mitochondrial proliferation and mitochondria-dependent apoptosis, and as a source of O 2 Ϫ and H2O2 appear well adapted to serve the proliferation-apoptosis sequence of the ovarian cycle. ovarian follicle; oxygen uptake; mitochondrial nitric oxide synthase; respiratory chain; oxidative damage OVARIAN CYCLE AND FOLLICULAR DEVELOPMENT are controlled by circulatory feedback between the ovarian hormones and the hypothalamic-pituitary axis (12) and the hormonal predominance of a dominant follicle determines its morphological changes and growth (13) by increasing diameter and the number of granulosa cells (28) whereas nondominant follicles become atretic.During each cycle, the increased FSH concentration recruits growing antral follicles, and the concept of "cyclic recruitment" has been proposed to describe this rescue of follicles from degeneration (27). Follicles in the antral stage express receptors for FSH and become dependent on FSH stimulation for survival, proliferation, and expression of the LH receptor that after stimulation by the hypophysis reach ovulation and formation of the corpus luteum. The number of corpora lutea formed depends, in a ratio of one to one, on the number of follicles that responded to the LH signal. In physiological conditions, FSH stimulates ovarian follicular growth, and LH controls their hormonal secretory capacity, with FSH and LH maximal levels at the end of the proestrus phase with maximal follicular growth simultaneous to ovulation. A decrease in the levels of LH pulse results in follicular cell death and in abortion of the generation of corpora lutea (10). The co...

Rat aging from 4 to 12 mo was accompanied by hippocampus and frontal cortex mitochondrial dysfunction, with decreases of 23 to 53% in tissue and mitochondrial respiration and in the activities of complexes I and IV and of mitochondrial nitric oxide synthase (mtNOS) (P < 0.02). In aged rats, the two brain areas showed mitochondria with higher content (35-78%) of oxidation products of phospholipids and proteins and with higher (59-95%) rates of O(2)(-) and H(2)O(2) production (P < 0.02). Dietary supplementation with vitamin E (2.0 or 5.0 g/kg of food) from 9 to 12 mo of rat age, restored in a dose-dependent manner, the decreases in tissue and mitochondrial respiration (to 90-96%) and complexes I and IV and mtNOS activities (to 86-88%) of the values of 4-mo-old rats (P < 0.02). Vitamin E prevented, by 73-80%, the increases in oxidation products, and by 62-68%, the increases in O(2)(-) and H(2)O(2) production (P < 0.05). High resolution histochemistry of cytochrome oxidase in the hippocampal CA1 region showed higher staining in vitamin E-treated rats than in control animals. Aging decreased (19%) hippocampus mitochondrial mass, an effect that was restored by vitamin E. High doses of vitamin E seem to sustain mitochondrial biogenesis in synaptic areas.

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