Brain mitochondrial dysfunction in aging

Abstract

SummaryAging of mammalian brain is associated with a continuous decrease of the capacity to produce ATP by oxidative phosphorylation. The impairment of mitochondrial function is mainly due to diminished electron transfer by complexes I and IV, whereas inner membrane H 1 impermeability and F 1 -ATP synthase activity are only slightly affected. Dysfunctional mitochondria in aged rodents show decreased rates of respiration and of electron transfer, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins, and increased size and fragility. In aging mice, the activities of brain mitochondrial enzymes (complexes I and IV and mtNOS) are linearly correlated with neurological performance (tightrope and T-maze tests) and with median life span and negatively correlated with the mitochondrial content of lipid and protein oxidation products. Conditions that increased mice median life span, such as moderate exercise, vitamin E supplementation, caloric restriction, and high spontaneous neurological activity; also improved neurological performance and mitochondrial function in aged brain. The diffusion of mitochondrial NO and H 2 O 2 to the cytosol is decreased in the aged brain and may be a factor for reduced mitochondrial biogenesis.2008 IUBMB IUBMB Life, 60(5): 308-314, 2008

Cognitive frailty: Rational and definition from an (I.A.N.A./I.A.G.G.) International Consensus Group

“…genes that are involved in apoptotic and transcription regulation pathways such as 5-methyltetrahydrofolate-homocysteine methyltranferase (MTR), Caspase 8 (CASP8), CREB-binding protein (CREBBP), lysine acetyltransferase 2B (KAT2B), and beta-transducin repeat containing (BTRC) loci) (49), and environmental factors (such as nutrition and physical activity) are also strongly related to frailty, both physical (50-52) and brain (53)(54)(55). Additional, pathophysiological mechanisms including oxidative damage and functional changes in the hippocampus and prefrontal cortex have been identified as important factors potentially mediating cognitive decline and potentially leading to dementia (56)(57)(58). Recently, Clegg et al have suggested that structural and functional changes in the aging brain in combination with frailty may identify elderly people at particularly high risk of adverse outcomes (8).…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…R edox imbalance between reactive species and endogenous antioxidants, which results in oxidative damage to biologic molecules and impairment in signaling pathways [(i.e., in oxidative stress (145)], has been widely implicated in many ailments, including central nervous system pathologies (46,51,61,122,219,330) [e.g., amyotrophic lateral sclerosis, (46), Parkinson's disease (219), bipolar disorder (330), Alzheimer's disease (61)], cardiovascular conditions (61,112), pulmonary conditions (65,153), diabetes (111,154), eye diseases (19,235), aging (290,323,236), cancer (52,70,317), radiation injury (220), pain=chronic morphine tolerance (89), Fanconi anemia (229). Reactive species, such as nitric oxide ( · NO), superoxide (O 2 ·À ), hydrogen peroxide (H 2 O 2 ), peroxynitrite (ONOO -), and others have been widely recognized as signaling species that, by affecting redox-based cellular transcriptional activity, control inflammatory and immune responses and enhance secondary oxidative stress (27,47,96,151,188,273,276,298,335,336).…”

Effects of short-term dietary nitrate supplementation on blood pressure, O2uptake kinetics, and muscle and cognitive function in older adults

“…In addition to brain shrinkage in senescence (71), the capacity of the brain to produce ATP via oxidative phosphorylation decreases (10) and, in combination with chronic ischemia of white matter (63), this results in a decline of cognitive function. Furthermore, age-related mitochondrial dysfunction has been associated with the neuronal loss, which is a feature of neurodegenerative diseases (13).…”