Aging is an inevitable process that normally starts at birth, or to be more particular, at conception, includes a general decline in the structural, molecular (including genomic), biochemical and physiological functions of different organs and predominantly brain. The progression of aging varies from one person to another and largely depends upon our genetic makeup, environmental influences and life style. One of the most widely accepted theory of aging is "free radical theory of aging" which states that organisms age because cells accumulate oxidative damage over time. The increased oxidative stress causes DNA damage, protein cross-linking, lipid peroxidation and other changes inside the cells of the body. Brain is more prone to aging due to oxidative stress contributed from relative high concentration of peroxidizable fatty acids, high oxygen consumption, high level of oxidizable dopamine molecules and poor cellular defense system i.e., antioxidant concentration. Aging has been implicated in the etiology of a host of degenerative diseases, including cancer, cardiovascular and neurological disorders. To expand the latter, aging is associated with several alterations in the neuronal networks including electro-tonic coupling, synaptic connectivity, the number of functionality of specific types of neurons, and receptor and channel properties. The changes related to aging in potassium and calcium buffering is known to affect neuronal excitability and synchronization.
Age related changes are associated with alterations in neural electrophysiological parameters such as synaptic potentials, action potentials, spontaneous field potentials (EEG). All these changes related to disorganization and impairment of electrical signals ultimately leads to decrement of neurological functions. EEG represents integrated post synaptic potential and reflects the state of neurophysiological activity of the cerebral cortex. A higher frequency in EEG activity (increased alpha and beta activity) indicates increased vigilance promoting influences and lower frequencies may be associated with the cognitive decline. The human EEG is reported to show altered frequencies and synchronization with aging. For example, the resting membrane potential of nerve cells remain unaffected whereas, the synaptic resting membrane potential decreases with age. Similarly, excitability of neuron decrease, while the rheobase was shown to increase in the CA1 hippocampal neurons in aged wistar rats. Velocity of nerve impulse conduction (action potential) in peripheral nerve fibers decreases during aging. Factors such as demylienation, axon shrinkage and intra-nodal distance influence conduction velocity.
Several neurons have ability to change their firing pattern during different states of arousal. Neurons which fire non-rhythmically during slow wave sleep, adopts burst-firing patterns during waking and REM sleep. This functional plasticity however, shown to decrease with aging. An increase in lipid peroxidation associated with aging significantly influences membrane excitability and synaptic transmission. As lipid peroxidation causes membrane's lipid environment change it adversely affects the membranes Na+-K+ ATPase activity. Age related impairment of Na+-K+ ATPase activity may also result from age related mitochondrial bioenergetics impairment. This enzyme is involved in maintaining the resting membrane potential at -70mV. Age related increase of lipid peroxidation is highly correlated with age related decrease in glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activity. These antioxidant enzymes have been shown to play an important role in scavenging free radicals.
Reports have demonstrated that aging is associated with significant synaptic loss in the dentate gyrus of the aged rat with reductions in the mean number of synapses per neuron for the entire synaptic population and within specific synaptic categories. Aging is associated with increased load of oxidative damage, which accelerates expression of glial fibrillary acidic protein (GFAP) mRNA and proteins in humans and inbred lab rodents. In situ hybridization of GFAP at cellular level with intronic cRNA probes accounts for the increased GFAP expression during aging. Increased GFAP level has also been observed in rabbits during aging. Age-related alterations in molecular functions are believed to modulate genetic expression of channel proteins. For example, number of channels and their subunit composition alter electrical signaling.
Behavioral studies have also shown poor synaptic plasticity for long-term potentiation in older rats' comparison to young ones. Aging process is also reported to alter inhibitory and excitatory post synaptic potential which mainly depends upon the number of binding sites (receptor density) available and the presynaptic release mechanism. Aged rats also exhibit a 30%-40% decrease in NMDA receptor binding density.
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