Iron Accumulation with Age, Oxidative Stress and Functional Decline

Identification of biological mediators in sarcopenia is pertinent to the development of targeted interventions to alleviate this condition. Iron is recognized as a potent pro-oxidant and a catalyst for the formation of reactive oxygen species in biological systems. It is well accepted that iron accumulates with senescence in several organs, but little is known about iron accumulation in muscle and how it may affect muscle function. In addition, it is unclear if interventions which reduced age-related loss of muscle quality, such as calorie restriction, impact iron accumulation. We investigated non-heme iron concentration, oxidative stress to nucleic acids in gastrocnemius muscle and key indices of sarcopenia (muscle mass and grip strength) in male Fischer 344 X Brown Norway rats fed ad libitum (AL) or a calorie restricted diet (60% of ad libitum food intake starting at 4 months of age) at 8, 18, 29 and 37 months of age. Total non-heme iron levels in the gastrocnemius muscle of AL rats increased progressively with age. Between 29 and 37 months of age, the non-heme iron concentration increased by approximately 200% in AL-fed rats. Most importantly, the levels of oxidized RNA in gastrocnemius muscle of AL rats were significantly increased as well. The striking age-associated increase in non-heme iron and oxidized RNA levels and decrease in sarcopenia indices were all attenuated in the calorie restriction (CR) rats. These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Acoustic to Electric Pitch Comparisons in Cochlear Implant Subjects with Residual Hearing

The aim of this study was to assess the frequency–position function resulting from electric stimulation of electrodes in cochlear implant subjects with significant residual hearing in their nonimplanted ear. Six cochlear implant users compared the pitch of the auditory sensation produced by stimulation of an intracochlear electrode to the pitch of acoustic pure tones presented to their contralateral nonimplanted ear. Subjects were implanted with different Clarion® electrode arrays, designed to lie close to the inner wall of the cochlea. High-resolution radiographs were used to determine the electrode positions in the cochlea. Four out of six subjects presented electrode insertions deeper than 450°. We used a two-interval (one acoustic, one electric), two-alternative forced choice protocol (2I-2AFC), asking the subject to indicate which stimulus sounded the highest in pitch. Pure tones were used as acoustic stimuli. Electric stimuli consisted of trains of biphasic pulses presented at relatively high rates [higher than 700 pulses per second (pps)]. First, all electric stimuli were balanced in loudness across electrodes. Second, acoustic pure tones, chosen to approximate roughly the pitch sensation produced by each electrode, were balanced in loudness to electric stimuli. When electrode insertion lengths were used to describe electrode positions, the pitch sensations produced by electric stimulation were found to be more than two octaves lower than predicted by Greenwood's frequency–position function. When insertion angles were used to describe electrode positions, the pitch sensations were found about one octave lower than the frequency–position function of a normal ear. The difference found between both descriptions is because of the fact that these electrode arrays were designed to lie close to the modiolus. As a consequence, the site of excitation produced at the level of the organ of Corti corresponds to a longer length than the electrode insertion length, which is used in Greenwood's function. Although exact measurements of the round window position as well as the length of the cochlea could explain the remaining one octave difference found when insertion angles were used, physiological phenomena (e.g., stimulation of the spiral ganglion cells) could also create this difference. From these data, analysis filters could be determined in sound coding strategies to match the pitch percepts elicited by electrode stimulation. This step might be of main importance for music perception and for the fitting of bilateral cochlear implants