Iron Accumulation with Age, Oxidative Stress and Functional Decline

Abstract

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.

Dietary Iron Overload: Short- and Long-Term Effects on Cecal Morphometry in Growing Rats

“…In Fe-overload situations, the liver increases its capacity for Fe storage and becomes susceptible to tissue damage because Fe is a catalyst in the Haber-Weiss reaction, which participates in the formation of reactive oxygen species (8,11,22). In fact, the present results show that hepatic Fe levels increase proportionally to dietary intake and that this increase was significant after 12 wk.…”

“…Apart from the enhanced risks of Fe overload as a result of higher Fe absorption in genetically susceptible individuals, the long-term effects of highly bioavailable Fe (as Fe supplements or heme Fe) and Fe-fortified food consumption in non-anemic individuals (to whom Fe fortification would not apply) have been discussed (3)(4)(5). This aspect is particularly relevant considering the association of elevated Fe stores with aging-related diseases, ranging from cancer to Alzheimer's, as well as other chronic diseases such as obesity, diabetes and cardiovascular diseases (22)(23)(24).…”

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

“…It is thus not surprising that invertebrate data (Drosophila) suggest that age-related iron accumulation is proportional to the rate of aging (Massie et al, 1985) and inhibition of iron absorption prolongs lifespan (Massie et al, 1993). Similarly, human gender differences in longevity have been proposed to relate to reproduction-related iron losses in women (Sullivan, 1989) and life-extending effects of calorie restriction have been associated with reduced dietary iron uptake and lowered iron deposits in tissue (Cook and Yu, 1998;Kastman et al, 2010;Valle et al, 2008;Xu et al, 2008).…”

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

“…Total RNA and DNA oxidation levels of cochleae were analyzed simultaneously using a HPLC/electrochemical detection (ECD) method (49,50). For detailed methods, see SI Materials and Methods.…”