Implication of Dietary Iron-Chelating Bioactive Compounds in Molecular Mechanisms of Oxidative Stress-Induced Cell Ageing

Abstract

One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as “lipofuscin,” “ceroid,” or “age pigment” is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) (“labile iron”), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.

Microvasculopathy-Related Hemorrhagic Tissue Deposition of Iron May Contribute to Fibrosis in Systemic Sclerosis: Hypothesis-Generating Insights from the Literature and Preliminary Findings

“…Previous studies in primary human fibroblasts and endothelial cells have shown that senescent cells accumulate intracellular iron [ 29 ]; in turn, the presence of intracellular labile iron (Fe(ΙΙ)) is a prerequisite for the development of oxidative stress-induced senescence and apoptosis [ 16 ]. Herein, we show that iron overload leads to oxidative DNA damage in both skin and synovial fibroblasts, suggesting that iron overload may be an additional source of the increased oxidative burden present in fibroblasts isolated from SSc patients [ 30 , 31 ].…”

“…Importantly, it is not the total amount of iron that is responsible for mediating the oxidative damage, but rather the labile Fe(II) fraction pool that is accessible for interaction with peroxides [ 15 ]. The depletion of intracellular labile iron by exogenous compounds would diminish the formation of damaging ROS and prevent the deleterious over-oxidation of cellular components [ 16 ]. Several lines of evidence suggest that ROS-induced oxidization of lipids and proteins promotes initiation and progression of fibrosis in a variety of organs [ 17 , 18 , 19 , 20 ].…”

Dietary Antioxidants in the Mediterranean Diet

“…A review paper by Barbouti et al [ 17 ], propose that dietary bioactive compounds present in the Mediterranean-type diet protect against oxidative stress-induced cellular ageing by acting as iron chelating compounds, rather than free-radical scavenges. Among several theories that have been proposed to explain the molecular basis of ageing, the so-called “free-radical theory of ageing” [ 18 ], has gained widespread acceptance.…”

“…In conditions of ongoing oxidative stress, the ability of cells to repair their damaged constituents reach saturation, and over-oxidized non-repairable “waste material” accumulates inside the cells. This chemically undefined material conventionally called “lipofuscin” is a common hallmark of ageing (senescent) cells [ 17 ]. A necessary requirement for the intracellular generation of highly reactive free radicals is the presence of “labile iron” [ 19 ].…”

“…For instance, it has been reported that phenolics with an ortho-dihydroxyl group protect human cell lines against oxidative stress conditions by chelating intracellular iron [ 3 , 22 , 23 , 24 , 25 ]. Based on these considerations, the review article by Barbouti et al [ 17 ] proposes that iron-chelating bioactive compounds contained in the Mediterranean-type diet represent crucial factors that may prevent lipofuscin formation and, consequently, cellular ageing. In order to exhibit cytoprotective effects, these diet-derived phytochemicals must be able to penetrate cellular membranes and chelate cellular labile iron, so as to diminish undesirable oxidations in critical cellular constituents.…”