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.

Keywords: Mediterranean diet; ageing mechanisms; bioactive dietary compounds; cellular senescence; free radicals; iron-chelating agents; labile iron; oxidative stress.

Figure 1

(A) Most of the oxygen (O₂) consumed by aerobic organisms is reduced with four electrons to H₂O in the last step of the mitochondrial respiratory electron transport chain by the enzyme cytochrome oxidase (complex IV). However, a small portion of O₂ undergoes single electron reduction, thus producing superoxide anion (O₂^•−), which is rapidly converted to hydrogen peroxide (H₂O₂) by the action of the enzyme superoxide dismutase (SOD). The generated H₂O₂ is further reduced, either enzymatically by two electrons to H₂O through the action of the enzymes catalase (Cat), glutathione peroxidase (Gpx), and peroxiredoxin (Prx), or non-enzymatically by one electron, thus leading to the generation of extremely reactive hydroxyl radicals (HO^•). The latter reaction, which requires available ferrous iron (Fe²⁺), is known as the “Fenton reaction” and generates reactive intermediates that are able to indiscriminately oxidize cell components. (B) Lipids and fatty acids located in membranes and lipoproteins can also incorporate O₂ and be peroxidized by the action of the enzyme “lipoxygenase” (LOX). The generated lipoperoxides (LOOHs) can be reduced to the corresponding alcohols by the specific membranous enzyme “glutathione peroxidase 4” (Gpx4). Like H₂O₂, LOOHs can interact with available ferrous iron (labile iron), leading to the generation of highly reactive lipid alcoxyl radicals (LO^•s), which can further promote the peroxidation of membrane lipids.

Figure 2

Schematic representation of sequential steps that lead to lipofuscin formation and contribute to cellular ageing. Note that Fe²⁺ is required for the generation of highly reactive ROS (HO^• and RO^•), which are responsible for the oxidation and over-oxidation of cellular macromolecules (A,B). Over-oxidized macromolecules can inhibit cellular repair systems (especially 20S proteasome), thus facilitating futile cycles of progressively increasing oxidation rates (C). Oxidatively modified, non-degradable cellular components are gradually accumulated into cells as covalently interconnected aggregates in the form of lipofuscin (D), a fact that is proposed to influence the process of cell ageing (E). Arrowheads and flatheads indicate the induction and inhibition, respectively, of processes.

Figure 3

(A) SenTraGorTM specifically reacts against lipofuscin, the non-degradable byproduct of cellular senescence, allowing for the accurate identification of senescent cells in vitro and ex vivo by applying an antibody-mediated detection method. (B) SenTraGor staining on Li-Fraumeni-p21WAF1/Cip1 Tet-OFF (left image) and OΝ cells (right image); original magnification: ×200.

Figure 4

Schematic presentation indicating that the plant-derived foods of the Mediterranean diet contain increasing amounts of iron-binding compounds able to chelate intracellular labile iron and to prevent the generation of highly reactive free radicals that are responsible for the unregulated oxidation of cell constituents.