A Comprehensive Overview of the Complex Role of Oxidative Stress in Aging, The Contributing Environmental Stressors and Emerging Antioxidant Therapeutic Interventions

Abstract

Introduction: Aging is a normal, inevitable, irreversible, and progressive process which is driven by internal and external factors. Oxidative stress, that is the imbalance between prooxidant and antioxidant molecules favoring the first, plays a key role in the pathophysiology of aging and comprises one of the molecular mechanisms underlying age-related diseases. However, the oxidative stress theory of aging has not been successfully proven in all animal models studying lifespan, meaning that altering oxidative stress/antioxidant defense systems did not always lead to a prolonged lifespan, as expected. On the other hand, animal models of age-related pathological phenotypes showed a well-correlated relationship with the levels of prooxidant molecules. Therefore, it seems that oxidative stress plays a more complicated role than the one once believed and this role might be affected by the environment of each organism. Environmental factors such as UV radiation, air pollution, and an unbalanced diet, have also been implicated in the pathophysiology of aging and seem to initiate this process more rapidly and even at younger ages.

Aim: The purpose of this review is to elucidate the role of oxidative stress in the physiology of aging and the effect of certain environmental factors in initiating and sustaining this process. Understanding the pathophysiology of aging will contribute to the development of strategies to postpone this phenomenon. In addition, recent studies investigating ways to alter the antioxidant defense mechanisms in order to prevent aging will be presented.

Conclusions: Careful exposure to harmful environmental factors and the use of antioxidant supplements could potentially affect the biological processes driving aging and slow down the development of age-related diseases. Maybe a prolonged lifespan could not be achieved by this strategy alone, but a longer healthspan could also be a favorable target.

Keywords: aging; antioxidants; envionmental pollution; mitochondria; oxidative stress; pathogenesis of aging; reactive oxygen species.

Figure 1

The electron transport chain and the reverse electron transport. (A) The conventional forward electron transport by the electron transport chain. (B) The reverse electron transport which leads to the overproduction of O₂^●− and occurs when coenzyme Q gets over-reduced by complex II or the succinate is overused due to hypoxia.

Figure 2

Endogenoussources of reactive oxygen species (ROS) production. Intracellular ROS is mainly produced by subcellular organelles such as the mitochondria, endoplasmic reticulum and peroxisomes. Another enzymatic system that produces ROS and is located on the cytoplasmic membrane is NADPH oxidase (NOX), which primarily generates superoxide anion radical (O₂^●−). In mitochondria, O₂^●− is mainly produced by complexes I and III. Nitric oxide synthase (NOS) catalyzes the formation of nitric oxide (NO^●) from L-arginine and tetrahydrobiopterin (BH₄), and subsequently NO^● can yield peroxynitrite (ONOO⁻) by direct reaction with O₂^●−. Cytosolic O₂^●− is then converted to hydrogen peroxide (H₂O₂) by endogenous superoxide dismutase (SOD). H₂O₂ can be further reduced to water (H₂O) by the antioxidant enzymes glutathione peroxidase (GPx), catalase (CAT) or peroxiredoxin (Prx), or react with metal cations in Fenton and Fenton-like reactions to generate hydroxyl radical (^●OH), which can cause immediate oxidative damage to biomolecules.

Figure 3

Sourcesof reactive oxygen species (ROS) that lead to oxidative stress and promote aging. Several endogenous and exogenous factors contribute to excess ROS formation. Any imbalance between the production of free radicals and ROS and their elimination by antioxidant systems can cause oxidative stress that ultimately promotes accelerated aging phenotypes through oxidative macromolecular alterations, such as the exemplary alterations depicted in the bottom right part of the figure.

Figure 4

Schematic diagram of endogenous and exogenous enzymatic and non-enzymatic antioxidants.

Figure 5

The process of lipid peroxidation of polyunsaturated fatty acids. First a free radical or reactive oxygen species (ROS) remove an electron from a methylene group between two double bonds of a polyunsaturated fatty acid (LH) leading to the formation of a new free radical (unsaturated lipid radical). The lipid radical formed is very unstable, resulting in its rapid rearrangement and the formation of a similar unsaturated lipid radical. This radical reacts with molecular oxygen towards a lipid peroxy radical. This peroxy radical can extract a hydrogen atom from an adjacent polyunsaturated fatty acid, thereby creating a new free radical and a lipid peroxide. These radical chain reactions further propagate and their main degradation end-products are malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), which are relatively stable. Hence, MDA and HNE can be used as a means of quantifying the levels of oxidative stress and lipid peroxidation within cells.

Figure 6

The interplay between oxidative stress, SASP factors and accelerated aging. Several senescence-associated secretory phenotype (SASP) factors that contribute to accelerated aging are affected by the increased production of reactive oxygen species (ROS) and oxidative stress. SASP, senescence-associated secretory phenotype; mTOR, mammalian target of rapamycin; IL-1α, interleukin-1α; MMPs, matrix metalloproteinases; FOXO, Forkhead box; Ca⁺⁺-ATPase, calcium ATPase; SIRT1, sirtuin 1; SIRT6, sirtuin 6.