Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

**Background:** Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated endogenously (e.g., mitochondria, NADPH oxidases) and exogenously (e.g., radiation, smoking, pollution). At low to moderate levels, they regulate physiological processes such as signal transduction (e.g., NF-κB, MAPK, Nrf2 pathways), a state termed oxidative eustress. However, excessive ROS/RNS production leads to oxidative stress (distress), characterized by damage to DNA, proteins, and membrane lipids. This review aims to synthesize the chemistry, sources, and pathological roles of ROS/RNS, and to evaluate antioxidant defense mechanisms and therapeutic interventions across a spectrum of chronic diseases and aging.

**Methods:** This is a narrative review that synthesizes findings from a wide range of published studies, including in vitro experiments, animal models, and clinical trials. The paper discusses the electronic structures and reaction kinetics of key ROS/RNS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radicals, nitric oxide, peroxynitrite). It describes the Fenton reaction (H2O2 + Fe2+ → ·OH + OH−, k = 7.6 × 10^1 M−1 s−1) and the formation of carbonate radical anions. The review covers endogenous sources (mitochondrial electron transport chain, cytochrome P450, peroxisomes, endoplasmic reticulum) and exogenous sources (radiation, cigarette smoke with ~10^15 radicals per puff, red meat, alcohol). It details the antioxidant system, including enzymes (SODs with k ~ 2 × 10^9 M−1 s−1, catalase, glutathione peroxidase) and low-molecular-weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine). Biomarkers of oxidative stress are discussed, including malondialdehyde (MDA), 4-hydroxynonenal (HNE), F2-isoprostanes, 8-oxo-guanine, protein carbonyls, and advanced glycation end products (AGEs).

**Key Results:** The review reports that oxidative stress is a common denominator in numerous chronic diseases. For example, in Alzheimer's disease, levels of copper and zinc are triple and iron nearly double in amyloid plaques compared to surrounding tissues. In the Alpha-Tocopherol/Beta-Carotene (ATBC) trial, supplementation with β-carotene (20 mg/day for 5–8 years) resulted in an 18% increased incidence of lung cancer among smokers. In cardiovascular disease, the CHAOS trial showed α-tocopherol reduced myocardial infarction but not mortality, while the HOPE trial found no benefit. In Parkinson's disease, intravenous glutathione (two 600 mg doses twice daily for 30 days) improved patient performance with nearly half a decline in disability. In lung cancer, antioxidants like vitamin E and N-acetylcysteine were shown to accelerate tumor progression in KRAS and BRAF mouse models by suppressing free heme and stabilizing the transcription factor BACH1. The review also notes that caloric restriction (10–50% reduction) modulates mitochondrial activity and suppresses oxidative damage through sirtuin regulation, with a 20% reduction in mice increasing SIRT1 expression and decreasing superoxide levels.

**Clinical Implications:** The review emphasizes that while oxidative stress is a key pathological factor, large-scale clinical trials of antioxidant supplements have yielded inconsistent or negative results, particularly for β-carotene and vitamin E in cancer and cardiovascular disease. The authors caution that many antioxidants exhibit prooxidant behavior under certain conditions (e.g., high oxygen partial pressure, presence of free redox metals). Promising therapeutic strategies include the use of weak prooxidants (e.g., certain flavonoids) that boost endogenous antioxidant systems via Nrf2 activation, and metal-based SOD/catalase mimetic compounds (e.g., Mn-cyclic polyamines, Mn-porphyrins) currently in clinical trials. The review highlights ergothioneine as a promising adaptive antioxidant with anti-aging properties, and sirtuin modulators (e.g., resveratrol, SRT1720) as potential targets for age-related diseases. The authors conclude that future interventions must carefully select target populations, optimize dosing, and use reliable biomarkers to establish causality between oxidative stress and disease progression.