The redox stress hypothesis of aging

Sohal, Rajindar S.; Orr, William C.

doi:10.1016/j.freeradbiomed.2011.10.445

Cited by 473Redox biology and oxidative stressGenetics, Aging, and Longevity in Model OrganismsAntioxidant Activity and Oxidative Stress

The redox stress hypothesis of aging

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Sohal, Rajindar S., Orr, William C.·2012·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2011.10.445PMC PMC3267846

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Abstract

The main objective of this review is to examine the role of endogenous reactive oxygen/nitrogen species (ROS) in the aging process. Until relatively recently, ROS were considered to be potentially toxic by-products of aerobic metabolism, which, if not eliminated, may inflict structural damage on various macromolecules. Accrual of such damage over time was postulated to be responsible for the physiological deterioration in the postreproductive phase of life and eventually the death of the organism. This "structural damage-based oxidative stress" hypothesis has received support from the age-associated increases in the rate of ROS production and the steady-state amounts of oxidized macromolecules; however, there are increasing indications that structural damage alone is insufficient to satisfactorily explain the age-associated functional losses. The level of oxidative damage accrued during aging often does not match the magnitude of functional losses. Although experimental augmentation of antioxidant defenses tends to enhance resistance to induced oxidative stress, such manipulations are generally ineffective in the extension of life span of long-lived strains of animals. More recently, in a major conceptual shift, ROS have been found to be physiologically vital for signal transduction, gene regulation, and redox regulation, among others, implying that their complete elimination would be harmful. An alternative notion, advocated here, termed the "redox stress hypothesis," proposes that aging-associated functional losses are primarily caused by a progressive pro-oxidizing shift in the redox state of the cells, which leads to the overoxidation of redox-sensitive protein thiols and the consequent disruption of the redox-regulated signaling mechanisms.

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The 'redox stress hypothesis' proposes that impairments in physiologic function are due to an age-related 'pro-oxidizing shift' in the redox state of cells that results in the over-oxidation of redox-sensitive thiol groups within cysteine residues of proteins, resulting in impairment of cellular signaling pathways.
“The alternative “redox stress hypothesis” [215] instead proposes that impairments in physiologic function are due to an age-related “pro-oxidizing shift” in the redox state of cells that results in the over-oxidation of redox-sensitive thiol groups within the cysteine residues of proteins, resulting in the impairment of cellular signaling pathways.”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [215]
A variety of phenomena have been proposed to contribute to the age-related heightened inflammatory state, including redox stress, immuno- and endocrine senescence, DNA damage, epigenetic modification, and a distortion of gut microbial homeostasis associated with increased levels of circulating endotoxin.
“A variety of phenomena have been proposed to contribute to this age-related heightened inflammatory state including redox stress [46], immuno- and endocrine senescence [47, 48], DNA damage [49], epigenetic modification [50], and a distortion of gut microbial homeostasis [51] that is associated with increased levels of circulating endotoxin [42].”
From Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis (2018) · cites this paper as [46]

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Thiol–Disulfide Balance: From the Concept of Oxidative Stress to that of Redox Regulation
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Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis
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Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster?
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The Rate of Living Theory: A Contemporary Interpretation
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Measurements of protein carbonyls, ortho- and meta-tyrosine and oxidative phosphorylation complex activity in mitochondria from young and old rats
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Prevention of flight activity prolongs the life span of the housefly, Musca domestica, and attenuates the age-associated oxidative damamge to specific mitochondrial proteins
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Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria
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The Effects of Varying Oxygen Concentrations on Osteogenesis and Embryonic Cartilage in Vitro
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Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila
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Mating behavior, physical activity and aging in the housefly, Musca domestica
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Redox Control of Neural Function: Background, Mechanisms, and Significance
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Age‐related impairment of mitochondrial matrix aconitase and ATP‐stimulated protease in rat liver and heart
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Interactions of Mitochondrial Thiols with Nitric Oxide
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[30]Dalle-Donne I Rossi R Colombo G Giustarini D Milzani A Trends Biochem Sci 2009 34 85 96 19135374
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[212]Sohal RS Allen RG Experimental Gerontology 1990 25 499 522 2097168
[231]Sohal RS Sohal BH Mech Ageing Dev 1991 57 187 202 1904965

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Authors: Sohal, R. S., & Orr, W. C.
Affiliations: University of Southern California (US)
Southern Methodist University (US)
Corresponding author: Sohal, Rajindar S.
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2012-02
Volume: 52
Issue: 3
Pages: 539-555
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2011.10.445
PMC: PMC3267846
OpenAlex: W1986589519
Cited by: 473
References: 244
Citations by year: 2026: 14 · 2025: 22 · 2024: 21 · 2023: 24 · 2022: 24 · 2021: 24 · 2020: 29 · 2019: 32 · 2018: 34 · 2017: 35 · 2016: 33 · 2015: 46 · 2014: 57 · 2013: 43 · 2012: 32
FWCI: 3.83
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Free Radical Biology and Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01 AG15122, R01 AG 17077, R01 AG13563, R01-AG 7657, R01 AG17526, R01AG020715, R01AG007657, R01AG013563, R01 AG20715, R01AG017526, R01AG015122, R01AG017077)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords: aging, reactive oxygen species, reactive nitrogen species, oxidative stress, redox regulation, protein thiol oxidation, antioxidant defense, lifespan extension, redox signaling
MeSH terms: Aging, Animals, Cell Differentiation, Humans, Oxidation-Reduction, Oxygen Consumption, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Reactive Nitrogen Species, Growth and Development

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