SOD2 deficiency promotes aging phenotypes in mouse skin
Open accessAbstract
Reactive oxygen species (ROS) are essential for survival but also pose serious risks to that survival. A particularly striking example was the demonstration in 2003 by the Campisi group that primary mouse fibroblasts have an indefinite proliferative lifespan in 3% oxygen, the amount found in the capillaries feeding the tissues, but greatly shortened ones under normal in vitro culturing conditions, i. e., 20% oxygen [1]. Now, the same group has generated some insights into how oxidative stress contributes to cellular senescence and aging phenotypes in mouse skin [2]. ROS may be produced in a regulated manner during cellular metabolism but they can also arise in an unregulated manner by metabolic dysfunctions and by exogenous stresses. ROS production is typically localized in cellular compartments by NAD(P)H oxidases, lipoxygenases, cyclooxygenases among others as well as by the mitochondrial electron-transport chain [3]. At physiological levels, ROS play beneficial or even essential roles as regulatory mediators in signalling or defence processes, including the promotion of endothelium-dependent vasorelaxation, apoptosis, angiogenesis, erythropoietin production and destruction of bacteria and other foreign substances by macrophages [4]. However, compromised homeostatic pathways lead to elevated ROS levels that may result in the damage of cellular components (i.e., proteins, lipids, DNA). A growing body of evidence implicates oxidative stress in both aging and a wide spectrum of human diseases including diabetes, atherosclerosis, hypertension, cancer, cardiovascular diseases and neurodegenerative diseases among others [5]. The counterpoint of deleterious and useful ROS roles may have provided evolutionary pressure to develop robust pathways for intracellular redox homeostasis including antioxidants such as glutathione peroxidases, peroxiredoxins, catalases and SODs. The first line of defence against ROS appears to be one of the superoxide dismutases, SOD2, (aka manganese superoxide dismutase (MnSOD)). SOD2 is a mitochondrial matrix protein that converts the superoxide anion (O2−) to hydrogen peroxide (H2O2), which is in turn, converted to molecular oxygen and water by catalase and peroxiredoxins. In this Aging paper, the Campisi group showed that normal aged mice exhibit impaired mitochondrial complex II activity and increased frequencies of senescent cells. They observed similar phenotypes in SOD2 knockout (KO) mice at very young ages and also reported that these mice exhibit significant epidermal thinning which is an age-associated phenotype in humans as well as mice. The epidermal thinning appeared to be due to decreased cellular proliferation in the senescent skin tissue rather than increased apoptosis. In addition, senescence in SOD2 KO mouse skin correlated with increased levels of two senescence markers, SA-βgal activity and the p16INK4a tumor suppressor, as well as amplified keratinocyte terminal differentiation (Figure (Figure1).1). Moreover, these features are accompanied by the presence of nuclear DNA damage in the epidermis, a characteristic linked to senescence in both mouse and human cells in culture [6]. Figure 1 Scheme illustrating the putative role of SOD2 in skin aging Similar to the observations made in mice, other studies in yeast and Drosophila also show a predominant role for SOD2 in increasing the lifespan [7-9]. However, the evidence of a direct link between aging and elevated ROS levels is not undisputed. For example, mice heterozygous for SOD2 exhibited accrued DNA damage and subsequent predisposition to cancer, but without any impact on the lifespan [10]. In mice with a mutated mitochondrial DNA polymerase, PolG, ROS production was not significantly increased but the mitochondria accumulated mutations which, in turn, resulted in dysfunctions leading to several aging phenotypes and early death [11, 12]. Other studies failed to find a direct link between SOD2 and aging. A study with mice showed that SOD2 overexpression, while resulting in decreased lipid peroxidation, did not alter either lifespan or age-related pathology [13]. In the nematode, depletion of SOD2 increased oxidative stress but lifespan could still be dramatically prolonged [14]. Also, in the human colorectal cancer cell line HCT116, SOD2 overexpression unexpectedly induced growth arrest and increased senescence [15]. These discrepancies may be explained by the differential responses between species and cell types to a rise in ROS levels. The shorter lifespan observed in SOD2 KO mice compared to wild-type and heterozygous mice may be reminiscent of previous studies showing that rates of mitochondrial O2− and H2O2 generation were inversely correlated to maximum life span potential with shorter-lived species producing relatively higher amounts of ROS [16]. Because SOD2 plays a role in aging in mice, it would be interesting to look if a correlation exists between age-related pathologies
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
MnSOD has been linked to radiation resistance, and its deficiency can promote appearance of accelerated aging phenotypes.
“MnSOD has been linked to radiation resistance, and its deficiency can promote the appearance of accelerated aging phenotypes (Hosoki et al., 2012; Velarde et al., 2012; Weyemi et al., 2012).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Weyemi et al., 2012
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Free radicals and antioxidants in normal physiological functions and human disease
Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T. D., Mazur, M., & Telser, J. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2006.07.001 · Cited by 14,269 · see citing works
Signal transduction by reactive oxygen species
Finkel, T. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201102095 · Cited by 2,322 · see citing works
Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts
Parrinello, S., Samper, E., Krtolica, A., Goldstein, J., Melov, S., & Campisi, J. (2003) · Nature Cell Biology · doi:10.1038/ncb1024 · Cited by 1,116 · see citing works
Van Remmen, H., Ikeno, Y., Hamilton, M., Pahlavani, M., Wolf, N., Thorpe, S. R., Alderson, N. L., Baynes, J. W., Epstein, C. J., Huang, T.-T., et al. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00122.2003 · Cited by 734 · see citing works
Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production
Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A. T., Dufour, E., Khvorostov, I., Spelbrink, J. N., Wibom, R., Jacobs, H. T., & Larsson, N.-G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508886102 · Cited by 555 · see citing works
Somatic Mitochondrial DNA Mutations in Mammalian Aging
Larsson, N. (2010) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060408-093701 · Cited by 543 · see citing works
Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans
Van Raamsdonk, J. M., & Hekimi, S. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000361 · Cited by 511 · see citing works
Ku, H., Brunk, U. T., & Sohal, R. S. (1993) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(93)90165-q · Cited by 488 · see citing works
Sun, J., Folk, D. G., Bradley, T. J., & Tower, J. (2002) · Genetics · doi:10.1093/genetics/161.2.661 · Cited by 381 · see citing works
Role of oxidatively induced DNA lesions in human pathogenesis
Sedelnikova, O. A., Redon, C. E., Dickey, J. S., Nakamura, A., Georgakilas, A. G., & Bonner, W. M. (2010) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2009.12.005 · Cited by 339 · see citing works
Velarde, M. C., Flynn, J. M., Day, N. U., Melov, S., & Campisi, J. (2012) · Aging · doi:10.18632/aging.100423 · Cited by 299 · see citing works
Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice
Jang, Y. C., Pérez, V., Song, W. J., Lustgarten, M. S., Salmon, A. B., Mele, J., Qi, W., Liu, Y., Liang, H., Chaudhuri, A. R., et al. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp100 · Cited by 201 · see citing works
Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence
Nakamura, A. J., Chiang, Y. J., Hathcock, K. S., Horikawa, I., Sedelnikova, O. A., Hodes, R. J., & Bonner, W. M. (2008) · Epigenetics & Chromatin · doi:10.1186/1756-8935-1-6 · Cited by 168 · see citing works
The role of mitochondria in neurodegenerative diseases
Filosto, M., Scarpelli, M., Cotelli, M. S., Vielmi, V., Todeschini, A., Gregorelli, V., Tonin, P., Tomelleri, G., & Padovani, A. (2011) · Journal of Neurology · doi:10.1007/s00415-011-6104-z · Cited by 140 · see citing works
Bonawitz, N. D., Rodeheffer, M. S., & Shadel, G. S. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02360-05 · Cited by 137 · see citing works
Manganese Superoxide Dismutase Induces p53-Dependent Senescence in Colorectal Cancer Cells
Behrend, L., Mohr, A., Dick, T., & Zwacka, R. M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.17.7758-7769.2005 · Cited by 108 · see citing works
Effects of Deleting Mitochondrial Antioxidant Genes on Life Span
Ünlü, E. S., & Koç, A. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1395.055 · Cited by 71 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Iglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.06.007 · Cited by 284 · see citing works
Aging in the dermis: Fibroblast senescence and its significance
Zhang, J., Yu, H., Man, M., & Hu, L. (2023) · Aging Cell · doi:10.1111/acel.14054 · Cited by 249 · see citing works
Reactive Molecule Species and Antioxidative Mechanisms in Normal Skin and Skin Aging
Wölfle, U., Seelinger, G., Bauer, G., Meinke, M. C., Lademann, J., & Schempp, C. M. (2014) · Skin Pharmacology and Physiology · doi:10.1159/000360092 · Cited by 142 · see citing works
Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis
Sosulski, M. L., Gongora, R., Feghali‐Bostwick, C. A., Lasky, J. A., & Sánchez, C. G. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw151 · Cited by 104 · see citing works
Mitochondria’s Role in Skin Ageing
Stout, R., & Birch‐Machin, M. A. (2019) · Biology · doi:10.3390/biology8020029 · Cited by 100 · see citing works
Transcriptome and ultrastructural changes in dystrophic Epidermolysis bullosa resemble skin aging
Breitenbach, J., Rinnerthaler, M., Trost, A., Weber, M., Klausegger, A., Guttmann‐Gruber, C., Bruckner, D., Reitsamer, H. A., Bauer, J. W., & Breitenbach, M. (2015) · Aging · doi:10.18632/aging.100755 · Cited by 69 · see citing works
Zou, X., Santa-Maria, C. A., O’Brien, J., Gius, D. R., & Zhu, Y. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6641 · Cited by 44 · see citing works
Mitochondrial membrane lipidome defines yeast longevity
Beach, A., Richard, V. R., Leonov, A., Burstein, M. T., Bourque, S. D., Koupaki, O., Juneau, M., Feldman, R., Iouk, T. L., & Titorenko, V. I. (2013) · Aging · doi:10.18632/aging.100578 · Cited by 43 · see citing works
In vitro model adapted to the study of skin ageing induced by air pollution
Lecas, S., Boursier, E., Fitoussi, R., Vié, K., Momas, I., Séta, N., & Achard, S. (2016) · Toxicology Letters · doi:10.1016/j.toxlet.2016.07.026 · Cited by 43 · see citing works
Silva, S. M. E., Calixto, G. M. F., Cajado, J., Carvalho, P. D., Rodero, C. F., Chorilli, M., & Leonardi, G. R. (2017) · Polymers · doi:10.3390/polym9090391 · Cited by 40 · see citing works
Skin aging and oxidative stress
Ahsanuddin, S., Lam, M. C., & Baron, E. D. (2016) · AIMS molecular science · doi:10.3934/molsci.2016.2.187 · Cited by 26 · see citing works
Moisturizing and Antioxidant Effects of Artemisia argyi Essence Liquid in HaCaT Keratinocytes
Wang, Z., Wang, Q.-L., Zhong, W., Liang, F., Guo, Y., Wang, Y., & Wang, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076809 · Cited by 21 · see citing works
Du, K., Yu, Y., Zhang, D., Luo, W., Huang, H., Chen, J., Gao, J., & Huang, C. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-06-0343 · Cited by 19 · see citing works
The Role of PGC-1α in Aging Skin Barrier Function
Luo, Y., & Bollag, W. B. (2024) · Cells · doi:10.3390/cells13131135 · Cited by 15 · see citing works
da Cruz, I. B. M., Bonotto, N. C. D. A., Turra, B. O., Teixeira, C. F., Azzolin, V. F., Ribeiro, E. A. M., Piccoli, J. D. C. E., & Barbisan, F. (2023) · Toxicology in Vitro · doi:10.1016/j.tiv.2023.105637 · Cited by 15 · see citing works
Proteomic and phosphoproteomic signatures of aging mouse liver
Mohallem, R., Schaser, A. J., & Aryal, U. K. (2025) · GeroScience · doi:10.1007/s11357-025-01601-0 · Cited by 8 · see citing works
Target action of antioxidants using iontophoresis
Silva, S. A. M. E., de Souza, J. G., Melo, P. S., Moreno, I. A. M., de Alencar, S. M., Lopez, R. F. V., & Leonardi, G. R. (2020) · Journal of Cosmetic Dermatology · doi:10.1111/jocd.13560 · Cited by 8 · see citing works
Aging and Aging-Related Senescence in Liver
Ganguly, S., Sakane, S., Hokutan, K., Zhang, V., Miciano, C., Wang, A., Brenner, D. A., & Kisseleva, T. (2025) · Seminars in Liver Disease · doi:10.1055/a-2637-2549 · Cited by 8 · see citing works
Tarbashevich, K., Ermlich, L., Wegner, J. W., Pfeiffer, J., & Raz, E. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1250643 · Cited by 5 · see citing works
Genetic regulation of newborn telomere length is mediated and modified by DNA methylation
Wang, C., Alfano, R., Reimann, B., Hogervorst, J. G. F., Bustamante, M., Vivo, I. D., Plusquin, M., Nawrot, T. S., & Martens, D. S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.934277 · Cited by 4 · see citing works
A consensus single-cell transcriptomic atlas of dermal fibroblast heterogeneityPreprint
Ascensión, A. M., & Izeta, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.05.611379 · Cited by 4 · see citing works
Kobayashi, K., Sudasinghe, K., Bender, R., Suzauddula, M., Li, C., Wu, C., Li, Y., & Wang, W. (2025) · Nutrients · doi:10.3390/nu17182954 · Cited by 2 · see citing works
Biswas, B. K., & Goswami, R. (2021) · Meta Gene · doi:10.1016/j.mgene.2021.100886 · Cited by 2 · see citing works
Multiscale analysis of acne connects molecular subnetworks with disease statusPreprint
Hall, J. B., Divaraniya, A. A., Lee, H.-C., Becker, C., McCauley, B. D., Glowe, P. K., Sebra, R., Pavel, A. B., Singer, G., Nelson, A. M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/587857 · Cited by 2 · see citing works
Zhou, Z., Zhao, L., Chen, L., Zhao, X., Xinwei, L., Luo, X., Zhang, B., Miao, J., & Liu, F. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1888269 · Cited by 1 · see citing works
Kageyama, S., Sato, Y., Escareal, Z. A. K. B., Amano, M., Maejima, Y., Kawabata, Y., & Namba, T. (2026) · Nutrients · doi:10.3390/nu18132163
Belova, Y. I., Fedorina, A. I., Дробинцева, А. О., Gracheva, S. G., Nasyrov, R. A., Kvetnoy, I. M., & Pinto, E. (2026) · Успехи геронтологии · doi:10.34922/ae.2026.39.3.016
Multi-omic profiling of cardiomyocyte ageing and functional decline
Yücel, D., Trembley, M. A., Ke, Q., Wu, Z., Bonde, D., Kang, P., & Pu, W. T. (2026) · Cardiovascular Research · doi:10.1093/cvr/cvag165
Tauser, R.-G., Ionescu, O.-M., Apotrosoaei, M., Lupaşcu, F., Profire, B.-Ș., Iacob, A.-T., Vasincu, I. M., Lupașcu, D., & Profire, L. (2026) · Cosmetics · doi:10.3390/cosmetics13050241
Takaya, K., Okura, M., & Reiter, R. J. (2026) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2026.10.009
- Authors
- Weyemi, U., Parekh, P. R., Redon, C. E., & Bonner, W. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Bonner, William M.
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2012-02-11
- Volume
- 4
- Issue
- 2
- Pages
- 116-118
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC3314173
- OpenAlex
- W2127962084
- Cited by
- 30
- References
- 17
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- manganese superoxide dismutase, skin aging, oxidative stress, cellular senescence, epidermal thinning, reactive oxygen species, succinate dehydrogenase, Sod2 knockout mice, redox homeostasis, superoxide, hydrogen peroxide, catalase, peroxiredoxin, glutathione peroxidase, epidermal keratinocytes
- MeSH terms
- Superoxide Dismutase 2, Animals, Models, Biological, Phenotype, Skin, Superoxide Dismutase, Skin Aging, Reactive Oxygen Species, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
