Iron as a target of chemoprevention for longevity in humans

Our plain-English summary of Iron as a target of chemoprevention for longevity in humans, by S. Toyokuni (Free Radical Research, 2011).

The study

• Author: S. Toyokuni
• Journal: Free Radical Research
• Published: 2011;45(8):906-17
• Type of article: Review
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.

In plain English

This article was a review by a single author at Nagoya University, Japan. It described no new study of its own, but mentioned some unpublished results from the author's laboratory. The author argued that excess body iron could be a target for preventing several major diseases, reviewing iron overload in atherosclerosis, cancer, neurodegenerative diseases and infection. On asbestos, the author cited the author's own earlier work suggesting that local iron overload is important for asbestos-induced cancer, and noted that crocidolite and amosite contain a high amount of iron. Citing unpublished results, the author wrote that chrysotile was the earliest commercial asbestos to induce peritoneal mesothelioma with massive iron deposits, and suggested it may be the main cause of pleural mesothelioma. The author also described earlier rat experiments in which iron saccharate injections, without fibres, caused peritoneal mesothelioma. The author acknowledged that for some diseases the data are still controversial. The author concluded that it is time to consider reducing iron stores to prevent common diseases in people in a good nutritional state for their age with no serious disease, and that more evidence is needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review article proposing iron reduction as disease prevention. It describes no new study of its own, but mentions some unpublished results from the author's laboratory without presenting their data.
• Who was studied: No study population. The author reviewed published and some unpublished research on iron metabolism and iron overload in atherosclerosis, cancer (including asbestos-related mesothelioma), neurodegenerative diseases and infection. That research covered humans, animals and laboratory work.
• Exposure: Iron overload. Asbestos was discussed as one condition associated with iron overload. This covered crocidolite and amosite, which the author described as iron-rich, and chrysotile. Iron compounds used in animal experiments, such as ferric nitrilotriacetate and iron saccharate, were also discussed.
• Main results:
  • The author cited a previous study from the author's own laboratory suggesting that local iron overload is important for asbestos-induced carcinogenesis.
  • Based on unpublished results from the author's laboratory, the author wrote that chrysotile was the earliest commercial asbestos type to induce peritoneal mesothelioma with massive iron deposits. The author then suggested that chrysotile may be the main cause of pleural mesothelioma, as others had previously suggested.
  • The author proposed that chrysotile, although not iron-rich like crocidolite and amosite, also acts in an iron overload-dependent way. In this account, chrysotile breaks down red blood cells and heme collects on its surface. This proposal was partly based on unpublished results.
  • Citing unpublished results, the author reported that homozygous deletion of CDKN2A/2B was a major genomic change in asbestos-induced mesothelioma in rats. The author noted that this change is also a major change in human mesothelioma.
  • The author cited earlier rat experiments in which intraperitoneal iron saccharate caused peritoneal mesothelioma. From these, the author argued that fibrous structure is not essential and that iron overload is the critical factor in mesothelial cancer.
  • The author discussed a 2008 report that iron reduction by phlebotomy was associated with decreased cancer risk in people with peripheral arterial disease. The author noted criticisms of that report, including that it was not designed to study cancer.
• The authors' conclusion: The author concluded that it is time to consider reducing iron stores to prevent common diseases, in people who are in a good nutritional state for their age and have no serious disease. The author added that more evidence of the preventive effects of iron removal is needed.
• Limitations the authors state:
  • The author acknowledged that the evidence linking iron overload to disease is solid for some diseases but still controversial for others.

Topics

Medical terms in this study, explained in our Lexicon: Homozygous Deletion, CDKN2A, Carcinogenesis.

Related studies

• Role of iron in carcinogenesis: cancer as a ferrotoxic disease — S. Toyokuni (2009)
• Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells — A. Baldys, A.E. Aust (2005)
• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Cancer risks among iron and steel workers in Anshan, China, Part I: Proportional mortality ratio analysis — Z. Xu, G.W. Pan, et al. (1996)
• Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model — D. Minami, N. Takigawa, et al. (2015)
• Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells — C.C. Chao, S.H. Park, et al. (1996)

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