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Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging

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Abstract

Cadmium (Cd) accumulates with aging and is elevated in long-lived species. Metallothioneins (MTs), small cysteine-rich proteins involved in metal homeostasis and Cd detoxification, are known to be related to longevity. However, the relationship between Cd accumulation, the role of MTs, and aging is currently unclear. Specifically, we do not know if long-lived species evolved an efficient metal stress response by upregulating their MT levels to reduce the toxic effects of environmental pollutants, such as Cd, that accumulate over their longer life span. It is also unknown if the number of MT genes, their expression, or both protect the organisms from potentially damaging effects during aging. To address these questions, we reanalyzed several cross-species studies and obtained data on MT expression and Cd accumulation in long-lived mouse models. We confirmed a relationship between species maximum life span in captive mammals and their Cd content in liver and kidney. We found that although the number of MT genes does not affect longevity, gene expression and protein amount of specific MT paralogs are strongly related to life span in mammals. MT expression rather than gene number may influence the high Cd levels and longevity of some species. In support of this, we found that overexpression of MT-1 accelerated Cd accumulation in mice and that tissue Cd was higher in long-lived mouse strains with high MT expression. We conclude that long-lived species have evolved a more efficient stress response by upregulating the expression of MT genes in presence of Cd, which contributes to elevated tissue Cd levels.

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Acknowledgements

We wish to thank Emilio Casanova, Richard Miller, and Thomas Weichhart for providing mouse tissues. Old mice were provided by Gerald de Haan and Ronald van Os through the Mouse Clinic for Cancer and Aging (MCCA), funded by a Large Infrastructure grant from the Netherlands Organization for Scientific Research (NWO). Finally, we are thankful to Isabella Capellini for discussion on the results of the phylogenetic comparative analyses and to Vincent Lynch for general discussion about metallothioneins and aging. We are thankful to Richard Miller for useful comments on this article. YC is grateful to the National Science Foundation (NSF) for supporting work related to this project.

Funding

This study was supported by Ricerca Corrente funding from Italian Ministry of Health to MP, MM, and RG as well as from Austrian Science Fund FWF (Grant: P22323-B17 and V 197-B17) to TV.

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Authors and Affiliations

  1. Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Wien, Vienna, Austria

    Kamil Pabis, Elisabeth Straka & Claudia Gundacker

  2. Department of Biology, George Mason University, Fairfax, VA, 22030, USA

    Ylenia Chiari

  3. Department of Physics and Astronomy, University of Bologna, 40126, Bologna, Italy

    Claudia Sala

  4. Advanced Technology Center for Aging Research, IRCCS INRCA, 60121, Ancona, Italy

    Robertina Giacconi, Mauro Provinciali & Marco Malavolta

  5. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA

    Xinna Li

  6. Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58203, USA

    Holly Brown-Borg

  7. Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Karin Nowikovsky

  8. Department of Animal Science and Technology, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of China

    Teresa G. Valencak

  9. Department of Experimental, Diagnostic and Specialty Medicine (DIMES), and Interdepartmental Centre “L. Galvani” (CIG), University of Bologna, Bologna, Italy

    Paolo Garagnani

  10. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Paolo Garagnani

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Contributions

Conception of the work: M.M., K.N., and M.P.

Data collection: K.P., E.S., R.G., H.B., Y.C.

Data analysis and interpretation: Y.C., K.P., C.G., E.S., M.M., C.S., P.G.

Drafting the article: Y.C., K.P., M.M.

Critical revision: Y.C., K.P., M.M., C.G., T.V., H.B.

Corresponding author

Correspondence to Marco Malavolta.

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All samples used in this study consisted of leftover samples stored in mouse tissues biobanks. These samples originated from different studies which were originally approved by the respective local ethical committees.

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The data that support the findings of this study are available in the Supplementary data 1 of this article.

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The authors declare no competing interests.

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Kamil Pabis and Ylenia Chiari shared first authorship.

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Pabis, K., Chiari, Y., Sala, C. et al. Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging. GeroScience 43, 1975–1993 (2021). https://doi.org/10.1007/s11357-021-00393-3

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