Metformin Promotes Lifespan Through Mitohormesis Via the Peroxiredoxin PRDX-2

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Jun 4

PMID 24889636

Citations 160

Authors

Wouter De Haes

Lotte Frooninckx

Roel Van Assche

Arne Smolders

Geert Depuydt

Johan Billen

Bart P Braeckman

Liliane Schoofs

Liesbet Temmerman

Affiliations

Soon will be listed here.

Abstract

The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

Citing Articles

NFAT5 exacerbates β-cell ferroptosis by suppressing the transcription of PRDX2 in obese type 2 diabetes mellitus.

Guan G, Liu J, Zhang Q, He M, Liu H, Chen K Cell Mol Life Sci. 2025; 82(1):64.

PMID: 39875646 PMC: 11775373. DOI: 10.1007/s00018-024-05563-y.

Mutations of the Electron Transport Chain Affect Lifespan and ROS Levels in .

osz F, Nazir A, Takacs-Vellai K, Farkas Z Antioxidants (Basel). 2025; 14(1).

PMID: 39857410 PMC: 11761250. DOI: 10.3390/antiox14010076.

Diet-Modifiable Redox Alterations in Ageing and Cancer.

Hine C, Patel A, Ponti A Subcell Biochem. 2024; 107():129-172.

PMID: 39693023 PMC: 11753504. DOI: 10.1007/978-3-031-66768-8_7.

Targeting immunosenescence for improved tumor immunotherapy.

Liu Z, Zuo L, Zhou Z, Liu S, Ba Y, Zuo A MedComm (2020). 2024; 5(11):e777.

PMID: 39473905 PMC: 11518697. DOI: 10.1002/mco2.777.

Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit.

Cai C, Gu C, Meng C, He S, Thashi L, Deji D Pharm Res. 2024; 41(10):1907-1920.

PMID: 39375240 DOI: 10.1007/s11095-024-03777-0.

References

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Anisimov V, Berstein L, Egormin P, Piskunova T, Popovich I, Zabezhinski M . Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008; 7(17):2769-73. DOI: 10.4161/cc.7.17.6625. View

Depuydt G, Xie F, Petyuk V, Shanmugam N, Smolders A, Dhondt I . Reduced insulin/insulin-like growth factor-1 signaling and dietary restriction inhibit translation but preserve muscle mass in Caenorhabditis elegans. Mol Cell Proteomics. 2013; 12(12):3624-39. PMC: 3861712. DOI: 10.1074/mcp.M113.027383. View

Stachowicz A, Suski M, Olszanecki R, Madej J, Okon K, Korbut R . Proteomic analysis of liver mitochondria of apolipoprotein E knockout mice treated with metformin. J Proteomics. 2012; 77:167-75. DOI: 10.1016/j.jprot.2012.08.015. View

Miller R, Buehner G, Chang Y, Harper J, Sigler R, Smith-Wheelock M . Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005; 4(3):119-25. PMC: 7159399. DOI: 10.1111/j.1474-9726.2005.00152.x. View

Schulz T, Zarse K, Voigt A, Urban N, Birringer M, Ristow M . Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007; 6(4):280-93. DOI: 10.1016/j.cmet.2007.08.011. View

Rattan S . Hormesis in aging. Ageing Res Rev. 2007; 7(1):63-78. DOI: 10.1016/j.arr.2007.03.002. View

Grandison R, Piper M, Partridge L . Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature. 2009; 462(7276):1061-4. PMC: 2798000. DOI: 10.1038/nature08619. View

Cabreiro F, Au C, Leung K, Vergara-Irigaray N, Cocheme H, Noori T . Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013; 153(1):228-39. PMC: 3898468. DOI: 10.1016/j.cell.2013.02.035. View

10.

Huang D, Sherman B, Tan Q, Collins J, Alvord W, Roayaei J . The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 2007; 8(9):R183. PMC: 2375021. DOI: 10.1186/gb-2007-8-9-r183. View

11.

Newgard C . Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012; 15(5):606-14. PMC: 3695706. DOI: 10.1016/j.cmet.2012.01.024. View

12.

Thamsen M, Kumsta C, Li F, Jakob U . Is overoxidation of peroxiredoxin physiologically significant?. Antioxid Redox Signal. 2010; 14(4):725-30. PMC: 3021361. DOI: 10.1089/ars.2010.3717. View

13.

Harman D . Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11(3):298-300. DOI: 10.1093/geronj/11.3.298. View

14.

Fuchs S, Bundy J, Davies S, Viney J, Swire J, Leroi A . A metabolic signature of long life in Caenorhabditis elegans. BMC Biol. 2010; 8:14. PMC: 2829508. DOI: 10.1186/1741-7007-8-14. View

15.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

16.

De Simone R, Vissicchio F, Mingarelli C, De Nuccio C, Visentin S, Ajmone-Cat M . Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta. 2013; 1832(5):650-9. DOI: 10.1016/j.bbadis.2013.02.001. View

17.

Ota S, Horigome K, Ishii T, Nakai M, Hayashi K, Kawamura T . Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun. 2009; 388(2):311-6. DOI: 10.1016/j.bbrc.2009.07.164. View

18.

Schmeisser S, Priebe S, Groth M, Monajembashi S, Hemmerich P, Guthke R . Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension. Mol Metab. 2013; 2(2):92-102. PMC: 3817383. DOI: 10.1016/j.molmet.2013.02.002. View

19.

Martin-Montalvo A, Mercken E, Mitchell S, Palacios H, Mote P, Scheibye-Knudsen M . Metformin improves healthspan and lifespan in mice. Nat Commun. 2013; 4:2192. PMC: 3736576. DOI: 10.1038/ncomms3192. View

20.

Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow D . Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab. 2012; 15(4):451-65. PMC: 4844853. DOI: 10.1016/j.cmet.2012.02.013. View