A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5'AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging.

Institute of Physiology Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic ; Department of Biochemistry and Microbiology Institute of Chemical Technology Prague Technická 5 166 28 Prague Czech Republic

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U. S. National Institute of Aging and World Health Organization. Global Health and Aging. Geneva, Switzerland: World Health Organization; 2011.

Harman D. The biologic clock: the mitochondria? Journal of the American Geriatrics Society. 1972;20(4):145–147. doi: 10.1111/j.1532-5415.1972.tb00787.x. PubMed DOI

Barja G. Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxidants & Redox Signaling. 2013;19(12):1420–1445. doi: 10.1089/ars.2012.5148. PubMed DOI PMC

Ristow M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nature Medicine. 2014;20(7):709–711. doi: 10.1038/nm.3624. PubMed DOI

Kawagishi H., Finkel T. Unraveling the truth about antioxidants: ROS and disease: finding the right balance. Nature Medicine. 2014;20(7):711–713. doi: 10.1038/nm.3625. PubMed DOI

Yan L. J. Positive oxidative stress in aging and aging-related disease tolerance. Redox Biology. 2014;2(1):165–169. doi: 10.1016/j.redox.2014.01.002. PubMed DOI PMC

Yun J., Finkel T. Mitohormesis. Cell Metabolism. 2014;19(5):757–766. doi: 10.1016/j.cmet.2014.01.011. PubMed DOI PMC

Ristow M., Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS) Dose-Response. 2014;12(2):288–341. doi: 10.2203/dose-response.13-035.ristow. PubMed DOI PMC

Hwang A. B., Ryu E. A., Artan M., et al. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans . Proceedings of the National Academy of Sciences of the United States of America. 2014;111(42):E4458–E4467. doi: 10.1073/pnas.1411199111. PubMed DOI PMC

Wang D., Malo D., Hekimi S. Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1alpha in long-lived Mclk1 +/– mouse mutants. Journal of Immunology. 2010;184(2):582–590. doi: 10.4049/jimmunol.0902352. PubMed DOI

Ristow M., Zarse K., Oberbach A., et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(21):8665–8670. doi: 10.1073/pnas.0903485106. PubMed DOI PMC

Liu C., Wu J., Zhu J., et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. The Journal of Biological Chemistry. 2009;284(5):2811–2822. doi: 10.1074/jbc.m806409200. PubMed DOI

Roland C. L., Arumugam T., Deng D., et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Research. 2014;74(18):5301–5310. doi: 10.1158/0008-5472.can-14-0319. PubMed DOI PMC

Hoque R., Farooq A., Ghani A., Gorelick F., Mehal W. Z. Lactate reduces liver and pancreatic injury in toll-like receptor- and inflammasome-mediated inflammation via gpr81-mediated suppression of innate immunity. Gastroenterology. 2014;146(7):1763–1774. doi: 10.1053/j.gastro.2014.03.014. PubMed DOI PMC

Tang F., Lane S., Korsak A., et al. Lactate-mediated glia-neuronal signalling in the mammalian brain. Nature Communications. 2014;5, article 3284 doi: 10.1038/ncomms4284. PubMed DOI PMC

Lauritzen K. H., Morland C., Puchades M., et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cerebral Cortex. 2014;24(10):2784–2795. doi: 10.1093/cercor/bht136. PubMed DOI

Hashimoto T., Hussien R., Oommen S., Gohil K., Brooks G. A. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. The FASEB Journal. 2007;21(10):2602–2612. doi: 10.1096/fj.07-8174com. PubMed DOI

Gambini J., Gomez-Cabrera M. C., Borras C., et al. Free [NADH]/[NAD+] regulates sirtuin expression. Archives of Biochemistry and Biophysics. 2011;512(1):24–29. doi: 10.1016/j.abb.2011.04.020. PubMed DOI

Lezi E., Lu J., Selfridge J. E., Burns J. M., Swerdlow R. H. Lactate administration reproduces specific brain and liver exercise-related changes. Journal of Neurochemistry. 2013;127(1):91–100. doi: 10.1111/jnc.12394. PubMed DOI PMC

Coco M., Caggia S., Musumeci G., et al. Sodium L-lactate differently affects brain-derived neurothrophic factor, inducible nitric oxide synthase, and heat shock protein 70 kDa production in human astrocytes and SH-SY5Y cultures. Journal of Neuroscience Research. 2013;91(2):313–320. doi: 10.1002/jnr.23154. PubMed DOI

Schiffer T., Schulte S., Sperlich B., Achtzehn S., Fricke H., Strüder H. K. Lactate infusion at rest increases BDNF blood concentration in humans. Neuroscience Letters. 2011;488(3):234–237. doi: 10.1016/j.neulet.2010.11.035. PubMed DOI

Sonveaux P., Copetti T., De Saedeleer C. J., et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE. 2012;7(3) doi: 10.1371/journal.pone.0033418.e33418 PubMed DOI PMC

Samuvel D. J., Sundararaj K. P., Nareika A., Lopes-Virella M. F., Huang Y. Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. Journal of Immunology. 2009;182(4):2476–2484. doi: 10.4049/jimmunol.0802059. PubMed DOI PMC

LeBleu V. S., O’Connell J. T., Herrera K. N. G., et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature Cell Biology. 2014;16(10):992–1003. doi: 10.1038/ncb3039. PubMed DOI PMC

Debacq-Chainiaux F., Erusalimsky J. D., Campisi J., Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nature Protocols. 2009;4(12):1798–1806. doi: 10.1038/nprot.2009.191. PubMed DOI

Koníčková R., Vaňková K., Vaníková J., et al. Anti-cancer effects of blue-green alga Spirulina platensis, a natural source of bilirubin-like tetrapyrrolic compounds. Annals of Hepatology. 2014;13(2):273–283. PubMed

Guo W., Jiang L., Bhasin S., Khan S. M., Swerdlow R. H. DNA extraction procedures meaningfully influence qPCR-based mtDNA copy number determination. Mitochondrion. 2009;9(4):261–265. doi: 10.1016/j.mito.2009.03.003. PubMed DOI PMC

Alán L., Špaček T., Zelenka J., et al. Assessment of mitochondrial DNA as an indicator of islet quality: an example in Goto Kakizaki rats. Transplantation Proceedings. 2011;43(9):3281–3284. doi: 10.1016/j.transproceed.2011.09.055. PubMed DOI

Votyakova T. V., Reynolds I. J. ΔΨm-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. Journal of Neurochemistry. 2001;79(2):266–277. doi: 10.1046/j.1471-4159.2001.00548.x. PubMed DOI

Emhoff C.-A. W., Messonnier L. A., Horning M. A., Fattor J. A., Carlson T. J., Brooks G. A. Direct and indirect lactate oxidation in trained and untrained men. Journal of Applied Physiology. 2013;115(6):829–838. doi: 10.1152/japplphysiol.00538.2013. PubMed DOI PMC

Lemons J. M. S., Feng X.-J., Bennett B. D., et al. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biology. 2010;8(10) doi: 10.1371/journal.pbio.1000514.e1000514 PubMed DOI PMC

Adeva M., González-Lucán M., Seco M., Donapetry C. Enzymes involved in L-lactate metabolism in humans. Mitochondrion. 2013;13(6):615–629. doi: 10.1016/j.mito.2013.08.011. PubMed DOI

Mullen A., Hu Z., Shi X., et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Reports. 2014;7(5):1679–1690. doi: 10.1016/j.celrep.2014.04.037. PubMed DOI PMC

de Bari L., Valenti D., Atlante A., Passarella S. L-Lactate generates hydrogen peroxide in purified rat liver mitochondria due to the putative L-lactate oxidase localized in the intermembrane space. FEBS Letters. 2010;584(11):2285–2290. doi: 10.1016/j.febslet.2010.03.038. PubMed DOI

Owusu-Ansah E., Song W., Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell. 2013;155(3):699–712. doi: 10.1016/j.cell.2013.09.021. PubMed DOI PMC

Jäer S., Handschin C., St-Pierre J., Spiegelman B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α . Proceedings of the National Academy of Sciences of the United States of America. 2007;104(29):12017–12022. doi: 10.1073/pnas.0705070104. PubMed DOI PMC

Wenz T., Rossi S. G., Rotundo R. L., Spiegelman B. M., Moraes C. T. Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(48):20405–20410. doi: 10.1073/pnas.0911570106. PubMed DOI PMC

Handschin C., Spiegelman B. M. The role of exercise and PGC1α in inflammation and chronic disease. Nature. 2008;454(7203):463–469. doi: 10.1038/nature07206. PubMed DOI PMC

Lagouge M., Larsson N. G. The role of mitochondrial DNA mutations and free radicals in disease and ageing. Journal of Internal Medicine. 2013;273(6):529–543. doi: 10.1111/joim.12055. PubMed DOI PMC

Ikeda Y., Sciarretta S., Nagarajan N., et al. New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart. Oxidative Medicine and Cellular Longevity. 2014;2014:13. doi: 10.1155/2014/210934.210934 PubMed DOI PMC

Barbieri E., Agostini D., Polidori E., et al. The pleiotropic effect of physical exercise on mitochondrial dynamics in aging skeletal muscle. Oxidative Medicine and Cellular Longevity. 2015;2015:15. doi: 10.1155/2015/917085.917085 PubMed DOI PMC

Rattan S. I. S. Targeting the age-related occurrence, removal, and accumulation of molecular damage by hormesis. Annals of the New York Academy of Sciences. 2010;1197:28–32. doi: 10.1111/j.1749-6632.2010.05193.x. PubMed DOI

Zoncu R., Efeyan A., Sabatini D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Reviews Molecular Cell Biology. 2011;12(1):21–35. doi: 10.1038/nrm3025. PubMed DOI PMC

Sarbassov D. D., Sabatini D. M. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. The Journal of Biological Chemistry. 2005;280(47):39505–39509. doi: 10.1074/jbc.m506096200. PubMed DOI

Campisi J. Aging, cellular senescence, and cancer. Annual Review of Physiology. 2013;75:685–705. doi: 10.1146/annurev-physiol-030212-183653. PubMed DOI PMC

Wu J. J., Quijano C., Chen E., et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging. 2009;1(4):425–437. PubMed PMC

Klionsky D. J., Abdalla F. C., Abeliovich H., et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8(4):445–544. PubMed PMC

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