Skip to main content
SpringerLink
Log in

Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis

  • ORIGINAL ARTICLE
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01 µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus’s ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug’s ability to restore multiple cellular homeostasis mechanisms.

Graphical Abstract

Everolimus inhibits mTORC1 and promotes autophagy in CD4 + T cells from O adults, which induces the activation and translocation of NRF2 to the nucleus. NRF2 induces the production of first-line antioxidant enzymes SOD1, SOD2, and catalase, thus lowering reactive oxygen species and proinflammatory cytokine production

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Single-cell RNA sequencing data is available on Gene Expression Omnibus (GEO), accession number GSE 241492. Graphical abstract was created using Biorender.

References

  1. Saxton RA, Sabatini DM. MTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mannick JB, Lamming DW. Targeting the biology of aging with MTOR inhibitors. Nat Aging. 2023;3:642–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, et al. MTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):ra179. https://doi.org/10.1126/scitranslmed.3009892.

    Article  CAS  Google Scholar 

  4. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang Y, Li YB, Yin JJ, Wang Y, Zhu LB, Xie GY, Pan SH. Autophagy regulates inflammation following oxidative injury in diabetes. Autophagy. 2013;9:272–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhu Q, Wang R, Nemecio D, Liang C. How autophagy is tied to inflammation and cancer. Mol Cell Oncol 2020;7 https://doi.org/10.1080/23723556.2020.1717908.

  7. Fujikake N, Shin M, Shimizu S. Association between autophagy and neurodegenerative diseases. Front Neurosci 2018;12.

  8. Wu DJ, Adamopoulos IE. Autophagy and autoimmunity. Clin Immunol. 2017;176:55–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bharath LP, Rockhold JD, Conway R. Selective autophagy in hyperglycemia‐induced microvascular and macrovascular diseases. Cells 2021;10.

  10. Goldberg EL, Dixit VD. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015;265:63–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity. 2021;54:437–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Conway R, Rockhold JD, Santacruz-calvo S, Zukowski E, Pugh GH, Hasturk H, Kern PA, Nikolajczyk BS, Bharath, LP. Obesity and fatty acids promote mitochondrial translocation of STAT3 through ROS-dependent mechanisms. 2022;3:1–11. https://doi.org/10.3389/fragi.2022.924003.

  13. Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, Jiang K, Liu R, Guo Z, Deeney J, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 2020;32:44-55.e6. https://doi.org/10.1016/j.cmet.2020.04.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Valente AJ, Maddalena LA, Robb EL, Moradi F, Stuart JA. A Simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem. 2017;119:315–26. https://doi.org/10.1016/j.acthis.2017.03.001.

    Article  CAS  PubMed  Google Scholar 

  15. Kirber MT, Chen K, Keany JF. YFP photoconversion revisited: confirmation of the CFP-like species. Nat Methods. 2007;4:767–8.

    Article  CAS  PubMed  Google Scholar 

  16. Bolte S, Cordelières FP. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2006;224:213–32. https://doi.org/10.1111/j.1365-2818.2006.01706.x.

    Article  CAS  PubMed  Google Scholar 

  17. Adler J, Parmryd I. Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander’s overlap coefficient. Cytometry A. 2010;77:733–42. https://doi.org/10.1002/cyto.a.20896.

    Article  PubMed  Google Scholar 

  18. Ip B, Cilfone NA, Belkina AC, Defuria J, Jagannathan-Bogdan M, Zhu M, Kuchibhatla R, McDonnell ME, Xiao Q, Kepler TB, et al. Th17 cytokines dif-ferentiate obesity from obesity-associated type 2 diabetes and promote TNFα production. Obesity. 2016;24:102–12. https://doi.org/10.1002/oby.21243.

    Article  CAS  PubMed  Google Scholar 

  19. Zukowski E, Sannella M, Rockhold JD, Kalantar GH, Yu J, SantaCruz‐Calvo S, Kuhn MK, Hah N, Ouyang L, Wang T. et al. STAT3 modulates CD4+ T mitochondrial dynamics and function in aging. Aging Cell 2023;22. https://doi.org/10.1111/acel.13996.

  20. Zheng GXY, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, Ziraldo SB, Wheeler TD, McDermott GP, Zhu J. et al. Massively parallel digital tran-scriptional profiling of single cells. Nat Commun 2017;8.https://doi.org/10.1038/ncomms14049.

  21. Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573-3587.e29. https://doi.org/10.1016/j.cell.2021.04.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bais AS, Kostka D. Scds: Computational annotation of doublets in single-cell RNA sequencing data. Bioinformatics. 2020;36:1150–8. https://doi.org/10.1093/bioinformatics/btz698.

    Article  CAS  PubMed  Google Scholar 

  23. Wold S, Ruhe A, Wold H, Dunn IWJ. The collinearity problem in linear regression. The partial least squares (PLS) approach to generalized inverses. SIAM J Sci Stat Comput. 1984;5:735–43. https://doi.org/10.1137/0905052.

    Article  Google Scholar 

  24. Geladi P, Kowalski BP. Partial least-squares regression: a tutorial. Anal Chim Acta. 1986;185:1–17.

    Article  CAS  Google Scholar 

  25. Thévenot EA, Roux A, Xu Y, Ezan E, Junot C. Analysis of the human adult urinary metabolome variations with age, body mass index, and gender by implementing a comprehensive workflow for univariate and OPLS statistical. J Proteome Res. 2015;14:3322–35.

    Article  PubMed  Google Scholar 

  26. Trygg J, Wold S. Orthogonal projections to latent structures (O-PLS). J Chemom. 2002;16:119–28.

    Article  CAS  Google Scholar 

  27. Galindo-Prieto B, Eriksson L, Trygg J. Variable influence on projection (VIP) for orthogonal projections to latent structures (OPLS). J Chemom. 2014;28:623–32.

    Article  CAS  Google Scholar 

  28. Lee JS, Lee WW, Kim SH, Kang Y, Lee N, Shin MS, Kang SW, Kang I. Age-associated alteration in naive and memory Th17 cell response in humans. Clin Immunol. 2011;140:84–91. https://doi.org/10.1016/j.clim.2011.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barbosa MC, Grosso RA, Fader CM. Hallmarks of aging: an autophagic perspective. Front Endocrinol (Lausanne) 2019;9. https://doi.org/10.3389/fendo.2018.00790.

  30. Chen J, Liu X, Zhong Y. Interleukin-17A: the key cytokine in neurodegenerative diseases. Front Aging Neurosci 2020;12. https://doi.org/10.3389/fnagi.2020.566922.

  31. Mohammadi Shahrokhi V, Ravari A, Mirzaei T, Zare-Bidaki M, Asadikaram G, Arababadi MK. IL-17A and IL-23: plausible risk factors to induce age-associated in-flammation in Alzheimer’s disease. Immunol Invest. 2018;47:812–22. https://doi.org/10.1080/08820139.2018.1504300.

    Article  CAS  PubMed  Google Scholar 

  32. Tan J, Dai A, Pan L, Zhang L, Wang Z, Ke T, Sun W, Wu Y, Ding P-H, Chen L. Inflamm-aging-related cytokines of IL-17 and IFN-γ accelerate osteoclasto-genesis and periodontal destruction. J Immunol Res. 2021;2021:1–12. https://doi.org/10.1155/2021/9919024.

    Article  CAS  Google Scholar 

  33. Chen W, Wang J, Yang H, Sun Y, Chen B, Liu Y, Han Y, Shan M, Zhan J. Interleukin 22 and its association with neurodegenerative disease activity. Front Pharmacol 2022;13. https://doi.org/10.3389/fphar.2022.958022.

  34. Chen X, Wang Y, Wang J, Wen J, Jia X, Wang X, Zhang H. Accumulation of T helper 22 cells, interleukin 22 and myeloid derived suppressor cells promotes gastric cancer progression in elderly patients. Oncol Lett. 2018. https://doi.org/10.3892/ol.2018.8612.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pollizzi KN, Powell JD. Regulation of T cells by MTOR: the known knowns and the known unknowns. Trends Immunol. 2015;36:13–20. https://doi.org/10.1016/j.it.2014.11.005.

    Article  CAS  PubMed  Google Scholar 

  36. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD. The MTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44. https://doi.org/10.1016/j.immuni.2009.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang K, Shrestha S, Zeng H, Karmaus PWF, Neale G, Vogel P, Guertin DA, Lamb RF, Chi H. T cell exit from quiescence and differentiation into Th2 cells depend on raptor-MTORC1-mediated metabolic reprogramming. Immunity. 2013;39:1043–56. https://doi.org/10.1016/j.immuni.2013.09.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Merkley SD, Chock CJ, Yang XO, Harris J, Castillo EF. Modulating T cell responses via autophagy: the intrinsic influence controlling the function of both anti-gen-presenting cells and T cells. Front Immunol 2018;9. https://doi.org/10.3389/fimmu.2018.02914.

  39. Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, Cuervo AM, Sen R, Ferrucci L. Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging. 2019;11:9234–63. https://doi.org/10.18632/aging.102438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:85. https://doi.org/10.1186/s12929-015-0194-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Redza-Dutordoir M, Averill-Bates DA. Interactions between reactive oxygen species and autophagy. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2021;1868:119041. https://doi.org/10.1016/j.bbamcr.2021.119041.

    Article  CAS  PubMed  Google Scholar 

  42. Zhao Z, Wang Y, Gao Y, Ju Y, Zhao Y, Wu Z, Gao S, Zhang B, Pang X, Zhang Y. et al. The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis. Proc Natl Acad Sci 2023;120. https://doi.org/10.1073/pnas.2212613120.

  43. Yang X, Gao X, Zhu Y, Li G, Zhang X, Xiao G, Cao H, Chen X, Yang Q, Lu B. ATF4 is induced by ROS and regulates Th1 and Th17 cells (P6219). J Immunol. 2013;190:115.5-115.5. https://doi.org/10.4049/jimmunol.190.Supp.115.5.

    Article  Google Scholar 

  44. Yarosz EL, Chang C-H. The role of reactive oxygen species in regulating T cell-mediated immunity and disease. Immune Netw 2018;18. https://doi.org/10.4110/in.2018.18.e14.

  45. Reinke EN, Ekoue DN, Bera S, Mahmud N, Diamond AM. Translational regulation of GPx-1 and GPx-4 by the MTOR pathway. PLoS One. 2014;9:e93472. https://doi.org/10.1371/journal.pone.0093472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yun HR, Jo YH, Kim J, Shin Y, Kim SS, Choi TG. Roles of autophagy in oxidative stress. Int J Mol Sci. 2020;21:3289. https://doi.org/10.3390/ijms21093289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chang K-C, Liu P-F, Chang C-H, Lin Y-C, Chen Y-J, Shu C-W. The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases. Cell Biosci. 2022;12:1. https://doi.org/10.1186/s13578-021-00736-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88. https://doi.org/10.1038/cdd.2014.150.

    Article  CAS  PubMed  Google Scholar 

  49. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD. Redox regulation by NRF2 in aging and disease. Free Radic Biol Med. 2019;134:702–7. https://doi.org/10.1016/j.freeradbiomed.2019.01.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Alsaleh G, Panse I, Swadling L, Zhang H, Richter FC, Meyer A, Lord J, Barnes E, Klenerman P, Green C. et al. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. Elife 2020;9. https://doi.org/10.7554/eLife.57950.

  51. Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, et al. Autophagy in healthy aging and disease. Nat Aging. 2021;1:634–50. https://doi.org/10.1038/s43587-021-00098-4.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Katsuragi Y, Ichimura Y, Komatsu M. Regulation of the Keap1–Nrf2 pathway by P62/SQSTM1. Curr Opin Toxicol. 2016;1:54–61. https://doi.org/10.1016/j.cotox.2016.09.005.

    Article  Google Scholar 

  53. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou Y-S, Ueno I, Sakamoto A, Tong KI, et al. The selective autophagy substrate P62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213–23. https://doi.org/10.1038/ncb2021.

    Article  CAS  PubMed  Google Scholar 

  54. Kageyama S, Saito T, Obata M, Koide R, Ichimura Y, Komatsu M. Negative regulation of the Keap1-Nrf2 pathway by a P62/Sqstm1 splicing variant. Mol Cell Biol 2018;38. https://doi.org/10.1128/MCB.00642-17.

  55. Tsang CK, Chen M, Cheng X, Qi Y, Chen Y, Das I, Li X, Vallat B, Fu L-W, Qian C-N, et al. SOD1 phosphorylation by MTORC1 couples nutrient sensing and redox regulation. Mol Cell. 2018;70:502-515.e8. https://doi.org/10.1016/j.molcel.2018.03.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kong H, Chandel NS. To claim growth Turf, MTOR says SOD off. Mol Cell. 2018;70:383–4. https://doi.org/10.1016/j.molcel.2018.04.015.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Y, Swanda RV, Nie L, Liu X, Wang C, Lee H, Lei G, Mao C, Koppula P, Cheng W, et al. MTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat Commun. 2021;12:1589. https://doi.org/10.1038/s41467-021-21841-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chávez MD, Tse HM. Targeting mitochondrial-derived reactive oxygen species in T cell-mediated autoimmune diseases. Front Immunol 2021;12. https://doi.org/10.3389/fimmu.2021.703972.

  59. Bharath LP, Mueller R, Li Y, Ruan T, Kunz D, Goodrich R, Mills T, Deeter L, Sargsyan A, AnandhBabu PV, et al. Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability. Can J Physiol Pharmacol. 2014;92:605–12. https://doi.org/10.1139/cjpp-2014-0017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bharath LP, Cho JM, Park S-K, Ruan T, Li Y, Mueller R, Bean T, Reese V, Richardson RS, Cai J, et al. Endothelial cell autophagy maintains shear stress–induced nitric oxide generation via glycolysis-dependent purinergic signaling to endo-thelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2017;37:1646–56. https://doi.org/10.1161/ATVBAHA.117.309510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vereb G, Matkó J, Vámosi G, Ibrahim SM, Magyar E, Varga S, Szöllösi J, Jenei A, Gáspár R, Waldmann TA, et al. Cholesterol-dependent clustering of IL-2Rα and its colocalization with HLA and CD48 on T lymphoma cells suggest their functional association with lipid rafts. Proc Natl Acad Sci U S A. 2000;97:6013–8. https://doi.org/10.1073/pnas.97.11.6013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Thuy Trang (Violet) T. Tran, Lab Manager, Department of Biology and Chemistry and the Departments of Biology and Chemistry, Merrimack College. We also thank Tara Daly, Research Program Manager, Center for Health Inclusion Research and Practice(CHIRP), Merrimack College. 

Funding

This work was supported by R15AG068957 (LPB), pilot award from the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging P30AG068635 (LPB), R56AG06985 (BSN), and T32NS115667 (MKK). This work was also supported by the Pasini Fellowship (LPB), College of Health Sciences Faculty Development grant (FDG) (LPB), and Sakowich Center for Undergraduate Research and Creative Activities grant (SCURCA), School of Nursing and Health Sciences, Merrimack College (LPB), and Barnstable Brown Diabetes Center, University of Kentucky (BSN).

Author information

Author notes

  1. Jack Donato Rockhold and Heather Marszalkowski contributed equally.

Authors and Affiliations

  1. Department of Health Sciences and Nutrition, Merrimack College, North Andover, MA, USA

    Jack Donato Rockhold, Marco Sannella, Kaleigh Gibney, Emelia Zukowski, Olivia Stefanik & Leena P. Bharath

  2. Department of Biology, Merrimack College, North Andover, MA, USA

    Heather Marszalkowski & Lyanne Murphy

  3. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA

    Sara SantaCruz-Calvo & Barbara S. Nikolajczyk

  4. Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA

    Sara SantaCruz-Calvo, Samantha N. Hart & Barbara S. Nikolajczyk

  5. Department of Neurosurgery, Pharmacology, and Biomedical Engineering and Center for Neural Engineering, Pennsylvania State University, Hershey, PA, USA

    Madison K. Kuhn & Elizabeth A. Proctor

  6. Department of Engineering Science & Mechanics, Pennsylvania State University, University Park, PA, USA

    Elizabeth A. Proctor

  7. Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Jingting Yu

  8. Dept of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA

    Gabriella H. Kalantar

  9. Forsyth Institute, Cambridge, MA, USA

    Hatice Hasturk

  10. Department of Chemistry and Biochemistry, Merrimack College, North Andover, MA, USA

    Gabrielle Chase

  11. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

    Samantha N. Hart

Authors
  1. Jack Donato Rockhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heather Marszalkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Sannella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kaleigh Gibney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lyanne Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emelia Zukowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriella H. Kalantar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sara SantaCruz-Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Samantha N. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Madison K. Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jingting Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Olivia Stefanik
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gabrielle Chase
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Elizabeth A. Proctor
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hatice Hasturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Barbara S. Nikolajczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Leena P. Bharath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: LPB. Methodology: LPB. Investigation: JDR, HM, MS, KG, LM, EZ, GK, SSC, SD, OS, GC, and LPB. Formal analysis: JDR, HM, MS, JY, EP, MKK, EAP, KG, LM, OS, and GC. Supervision: LPB. Writing: LPB. Editing: BSN, HH. Funding: LPB, BSN. Resources: HH.

Corresponding author

Correspondence to Leena P. Bharath.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 467 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rockhold, J.D., Marszalkowski, H., Sannella, M. et al. Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis. GeroScience (2024). https://doi.org/10.1007/s11357-024-01187-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-024-01187-z

Keywords

Search

Navigation