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

Jack Donato Rockhold, Heather Marszalkowski, Marco Sannella, Kaleigh Gibney, Lyanne Murphy, Emelia Zukowski, Gabriella H. Kalantar, Sara SantaCruz-Calvo, Samantha N. Hart, Madison K. Kuhn, Jingting Yu, Olivia Stefanik, Gabrielle Chase, Elizabeth A. Proctor, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Research output: Contribution to journalArticlepeer-review

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 (Figure presented.)

Original languageEnglish
JournalGeroScience
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to American Aging Association 2024.

Keywords

  • Autophagy
  • CD4 T cells
  • Everolimus
  • Inflammaging
  • NRF2
  • ROS
  • Th17 cytokines

ASJC Scopus subject areas

  • Aging
  • Veterinary (miscellaneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine

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