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IL-6 can singlehandedly drive many features of frailty in mice

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Abstract

Frailty is a geriatric syndrome characterized by age-related declines in function and reserve resulting in increased vulnerability to stressors. The most consistent laboratory finding in frail subjects is elevation of serum IL-6, but it is unclear whether IL-6 is a causal driver of frailty. Here, we characterize a new mouse model of inducible IL-6 expression (IL-6TET-ON/+ mice) following administration of doxycycline (Dox) in food. In this model, IL-6 induction was Dox dose-dependent. The Dox dose that increased IL-6 levels to those observed in frail old mice directly led to an increase in frailty index, decrease in grip strength, and disrupted muscle mitochondrial homeostasis. Littermate mice lacking the knock-in construct failed to exhibit frailty after Dox feeding. Both naturally old mice and young Dox-induced IL-6TET-ON/+ mice exhibited increased IL-6 levels in sera and spleen homogenates but not in other tissues. Moreover, Dox-induced IL-6TET-ON/+ mice exhibited selective elevation in IL-6 but not in other cytokines. Finally, bone marrow chimera and splenectomy experiments demonstrated that non-hematopoietic cells are the key source of IL-6 in our model. We conclude that elevated IL-6 serum levels directly drive age-related frailty, possibly via mitochondrial mechanisms.

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Funding

This study was supported by the Bowman Professorship in Medical Sciences and by generous philanthropic support of Sperry and Donnalyn van Langevelt to J. N-Ž.

Author information

Author notes

  1. Heather L. Thompson

    Present address: Ventana-Roche Medical Systems, Oro Valley, AZ, USA

Authors and Affiliations

  1. Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA

    Mladen Jergović, Heather L. Thompson, Christine M. Bradshaw, Sandip Ashok Sonar, Arveen Ashgar, Niels Mohty & Janko Nikolich-Žugich

  2. University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, P.O.Box. 249221, 1501 N. Campbell Ave., Tucson, AZ, 85724, USA

    Mladen Jergović, Heather L. Thompson, Christine M. Bradshaw, Sandip Ashok Sonar, Arveen Ashgar, Niels Mohty, Mindy J. Fain & Janko Nikolich-Žugich

  3. Division of Trauma Surgery, Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA

    Bellal Joseph

  4. Division of Geriatrics, General Internal Medicine and Palliative Medicine, Department of Medicine, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA

    Mindy J. Fain

  5. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA

    Kristan Cleveland & Rick G. Schnellman

  6. Southern Arizona Veterans Affairs Health Care System, Tucson, AZ, USA

    Rick G. Schnellman

  7. Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ, USA

    Rick G. Schnellman

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  1. Mladen Jergović
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Jergović, M., Thompson, H.L., Bradshaw, C.M. et al. IL-6 can singlehandedly drive many features of frailty in mice. GeroScience 43, 539–549 (2021). https://doi.org/10.1007/s11357-021-00343-z

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  • DOI: https://doi.org/10.1007/s11357-021-00343-z

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