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

Mladen Jergović, Heather L. Thompson, Christine M. Bradshaw, Sandip Ashok Sonar, Arveen Ashgar, Niels Mohty, Bellal Joseph, Mindy J. Fain, Kristan Cleveland, Rick G. Schnellman, Janko Nikolich-Žugich

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
Issue number2
StatePublished - Apr 2021


  • Frailty
  • IL-6
  • Mouse
  • Transgenic models

ASJC Scopus subject areas

  • Aging
  • veterinary (miscalleneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine


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