The inflammaging clock strikes IL-11!

Abstract

Chronic inflammation is considered a hallmark of aging. In a recent issue of Nature, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.

Figure 1:. IL-11 promotes age-associated metabolic dysfunction, inflammation, and frailty.

With aging, various pathogen- and damage- associated molecular patterns (PAMPs/DAMPs) arising from diverse sources, such as senescent cells, gut dysbiosis, damaged tissues, proteotoxic and cellular stress, DNA damage, and reactive oxygen species (ROS), may influence the release of IL-11. This IL-11 accumulates in aging tissues, including the liver, skeletal muscle, and visceral adipose tissue (VAT). Mechanistically, in tissues, increased IL-11 signaling results in increased production of inflammatory cytokines and chemokines and the development of tissue fibrosis. These processes are likely influenced by IL-11 differentiating stromal fibroblasts into myofibroblasts, and by IL-11 action on pro-inflammatory immune cells, such as myeloid cells that may act via the NLRP3 inflammasome. Age-related IL-11 leads to increased ERK-mTORC1 signaling, tissue senescence, production of senescence associated secretory phenotype (SASP) factors, inflammation, mitochondrial dysfunction, telomere attrition, and organ dysfunction. Cumulatively, these features support the development of metabolic dysfunction, worsened frailty outcomes, and diminished longevity. This pathogenic IL-11 axis may be targeted via the use of anti-IL-11 neutralizing antibodies, which curb metabolic dysfunction and frailty, and promote longevity.