Chronic, unresolved inflammatory signaling is a feature of aging. It arises from multiple contributing mechanisms, such as the accumulation of senescent cells and the innate immune reaction to mislocalized mitochondrial DNA. The worse the state of accumulated molecular damage, the worse the constant inflammatory response. Ultimately, all of this damage will need to be repaired, but if there are ways to inhibit this maladaptive inflammation without suppressing the entire immune system, then this should improve late life health and life span. Chronic inflammation is highly disruptive to tissue structure and function, and is major contributing component of all of the common fatal age-related conditions.
In today’s open access paper, researchers report on the discovery that IL-11 is more important to the chronic inflammation of aging than previously thought. IL-11 is an immune signaling molecule, an inflammatory cytokine. Like most cytokines IL-11 has been shown to influence many fundamental cellular mechanisms and activities. The researchers show that inhibition of IL-11 signaling can extend life in mice by as much as 25{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497}. Few approaches have been shown to robustly increase life span in mice by more than 20{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497}, and now IL-11 inhibition adds to that small selection of interventions. As reported, IL-11 inhibition may work through essentially the same pathways as mTOR inhibition. The degree of life extension is similar to that achieved via mTOR inhibitors such as rapamycin.
Inhibition of IL-11 signalling extends mammalian healthspan and lifespan
The major signalling mechanisms that regulate lifespan across species include ERK, STK11 (also known as LKB1), AMPK, mTORC1, and IGF1–insulin modules. These pathways are collectively perturbed in old age to activate hallmarks of ageing, which include mitochondrial dysfunction, inflammation, and cellular senescence. In aged organisms, the AMPK-mTORC1 axis is uniquely important for metabolic health, with notable effects in adipose tissue, and therapeutic inhibition of mTOR extends lifespan in mice.
The importance of chronic sterile inflammation for ageing pathologies is increasingly recognized and inflammation itself is a central hallmark of ageing. In simplified terms, ageing is associated with a dysfunctional adaptive immune system that is characterized by immunosenescence and thymic involution along with inappropriate activation of innate immune genes such as IL-6, The pro-inflammatory signalling factors NF-κB and JAK–STAT3 are specifically implicated in ageing and JAK inhibitors can alleviate age-related dysfunction.
We proposed that IL-11, a pro-inflammatory and pro-fibrotic member of the IL-6 family, may promote age-associated pathologies and reduce lifespan. This premise was founded on studies showing that IL-11 can activate ERK-mTORC1 and/or JAK-STAT3, the observation that IL-11 is upregulated in older people, and the fact that IL-11 is increasingly recognized to have a role in senescence, a hallmark of ageing. Here, using a range of genetic and pharmacological approaches, we tested the hypothesis that IL-11 signalling has a negative effect on healthspan and lifespan in mice.
Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity, and frailty in old age. Administration of anti-IL-11 antibodies to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} and of female mice by 25{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497}.
Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
