Humans have been trying to halt aging and extend maximal lifespan for millenia. According to the influential biomedical researcher Leonard Hayflick, who recently passed away at the age of 96, the quest is hopeless. Following his game-changing discovery in the 1960s that normal cells have a limit to the number of times they can divide before becoming senescent, he believed that cell senescence imposed an unbreakable ceiling on the potential length of human life at ~125 years. But what if we could interrupt or slow the processes that lead to cell senescence in the first place?
Ironically, a study attempting just this strategy was published in Nature shortly before Hayflick’s death. The authors reported significant lifespan extension in mice through inhibition of interleukin-11 (IL-11), a protein thought to have a role in promoting cell senescence.1 Do these results suggest that IL-11 may have promise as a target for lifespan extension in humans? Or do they represent another example of what Hayflick believed was a fool’s errand?
Laying the foundation
IL-11 is a small protein involved in cell signaling and has previously been shown to be expressed more highly in centenarians than in healthy middle-aged individuals, which suggests a possible correlation with aging.2 Further, earlier work in a transgenic mouse model of premature cell senescence has indicated that senescence is associated with secretion of IL-11.3 In the present study, authors Widjaja et al. thus sought to substantiate these findings as the basis for their subsequent investigations on lifespan.
Indeed, IL-11 expression was found to increase progressively throughout the mouse adult lifespan in the three tissues they sampled (liver, fat, and skeletal muscle). Additionally, molecular markers of cell senescence were upregulated in aged wild-type mice relative to young wild-type mice, but this difference was lost when comparing aged and young mice that were genetically deficient in the receptor for IL-11, indicating that IL-11 signaling is necessary for the increase in senescence associated with aging. Treatment of human cells with IL-11 in vitro also led to increases in markers of senescence. Together, these results validated earlier indications that IL-11 helps to drive the progressive increases in cell senescence seen with advancing age, which in turn suggests that IL-11 may be a promising target for interventions aimed at slowing the aging process and extending lifespan.
How does IL-11 impact health and lifespan?
Based on this foundation, Widjaja et al. then investigated whether interfering with IL-11 signaling might impact health and longevity in mice. The investigators treated mice with an antibody (X203) to neutralize IL-11 once every three weeks for 25 weeks, starting at 75 weeks of age – roughly equivalent to humans in their late 50s or early 60s. They found that mice treated with X203 were more glucose tolerant and exhibited lower serum cholesterol and fat mass than mice given a control treatment, as well as having greater muscle mass and muscle strength. Indeed, mice on X203 for 25 weeks (i.e., 100 weeks of age at the time of analysis) appeared healthier in these parameters than even 75-week-old mice, indicating that inhibition of IL-11 improved glucose tolerance and body composition relative to baseline rather than merely delaying age-related deterioration in these metrics. Additional experiments in transgenic mice deficient in IL-11 (Il11-/- mice) corroborated these findings.
While these effects on overall health are noteworthy, most of the excitement surrounding Widjaja et al.’s work concerns the impact of anti-IL-11 therapy on lifespan. Indeed, monthly treatment with X203 from 75 weeks of age until death extended the median lifespan of mice by an average of 28.7% (Figure 1, left), with female mice exhibiting a slightly greater extension (25%) than male mice (22.5%) relative to animals treated with a control antibody. (Yes, both sex-specific cohorts showed smaller extension of median lifespan than the pooled cohort, and yes, we have verified that this is mathematically possible and doesn’t represent an error in the reported data.)
Again, these results were replicated in Il11-/- mice, as genetic deletion of Il-11 was found to extend median lifespan by 24.9% on average for both sexes (Figure 1, right). (It’s worth noting that although some control animals in the genetic experiment died at unusually young ages, this would not have impacted results, as the metric of interest was median lifespan, which, unlike average lifespan, is generally unaffected by outliers. Median lifespan for all control groups fell within ranges expected based on broader literature.) Further, these Il11-/- mice and mice treated with X203 were found to have significantly lower incidence of visible tumors during autopsy than their respective control groups.
What’s mediating IL-11’s lifespan effects?
While Widjaja et al.’s results need to be replicated, they are nevertheless compelling. A closer look at the biology of IL-11, demonstrated by the authors in additional in vitro experiments, suggests IL-11 impacts multiple downstream signaling pathways (Figure 2), including JAK-STAT3, ERK, mTOR, and others. The investigators conclude that all are likely contributing to the apparent reduction in cell senescence markers and extension in lifespan that comes with IL-11 inhibition, and indeed, all have been linked to lifespan effects in past research. But developing a more complete understanding of the relative contributions of each specific pathway and signaling target is critical to answering the question of how IL-11 inhibition might fit within the larger scope of longevity interventions.
The lifespan extension observed by Widjaja et al. was equivalent to that observed in previous experiments with mice treated with rapamycin, a molecule that specifically targets mTOR and inhibits downstream mTOR signaling.4 (In the case of rapamycin, mice began treatment at 9 months of age, which translates to roughly half the age at which mice started X203 in the present study but is certainly less than the lifelong “exposure” of Il11-/- mice. Other studies with different durations of rapamycin treatment have also been conducted, yielding various degrees of lifespan extension.)
Thus, we’re left with two possible explanations for the comparable lifespan effects of rapamycin and IL-11 inhibition: 1) the life extension associated with inhibiting IL-11 is primarily (or exclusively) attributable to a reduction in mTOR signaling, making this intervention equivalent to rapamycin; or 2) genetic or pharmacological disruption of IL-11 signaling is less effective than rapamycin at reducing mTOR signaling but nevertheless results in comparable net extension in lifespan by making up for the difference via effects on alternative signaling pathways. If (1) represents the true explanation, anti-IL-11 therapy may someday be an alternative to rapamycin depending on their relative safety and side effect profiles, but it is very unlikely to exceed the life-extending effects of rapamycin (which remain unclear in humans). However, in the event that (2) is true, anti-IL-11 therapy may represent a means of targeting entirely new lifespan-associated processes, which in turn would mean that anti-IL-11 therapy combined with rapamycin would likely have additive effects on longevity. Indeed, it would also suggest that targeting IL-11 might hold promise even if rapamycin and mTOR inhibition is eventually revealed to be a dead-end with respect to human lifespan extension. Obviously, the next experiment one would want to see is one that compares both interventions, head-to-head and in combination, though it seems unlikely such an experiment will be done.
The bottom line
The results by Widjaja et al. certainly offer fuel to those who believe meaningful lifespan extension is within our reach. Indeed, the extension in median lifespan observed with inhibition of IL-11 in both male and female mice is impressive and is backed by compelling mechanistic data on senescence and other markers of cellular aging.
These findings hold plenty of promise, but a long road still lies ahead before we can estimate the potential utility of this new intervention for human longevity. Elucidating the cellular signaling mechanisms at play will be one of the next hurdles, along with more thorough characterization of any possible unintended negative effects, some of which may not readily be detected in animal studies. For instance, IL-11 can modulate immune function through both pro- and anti-inflammatory downstream effects, yet negative impacts on immune function are less likely to make noticeable differences in animal health and lifespan in the pathogen-free environments in which laboratory mice are housed.
Thus, even if anti-IL-11 therapy gets a green light from preclinical experiments, there are no guarantees that it will be successful in human applications. But the starting point is strong, and with each step and each experiment – indeed, even those that fail – we learn a little more about the nature of aging itself. Who knows? Maybe someday it will be enough to break through the so-called “Hayflick Limit.”
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References
- Widjaja AA, Lim WW, Viswanathan S, et al. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 2024;632(8023):157-165. doi:10.1038/s41586-024-07701-9
- Pinti M, Gibellini L, Lo Tartaro D, et al. A comprehensive analysis of cytokine network in centenarians. Int J Mol Sci. 2023;24(3):2719. doi:10.3390/ijms24032719
- Chen H, Chen H, Liang J, et al. TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency. Exp Mol Med. 2020;52(1):130-151. doi:10.1038/s12276-019-0371-7
- Miller RA, Harrison DE, Astle CM, et al. Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468-477. doi:10.1111/acel.12194
