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Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

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Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

TL;DR

Widjaja et al. combined germline deletion of il-11 or il-11-receptor-alpha-1 with late-life antibody neutralization of IL-11 in mice. Anti-IL-11 (X203; 40 mg/kg intraperitoneally) given on the nominal 75-to-100-week schedule preserved grip strength and prevented frailty progression while improving adiposity, glucose handling, liver injury, fibrosis and inflammatory/senescence-associated readouts in both sexes. In separate survival cohorts, monthly X203 from approximately 75 weeks until death increased reported median lifespan by 22.5% in males and 25.0% in females; Il11 deletion also shifted survival in both sexes. The mechanism proposed is suppression of an age-induced IL-11–ERK–mTORC1 programme, restoration of AMPK activity and white-adipose beiging. These are compelling single-centre mouse data, not evidence that IL-11 inhibition extends human lifespan: the human experiments used one cardiac-fibroblast donor and one fetal-hepatocyte donor, and the published survival curves were still substantially censored. gap/needs-human-replication gap/needs-replication

Design

Experimental systems and group sizes

The paper contains several distinct cohorts; no single animal count describes the study.

ExperimentGroups and sample sizesPurpose
Age courseMale mice aged 12, 25, 50, 75 or 110 weeks; n=5/ageTissue IL-11 and ERK–AMPK–mTORC1 signalling
Il11ra1 deletionMixed C57BL/6–129 background; across non-blot assays: young males WT n=7–8, knockout n=7–8; old males WT n=11–12, knockout n=15–17; young females WT n=7, knockout n=8; old females WT n=14–15, knockout n=12–13; immunoblots n=5/groupCross-sectional metabolism, body composition, tissue signalling and ageing biomarkers
Il11 deletion, femalesC57BL/6J; most assays: young WT n=8, knockout n=9; old WT n=16, knockout n=18. Exceptions included forepaw grip young WT n=10; BAT young WT n=5, knockout n=7 and old n=16/genotype; immunoblots n=6/groupFrailty, strength, glucose homeostasis, adipose/liver/muscle phenotypes
Il11 deletion, malesC57BL/6J; most assays: young WT and knockout n=9; old WT n=15, knockout n=14. Metabolic-cage and fecal-calorimetry cohorts n=10/group; selected fat, strength, GTT and ITT panels used n=6–12/group; immunoblots n=6/groupMale replication plus metabolic-cage and organ phenotypes
Anti-IL-11 healthspan, malesReference n=14 for most terminal biochemical/tissue assays (grip n=10; BAT n=6); untreated endpoint n=6 (liver mass n=5); IgG n=13; X203 n=12; metabolic-cage n=10/groupLate-life therapeutic test nominally from 75 to 100 weeks
Anti-IL-11 healthspan, femalesIgG n=13 at baseline, with 2 deaths before endpoint (endpoint n=11; forepaw grip n=10); X203 n=13Sex replication of late-life therapy
Anti-IL-11 RNA sequencingMale liver and gastrocnemius n=8/group; visceral white adipose tissue: IgG n=7, X203 n=6Tissue transcriptional mechanism
Genetic lifespanMale WT n=41, Il11−/− n=34; female WT n=49, Il11−/− n=37; total n=161Survival and gross autopsy
Therapeutic lifespanMale IgG n=25, X203 n=24; female IgG n=13, X203 n=13; total n=75Survival after late-life IL-11 neutralization
Human cellsCardiac fibroblasts from one 52-year-old male donor and hepatocytes from one 22-week-gestation fetal donor; reported assay n=4–8/group are measurements from these single-donor cultures, not independent donorsIL-11-induced and replicative-senescence mechanisms

Interventions

  • Healthspan antibody regimen: X203 anti-IL-11 or 11E10 IgG control, 40 mg/kg intraperitoneally every 3 weeks, nominally starting at 75 weeks for 25 weeks with assessment or euthanasia at 100 weeks. The male frailty table records about 74.4 to 100.4 weeks; the female table instead records about 73.9–74.0 to 96.1 weeks, which is internally inconsistent with the article caption and 25-week schedule.
  • Lifespan antibody regimen: X203 or IgG, 40 mg/kg intraperitoneally monthly, nominally from 75 weeks until death or humane euthanasia. The source tables record two male batches starting at 74 or 76 weeks and the female batch at 74.14 weeks.
  • Genetic models: constitutive Il11−/− mice on C57BL/6J and Il11ra1−/− mice on a mixed C57BL/6–129 background, compared with wild-type littermates.
  • Human-cell perturbations: IL-11 at 5 ng/ml in cardiac fibroblasts or 10 ng/ml in hepatocytes for up to 24 h, with U0126 (10 µM) or rapamycin (10 nM); serially passaged cardiac fibroblasts received anti-IL11RA X209 or IgG at 2 µg/ml from passage 2 to passage 14.

Endpoints and analysis

Healthspan endpoints included body weight and composition, 27-item frailty score, full-body and forepaw grip strength, glucose and insulin tolerance, respiratory exchange ratio, food intake, locomotion, fecal caloric density, core temperature, serum lipids and liver enzymes, tissue mass, triglyceride and collagen content, telomere length, mitochondrial-DNA copy number, histology, immunoblotting and bulk RNA sequencing. Lifespan was time to spontaneous death or protocol-defined humane euthanasia; Kaplan–Meier curves were compared with two-sided log-rank and Wilcoxon tests. Mice were randomized on the day of pharmacological treatment; germline-genotype groups were not randomizable. Treatment or genotype was concealed from investigators generating quantitative readouts during collection but revealed for analysis, and histology acquisition and analysis were separately blinded. The reporting summary states that in-vitro cultures were randomly allocated but that their collection and analysis were not blinded.

Key results

Lifespan

ComparisonReported median lifespanChangeLog-rank PWilcoxon PEvents / enrolled at 20 May 2024 source-data cutoff
Male WT vs Il11−/−128.7 weeks vs not determinednot estimable4.69×10−54.70×10−535/41 vs 6/34
Female WT vs Il11−/−118.9 vs 148.3 weeks+24.7%2.01×10−87.28×10−749/49 vs 19/37
Sex-pooled WT vs Il11−/−120.9 vs 151.0 weeks+24.9%5.78×10−112.80×10−1084/90 vs 25/71
Male IgG vs X203130.3 vs 159.6 weeks+22.5%7.61×10−52.25×10−423/25 vs 12/24
Female IgG vs X203117.1 vs 146.4 weeks+25.0%9.30×10−65.56×10−513/13 vs 7/13
Sex-pooled IgG vs X203120.9 vs 155.6 weeks+28.7%2.41×10−81.06×10−736/38 vs 19/37

Both survival tests agreed in direction and significance. The event/enrolment counts matter: most Il11−/− males, half of X203-treated males and nearly half of treated females remained right-censored in the source data. The male genetic median was explicitly reported as undetermined. The percentage extensions are therefore publication-time Kaplan–Meier estimates rather than results from fully completed cohorts, and the final magnitudes could change as follow-up matures.

The authors reported macroscopic tumours in 49/84 WT versus 3/25 Il11−/− mice (pooled sexes; P<0.0001), and in 22/36 IgG versus 3/19 X203 mice (P=0.0013). The denominators equal the deaths/events recorded at the source-data cutoff, not all enrolled animals; the individual tables include missing or explicitly unavailable autopsies, so they should not be described as 84, 25, 36 and 19 confirmed necropsies. Gross inspection was not blinded histopathological adjudication of cancer incidence or cause of death.

Late-life antibody treatment improves measured healthspan

In males, 25 weeks of X203 (n=12) reduced fat mass by a mean 8.55 percentage points and increased lean mass by 8.46 percentage points; IgG controls (n=13) changed by +0.01 and −0.45 points, respectively (X203 versus IgG corrected P=1.53×10−8 and 1.69×10−8). Mean frailty changed from 3.88 to 3.63 with X203 but from 3.81 to 6.65 with IgG (P=2.08×10−9 at endpoint). Full-body grip strength was 6.56 versus 5.04 g/g body weight (P=2.64×10−9). Glucose- and insulin-tolerance trajectories, serum lipids, IL-6, alanine aminotransferase, tissue collagen and indexed gastrocnemius mass also favoured X203.

In females, X203 (n=13) reduced fat mass by 5.97 percentage points and increased lean mass by 5.05 points, whereas IgG (n=11) produced +7.04 and −7.23 points (P=2.53×10−8 and 2.04×10−8). Mean frailty fell from 4.15 to 2.62 with X203 but rose from 4.05 to 5.73 with IgG (P=1.81×10−7). X203 preserved full-body strength and improved forepaw strength while both declined under IgG.

Both constitutive deletion models broadly converged with the therapeutic experiment: old knockout mice were leaner, had greater indexed muscle mass and strength, lower frailty, better glucose and insulin tolerance, lower serum lipids and liver-injury markers, and preservation of tissue telomere length and mitochondrial-DNA copy number relative to old WT controls. Some muscle and metabolic differences were already present in young knockout animals, which limits interpretation as reversal of ageing rather than lifelong developmental or physiological effects.

Proposed mechanism

IL-11 protein rose progressively with age in liver, gastrocnemius and white-adipose-tissue. Ageing was accompanied by ERK–p90RSK activation, inhibitory LKB1 phosphorylation, reduced ampk activity and activation of mtor, p70S6K and S6 ribosomal protein. Old Il11ra1−/− tissues and X203-treated old mice showed the opposite pattern, with lower p16/p21 and inflammatory markers. The data support a non-canonical IL-11–ERK–AMPK–mTORC1 axis while also showing NF-κB and canonical JAK–STAT3 engagement; the relative causal contribution of these branches was not resolved.

In primary human cardiac fibroblasts and fetal hepatocytes, recombinant IL-11 increased ERK–mTOR signalling, p16/p21 and senescence-associated secretory factors while reducing proliferating-cell nuclear antigen and cyclin D1. U0126 or rapamycin prevented many of these changes. Anti-IL11RA X209 during serial passage attenuated p16/p21 accumulation, inflammatory signalling, telomere and mitochondrial-DNA loss and impaired respiration in the single cardiac-fibroblast line. This is mechanistic human-cell support, not clinical evidence.

Visceral-adipose RNA sequencing after X203 identified Ucp1 as the most strongly upregulated transcript, together with a broader beiging, mitochondrial-biogenesis and oxidative-phosphorylation programme. Protein assays confirmed higher UCP1 and PGC1α. X203-treated adipose had smaller lipid droplets, beige-adipocyte foci, fewer CD68+ macrophages and reduced inflammatory and senescence-associated transcripts. This documents a white-adipose thermogenic programme as a candidate contributor to fat loss, but the study did not demonstrate a between-group difference in energy expenditure.

Null, negative and unresolved findings

  • X203 increased respiratory exchange ratio relative to aged IgG controls after 6 weeks but did not restore it fully to the young-mouse level.
  • Although indirect-calorimetry cages recorded oxygen consumption and carbon-dioxide production, the article did not report or demonstrate a treatment effect on energy expenditure. These experiments were performed in males, with no female metabolic-cage cohort.
  • Locomotor activity and fecal caloric density were similar between treatment groups; knockout mice ate more despite being leaner, and bomb calorimetry did not support calorie-losing enteropathy.
  • The anti-IL-11 fecal-calorimetry caption reports 115-week-old males (IgG n=8, X203 n=10), which is not reconciled with the nominal male healthspan cohort ending at 100 weeks.
  • Liver mass indices were similar between old WT and Il11ra1−/− mice despite improvements in liver triglycerides and injury markers.
  • Brown-adipose mass was unchanged in the constitutive models, and X203 did not significantly raise Ucp1 expression in brown adipose tissue (IgG versus X203 P>0.9999). The strongest thermogenic response occurred in white adipose tissue.
  • Senescence-transcript suppression in liver and muscle was present but less pronounced than in visceral white adipose tissue.
  • The investigators did not identify the cell type(s) necessary for the organismal phenotype, the physiology responsible for weight loss, or the relative roles of ERK versus JAK–STAT3 signalling.
  • Treatment beginning later than 75 weeks and shorter treatment courses were not tested for survival. gap/dose-response-unclear

Safety and adverse observations

No treatment-associated toxicity signal or excess mortality was reported, and X203-treated mice generally had lower liver enzymes and fibrosis than controls. Core temperature and food intake rose mildly, and marked fat/weight loss was a consistent pharmacodynamic effect. The study did not include a dedicated toxicology arm, antibody pharmacokinetics, anti-drug-antibody or immunogenicity testing, haematology, infection susceptibility, or systematic adverse-event reporting. The authors’ description of anti-IL-11 as having a “reassuring safety profile” refers to the broader therapeutic programme, not to a formal safety demonstration in this ageing study. gap/long-term-unknown

Extrapolation to humans

DimensionStatusNotes
Pathway conserved in humans?yesIL-11 activated ERK–mTORC1 and senescence-associated outputs in primary human fibroblasts and hepatocytes; receptor blockade attenuated replicative senescence in fibroblasts.
Phenotype conserved in humans?partialFrailty, sarcopenia, metabolic dysfunction and fibrosis are human-relevant, but organism-level benefit was tested only in mice. The human work used one adult fibroblast donor and one fetal hepatocyte donor.
Replicated in humans?noNo human healthspan, frailty or lifespan intervention was performed. The paper notes early-stage anti-IL-11 development for fibroinflammatory disease, not ageing efficacy.

The authors compare starting treatment at 75 mouse-weeks to approximately 55 human years, but this is a heuristic age equivalence, not a dose or efficacy bridge. Human translation requires evidence that sustained systemic IL-11 blockade is safe in older adults and changes functional clinical outcomes, not only signalling or fibrosis biomarkers. gap/needs-human-replication

Limitations and conflicts

  • Immature survival data: event counts were low in several treated/knockout groups, especially male Il11−/− mice (6/34 deaths). Administrative censoring from staggered birth cohorts makes the reported medians and percentage extensions less stable than a completed survival study.
  • Single centre and conventional mouse backgrounds: survival was not independently replicated or tested in genetically heterogeneous mice. The genetic models used C57BL/6J or mixed C57BL/6–129 backgrounds.
  • Developmental confounding: germline deletion altered strength and muscle mass even in young mice. The late-life antibody arms reduce, but do not eliminate, concern that lifelong knockout phenotypes are not ageing-specific.
  • Environment: mice were housed at 21–24 °C, below thermoneutrality, and no thermoneutral cohort was studied. The authors note that white-adipose beiging can be particularly prominent in mice.
  • Colony and facility specificity: the reporting summary identifies the facility as mouse-norovirus- and Helicobacter-positive (acceptable specific-pathogen-free status). A single conventional colony microbiological context may matter for inflammatory phenotypes.
  • Frailty construct: the 27-item mouse clinical frailty score is an equal-weight, semiquantitative deficit count. It is useful for within-study comparisons but is not a validated surrogate for human clinical frailty or lifespan-independent healthspan.
  • Many secondary endpoints: healthspan was assessed across numerous molecular, metabolic and functional measures. Tests used within-analysis multiplicity correction, but the report does not specify a study-wide correction across the full endpoint set.
  • Exclusions incompletely reported: the reporting summary specifies ROUT outlier exclusion (maximum false-discovery rate 1%), and RNA-seq methods say samples outside the expected principal-component cluster were removed, but the article does not enumerate exclusions by experiment or give the number of RNA-seq outliers removed.
  • Human evidence is narrow: both human-cell systems came from single commercial donors, and the hepatocytes were fetal. Neither models an intact aged human immune, metabolic or endocrine system.
  • White-adipose translation: beige-fat thermogenesis is especially sensitive to mouse housing temperature, and its quantitative contribution to energy balance is less established in older humans; the mouse fat-loss mechanism cannot be assumed to translate.
  • Cancer ascertainment: tumour data came from gross autopsy rather than blinded histopathology. The reported denominators equal deaths/events at cutoff even though individual records include missing or unavailable autopsies, and the data do not establish cancer-specific mortality.
  • No dedicated safety package: benefit-oriented phenotyping cannot substitute for chronic toxicology or immunological safety testing.
  • Conflicts of interest: A.A.W., B.C., B.K.S., S.S. and S.A.C. were co-inventors on patent families WO2022090509A (healthspan/age-related disease) and WO2018109174 (IL-11 antibodies). S.S. and S.A.C. were co-founders/shareholders of Enleofen Bio and VVB Bio; A.A.W. had consulted for VVB Bio on unrelated work. J.G. disclosed consulting, funding, equity and senolytic-patent relationships stated to be unrelated to this study. Enleofen and Boehringer Ingelheim permitted use of X203; neither was listed as a study funder.

Publication status and supersession

As of 9 August 2026, the current Nature and PubMed records showed no correction, retraction or expression of concern. A date-filtered search found reviews and studies of IL-11 inhibition in adjacent ageing-related disease models, but no independent direct replication of the late-life X203 lifespan experiment and no updated final survival dataset. The lifespan estimates on this page therefore remain anchored to the authors’ 20 May 2024 administrative cutoff.

gap/needs-replication gap/needs-human-replication gap/long-term-unknown gap/dose-response-unclear

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