🧬 Aging Wiki

caspase-1

Properties1
aliasesCASP1, ICE, interleukin-1 converting enzyme, interleukin-1β converting enzyme, IL-1 converting enzyme

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Caspase-1 (CASP1)

The pyroptosis executioner — a cysteine protease assembled on inflammasome platforms that cleaves pro-IL-1β, pro-IL-18, and gasdermin D (GSDMD) to drive inflammatory cytokine release and lytic cell death. In the context of aging, caspase-1 hyperactivation downstream of the nlrp3-inflammasome is a core molecular driver of inflammaging.

Identity

  • UniProt: P29466 (CASP1_HUMAN) — Swiss-Prot (manually curated)
  • NCBI Gene: 834
  • HGNC: 1499; symbol CASP1
  • Ensembl: ENSG00000137752
  • Mouse ortholog: Casp1 (one-to-one; mouse caspase-1 is the direct functional equivalent)
  • Length: 404 amino acids (canonical zymogen); ~45 kDa
  • Originally named: ICE (interleukin-1 converting enzyme) — named before the caspase nomenclature was established 1 2

Domain structure

DomainResidues (approx.)Role
CARD1–91Recruits CASP1 to ASC via CARD–CARD interaction
Prodomain linker92–119Cleaved during activation
p20 catalytic subunit120–297Catalytic domain; contains active-site Cys285
Interdomain linker298–316Autoproteolytic cleavage site; required for pyroptosis
p10 catalytic subunit317–404Heterodimerizes with p20 to form active enzyme

The mature active form is a (p20/p10)₂ heterotetramer; two zymogen molecules assemble on the inflammasome scaffold, undergo autoproteolytic processing, and dimerize.

Activation mechanism

Caspase-1 is constitutively expressed as an inactive ~45 kDa zymogen (procaspase-1). Activation requires oligomerization on an inflammasome platform:

  1. Danger signals (PAMPs, DAMPs) activate a sensor protein (NLRP3, NLRC4, AIM2, pyrin).
  2. The sensor recruits the adaptor protein asc via PYD–PYD interaction.
  3. ASC’s CARD domain nucleates procaspase-1 recruitment via CARD–CARD interaction.
  4. Proximity-induced autoproteolysis liberates the p20 and p10 subunits, which dimerize into the active (p20/p10)₂ complex 2.

The nlrp3-inflammasome platform is the most studied in the context of sterile aging-associated inflammation and is gated by signals including ATP, cholesterol crystals, fatty acids, and mitochondrial ROS — all of which accumulate with age.

Substrates and downstream effectors

IL-1β maturation

Procaspase-1 cleaves pro-IL-1β (31 kDa) at Asp116–Ser117 to generate mature IL-1β (17 kDa). Mature IL-1β is then released via GSDMD pores or unconventional secretion. This is the founding function that gave CASP1 its original name “interleukin-1 converting enzyme” 1 2.

IL-18 maturation

Pro-IL-18 (24 kDa) is cleaved to mature IL-18 (18 kDa), which drives IFN-γ production and NK/T-cell activation. IL-18 does not require an exogenous signal peptide and is released similarly via pores. See il-18 (R25) for the dedicated page.

GSDMD cleavage → pyroptosis

Caspase-1 cleaves gsdmd (gasdermin D, 53 kDa) at Asp275, releasing the N-terminal GSDMD-N fragment (30 kDa) 3. GSDMD-N inserts into the plasma membrane to form ~18 nm pores, causing osmotic lysis (pyroptosis) and simultaneous release of IL-1β, IL-18, ATP, and HMGB1. The C-terminal fragment acts as an autoinhibitory domain that sequesters GSDMD-N in the resting state.

A parallel pathway: caspase-11 (mouse) / caspase-4 and caspase-5 (human) can also cleave GSDMD independently of caspase-1 (non-canonical inflammasome signaling) 4. needs-human-replication — the canonical vs non-canonical partition in aged human tissues is unclear.

Role in aging

Inflammasome hyperactivation with age

NLRP3 inflammasome activity and caspase-1 processing increase in aged macrophages, microglia, adipose stromal-vascular fraction, and liver. Key evidence:

  • Youm 2013: Genetic ablation of NLRP3 (Nlrp3-/-) or the inflammasome adaptor ASC (Asc-/-) in mice prevented age-associated systemic low-grade inflammation and improved glucose homeostasis and physical function across multiple aged cohorts (14–24 months); caspase-1 activity was reduced as a downstream consequence. Casp11-/- mice were not protected, confirming the canonical NLRP3 → caspase-1 axis is the effector arm (n = 4–13/group depending on endpoint) 5. needs-human-replication
  • Camell 2017: In aged mice (21–24 months), NLRP3 inflammasome activation in adipose tissue macrophages (ATMs) upregulates GDF3, which in turn drives MAO-A (MAOA) expression; MAOA degrades norepinephrine in ATMs, reducing catecholamine bioavailability to adipocytes and suppressing lipolysis. Nlrp3-/- aged mice and pharmacological MAOA inhibition (clorgyline) restored lipolytic capacity 6. needs-human-replication
  • Caspase-1-null (Casp1⁻/⁻) mice are protected from multiple sterile inflammatory disease models (colitis, gout, metabolic syndrome), though longevity effects have not been robustly demonstrated in a controlled lifespan study. needs-replication

β-hydroxybutyrate as an indirect inhibitor

The ketone body β-hydroxybutyrate (BHB), elevated during caloric restriction, fasting, or ketogenic diet, inhibits NLRP3 inflammasome assembly upstream of caspase-1 — not by directly inhibiting the protease, and not by blocking NLRP3 ATPase activity (that is MCC950’s mechanism). Instead, BHB prevents K⁺ efflux from macrophages and inhibits ASC oligomerization and speck formation, blocking NLRP3-specific activation independently of AMPK, ROS, autophagy, TCA cycle, GPR109a, or HDAC inhibition 7. BHB does not inhibit AIM2, NLRC4, or non-canonical caspase-11 inflammasomes. This is one proposed mechanism linking ketogenic diets to reduced inflammaging. needs-human-replication

DimensionStatusNotes
Pathway conserved in humans?yesCASP1 pathway structure identical in human; ASC, NLRP3, GSDMD all conserved
Phenotype conserved in humans?partialElevated IL-1β/IL-18 in human aging confirmed; direct caspase-1 activity in aged human tissue less studied
Replicated in humans?noGenetic ablation studies are mouse-only; pharmacological evidence in humans is indirect (CANTOS, see below)

Disease associations

  • CAPS (cryopyrin-associated periodic syndrome) — gain-of-function mutations in NLRP3 (upstream of CASP1) cause constitutive NLRP3 inflammasome assembly → unregulated caspase-1 activation → recurrent fevers, urticaria, sensorineural hearing loss 8. Validates caspase-1 as a central effector in gain-of-function inflammasome disease.
  • Type 2 diabetes / metabolic syndrome — NLRP3/caspase-1-mediated IL-1β promotes pancreatic β-cell dysfunction and insulin resistance; supported by Anakinra (IL-1R antagonist) trials in T2D.
  • Neuroinflammation — caspase-1 activated in microglia in Alzheimer’s, Parkinson’s disease models; whether this is causal or consequential in humans is unresolved. no-mechanism

Therapeutic targeting

Upstream NLRP3 inhibitors (indirect caspase-1 inhibition)

  • MCC950 (CMPD-4) — potent, selective small-molecule NLRP3 inhibitor; blocks ATPase activity; not yet in clinical trials for aging indications as of 2026.
  • Anakinra / canakinumab — IL-1β neutralization downstream of caspase-1; canakinumab (CANTOS trial) reduced cardiovascular events by ~15% in post-MI patients with elevated hsCRP, providing indirect human-level validation of caspase-1–IL-1β axis in chronic sterile inflammation 9. needs-human-replication for direct aging benefit.

Direct caspase-1 inhibitors

  • VX-740 (pralnacasan) — first-in-class oral caspase-1 inhibitor; Phase 2 trials in rheumatoid arthritis showed modest disease-activity reduction; development discontinued due to hepatotoxicity signal in long-term rodent studies. No aging-indication trial.
  • VX-765 (belnacasan) — improved safety window over VX-740; Phase 2 completed in epilepsy (2013); no robust efficacy signal in that indication. No current aging-indication trial. long-term-unknown

Indirect via BHB

Dietary or exogenous β-hydroxybutyrate suppresses NLRP3 upstream of caspase-1; see ketogenic-diet for the dietary intervention. The beta-hydroxybutyrate compound page is pending. needs-stub

Druggability — tier-2 (re-rated 2026-05-08). Direct caspase-1 inhibitors (VX-740 pralnacasan, VX-765 belnacasan) reached Phase 2 for rheumatoid arthritis and epilepsy respectively but were discontinued (hepatotoxicity / no efficacy signal); no direct caspase-1 inhibitor is FDA-approved or active in clinical development for any indication. The earlier tier-1 assignment leaned on indirect support from upstream/downstream pharmacology — canakinumab (FDA-approved IL-1β mAb; CANTOS Phase 3 RCT validated the NLRP3 → caspase-1 → IL-1β axis) and broader inflammasome-pharmacology programs (MCC950, OLT1177) — but the strict Open Targets criterion is for caspase-1 itself, and there is no direct-acting drug. Tier-2 (“high-quality probe”) accurately reflects the current state: discontinued clinical-stage chemistries plus active probe-grade research compounds. Aging relevance via the NLRP3-inflammasome / IL-1β axis is unchanged.

Cross-references

  • nlrp3-inflammasome — upstream activating platform (R10c draft)
  • asc — adaptor bridging sensor to caspase-1 (R24d sibling page)
  • gsdmd — primary pyroptosis effector substrate (R24d sibling page)
  • pyroptosis — lytic cell death process downstream (R24d sibling process page)
  • il-1b — proteolytic product and key aging cytokine
  • il-18 — proteolytic product; IFN-γ inducer (R25)
  • chronic-inflammation — hallmark driven by caspase-1 activity
  • canakinumab — downstream IL-1β therapeutic with human trial data
  • nlrc4 — alternative inflammasome platform activating CASP1 needs-stub
  • aim2 — DNA-sensing inflammasome platform activating CASP1 needs-stub

Limitations and open gaps

  • #gap/needs-human-replication — most caspase-1 / NLRP3 aging data is from mouse models; direct tissue measurement of caspase-1 activity in aged humans is limited.
  • #gap/no-mechanism — the relative contribution of canonical (caspase-1-dependent) vs non-canonical (caspase-4/5-dependent) GSDMD cleavage in human inflammaging is unquantified.
  • #gap/long-term-unknown — no direct-caspase-1-inhibitor clinical trial in an aging or inflammaging population has been completed; belnacasan data is from epilepsy.
  • #gap/needs-canonical-id — GenAge entry for CASP1: no GenAge ID confirmed at time of drafting; field set null. Recommend cross-check at next lint pass.
  • #gap/needs-replication — the lifespan extension associated with caspase-1 ablation in mice (implied by Youm 2013 functional data) has not been tested in a dedicated controlled longevity study.

Footnotes

Footnotes

  1. doi:10.1126/science.1373520 · Cerretti DP et al. · Science 1992 · in-vitro (cloning/biochemistry) · original cloning of ICE/CASP1 cDNA and identification as pro-IL-1β processing protease no-fulltext-access (not_oa; cleavage-site residue confirmed via UniProt P01584 annotation) ↩ ↩2

  2. doi:10.1038/356768a0 · Thornberry NA et al. · Nature 1992 · n=purified enzyme · in-vitro (biochemical) · characterized ICE as a heterodimeric cysteine protease (p20/p10) required for IL-1β processing in monocytes no-fulltext-access (not_oa; p20/p10 subunit structure confirmed via UniProt P29466 annotation) ↩ ↩2 ↩3

  3. doi:10.1038/nature15514 · Shi J et al. · Nature 2015 · in-vitro / in-vivo · identified GSDMD as direct substrate of inflammatory caspases including caspase-1; defined GSDMD-N pore-forming fragment (cleavage at Asp275, confirmed UniProt P57764) no-fulltext-access (not_oa; cleavage site Asp275 independently confirmed via UniProt P57764) ↩

  4. doi:10.1038/nature15541 · Kayagaki N et al. · Nature 2015 · in-vitro / in-vivo · parallel identification of GSDMD as caspase-11 substrate; non-canonical inflammasome pathway no-fulltext-access (not_oa) ↩

  5. doi:10.1016/j.cmet.2013.09.010 · Youm YH et al. · Cell Metab 2013 · in-vivo (aged mice, 14–24-month cohorts; n=4–13/group) · randomized · Nlrp3-/- and Asc-/- mice (not Casp1-/-) protected against age-associated low-grade inflammation, glucose intolerance, thymic involution, cognitive decline, and bone loss; Casp11-/- mice unprotected; caspase-1 activity downstream of NLRP3 is the inferred effector arm · model: C57BL/6 and congenic knockout mice; PDF verified ↩

  6. doi:10.1038/nature24022 · Camell CD et al. · Nature 2017 · in-vivo (aged C57Bl6/J mice, 4-month vs 21–24-month) + in-vitro BMDMs · NLRP3 inflammasome in aged adipose tissue macrophages (ATMs) upregulates GDF3, which drives MAOA expression; MAOA degrades norepinephrine → blunts catecholamine-induced lipolysis; Nlrp3-/- 2-year-old mice protected from fasting lipolysis defect; MAOA inhibition (clorgyline) restores lipolysis in aged mice; model: C57Bl6/J; PDF verified ↩

  7. doi:10.1038/nm.3804 · Youm YH et al. · Nat Med 2015 · in-vitro + in-vivo (mouse BMDMs + NLRP3 gain-of-function knockin disease models) · BHB (not acetoacetate or butyrate) selectively inhibits NLRP3 inflammasome by preventing K⁺ efflux and blocking ASC oligomerization/speck formation; NLRC4, AIM2, caspase-11 inflammasomes unaffected; mechanism independent of AMPK, ROS, autophagy, GPR109a, Sirt2, UCP2; PDF verified ↩

  8. doi:10.1038/ng756 · Hoffman HM et al. · Nat Genet 2001 · observational/genetic · four missense mutations in CIAS1 (now NLRP3) exon 3 identified in three FCAS families and one MWS family; mutations in the NACHT domain cause constitutive NLRP3 assembly and unregulated caspase-1 activation → recurrent fevers, urticaria, conjunctivitis, sensorineural hearing loss; validates upstream NLRP3 → caspase-1 axis in human gain-of-function disease · PDF verified ↩

  9. doi:10.1056/NEJMoa1707914 · Ridker PM et al. (CANTOS trial) · NEJM 2017 · n=10,061 · rct · canakinumab 150 mg q3mo (HR 0.85, 95% CI 0.74–0.98, P=0.021) reduced primary CV endpoint (nonfatal MI, nonfatal stroke, CV death) in post-MI patients with hsCRP ≥2 mg/L at median 3.7-year follow-up; 37% median hsCRP reduction; LDL unchanged; higher fatal infection rate with canakinumab; indirect human validation of IL-1β/caspase-1 axis in chronic sterile inflammation · PDF verified needs-replication for aging-specific outcome ↩

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