🧬 Aging Wiki

liver

Properties1
aliaseshepatic tissue, hepatic parenchyma, hepatic organ

19 min read

Liver

The liver is the body’s central metabolic clearinghouse — responsible for glucose and lipid homeostasis, xenobiotic detoxification via the CYP450 system, bile acid synthesis, coagulation-factor and vitamin-K-dependent protein synthesis (see vitamin-k-cycle), acute-phase inflammatory signaling, and the production of roughly 75% of circulating IGF-1 1. No other organ integrates as many aging-relevant hallmarks simultaneously, making the liver both a critical sensor of systemic aging and an early effector of multi-organ deterioration.

From a translational standpoint, the liver is also the leading near-term target for nucleic-acid-based aging interventions: systemically administered lipid nanoparticles (LNPs) accumulate preferentially in the liver via the ApoE–ASGR1 pathway, enabling mRNA delivery at doses that are non-toxic in validated platforms. This hepatotropism is a delivery advantage for partial-epigenetic-reprogramming approaches but also means the liver is where most systemic LNP-mRNA therapies exert their off-target effects — concentrating both the therapeutic opportunity and the adverse-effect risk.

Anatomy and zonation

The liver is a ~1.4 kg organ (adult human) organized into functional units called hepatic lobules. Blood flows from the portal triad (portal vein + hepatic artery + bile duct) at the periphery toward the central vein, creating an oxygen and nutrient gradient that imposes distinct metabolic identities on hepatocytes according to their position along the porto-central axis — a phenomenon called metabolic zonation.

ZoneLocationMetabolic specializationAging vulnerability
Zone 1 (periportal)Adjacent to portal triads; highest O₂/nutrientGluconeogenesis, β-oxidation, ureagenesis, first-pass drug metabolismMitochondrial gene expression declines most here with age 2; relatively best-preserved metabolic function overall
Zone 2 (mid-zonal)IntermediateMixed metabolic functions; bridge between zones 1 and 3Intermediate aging changes; least studied
Zone 3 (pericentral)Adjacent to central vein; lowest Oâ‚‚Glycolysis, lipogenesis, dominant CYP450 detoxification (CYP3A4-concentrated); receives nutrient-depleted bloodGreatest vulnerability to lipid accumulation and SREBP hyperactivation 3; lipid droplet accumulation on aging 2

Zonation is maintained by Wnt/β-catenin (zone-3 pericentral identity) and BMP/Ras signaling. With aging, the sharp transcriptional boundaries between zones are disrupted — a finding reported in both mouse and human liver tissue 4, though this is recent and awaits independent replication. gap/needs-replication

Cell composition

The liver contains a stereotyped cell community of six major types. Each has a dedicated wiki page built in the same campaign:

Cell typeFraction of total cellsKey aging changes
hepatocytes~60–65% by number; ~80% by volumePolyploidy (4n–8n enrichment); senescence accumulation; CMA decline; SREBP-2 hyperactivation; impaired regeneration
liver-sinusoidal-endothelial-cells (LSECs)~15–20%Pseudocapillarization: reduction in number AND size of fenestrae (50–250 nm; sieve plates cover ~5% of cell surface) + endothelial thickening + basal-lamina and collagen deposition 5
kupffer-cells~8–12%Increased CD68+ cells; elevated IL-6; increased adhesion to LSECs; low-grade hepatic inflammation. No age-related change in TNFα, Mrc1, Arg1, or IL-10 5. Do not frame as “M1 polarization” — this framing is unsupported. gap/needs-replication
hepatic-stellate-cells~5–8%Partial activation toward myofibroblast state with age; sensitized to SASP-TGF-β from senescent hepatocytes → fibrosis
cholangiocytes~3–5%Age-related biliary dysfunction; senescence contributes to cholestatic phenotypes
hepatic-progenitor-cells<1% (quiescent at rest)In-vivo activation after injury is blunted with old age in mice; in-vitro proliferative capacity is preserved → impairment is niche-driven, not intrinsic 5

For mechanistic depth on each cell type, see the linked pages above. This tissue page provides the organ-level synthesis.

Normal physiology relevant to aging

Glucose and lipid homeostasis — the selective insulin-resistance paradox

The liver is the primary site of insulin-regulated glucose and lipid metabolism. In healthy states:

  • Postprandial insulin activates PI3K→Akt→FOXO1 (suppressing gluconeogenesis) and PI3K→Akt→SREBP-1c (activating lipogenesis)

In hepatic aging and metabolic disease, this coordination breaks down into selective insulin resistance: FOXO1-driven gluconeogenesis becomes resistant to insulin suppression while SREBP-1c-driven lipogenesis persists. The result is simultaneous fasting hyperglycemia and hepatic fat accumulation — the biochemical core of masld and type-2 diabetes overlap. The upstream driver is mTORC1 hyperactivation, which also independently elevates SREBP-2 activity (via lipin-1 cytoplasmic retention), amplifying cholesterol synthesis 3.

CYP450 drug clearance

The CYP450 enzyme system (predominantly CYP3A4, CYP2D6, CYP1A2, CYP2C9 in humans) mediates phase-I xenobiotic metabolism. Hepatic CYP450 capacity declines with age: phase-I clearance drops by up to ~30% by age 70–80, while phase-II conjugation reactions (glucuronidation, sulfation) are relatively preserved 6. Practical consequence: age-related prolonged drug half-lives, increased toxicity at standard doses, and accumulation of reactive intermediates.

IGF-1 synthesis and the somatotropic axis

The liver is the dominant source of circulating IGF-1 — liver-specific IGF-1 knockout reduces blood IGF-1 by ~75%, though postnatal somatic growth is surprisingly preserved 1. With aging, hepatic GH signaling declines (reduced hepatic GH receptor expression), resulting in lower hepatic IGF-1 output, contributing to the somatopause phenotype (decreased muscle mass, bone density, and metabolic rate). See insulin-igf1 for the broader axis.

Coagulation factor and vitamin-K-dependent protein synthesis

The liver synthesizes all coagulation factors (I/fibrinogen, II/prothrombin, V, VII, VIII, IX, X, XI, XII, XIII) and the vitamin-K-dependent proteins (factors II, VII, IX, X; protein C, S, Z). Aging-associated hepatocyte senescence and synthetic dysfunction progressively impair this output. The vitamin-k-cycle — in which VKORC1 recycles vitamin K epoxide for repeated use — operates in hepatocytes; its efficiency declines with aging-related oxidative modification of VKORC1.

Hallmarks of aging in the liver

Cellular senescence and the 13-HODE paracrine cascade

Hepatocyte senescence accumulates with chronological age and repeated injury (steatohepatitis, viral hepatitis, toxin exposure). Senescent hepatocytes express p16INK4a, p21CIP1, SA-β-galactosidase, and γH2AX foci, and secrete a hepatocyte SASP including IL-6, IL-8, PAI-1, and TGF-β.

A 2023 Nature Communications study identified a lipid-mediated senescence-to-steatosis axis: senescent hepatocytes and macrophages secrete 13-hydroxy-9,11-octadecadienoic acid (13-HODE) via upregulated ALOX15 (15-lipoxygenase) 7. 13-HODE inhibits catalase by blocking its tetramerization (dissociation constant KD ~2.4 µM), increasing hepatocyte ROS. This oxidative shift stabilizes cleaved SREBP1, activating the lipogenic gene program → steatosis. Catalase overexpression rescued 13-HODE-induced liver steatosis in this model.

Separately, macrophage-derived TGFβ1 drives paracrine senescence in regenerating liver epithelium: macrophage ablation with liposomal clodronate in the partial ΔMdm2Hep genetic mouse model reduced hepatic TGFβ1 expression by 87%; TGFβR1 blockade in acetaminophen and CCl₄ injury models restored regeneration and improved survival beyond the standard treatment window 8. Note that the primary driver here is macrophage-derived TGFβ1 — not Kupffer-cell-specific TGFβ1 per se (macrophages include both resident Kupffer cells and infiltrating monocyte-derived macrophages; Bird 2018 did not specifically partition this between populations).

Upstream: KAT7-driven hepatocyte senescence. A genome-wide CRISPR screen identified KAT7 (histone acetyltransferase) as a driver of hepatocyte senescence via H3K14 acetylation and p15/CDKN2B induction; AAV-mediated Kat7 knockdown in aged mice extended median lifespan ~17% and reduced liver senescence markers 9. Single-lab result; independent replication pending. gap/needs-replication

Declining regenerative capacity

The liver’s exceptional regenerative capacity — full mass restoration within ~7 days after 70% hepatectomy in young rodents, driven predominantly by hepatocytes re-entering the cell cycle — declines markedly with age. In young (4-week) vs old (40-week) male mice, aged animals show significantly reduced liver weight/body weight recovery at 48–72 h, lower expression of HGF, cMet, cyclin D1, cyclin A2, and PCNA, and elevated LC3 and caspase-3 (increased autophagy and apoptosis relative to proliferation) 10.

Mitochondrial NAD+ content in hepatocytes, controlled by the inner-membrane transporter SLC25A51, is rate-limiting for this regeneration; this pathway declines with age and was identified as a potential target for NAD+ precursor supplementation 11.

Hepatic progenitor cell (HPC) activation after injury is also blunted in aged mice, but in-vitro proliferative capacity of aged HPCs is preserved, indicating the impairment is niche-driven rather than intrinsic 5.

Mitochondrial dysfunction

Hepatocytes have among the highest mitochondrial content of any cell type (~1,000–2,000 per cell), supporting gluconeogenesis, β-oxidation, and ureagenesis under constitutively high metabolic load. Age-related mitochondrial changes include reduced OXPHOS complex I and IV activity, impaired mitophagy (accumulation of damaged mitochondria that divert fatty acids into triglyceride storage), and elevated mitochondrial ROS. The SLC25A51/NAD+ axis connects mitochondrial function to regenerative capacity 11.

DimensionStatus
Mitochondrial dysfunction conserved in humans?partial — primate data (cynomolgus, baboon) support similar declines; matched-age human hepatocyte bioenergetics directly measured in limited studies
Replicated in humans?no — most mechanistic data are rodent; SLC25A51 regeneration data are mouse-only gap/needs-human-replication

Loss of proteostasis — CMA decline

Hepatocytes are high-volume protein-secretion factories (albumin, coagulation factors, lipoproteins, acute-phase proteins) and carry constitutively high proteostasis demand. Chaperone-mediated autophagy (CMA) decline is a key age-related failure mode: LAMP2A expression falls in aged liver, reducing CMA flux; accumulated NCoR1 (a PPARα co-repressor normally cleared by CMA) inactivates PPARα-driven fatty acid oxidation, directly contributing to age-related steatosis 12. Impaired lipophagy (selective lipid-droplet autophagy) compounds the steatosis burden. See chaperone-mediated-autophagy and disabled-macroautophagy.

Epigenetic alterations and SREBP-2 hyperactivation

The liver has some of the most robust epigenetic aging signals across DNA-methylation clock platforms. Spatially resolved multi-omic profiling in mouse liver confirms that periportal and pericentral hepatocytes follow distinct aging epigenetic trajectories 2.

Single-nucleus transcriptomics in aged primate (cynomolgus monkey) liver demonstrates per-hepatocyte hyperactivation of SREBP-2 — most pronounced in zone-3 pericentral hepatocytes — and shows that forced SREBP2 activation in human primary hepatocytes recapitulates aging phenotypes including impaired detoxification and accelerated senescence 3. This primate finding directly confirms the mechanistic prediction from the mTORC1–lipin-1–SREBP-2 axis. Extrapolation to humans: partial (primate data support conservation; human in-vivo aged-liver biopsy confirmation pending).

DimensionStatus
SREBP-2 hyperactivation conserved in humans?partial — primate in vivo + human primary hepatocyte in vitro; no aged human liver biopsy snRNA-seq replication yet
Replicated in humans?no — single primate cohort; independent human-liver study needed

Hepatocyte polyploidy — a compensatory buffer

Unlike most mammalian somatic cells, hepatocytes are normally polyploid. In young adult mice, ~35–40% of hepatocyte nuclei are tetraploid (4n); with aging, the proportion of octaploid (8n) nuclei increases. Importantly, this polyploidization appears compensatory and buffering rather than a driver of pathology: tetraploid hepatocytes maintain more robust transcriptional regulatory networks, undergo non-random allelic segregation (preferentially retaining wild-type alleles), and haploinsufficiency of hepatocyte master regulators (HNF4A, CEBPA, CTCF) triggers early tetraploid enrichment that suppresses age-related steatosis 13.

Important scope caveat: all polyploidy-buffering mechanistic data are from C57BL/6J mice. Human hepatocytes are known to be polyploid, but the protective allele-selection mechanism has not been directly tested in human liver aging. gap/needs-human-replication

Age-associated phenotypes

The liver’s aging trajectory converges on four major clinical phenotypes, each with a dedicated page:

  • masld (metabolic-associated steatotic liver disease) — hepatic fat accumulation driven by CMA failure, AMPK decline, SASP-driven lipogenesis, and selective insulin resistance; the most prevalent aging-associated liver condition
  • liver-fibrosis — progressive collagen deposition driven by SASP-TGF-β activation of hepatic stellate cells into myofibroblasts; cirrhosis is the end-stage
  • age-related-cholestasis — biliary dysfunction in the aging liver; cholangiocyte senescence, bile acid composition changes, altered biliary secretion
  • hepatocellular-carcinoma — arising on a background of chronic hepatocyte senescence, genomic instability, cirrhosis, and immune surveillance failure; age is the dominant non-infectious risk factor
  • Altered drug metabolism — reduced CYP450 capacity (~30% decline by age 70–80 6) contributes to polypharmacy toxicity risk in older adults

Pathway intersections

PathwayRole in hepatic aging
mtormTORC1 hyperactivation → lipin-1 cytoplasmic retention → SREBP-2 nuclear entry → cholesterol synthesis ↑; suppresses autophagy/CMA; rapamycin normalizes in rodent models
ampkDeclines with age; counter-regulatory — normally phosphorylates/inactivates HMGCR, FASN, SREBP-1c; metformin acts via hepatic AMPK; AMPK decline accelerates lipogenesis
insulin-igf1GH/IGF-1 axis declines; liver produces ~75% of circulating IGF-1; selective insulin resistance produces FOXO1-driven gluconeogenesis + persistent SREBP-1c lipogenesis
wnt-beta-cateninMaintains zone-3 pericentral identity (CYP450 concentration, ASGR1 expression); disrupted in aging; regulates AXIN2+ hepatocyte self-renewal
cgas-stingActivated by cytoplasmic DNA from senescent/damaged hepatocytes; drives type-I interferon and NF-ÎşB SASP amplification; paracrine spread of senescence
autophagy / chaperone-mediated-autophagyBoth pathways impaired in aged liver; lipophagy failure → steatosis; CMA failure → NCoR1 accumulation → PPARα inactivation → impaired β-oxidation

Partial epigenetic reprogramming — liver as the lead target

Among all tissues targeted by in-vivo partial reprogramming approaches, the liver is the nearest-term lead target for several reinforcing reasons:

  1. LNP hepatotropism. Systemically administered LNPs accumulate in the liver via ApoE–ASGR1 interaction — the same platform proven in ~100 million COVID-19 vaccine recipients delivers mRNA to hepatocytes without organ-specific engineering.
  2. Well-validated functional endpoints. Liver regeneration, fibrosis scoring (Metavir/Ishak), ALT/AST normalization, albumin output, and CYP3A4 activity provide quantitative surrogate endpoints for efficacy.
  3. Disease-relevant regulatory entry. MASLD and liver fibrosis are mechanistically linked to epigenetic aging, clinically prevalent, and represent tractable first-in-human indications.

Preclinical evidence: Zhang et al. (2026) demonstrated that hepatocyte-specific delivery of OSK (OCT4/SOX2/KLF4) mRNA via a three-component ionizable LNP (H4T3_F6) attenuated liver fibrosis in a mouse model; transient reprogramming shifted hepatocytes from a fibrotic to a progenitor-like state and reduced extracellular matrix deposition 14. gap/needs-replication — single lab, single fibrosis model, very recent; no independent replication as of 2026-06-05.

Company-reported interest: NewLimit has reportedly identified liver as a lead program based on LNP hepatotropism. This is company-disclosed / non-peer-reviewed; no published preclinical or clinical data. gap/unsourced — do not present as established evidence.

Safety caution: Classic OSKM gain-of-function in the liver caused hepatocyte dysplasia and hepatocellular tumors in the original Yamanaka-factor mouse systems. Transient pulsed OSK (without MYC) shows a more favorable preclinical safety profile, but the therapeutic window — sufficient epigenetic rejuvenation without oncogenic risk — has not been characterized in aged human liver. Given that the liver is the primary site of HCC development, this safety question is especially critical. gap/long-term-unknown

For the full intervention pipeline and biology of transient reprogramming, see partial-reprogramming and in-vivo-partial-reprogramming-therapy.

Other interventions touching liver aging

InterventionMechanism in liverEvidence level
caloric-restrictionReduces hepatic fat (MASLD reversal); reduces LSEC pseudocapillarization and partially restores fenestrae; reduces Kupffer-cell inflammationStrong preclinical; moderate human (observational + weight-loss RCTs)
rapamycin / mTOR inhibitionNormalizes mTORC1 hyperactivation; restores autophagy/CMA; reduces SREBP-2 nuclear entry; extends lifespan in mice with liver metabolic benefitPreclinical well-supported; limited aging-specific human hepatic data
Senolytics (dasatinib + quercetin, navitoclax) — dasatinib, quercetin, fisetinClear senescent hepatocytes and stellate cells; reduce SASP-TGF-β; reduce fibrosis in mouse modelsPreclinical; no liver-specific human senolytic RCT completed as of 2026-06-05 gap/needs-human-replication
NAD+ precursors (nmn, nr)Restore hepatocyte mitochondrial NAD+ (SLC25A51) → improve β-oxidation and regenerative capacity 11Preclinical mechanistic; human hepatic NAD+ repletion effect on regeneration not yet demonstrated gap/needs-human-replication
CMA activatorsRestore LAMP2A → degrade NCoR1 → rescue PPARα fatty acid oxidation 12Preclinical only; no clinical-stage compound
Metformin (AMPK activation)Hepatic AMPK activation restrains gluconeogenesis and lipogenesis; modest MASLD benefitModerate human evidence; TAME trial ongoing

Hallmark connections

HallmarkLiver-specific mechanism
cellular-senescenceHepatocyte + Kupffer-cell senescence; 13-HODE/ALOX15/catalase/SREBP1 lipogenesis cascade 7; macrophage-TGFβ1 paracrine senescence spread 8; KAT7 driver 9; senescent LSECs in pseudocapillarization
loss-of-proteostasisLAMP2A-CMA decline → NCoR1 accumulation → PPARα inactivation 12; lipophagy failure; UPS impairment in aged hepatocytes
deregulated-nutrient-sensingmTORC1/lipin-1/SREBP-2 axis 3; AMPK decline; selective insulin resistance (FOXO1 gluconeogenesis + SREBP-1c lipogenesis); IGF-1 output decline 1
epigenetic-alterationsZonation-dependent epigenetic drift 2; SREBP-2 hyperactivation partly epigenetically mediated 3; target of OSK reprogramming
mitochondrial-dysfunctionOXPHOS complex I/IV decline; SLC25A51/NAD+ limitation for regeneration 11; impaired mitophagy → fat accumulation
chronic-inflammationKupffer-cell IL-6 elevation; 13-HODE-driven ROS → SASP amplification; low-grade hepatic inflammaging; NF-κB activation via cGAS-STING
genomic-instabilityHepatocyte somatic mutation accumulation; polyploidy as partial compensatory buffer 13; HCC risk accumulation with age

Limitations and gaps

GapTagNotes
Kupffer-cell M1/M2 polarization framinggap/needs-replicationHunt & Cogger 2019 found no age-related change in TNFα, Mrc1, Arg1, IL-10 in Kupffer cells; M1-polarization framing is unsupported
Polyploidy buffering in human livergap/needs-human-replicationAll allele-selection / buffering data are C57BL/6J mice; human in-vivo polyploidy-aging studies pending
SREBP-2 hyperactivation in human aged livergap/needs-human-replicationPrimate + human in-vitro data; no human in-vivo snRNA-seq liver biopsy series yet
Zonation disruption in human aginggap/needs-replicationSinha 2025 very recent; independent replication in a second human cohort pending
SLC25A51/NAD+ in human liver regenerationgap/needs-human-replicationMukherjee 2025 data are mouse-only; human replication pending
OSK reprogramming safety window in aged human livergap/long-term-unknownTherapeutic window (rejuvenation vs HCC risk) undefined in aged human hepatocytes
KAT7 lifespan extensiongap/needs-replicationWang 2021 single-lab; independent replication not confirmed as of 2026-06-05
CYP450 quantitative decline figure (~30%)gap/needs-replicationKlotz 2009 is a review; primary pharmacokinetic study citations needed
Caloric restriction LSEC fenestrae restorationgap/needs-human-replicationPrimary citation needed; claim well-established in rat models, human direct evidence limited
NewLimit liver programgap/unsourcedCompany-disclosed; not peer-reviewed

Cross-references

Cell types (liver community):

Hallmarks and processes:

Pathways:

Phenotypes:

Interventions:

Parent system:

Footnotes

Footnotes

  1. doi:10.1073/pnas.96.12.7088 · Sjögren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V et al. · “Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice” · Proc Natl Acad Sci USA 96(12):7088-7092 · 1999 · in-vivo · model: liver-specific IGF-1 KO mouse · key finding: liver produces ~75% of circulating IGF-1; growth preserved despite hepatic IGF-1 loss ↩ ↩2 ↩3

  2. doi:10.1038/s43587-023-00513-y · Nikopoulou C, Kleinenkuhnen N, Parekh S et al. · “Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver” · Nature Aging 3(11):1430-1445 · 2023 · in-vivo · model: male C57BL/6 mice (young vs old); spatial transcriptomics + scATAC-seq + scRNA-seq + lipidomics · key finding: periportal hepatocytes show mitochondrial gene expression decline; pericentral hepatocytes accumulate lipid droplets; epigenome changes are zonation-dependent ↩ ↩2 ↩3 ↩4

  3. doi:10.1093/procel/pwad039 · Yang S, Liu C, Jiang M et al. · “A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes” · Protein Cell 15(2):98-120 · 2024 · in-vivo (snRNA-seq) + in-vitro · model: Macaca fascicularis (cynomolgus monkey); human primary hepatocytes (forced SREBP2 activation) · key finding: SREBP-2 hyperactivated per-hepatocyte in aged primate liver; zone-3 most pronounced; forced SREBP2 in human hepatocytes recapitulates aging phenotypes ↩ ↩2 ↩3 ↩4 ↩5

  4. doi:10.1097/hep.0000000000001451 · Sinha S, Ali Q, Zhang T et al. · “Aging disrupts hepatocyte zonation homeostasis in mice and humans” · Hepatology 83(5):1143-1157 · 2025 · in-vivo + human tissue · model: mouse + human liver; spatial transcriptomics · key finding: aging disrupts periportal/pericentral transcriptional boundaries; hepatocytes lose zone-specific identity ↩

  5. doi:10.1016/j.csbj.2019.07.021 · Hunt NJ, Kang SWS, Lockwood GP, Le Couteur DG, Cogger VC · “Hallmarks of Aging in the Liver” · Comput Struct Biotechnol J 17:1151-1161 · 2019 · review · key findings: LSEC fenestrae 50–250 nm / sieve plates ~5% of cell surface; pseudocapillarization = fenestrae reduction in number AND size + endothelial thickening + basal lamina/collagen deposition; no age-related change in Kupffer-cell TNFα/Mrc1/Arg1/IL-10; HPC niche-driven (not intrinsic) impairment; Kupffer CD68+ and IL-6 elevated with age ↩ ↩2 ↩3 ↩4

  6. doi:10.1080/03602530902722679 · Klotz U · “Pharmacokinetics and drug metabolism in the elderly” · Drug Metab Rev 41(2):67-76 · 2009 · review · key finding: hepatic phase-I CYP450 clearance declines up to ~30% by age 70–80; phase-II conjugation relatively preserved; renal excretion declines ~50% ↩ ↩2

  7. doi:10.1038/s41467-023-44026-z · Duan J, Dong W, Wang G, Xiu W, Pu G, Xu J, Ye C, Zhang X, Zhu Y, Wang C · “Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity” · Nat Commun 14(1):8151 · 2023 · in-vivo + in-vitro · model: male mice (aged) + primary hepatocytes and macrophages · key finding: senescent hepatocytes and macrophages secrete 13-HODE via ALOX15; 13-HODE inhibits catalase tetramerization (KD ~2.4 µM) → ↑ROS → stabilizes cleaved SREBP1 → lipogenesis → steatosis; CAT overexpression rescues ↩ ↩2

  8. doi:10.1126/scitranslmed.aan1230 · Bird TG, Müller M, Boulter L et al. · “TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence” · Sci Transl Med 10(454):eaan1230 · 2018 · in-vivo · model: mouse ΔMdm2Hep genetic model + acetaminophen + CCl₄ liver injury + human liver biopsy/transplant tissue · key finding: macrophage-derived TGFβ1 drives paracrine senescence; macrophage ablation (liposomal clodronate in ΔMdm2Hep model) reduced hepatic TGFβ1 expression by 87%; TGFβR1 blockade in acetaminophen/CCl₄ models restored regeneration and improved survival ↩ ↩2

  9. doi:10.1126/scitranslmed.abd2655 · Wang W, Zheng Y, Sun S et al. · “A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence” · Sci Transl Med 13(599):eabd2655 · 2021 · in-vivo (aged mouse) + in-vitro · key finding: KAT7 knockdown extended median mouse lifespan ~17%; reduced liver senescence markers; single-lab gap/needs-replication ↩ ↩2

  10. doi:10.1111/jgh.12930 · Enkhbold C, Morine Y, Utsunomiya T et al. · “Dysfunction of liver regeneration in aged liver after partial hepatectomy” · J Gastroenterol Hepatol 30(7):1217-24 · 2015 · in-vivo · model: young (4-week) vs old (40-week) male mice, 70% hepatectomy · key finding: aged mice show impaired liver-weight recovery at 48–72 h; reduced HGF, cMet, cyclin D1/A2, PCNA; elevated LC3 and caspase-3 ↩

  11. doi:10.1038/s42255-025-01408-5 · Mukherjee S, Velázquez Aponte RA, Perry CE et al. · “Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration” · Nat Metab 7:2424-2437 · 2025 · in-vivo · model: mouse partial hepatectomy; Slc25a51 haploinsufficiency + hepatocyte-specific AAV-SLC25A51 overexpression · key finding: mitochondrial NAD+ content (set by SLC25A51) is rate-limiting for hepatocyte regeneration; Letter (Nat Metab 7:2424-2437) gap/needs-human-replication ↩ ↩2 ↩3 ↩4

  12. doi:10.1016/j.molmet.2023.101784 · Choi YJ, Yun SH, Yu J et al. · “Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1” · Mol Metab 76:101784 · 2023 · in-vivo + in-vitro · model: aged mouse liver + primary hepatocytes · key finding: LAMP2A decline → NCoR1 accumulation → PPARα inactivation → impaired fatty acid oxidation; CMA activator AR7 rescues phenotype ↩ ↩2 ↩3

  13. doi:10.1016/j.jhep.2024.03.043 · Yin K, Büttner M, Deligiannis IK et al. · “Polyploidisation pleiotropically buffers ageing in hepatocytes” · J Hepatol 81(2):289-302 · 2024 · in-vivo · model: wild-type C57BL/6J mice (young 3 months, old 24 months) + haploinsufficient strains (Hnf4a+/0, Cebpa+/0, Ctcf+/0) · key finding: ~35–40% of hepatocyte nuclei are 4n in young adult mice; 8n enrichment with aging; polyploidy is compensatory/buffering with non-random wild-type allele selection; mouse-only data gap/needs-human-replication ↩ ↩2

  14. doi:10.1016/j.jconrel.2025.114569 · Zhang C, Bai Y, Yin Q, Li J, Huang K, Qiu M · “Hepatocyte-specific partial cellular reprogramming via selective OSK mRNA lipid nanoparticle attenuates liver fibrosis” · J Control Release 390:114569 · 2026 · in-vivo · model: mouse liver fibrosis model · key finding: ionizable LNP-delivered OSK mRNA shifts hepatocytes toward progenitor-like state; reduces ECM deposition; single lab gap/needs-replication ↩

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