A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

⚠️ Auto-extracted by Claude on 2026-05-21 from PubMed abstract + Crossref metadata. PDF not yet read end-to-end; full quantitative claims pending verification against the published full text (Gold OA, PMC10833472).

Yang 2024 — primate liver aging snRNA-seq atlas; SREBP2 pro-senescence

Single-nucleus transcriptomic atlas of primate (Macaca fascicularis / cynomolgus monkey) liver aging — the first cell-type-resolved survey of how hepatocyte gene programs shift with age across the three canonical liver zonations (periportal, mid-zonal, pericentral). Identifies hyperactivated SREBP (sterol regulatory element-binding protein) signaling as a hallmark of the aged liver, and demonstrates causality via human primary hepatocyte transduction: forced SREBP2 activation recapitulates aging phenotypes including impaired detoxification and accelerated cellular senescence.

Why this paper matters for the wiki

Resolves a long-standing mechanistic ambiguity in the aging-lipid-metabolism literature: does hepatic SREBP-2 activity go up or down with age? Cross-sectional human bulk RNA-seq (e.g., GTEx v10) shows weak, non-significant age trends for hepatic SREBF2 mRNA (Spearman ρ ≈ −0.07 in our 2026-05-21 query, n=262), but Yang’s single-nucleus data tells a different story — per-hepatocyte SREBP signaling is upregulated, which bulk RNA-seq is methodologically blind to (cell-composition confound: aged liver has fewer hepatocytes per gram, more immune/stellate cells, so per-cell hepatocyte increases can be invisible in bulk).

This makes Yang 2024 the empirical anchor for the wiki’s prior mechanistic prediction that age-associated mTORC1 hyperactivation would elevate SREBP-2 nuclear activity (see srebp-2 § Aging relevance, prior #gap/needs-replication). The Peterson 2011 mTORC1–lipin-1–SREBP-2 axis + Yang 2024 phenotype together support a unified model:

aging → hepatic mTORC1 hyperactivity → lipin-1 cytoplasmic retention
     → SREBP-2 nuclear activity ↑ per hepatocyte (Yang 2024)
     → SREBP-2 transcribes LDLR + PCSK9 (Dubuc 2004 / Jeong 2008 feedback paradox)
     → PCSK9 protein dominates over LDLR transcriptional drive
     → net hepatic surface LDLR ↓
     → plasma LDL/ApoB clearance ↓
     → cumulative LDL exposure rises (Ference 2024 LDL-years framework)

The Yang result does not yet directly test the mTORC1 dependency (no rapamycin arm in primate liver), nor does it directly quantify hepatic LDLR/PCSK9 protein by age — those remain open mechanistic gaps.

Key findings from abstract

1. First single-nucleus transcriptomic atlas of primate liver aging — cynomolgus monkey, multiple age groups, single-nucleus RNA-seq across hepatocytes + niche cells.
2. Zonation-resolved hepatocyte aging — gene expression fluctuations differ across the three canonical hepatocyte zonations (periportal / mid-zonal / pericentral). Aging is not uniform across the lobule.
3. Aberrant cell–cell interactions between hepatocytes and niche cells in aged liver.
4. Impaired lipid metabolism + upregulation of chronic inflammation–related genes prominently associated with declined liver function during aging.
5. Hyperactivated SREBP signaling is a hallmark of the aged liver — the headline mechanistic finding.
6. Causality demonstration: forced activation of SREBP2 in human primary hepatocytes recapitulates aging phenotypes — impaired detoxification + accelerated cellular senescence.

Caveats and what this does NOT resolve

• Species: cynomolgus monkey, not human. The in vitro mechanistic follow-up uses human primary hepatocytes but with forced SREBP2 activation, not aged hepatocytes per se.
• Cleavage vs transcription: the paper reports SREBP signaling hyperactivation (target gene programs); the abstract does not specify whether the upstream change is nuclear-fragment abundance, SREBF2 transcript, or cleavage-rate changes. Methods need to be read for resolution.
• mTORC1 dependency: not tested. The mTORC1 → lipin-1 → SREBP-2 axis is mechanistic prediction; Yang shows phenotype consistent with it but not dependency.
• LDLR/PCSK9 quantification by age: not foregrounded in the abstract. Supplementary data may contain it but extraction is pending PDF read.
• PCSK9 transcriptional vs post-translational regulation: Yang’s SREBP2-hyperactivation finding plus the SREBP-2 → PCSK9 SRE (Dubuc 2004, Jeong 2008) predicts elevated PCSK9 transcript with age, but GTEx v10 bulk RNA-seq shows ρ = +0.08 (weak, n=262 hepatocytes; not significant). The bulk-vs-snRNA discordance remains a methodological consideration.

Verification status

• ⚠️ Not yet PDF-verified. Frontmatter verified: false. Abstract verified via PubMed efetch 2026-05-21; Crossref metadata cross-checked. Full PDF read end-to-end is pending.
• Gold OA via PMC (PMC10833472) — full text accessible without paywall, fits standard verifier workflow.
• Quantitative claims from this paper currently propagated to the wiki (Yang-2024 hyperactivation framing on srebp-2, ldlr, pcsk9, lipoprotein-metabolism) carry inherited verified: false until this study page is verified.

Extrapolation

Dimension	Status
Mechanism conserved in humans?	yes — primates share the SREBP-2 / SCAP / INSIG / S1P / S2P machinery one-to-one with humans; cynomolgus is the closest standard NHP model to humans
Phenotype conserved in humans?	partial — the hyperactivation signal is primate-anchored; human in-vivo confirmation in aged liver biopsies/autopsy is not yet published
Replicated in humans?	no — single primate cohort + human in-vitro mechanistic follow-up; human in-vivo aged-liver replication absent

Cross-references

• srebp-2 — primary entity page; aging-relevance section now cites this study as direct empirical anchor for SREBP-2 hyperactivation
• ldlr — receives downstream effect; aging-relevance reframed around PCSK9-feedback dominance
• pcsk9 — co-induced by SREBP-2; this paper supports the PCSK9-elevation-with-age claim mechanistically
• lipoprotein-metabolism — pathway-level aging section now anchored on Yang 2024
• deregulated-nutrient-sensing — hallmark in which the mTORC1-SREBP-2 axis is embedded
• cellular-senescence — Yang’s causality demonstration directly links SREBP-2 to hepatocyte senescence
• cardiovascular-aging — downstream phenotype linking hepatic SREBP-2 dysregulation to plasma LDL trajectory

Methods (from abstract; full extraction pending)

• Species: Macaca fascicularis (cynomolgus monkey)
• Modality: single-nucleus RNA sequencing (snRNA-seq)
• Tissue: liver (cell-type-resolved; hepatocytes across three zonations + niche cells)
• Validation: human primary hepatocytes with forced SREBP2 activation
• Outcomes: gene expression atlas; SREBP2 pathway activity; cellular senescence markers; detoxification function