This study investigated whether youthful systemic factors can restore aged liver regeneration, using a split liver transplantation (SLT) cohort (n=36 pairs) and heterochronic parabiosis in 18-month-old vs. 2-month-old mice followed by 70% partial hepatectomy, with single-cell transcriptomics and lineage tracing to map mechanisms.
Young recipients showed significantly higher liver regeneration ratios than aged recipients in the SLT cohort; in mice, heterochronic parabiosis accelerated aged liver regeneration via young B-cell-derived lymphotoxin β (LTβ), which triggered transient somatic reprogramming of periportal hepatocytes through LTβ/LTBR signaling — and agonistic LTBR antibody administration replicated this effect.
The SLT cohort was small (n=36 pairs) and retrospective, limiting statistical power and causal inference in humans; parabiosis is an artificial shared-circulation model that may not fully replicate physiological aging dynamics; direct translation of LTBR agonist therapy to clinical use requires safety and efficacy validation in humans.
Short-term pharmacological LTBR agonism may offer a strategy to 'pre-condition' elderly donor livers before transplant or boost post-hepatectomy regeneration in older patients; clinicians working with aged liver grafts or elderly surgical candidates should watch for early-phase trials of LTβ-based therapies.
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