Altering Hepatocyte Metabolism Can Improve the Aged Immune System
This research is chiefly interesting as a demonstration that liver cells can collectively influence immune function. Beyond the improvement in immune function attained in aged mice as a proof of concept, one might think that this should lead to further investigation as to how exactly aging in the liver can affect the aging of the immune system. It is unlikely that the specific signaling systems identified by the authors of this paper and used as a basis for therapy are the only relevant paths of communication. Thus other approaches likely exist.
Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy, and vaccine failure. Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility. Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age.
Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8+ immune cell infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments. These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.