Organ communication in ageing.

Abstract

Ageing is a systemic process in which local damage in one organ propagates to others and coordinates organism-wide decline. The hallmarks of ageing are established, but the causal relations between them, and the routes by which local damage becomes organismal decline, remain undefined. We propose an initiator-communicator-effector framework in which the three terms denote causal roles assigned by intervention rather than fixed classes of lesion. Initiators are organ-intrinsic lesions whose organ-restricted correction restores function in distant, untreated organs; telomere attrition in the zebrafish gut is the paradigm. Communicators are the organs, routes and mediators whose interruption uncouples distant phenotypes from the initiating lesion without correcting it, including sterile inflammation, cGAS-STING signalling, endocrine and metabolic factors, immune-cell trafficking and neuroimmune outputs. Effectors are states induced in recipient organs lacking a sufficient local lesion, notably stem-cell exhaustion, bioenergetic decline, epigenetic reprogramming, fibrosis and endothelial dysfunction. Because roles are defined by perturbation rather than molecular identity, the same process may initiate on one axis and act as an effector on another; the architecture is a directed graph containing feedback loops, not a linear chain. Ageing may therefore be slowed by interrupting chronically engaged organ-to-organ communication as well as by repairing initiating damage. This article is part of the theme issue 'Developmental circuits in ageing'.