The EV-mitochondrial outsourcing network as a therapeutic target for age-related testosterone deficiency: from network collapse to clinical intervention.

The longevity and functional maintenance of Leydig cells (LCs) depend on an extracellular vesicle (EV)-mediated mitochondrial outsourcing system. In contrast to the conventional focus on intracellular quality control, LCs orchestrate a bidirectional EV transfer network with testicular macrophages: they export EVs containing defective mitochondria to CD206+ macrophages for clearance (the scavenger pathway), while importing EVs with healthy mitochondria from MHCII+ macrophages (the donor pathway). During aging, this network undergoes three-dimensional disruption-donor-side collapse characterized by diminished PGC-1α, a shift toward Drp1 predominance over Mfn2, and NAD+ depletion; scavenger-side obstruction reflected in reduced TREM2 and impaired phagosome-lysosome fusion; and communication uncoupling driven by decay of the VCAM1/ITGβ1 axis. These coordinated failures precipitate a mitochondrial quality crisis, steroidogenic enzyme dysfunction, and progressive loss of LCs, thereby initiating and driving late-onset hypogonadism (LOH). Individual variability in EV network efficiency dictates LOH susceptibility, and the point of network decompensation marks the transition from a compensated state to clinical disease. In-depth dissection of this network and its dysregulation may yield novel strategies for early diagnosis (INSL3, EV-miRNA signatures, mtDNA mutation burden) and targeted therapy (MSC-EVs, NAD+ precursors, TREM2 activation).