Aging disrupts tissue homeostasis and constrains blastema-mediated regeneration in the Cladonema medusa

Abstract Regenerative capacity varies widely across animals, yet aging is often accompanied by declining tissue homeostasis and regenerative potential. In many species, regeneration of complex structures relies on epimorphic programs that form a blastema, coordinating cell proliferation and pattern reorganization after injury. Although aging-associated regeneration defects have been documented in several bilaterian models, how aging shapes regeneration in early-branching metazoans with robust regenerative abilities remains unclear. Here, we investigate aging and regeneration in the medusa stage of Cladonema pacificum, a cnidarian that retains high regenerative capacity within a finite lifespan. We show that aging in Cladonema medusae is accompanied by progressive deterioration of tissue homeostasis, including shrinkage of the umbrella and manubrium, tentacle shortening, and reduced reproductive output. At the cellular level, aging is associated with depletion of differentiated cell populations, including nematocytes and neurons, together with a reduction in resident homeostatic stem cells in the tentacle bulb. Consistent with these changes, tentacle regeneration is markedly impaired in aged medusae and is characterized by defective blastema formation. Together, our findings indicate that aging disrupts both tissue homeostasis and blastema-mediated regeneration in Cladonema medusae, establishing a tractable model for studying aging–regeneration interactions and supporting the view that aging is a conserved constraint on regenerative systems across metazoan evolution. Competing Interest Statement The authors have declared no competing interest.