Cladonema pacificum has recently emerged as a tractable laboratory model for studying regeneration in medusae, the free-swimming, sexually reproducing stage of the cnidarian life cycle. Unlike the sessile polyp Hydra, which can display negligible senescence under laboratory conditions, medusae follow a finite and reproducible lifespan, making them an ideal system in which to ask how aging reshapes tissue homeostasis within a single life-history context. The jellyfish retains robust regenerative capacity during early adulthood, so the researchers could track precisely when and how that capacity begins to fail. Their findings, published in Aging Cell, reveal a coordinated breakdown across multiple cellular systems rather than a single point of failure.

The team began by monitoring medusae under standardized culture conditions, taking longitudinal measurements of the three major organs: the umbrella that powers swimming, the manubrium that handles feeding and gametogenesis, and the tentacles used for prey capture and defense. As the animals aged, all three structures deteriorated. Umbrellas shrank significantly, manubria regressed relative to body size, and tentacles became markedly shorter. The researchers classified animals up to 40 days old as young, those between 41 and 60 days as middle-aged, and those 61 days and beyond as aged, a scheme grounded in the consistent, measurable changes they observed across dozens of individuals.

Histological analysis deepened the picture of decline. In young medusae, the manubrium displays a well-organized bilayered structure with oocytes nestled in its interior; in aged animals, the outer ectodermal layer thinned dramatically and oocyte numbers appeared reduced. Egg production, tracked longitudinally in the same individuals, peaked during the young phase and then fell steadily. The tentacles told a similar story: the photoreceptor organs called ocelli, neatly circular in youth, became irregular and disrupted with age, while the spherical clusters of stinging nematocytes at the tentacle tips grew less prominent. Critically, the accumulation of phosphorylated histone H2AX, a widely used molecular marker of DNA damage, rose in the tentacle bulbs as the animals aged, linking the visible morphological decay to cellular-level damage.

Because tentacles are the best-characterized regenerative tissue in Cladonema, the researchers focused their cellular analysis there. Hydrozoan tentacles harbor multipotent interstitial stem cells, or i-cells, concentrated near the tentacle base, which act as resident homeostatic stem cells supplying both progenitors and differentiated cells. Using fluorescence in situ hybridization and immunostaining, the team found that mature nematocytes, identified by the poly-γ-glutamate they synthesize, declined significantly in aged tentacles. Their precursors, the nematoblasts marked by the genes Mcol1 and Nanos2, were also reduced, and an independent, marker-independent histological scoring of the nematoblast-rich region confirmed the shrinkage of this lineage. Neuronal cell bodies near the tentacle base, labeled with anti-FMRFamide staining, likewise dropped in number.

The stem cells themselves showed clear signs of functional decline. Quantification based on β-catenin staining and nuclear morphology revealed a modest reduction in the proportion of i-cell-like cells in aged tentacle bulbs, alongside an increased share of epithelial cells, and FISH for the stem cell marker Piwi showed a marked drop in Piwi-positive cells. Proliferation collapsed across the board: EdU incorporation assays revealed far fewer S-phase cells in aged bulbs, and phospho-histone H3 staining showed fewer mitotic figures. Notably, when the researchers combined EdU labeling with Piwi FISH, they found that DNA synthesis declined both in Piwi-positive stem-like cells and in the broader Piwi-negative population, indicating that the proliferative slowdown was not confined to the stem cell compartment but swept through the entire tissue.

Did this cellular erosion translate into regenerative failure? To find out, the team amputated tentacles from medusae aged 30 to 70 days and monitored regrowth. Young tentacles elongated steadily, formed branches, and rebuilt their nematocyte clusters, but regeneration grew progressively weaker with age, with the decline becoming especially pronounced between 50 and 60 days. Functional recovery fared even worse. Seven days after amputation, every regenerated tentacle in young medusae captured and ingested prey, whereas most aged tentacles failed to capture prey at all and none completed ingestion. Even the earliest step of regeneration, wound closure driven by remodeling of the actin cytoskeleton, was substantially delayed: while most young tentacles achieved complete epithelial closure within two days, few aged tentacles managed it even by three days.

The mechanistic culprit appears to be the blastema, the localized mass of proliferative, undifferentiated cells that assembles at the wound site and orchestrates regrowth. Previous work established that Cladonema blastema formation depends on repair-specific proliferating cells, a lineage largely distinct from the resident homeostatic stem cells, and that blocking proliferation anywhere in the system impairs regeneration. In the aged medusae, EdU incorporation at wound sites was severely reduced, mitotic cells were scarce, and FISH revealed far fewer Piwi- and Nanos1-positive cells accumulating at injuries. Morphology-based classification confirmed a loss of i-cell-like cells near aged wounds. Intriguingly, a substantial population of morphology-defined stem-like cells remained at the injury sites even in old animals, but these cells had largely lost the molecular markers and proliferative activity that define a functional blastema, suggesting that aging impairs the ability of existing cells to enter the regenerative state rather than simply depleting them.

The authors interpret blastema failure not as a primary cause of regenerative decline but as an integrated outcome of broader aging defects: reduced baseline proliferation, weakened injury responses, and deteriorating stem cell support all precede or accompany the blastema’s collapse. They also note that changes in the stem cell niche, the local tissue environment that provides instructive cues, may contribute alongside intrinsic changes in the stem cells themselves. Because regeneration-specific cell lineages are distinct from homeostatic ones, aging may selectively compromise the activation or coordination of repair programs, perhaps through alterations in cellular state or the surrounding tissue architecture.

The comparative implications are striking. In the African turquoise killifish, aging disrupts progenitor activation and early regenerative events in brain and fins; in axolotls, limb regeneration slows with age rather than disappearing outright. Cladonema now extends this pattern to a cnidarian, an animal lacking dedicated mobile immune cells and classical inflammatory responses, implying that aging targets core components of regenerative systems, stem and progenitor cell dynamics and their coordination with surrounding tissues, across the breadth of metazoan evolution. The study also joins a growing body of work showing that strong regenerative capacity does not guarantee escape from senescence: sexual Hydra oligactis deteriorates after induced reproduction, and sexual planarians show clear aging despite their legendary plasticity. Cladonema, with its short life cycle, easy laboratory culture, and experimentally accessible tentacles, now offers researchers a powerful new platform for dissecting how the biology of aging collides with the biology of repair, and why, in the end, regeneration alone cannot hold back the tide of time.

Subject of Research: Age-related decline in tissue homeostasis and blastema-mediated tentacle regeneration in the cnidarian medusa Cladonema pacificum

Article Title: Aging Disrupts Tissue Homeostasis and Constrains Blastema‐Mediated Regeneration in the Cladonema Medusa

Article References: Kanehisa, R., Nakatani, H., Takatori, S., Tomita, T., Miura, M., & Nakajima, Y.-I. (2026). Aging Disrupts Tissue Homeostasis and Constrains Blastema‐Mediated Regeneration in the Cladonema Medusa. Aging Cell, 25(10), Article e70727. https://doi.org/10.1111/acel.70727

Image Credits: AI Generated

DOI: 10.1111/acel.70727

Keywords: Cladonema pacificum, aging, regeneration, blastema, stem cells, cnidarians, medusa, tissue homeostasis, nematocytes, DNA damage, proliferation, hydrozoa

The central paradox the authors confront is chemical. ROS—including superoxide, hydrogen peroxide and hydroxyl radicals—are inherently reactive, which is precisely why uncontrolled ROS production is toxic. Yet evolution has exploited this very reactivity. Hydrogen peroxide, in particular, is small, electrically neutral and membrane-permeable, allowing it to diffuse rapidly through tissue and act as a broadcast signal. At wound margins, ROS can oxidize the cysteine residues of target proteins, reversibly altering the activity of phosphatases, kinases and transcription factors. In this way, a transient oxidative pulse functions as a second-messenger system, converting the physical fact of injury into a coordinated genetic and cellular response. The review frames this as oxidative eustress—beneficial, regulated stress—as opposed to the destructive oxidative distress associated with pathology.

What makes the new synthesis compelling is its comparative breadth. The authors assemble evidence spanning the metazoan tree, from cnidarians such as Hydra and Nematostella, which can rebuild entire bodies from small fragments, to planarian flatworms, annelids, echinoderms, fish, amphibians and mammals. In nearly every regenerative model examined, pharmacological or genetic suppression of ROS production—most often by blocking the NADPH oxidase enzymes, or NOXes, that generate superoxide at the wound—impairs regeneration. Conversely, exogenous hydrogen peroxide can, in some systems, partially rescue defective regenerative responses. The consistency of this pattern across such distantly related animals raises the tantalizing possibility that ROS signaling is not a collection of independent evolutionary accidents but a deeply rooted, possibly ancestral, component of the regeneration program.

The review is careful, however, to emphasize that conserved does not mean uniform. The regulatory roles and modes of action of ROS vary considerably among species, tissues and regenerative contexts. In some animals, ROS act primarily in the earliest wound-healing phase, recruiting immune cells and initiating proliferation; in others, oxidative signals persist into blastema formation, the mass of progenitor cells from which the new structure grows. The downstream targets differ as well: ROS have been implicated in activating Wnt, FGF, ERK and JNK signaling pathways, in modulating apoptosis, and in shaping the extracellular matrix, but the specific wiring differs from one organism to the next. This variability, the authors argue, is precisely why continued comparative study is essential. Only by mapping ROS involvement across many species can researchers distinguish genuinely common mechanisms from species-specific embellishments.

This comparative logic carries the review into deeper evolutionary waters. The evolutionary history of regeneration remains one of the great unresolved puzzles in biology. Why can a salamander regrow an entire limb while a mouse cannot? Why do some annelids regenerate their whole posterior body axis while closely related species fail at the same task? Two competing frameworks dominate the field: regeneration as an ancestral capacity repeatedly lost in lineages that traded it for other advantages, or regeneration as a trait independently gained, assembled from pre-existing wound-healing and developmental machinery. The authors argue that ROS data can inform this debate. If ROS signaling sits at the base of regenerative responses across the animal tree, it may represent an ancient, conserved layer of the process—one that lineages with poor regenerative abilities have not necessarily lost, but perhaps fail to deploy correctly.

That reframing has direct therapeutic implications, and it is here that the review makes its most forward-looking argument. Humans regenerate well in the liver, moderately in skin and bone, and hardly at all in the heart, spinal cord and limbs. If ROS signaling is a conserved trigger of regenerative programs, then modulating redox state could offer a lever to reactivate latent regenerative capacity in poorly regenerating human tissues. The concept is not fanciful. Studies in zebrafish and axolotl have shown that adjusting ROS levels can influence heart regeneration and appendage regrowth, and redox-sensitive pathways such as ERK and Wnt are already major targets of regenerative medicine research. The review suggests that a rigorous understanding of when, where and at what concentration ROS act could enable precisely timed redox interventions—boosting regeneration without tipping tissues into the oxidative damage that fuels fibrosis, inflammation and cancer.

The authors are equally candid about the obstacles. ROS are fleeting, highly reactive and difficult to measure with spatial and temporal precision, and many of the tools used to manipulate them—broad-spectrum antioxidants, generic NOX inhibitors—are blunt instruments with off-target effects. To address this, the review includes a supplementary compendium of the functional tools available to modulate ROS production in regeneration studies, cataloguing the main pharmacological inhibitors and activators as well as the principal targets for RNA interference, morpholino and knockout approaches. Standardizing and refining this toolkit, the authors contend, is a prerequisite for the field’s maturation. Without it, discrepancies between studies may reflect technical artifacts rather than genuine biological differences, muddying the comparative analyses on which evolutionary conclusions depend.

The review also identifies major knowledge gaps that will shape the next decade of work. The precise molecular targets of ROS during regeneration remain incompletely defined in most models; the dose, duration and gradients of oxidative signals at wounds are poorly quantified; and the interplay between ROS and other injury-induced signals—calcium fluxes, bioelectric gradients, mechanical forces and immune-derived cytokines—is only beginning to be explored. Another open question is whether ROS participate in the establishment of positional memory, the information that tells a regenerating blastema whether to build a hand, a tail or a head. Answering these questions will require combining live redox biosensors, genetic models and comparative approaches across species that span the breadth of regenerative ability, from master regenerators to refractory ones.

What emerges from the synthesis is a view of regeneration as a redox-gated process whose ancient logic may still be latent within our own cells. The authors, based at institutions including Université Paris Cité, Université Côte d’Azur, the University of Manchester, Sorbonne Université and École Normale Supérieure, argue that studying ROS across metazoan diversity serves a dual purpose: it illuminates how regeneration evolved, and it reveals why some species, including our own, regenerate poorly. Both lines of inquiry converge on the same practical prize—new strategies in regenerative medicine grounded in evolutionary insight rather than trial and error. If the oxidizing burst that follows injury truly is a conserved call to rebuild, then learning to read, and perhaps to amplify, that ancient signal could one day help human tissues do what salamanders have done for millions of years: grow back.

Subject of Research: The role of reactive oxygen species signaling in animal regeneration and its evolutionary and therapeutic implications

Article Title: Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches

Article References: Vullien, A., John, J., Rampon, C., Amaya, E., Röttinger, E., & Gazave, E. (2026). Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06392-x

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06392-x

Keywords: reactive oxygen species, ROS signaling, regeneration, regenerative medicine, oxidative eustress, NADPH oxidase, evolutionary developmental biology, blastema, wound healing, redox biology, hydrogen peroxide, comparative biology