Biology and Life Sciences

Abstract: Vascular aging is a key factor in late-life health issues, including cardiovascular disease, stroke, and organ decline. It results from accumulated molecular, cellular, and structural damage like endothelial dysfunction, smooth muscle maladaptation, extracellular matrix failure, calcification, inflammation, and barrier breakdown. This accumulated damage interacts in ways that cause lasting changes to vascular mechanics and permeability. This chapter categorizes vascular damage into distinct physiologically recognizable groups, distinguishing root causes from signaling responses and emphasizing persistent structural and biochemical damage over transient dysregulation. This explains the limited durability of many signaling therapies and suggests that direct damage repair may provide more lasting and comprehensive benefits. We review evidence on endothelial cells, smooth muscle, extracellular matrix, mineralization, immune-vascular interactions, and hemodynamics, focusing on mechanisms that cause long-term damage. We discuss therapeutic strategies and risks of manipulating signaling pathways that vary across tissues. Finally, we explore the need for biomarkers reflecting specific vascular damage, advocating for a divide-and-conquer approach with targeted repairs and suitable endpoints to improve interventions that preserve vascular function.

Abstract: Ageing remains one of biology’s most fundamental unresolved questions. Existing explanations often attribute ageing to stochastic damage accumulation, adaptive programmes, or interacting hallmarks, yet none fully explains why ageing emerges so broadly in organisms that undergo development. Here, I introduce the Double Code Hypothesis of Ageing, which frames ageing as a consequence of life’s dual inheritance system: the genome and the epigenome. In this manuscript, ‘code’ is used in a computer-science-like sense, closer to source code than to the specialised meaning used in code biology: an organised set of biological instructions whose effects depend on being read, interpreted, maintained, and executed by cellular machinery.I propose that ageing is not merely the progressive accumulation of epigenetic noise within an individual, but the consequence of an inherent instability in a dual inheritance system whose two informational layers must remain functionally aligned across cellular and organismal generations. The relative stability of the genome allows long-term information preservation, whereas the plasticity of the epigenome enables development, differentiation, adaptation, and the emergence of complex phenotypes, but also makes this layer vulnerable to cumulative misalignment.Within this framework, ageing is interpreted as the individual-level cost of an information-management architecture that preserves and renews biological information across generations. In complex organisms, mitotically dividing cells progressively lose or misalign epigenetic information, whereas meiotic/germline-associated processes can restore or re-establish a functional genome–epigenome configuration for the next generation. This falsifiable framework offers experimental predictions in model systems such as Schizosaccharomyces pombe and provides a mechanistic explanation for why ageing exists.

Abstract: The concept of inflammaging — referring to the persistent, low-grade inflammatory state that accompanies biological ageing — has progressively positioned itself as a unifying framework for understanding age-related chronic disease. Unlike acute inflammation, which is adaptive, transient, and fundamentally protective, inflammaging reflects a persistent dysregulation of immune signalling. Its hallmarks include failure to resolve inflammatory signals, alongside mitochondrial decline and the gradual erosion of tissue homeostasis driven by persistent cytokine activity. Increasing evidence suggests that inflammaging is not merely a consequence of ageing, but rather an active systems-level process capable of reshaping metabolic, vascular, neurological, and musculoskeletal physiology. Persistent inflammatory activation contributes to frailty, cardiovascular disease, neurodegeneration, sarcopenia, metabolic dysfunction, and osteoarthritis through interconnected molecular and cellular pathways involving immunosenescence, cellular senescence, oxidative stress, inflammasome activation, and epigenetic remodelling [1]. Recent advances in geroscience have reframed inflammation as a multidirectional biological network integrating immune, endocrine, metabolic, microbiological, and biomechanical signalling. This perspective moves beyond reductionist cytokine models and instead conceptualises inflammation as a distributed regulatory architecture operating across tissues and organ systems. Within this framework, chronic disease may emerge not solely from isolated organ pathology, but from progressive failure of intersystem communication and adaptive resilience [2]. This invited review examines the biological foundations of inflammaging, with particular emphasis on immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation. We propose that inflammaging may be best understood as a form of multiscale biological interface failure in which persistent inflammatory signalling progressively destabilises tissue integration across physiological systems. Such a framework may facilitate the development of more precise biomarkers, systems-oriented therapeutic strategies, and translational approaches aimed at extending healthspan rather than merely prolonging survival.

Abstract: Telomeres and the extracellular matrix (ECM) are often studied as distinct contributors to aging and chronic diseases, yet growing evidence suggests they are deeply interconnected. This review explores the relationship between these two systems in both directions. Telomere shortening, shelterin defects, and loss of telomerase activity can promote senescence, stress responses, myofibroblast transition, and progressive matrix deposition. In turn, stiffness of the ECM, collagen-rich environments, and hyaluronan-linked signaling can shape telomerase activity, proliferative capacity, and telomere-associated damage responses. We bring together evidence from genetic mouse models, mechanistic cell-based studies, and human tissue analyses across the lung, kidney, vasculature, and heart to examine how telomere dysfunction and ECM remodeling influence one another during aging and disease progression. We focus on epithelial cells, fibroblasts, smooth muscle cells, and tubular cells, and discuss key pathways linking telomere biology and ECM regulation, including TRF1, TERT, TGF-β, cGAS–STING, VCAM-1, and mechanotransduction signaling. Taken together, the current findings suggest that telomere dysfunction is not only a marker of tissue aging but it is also an active driver of persistent ECM remodeling and fibrosis, while signals from the ECM can in turn influence telomere maintenance and cellular senescence. This bidirectional relationship provides a clearer framework for understanding how age-related cellular damage progresses into chronic tissue scarring.

Abstract: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is a major contributor to frailty, disability, and mortality in older adults. Store-operated calcium entry (SOCE) is a crucial regulator of skeletal muscle calcium homeostasis, and impaired SOCE has been linked to age-related muscle weakness. Here, we investigated the role of the synaptophysin family member synaptophysin-like protein 2, also known as mitsugumin 29 (MG29/SYPL2) in regulating SOCE, muscle structure, and lipid signaling during aging. Using knockout mice (mg29−/−) as a model of accelerated sarcopenia, in combination with RNA interference against MG29/SYPL2 in adult muscle and primary myotubes, we quantified changes in muscle morphology, contractile function, SOCE activity, and targeted lipidomic profiles. We found that reduced MG29/SYPL2 expression leads to decreased muscle fiber cross-sectional area, reduced specific force, blunted SOCE, and marked alterations to membrane cholesterol content as well as fatty acid–derived lipid mediators. Cholesterol depletion by methyl-β-cyclodextrin in wild-type myotubes produced similar SOCE defects as those observed in aged wild-type and young mg29−/− muscles, indicating that MG29/SYPL2-dependent maintenance of membrane cholesterol is required for normal SOCE. Acute MG29/SYPL2 knockdown also modified myogenic differentiation, expression of calcium-handling and stress-response genes, and the release and consumption of specific polyunsaturated fatty acid–derived lipid mediators. Together, these findings identify MG29/SYPL2 as a critical regulator of SOCE and lipid signaling in skeletal muscle and suggest that its age-related decline contributes to sarcopenia by disrupting triad membrane organization and excitation-contraction coupling.

Abstract: 1) Background: Coumestrol is a bioactive compound that inhibits HASPIN activity and prevents tau and H3 phosphorylation. Oral ingestion of CBSs increases blood testosterone levels, which decline with age causing late-onset hypogonadism. Oral ingestion of coumestrol-rich bean sprouts (CBSs) has been shown to suppress the onset of Alzheimer’s disease in 5xFAD mice and the onset of colon cancer in APC^min/+ mice. 2) Methods: We investigated the effect of oral ingestion of CBSs on the progression of aging in male senescence-accelerated prone 1 (SAMP1) mice allowed voluntary exercise or no exercise. The SAMP1 mice were divided into two groups fed either a standard diet or a diet including bean sprouts from 12 to 18 weeks of age. Each group was divided into two groups with voluntary exercise or no exercise. 3) Results: Voluntary exercise accelerated aging-related declines in blood testosterone levels, nerve growth factor levels, and spatial working memory, and oral ingestion of CBSs suppressed these age-related phenotypes, regardless of exercise. 4) Conclusion: Ingestion of CBSs prevented aging-related phenotypes in the experimental mice. A detailed analysis of the molecular mechanisms of coumestrol will be useful for understanding aging and preventing age-related diseases such as cancer, Alzheimer’s disease, and LOH.

Abstract: Dementia represents a growing global public health challenge, driving the rapid expansion of educational interventions aimed at improving awareness and promoting risk-reduction behaviours. Despite this growth, existing research demonstrates a persistent gap between knowledge acquisition and meaningful behavioural change. This paper presents a realist-informed conceptual analysis and proposes an integrative conceptual framework for evaluating the real-world effectiveness of digital dementia education. Integrating health literacy theory, the Capability–Opportunity–Motivation Behaviour (COM-B) model, and implementation science, the framework conceptualises dementia education as a dynamic, multi-component process involving resource availability, user engagement, interpretative engagement, behavioural readiness, contextual influences, and real-world outcomes. Particular emphasis is placed on interpretative engagement, grounded in constructivist and sensemaking perspectives, as a key mechanism linking exposure to educational content with behavioural intention and action. The paper identifies critical limitations in current evaluation approaches, including overreliance on knowledge-based outcomes and insufficient consideration of contextual, emotional, and implementation influences. By advancing a user-centred and context-sensitive framework, this study contributes to the development of more theoretically informed and implementation-oriented approaches for evaluating digital dementia risk-reduction education, particularly among midlife populations.

Abstract: Old murine bone marrow-derived monocytes and macrophages (BMMs) display enhanced CD38 protein, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, and reduced NAD⁺ level after infection with oral pathogens compared with young controls. We aimed to determine whether treatment with a CD38-specific inhibitor (78c) in mice with experimental periodontitis could alleviate alveolar bone loss and enhance NAD⁺ levels in tissues compared with vehicle treatment. Twenty young (2-month-old) and twenty old (18-month-old) C57BL/6J mice with experimental periodontitis were treated with either vehicle or 78c twice daily via intraperitoneal injection for 4 weeks. The liver, spleen, and right maxillary tissues were harvested to analyze NAD⁺ levels. The left maxillary tissues were scanned by micro-CT, processed for tissue sectioning, and stained with hematoxylin and eosin (H&E) and tartrate-resistant acid phosphatase (TRAP). Treatment with 78c significantly enhanced NAD⁺ levels in the liver and spleen of both young and old mice, and significantly increased NAD⁺ in the right maxilla of old mice compared with vehicle treatment. Additionally, treatment with 78c alleviated alveolar bone loss in both young and old mice. Our results support the notion that 78c is a promising therapeutic strategy for treating periodontal disease associated with aging.

Abstract: Aging causes exhaustion of stem cells (SCs), loss of regenerative potential, and thereby makes them susceptible to age-related diseases (ARDs), known as cellular senescence. Senescent stem cells (SenSCs) secrete Senescence-Associated Secretory Phenotypes (SASPs) that synergistically exacerbate inflammation. Alongside this, they secrete Senescence-Derived extracellular vesicles (SenEVs) that carry a diverse array of molecules that transmit senescence-inducing signals to distant cells and tissues throughout the body, intensifying the detrimental effects of ageing and fostering a pro-tumorigenic microenvironment (PTME). In this review, we comprehensively assess these EVs, their distinct microRNA (miRNA) landscape, protein cargo, including extracellular matrix (ECM) remodeling enzymes and inflammatory cytokines, lipid profiles, and metabolomic signatures. Critically, we elucidate how SenEVs drive systemic ageing through paracrine transmission of senescence, impairing tissue regeneration by propagating oxidative stress, disrupting stem cell niches, and contributing to organ-specific ageing. Furthermore, we discussed their role as pro-cancer factors by remodeling the tumor microenvironment (TME), as they carry oncogenic miR-21 and miR-34a, which promote immune evasion and facilitate metastatic spread. Given their pervasive influence, SenEVs offer significant therapeutic opportunities, ranging from biomarkers of biological ageing to strategies to block harmful EVs and to engineer therapeutic EVs for targeted delivery. Future directions on SenEV research should focus on standardization, single-cell EV biology, organ-specific EV mapping, multi-omics integration, and AI-driven research. This integrated perspective underscores the profound clinical and global relevance of SenEVs as innovative targets for combating cancer and ARDs.

Abstract: Objectives: This prospective, open‑label, non‑randomized study evaluated a specific combination of cystine, B vitamins, and minerals (Pantovigar^® vegan) in 34 women (aged 30-75 years) with diffuse hair loss (Modified Savin Score 1–3) for improvements in hair condition and product acceptance and safety following up to 6 months of intake of one test product capsule three times daily. Methods: Hair condition was assessed using phototrichogram analysis, and participants completed a product acceptance questionnaire. Blood nutrient levels associated with hair loss were measured at baseline, and at 3 and 6 months. Results: From baseline to 6 months, a significant increase of 2.35% in the rate of anagen (p = 0.012) and a decrease of 2.35% in the rate of telogen (p = 0.012) hairs resulted in an increase of 2.37% in the ratio of anagen/telogen hair rate (p = 0.013), reflecting a proportionate increase in the number of terminal hairs in the anagen phase. Most participants agreed with positive questionnaire hair condition statements. Increased levels of B vitamins, ferritin, and hematocrit did not exceed established tolerable upper limits, and no serious undesired effects were reported. Conclusion: The study results suggested that the specific nutrient combination of cystine, B vitamins, and minerals in the test product is beneficial to hair condition, is well‑accepted, and safe for use in the management of diffuse hair loss in women. Clinical Trial Registration: [https://clinicaltrials.gov/study/NCT05943860]; identifier [NCT05943860]; date of registration: June 21, 2023; retrospectively registered.

Abstract: Purpose: Six million people use crutches as mobile aids in the US. Rigid designs with no axial mobility limit sensory feedback and lead to secondary injury on the upper joints. Spring-loaded designs offer compliance but may compromise stability. We designed a biologically inspired tensegrity crutch with a compliant module aiming to achieve favorable mechanical properties. The terminal module was a pre-stressed self-tensile two-cell tensegrity structure. We compared the tensegrity crutch to commercial rigid and spring-loaded crutches in mechanical tests using axial loading, in overground straight and turning walking, and in participant experience.Methods: In human trials, healthy young adults (N=18) with no recent lower-body injury performed straight walking and turning trials at a comfortable self-selected pace. A knee blocker simulated unilateral injury of the dominant leg. After using each type of crutch, participants reported their perceived levels of effort, comfort, pain, stability, and usability.Results: Compared to the rigid design, both spring-loaded and tensegrity conditions reduced peak loading rates. The tensegrity design improved effort, comfort, pain, and usability. Spring-loaded crutches reduced perceived stability and walking speed.Conclusion: The biologically inspired tensegrity crutches were an overall improvement to existing designs. Simulations and mechanical testing suggest that nonlinear stiffness, ground-following, and force feedback are among the beneficial mechanical properties that underlie this improvement.

Abstract: Selenium (Se), a vital trace element, plays a significant role in maintaining vascular health and may offer protective effects against atherosclerosis. Its actions are mediated through Se-dependent selenoenzymes and selenoproteins, which enhance antioxidant defense, modulate inflammatory responses, and promote autophagy. These processes collectively help prevent cellular senescence - a state associated with age-related vascular decline characterized by oxidative stress, DNA damage, pro-inflammatory activity, and endothelial dysfunction. Epidemiological evidence consistently shows that low Se status is associated with increased risk of atherosclerotic cardiovascular disease within a narrow concentration range. However, clinical trials have not demonstrated clear reductions in cardiovascular events or mortality with Se supplementation alone. Overall, current evidence indicates that Se modulates key mechanisms involved in vascular aging and atherosclerosis, particularly redox balance, immune activation, and vascular cell homeostasis. This comprehensive review summarizes current epidemiological, clinical, and experimental research on the role of Se in cardiovascular health. It underscores Se's potential as a promising strategy for the prevention and treatment of atherosclerosis, while also acknowledging the complexities and nuances of its effects on vascular health. A deeper understanding of the cellular and molecular mechanisms involved could pave the way for targeted interventions aimed at reducing the burden of atherosclerotic cardiovascular disease.

Abstract: Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a crucial role in immune responses and tissue homeostasis. The expression of IL-17A is strictly regulated by transcription factors including RORγt and is mainly produced by Th17 cells, γδT cells, and innate lymphoid cells. IL-17A signals through a heterodimeric receptor complex consisting of IL-17RA and IL-17RC, leading to the activation of NF-κB and MAPK pathways. Recent studies have highlighted its functions in the central nervous system, with reported associations with multiple sclerosis and autism spectrum disorder. Furthermore, the development of IL-17A inhibitors has progressed significantly, showing high therapeutic efficacy particularly in autoimmune diseases. This review provides an overview of current knowledge regarding IL-17A, from its molecular characteristics to clinical applications.

Abstract: Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer’s dis-ease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here we determine how metabolic stress associated with spreading depolarization (SD)—a hallmark of stroke, hypoxia, TBI, and migraine—modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD acceler-ates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.

Abstract: Aging is characterized by a progressive decline in physiological functions driven by cellular senescence, chronic inflammation, and alterations in the gut microbiota. Quercetin is a potential anti-aging compound; however, its clinical application is limited by low bioavailability. In this study, we investigated whether enhancing quercetin bioavailability using EubioQuercetin (EQN) improves aging phenotypes by modulating the gut microbiota–intestinal axis. Male C57BL/6J mice were treated with EQN or conventional quercetin for 12 weeks. Aging phenotypes were assessed using a composite aging score based on hair glossiness, hair loss, and the presence of white hair. Gut microbiota composition was analyzed via 16S rRNA sequencing with centered log-ratio transformation, and intestinal gene expression was evaluated via quantitative reverse transcription-polymerase chain reaction. Notably, EQN significantly reduced the aging score compared to the control (median = 4.5 vs. 8; p < 0.01), with greater efficacy than conventional quercetin. Microbiota analysis identified taxa that were positively (Lactobacillus, Romboutsia, Desulfovibrio, and Lachnoclostridium) and negatively (Akkermansia and Christensenellaceae) associated with aging. EQN selectively suppressed aging-associated taxa and increased the abundance of beneficial bacteria. It also downregulated the expression levels of senescence-related genes (p21, proliferating cell nuclear antigen, and leucine-rich repeat-containing G protein-coupled receptor 5) and upregulated those of tight junction genes (claudin-1 and -6), indicating improved intestinal barrier function. No significant associations were observed between the aging score and levels of short-chain fatty acids or most circulating proteins. Overall, these findings suggest that enhancing quercetin bioavailability amplifies its anti-aging effects through the coordinated modulation of gut microbiota and intestinal barrier function. Therefore, targeting the gut microbiota–intestinal axis via bioavailable dietary polyphenols represents a promising strategy for promoting healthy aging.

Abstract: The antagonistic pleiotropy (AP) mechanism of aging was first proposed by G.C. Williams in 1957. However, practical application of this theory for the targeted search of longevity interventions has lagged, owing to a lack of clear understanding of the conditions under which the same gene or trait may have opposite effects on fitness in young versus old organisms. We propose that changes in the somatic environment may result from allometric growth, physiological differences between adult and juvenile life stages beyond those caused by aging, and ontogenetic niche shifts, and we provide well-documented examples of AP mechanisms corresponding to these conditions. We then test this understanding through testable predictions. Specifically, we demonstrate that (1) traits that have diverged the most between developmental stages contribute the most to aging; (2) organisms with negligible senescence exhibit minimal differences between adult and juvenile life stages; and (3) among taxonomically close organisms, stronger differences between adult and juvenile stages are associated with higher aging rates, while greater similarity is associated with lower aging rates. This understanding opens opportunities for the targeted identification of AP mechanisms based on the analysis of organisms' developmental trajectories. Additionally, it suggests two potential approaches for mitigating AP: suppression of adverse genes or traits in late life, or prevention or reversal of alterations in the somatic environment that convert previously beneficial traits into detrimental ones.

Abstract: Background/Objectives: Peripheral artery disease (PAD) is frequently asymptomatic, requiring non-invasive approaches for disease evaluation and therapy monitoring. This study demonstrates that multispectral optoacoustic tomography (MSOT) and laser speckle contrast imaging (LSCI) can non-invasively assess changes in tissue vascular oxygenation and perfusion, respectively, in a mouse hind-limb PAD model, enabling comparison of age-dependent vascular responses. Methods: PAD was induced by cauterization of the femoral artery in young (2 months) and old (18 months) mice, which were imaged using MSOT and LSCI at baseline (Day 0) and on Days 3, 7, and 14 post-surgery. Correlative histology including Hematoxylin and Eosin (H&E), Masson’s trichrome for collagen, and immunofluorescence for CD31 and Ki-67 were performed. Results: Reduced tissue oxygenation was observed by MSOT in the ischemic limb shortly after surgery and faster recovery occurred in young compared to old mice. LSCI revealed time-dependent perfusion recovery in both groups, with consistently better recovery in young mice. Histological analyses confirmed ischemic damage and demonstrated enhanced angiogenesis and cellular proliferation in young muscle tissues. The observations were consistent for each methodology. Conclusions: These results indicate that both MSOT and LSCI serve as effective, non-invasive tools for longitudinal monitoring of muscle injury, capable of revealing age-dependent vascular responses without the need for exogenous contrast agents.

Abstract: Reaction time (RT) is widely used as a fundamental indicator of central nervous system processing speed. Numerous studies have shown that RT increases with age, generally in-terpreted as a decline in information processing efficiency. However, most previous studies have focused on absolute RT values, and it remains unclear whether aging also alters the relative relationships between responses under different task conditions. The present study investigated whether aging affects the relative difference between inside and outside pedal reaction times in a Foot Psychomotor Vigilance Test (Foot PVT). A total of 44 participants were analyzed, including 20 younger adults (24 ± 3 years) and 24 older adults (73 ± 5 years). Participants responded to visual stimuli by pressing either the left or right pedal with the right foot. The difference between inside and outside RT (dRT) was calculated for each participant as an index of relative response structure. Group compari-sons and correlation analyses were conducted to examine associations with age, height, physical activity level (PAL), and sleep-related factors. As expected, RTs were consistently longer in older adults across conditions. In contrast, dRT did not differ significantly be-tween younger and older groups, with negligible effect sizes(|d|< 0.1). Furthermore, dRT showed no significant correlations with height, PAL, or sleep-related indices. These find-ings indicate that while aging affects the overall speed of motor responses, the relative temporal structure between response conditions is preserved. This dissociation between global slowing and stable response structure may represent a fundamental characteristic of neuromotor aging.

Abstract: Complex multicellular systems face an intrinsic reliability problem in which the machinery that maintains order is itself subject to degradation. While the molecular hallmarks of aging are well characterised, how stochastic cellular damage is translated into tissue-level decline remains incompletely understood. Tissue maintenance may in part be constrained by a sensing bottleneck in which cells access only a compressed and incomplete representation of their microenvironment and of neighbouring cells’ internal states. Consequently, tissue decline may depend in part on how effectively multicellular systems can sense and stabilise collective tissue states across scales. We explore how dysregulation may arise at the tissue scale through coordination properties such as architectural topology, coupling fidelity, and context dependence. Erosion of these interacting features may compromise the tissue’s ability to constrain local function, permitting recurrent but non-uniform forms of deterioration. We consider failure patterns such as the emergence of coordination traps: dysfunctional but self-stabilising tissue configurations that arise when drift becomes consolidated in slow-turnover substrates such as structural, contextual, or epigenetic layers. If youthful tissue organisation is distributed across these layers rather than stored as a single recoverable reference, then tissue state itself may be prone to collective drift. This view may help explain why different organs exhibit distinct age-related trajectories and suggests that effective interventions may need to restore or reconfigure the interdependent layers that sustain tissue coordination.

Abstract: Toxoplasma gondii infects most warm-blooded vertebrates and establishes lifelong persistence by encysting as latent bradyzoites within long-lived tissues, a state typically regarded as innocuous in immunocompetent hosts. We propose an alternative hypothesis: bradyzoite persistence may represent an evolved program of delayed virulence. Because T. gondii completes sexual reproduction only in felids after ingestion of infected tissues, parasite fitness is enhanced when infected tissues are consumed by felids. Host debilitation may increase vulnerability to predation or scavenging, but pathogenic effects expressed too early could jeopardize host populations; thus, selection should favor virulence that emerges after the host’s reproductive window, preserving population continuity. Multiple observations align with this hypothesis. Bradyzoite biology supports lifelong persistence across diverse host species. Pharmacologic suppression of protozoa has been associated with large and durable reductions in all-cause mortality and morbidity, including dementia, schizophrenia, and malignancy, across independent human cohorts. Viral coinfections provide plausible triggers for parasite reactivation. In parallel, T. gondii DNA increases progressively along the adenoma-to-carcinoma sequence in gastrointestinal malignancies. Together, these findings motivate a testable hypothesis: a fraction of late-life morbidity may reflect the delayed virulence of a parasite whose transmission is enhanced as hosts weaken. We present falsifiable predictions associated with this hypothesis.