BACKGROUND:Population ageing is reshaping cancer burden in later life. For stomach cancer, declining age-standardised mortality may coexist with sustained or increasing absolute deaths as older populations expand. We assessed stomach cancer burden among adults aged 65 years or older in aged and super-aged societies from 1990 to 2023. METHODS:Using Global Burden of Disease Study 2023 estimates, we analysed deaths, disability-adjusted life-years (DALYs), age-standardised rates, age-specific mortality, sex-specific patterns, estimated annual percentage change, decomposition of changes in deaths, and trajectories around transition into super-aged status. Countries and territories were included if adults aged 65 years or older accounted for at least 14% of the population in 2023; super-aged societies were defined by a proportion of 21% or higher. RESULTS:Sixty countries and territories were included: 33 aged and 27 super-aged societies. In aged societies, deaths increased from 307,928 (95% UI 252,700-378,610) in 1990 to 336,454 (250,465-441,049) in 2023, despite a decline in the age-standardised death rate (ASDR) from 203.69 per 100,000 (166.46-251.77) to 90.12 (66.98-118.05). In super-aged societies, deaths decreased modestly from 105,330 (95,791-113,945) to 101,143 (81,472-116,462), while the ASDR declined from 162.13 (146.60-176.00) to 69.05 (57.17-78.77). ASDRs declined significantly in 59 of 60 countries and territories; Georgia showed a non-significant increase. Reductions were smaller at older ages, falling by 65% at ages 65-69 years but only 9% at ages 95 years or older. Decomposition showed that epidemiological improvements reduced deaths in nearly all countries, but population growth and ageing offset these gains in several settings, particularly China, Japan, and the Republic of Korea. CONCLUSIONS:Stomach cancer mortality rates declined substantially among adults aged 65 years or older, but absolute deaths declined less because demographic growth and ageing offset epidemiological gains, with burden increasingly concentrated at the oldest ages. Progress should therefore be assessed using both age-standardised rates and absolute burden.
Endocrine organs translate nutrient, stress and circadian cues into hormone outputs that coordinate whole-body physiology. Cellular senescence can distort this communication by changing endocrine-cell identity, stimulus-secretion coupling, secretory timing and local immune or paracrine signaling. Evidence is strongest in pancreatic β-cells and the adrenal zona fasciculata, where composite senescence phenotypes have been linked to endocrine dysfunction and modified by targeted perturbations. β-cell senescence is not uniformly deleterious. Some states retain insulin production, support functional maturation or restrain immune injury, whereas others propagate inflammatory and paracrine dysfunction. Pituitary and thyroid findings support direct but narrower mechanisms, while parathyroid and pineal evidence remains largely downstream or axis level. No single marker identifies endocrine senescence across tissues, and therapeutic evidence remains predominantly preclinical. A state-resolved approach combining lineage localization, multiple senescence domains and dynamic endocrine readouts is needed to identify pathogenic states and evaluate intervention.
Recent advances in biomarker profiling, wearable sensing, and high-density longitudinal self-monitoring have generated detailed individual-level datasets demonstrating that many ageing-associated measures, including cardiometabolic markers, inflammatory signals, functional performance metrics, and epigenetic age estimates remain highly modifiable in adulthood. However, these data also reveal substantial heterogeneity in response timescales and durability, with rapid reversibility of many biomarkers occurring alongside relative stability of structural and functional traits. In the absence of formal temporal and mechanistic models, such observations remain difficult to interpret and are frequently conflated with modification of the underlying ageing process itself. Here, we propose a formal digital twin framework for healthy ageing and longevity that treats ageing as a latent dynamical system rather than a collection of static biomarkers. Through critical synthesis of longitudinal ageing and digital-twin evidence, we derive a testable state-space model that distinguishes observable physiological change from latent ageing dynamics. This framework enables simulation of ageing trajectories, counterfactual testing of interventions, and explicit separation of transient biomarker optimisation from durable changes in ageing dynamics. We describe the model architecture, key state variables, system coupling across biological domains, and strategies for longitudinal validation. By grounding digital twin design in the structure of real high-frequency ageing data, this approach provides a predictive and mechanistically interpretable foundation for modelling health span and longevity.
Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.
Chronic kidney disease (CKD) is increasingly recognized as a model of accelerated biological aging, characterized by premature cardiovascular disease and frailty. Although frailty has become a cornerstone of gero-nephrology, current frailty models primarily emphasize physical performance and functional decline, providing limited insight into the vascular mechanisms underlying biological vulnerability. Conversely, vascular aging is traditionally framed within cardiovascular medicine, with little integration into contemporary frailty research, limiting our understanding of how vascular dysfunction contributes to biological aging in CKD. In this review, we propose vascular frailty as a unifying framework that bridges geroscience, nephrology, and vascular medicine. We summarize the mechanisms through which CKD accelerates vascular aging and discuss vascular reserve and vascular resilience as key biological concepts linking vascular aging to systemic frailty. This underlies our claim that vascular frailty could be a multidimensional phenotype integrating structural vascular remodeling, functional vascular impairment, and conventional frailty assessment. Emerging approaches for operationalizing vascular frailty through vascular imaging, physiological assessment, and biomarker profiling are also highlighted. Rather than representing another frailty subtype, vascular frailty provides a conceptual framework linking vascular aging, loss of vascular reserve, and systemic vulnerability in CKD. Emerging evidence supports the feasibility of integrating structural and functional vascular measures with conventional frailty assessment, although its incremental prognostic and clinical value remain to be established. Further longitudinal and interventional studies are needed to determine whether vascular frailty can contribute to risk stratification, individualized management, and strategies aimed at preserving vascular resilience in CKD and other aging-related conditions.
BACKGROUND:Alzheimer's disease (AD) is an age-dependent neurodegenerative syndrome in which microglial senescence bridges biological ageing and Aβ-tau pathology. Senescent microglia undergo permanent cell-cycle arrest, upregulate p16INK4a and SA-β-gal, and secrete a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation. Mitochondria-endoplasmic reticulum contact sites (MERCS) are dynamic physical junctions between the endoplasmic reticulum (ER) and mitochondria, whereas mitochondria-associated membranes (MAM) are biochemically enriched ER subdomains located at MERCS. MERCS coordinate calcium shuttling, mitochondrial dynamics, lipid trafficking and the unfolded protein response (UPR); however, whether their dysfunction drives microglial senescence in vivo remains largely untested. MAIN TEXT:This review critically integrates five MERCS-linked signalling axes that are hypothesised to drive microglial senescence, namely calcium overload, mitochondrial fission-fusion imbalance, inflammatory amplification, lipid dysregulation and unresolved ER stress. We apply a standardized four-tier evidence-grading framework to stratify causal evidence, systematically distinguish dystrophic, disease-associated (DAM) and bona-fide senescent microglia on the basis of transcriptomic and proteomic data from AD models and human tissues, and address underexplored dimensions including APOE/TREM2 crosstalk, mitophagy, epigenetic regulation, peripheral inflammation and senolytic combinations. We stress that inflammatory activation, oxidative stress and mitochondrial dysfunction represent common cellular stress responses that cannot independently define bona-fide microglial senescence. Because more than 90% of current mechanistic evidence is derived from non-microglial models, MERCS dysfunction in microglia remains a compelling hypothesis that requires rigorous in-vivo validation. Notably, MERCS dysfunction and AD-relevant APOE/TREM2 signalling engage in mutually modulatory crosstalk rather than a simple linear upstream-downstream hierarchy. CONCLUSION:Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts, intravital imaging and bidirectional interventions. Overall, MERCS dysfunction is proposed as a candidate multimodal upstream hub for calcium, mitochondrial, inflammatory, lipid and ER-stress signalling, and rigorous in-vivo validation together with microglia-selective delivery platforms is essential for therapeutic translation.
Cardiac fibrosis is a central pathological hallmark of diverse cardiovascular disorders, driving myocardial stiffening, ventricular dysfunction, and the progression of heart failure. Following cardiac injury, resident quiescent fibroblasts activate into pro‑fibrotic myofibroblasts, which overproduce extracellular matrix and perpetuate maladaptive cardiac remodeling. Current clinical interventions fail to specifically target pathological cells or reverse established fibrosis, leaving a major unmet therapeutic need. Chimeric antigen receptor (CAR)-based immunotherapy, originally revolutionizing oncology, has emerged as a precision strategy to selectively recognize, eliminate, or regulate cardiac fibrotic drivers. Its application to cardiac fibrosis, primarily through targeting activated fibroblasts and fibrotic niches, shows preclinical promise in halting or reversing disease. Although most evidence remains preclinical, early clinical translation has begun for selected fibrosis-targeted immunomodulatory cell therapies. This Review synthesizes advances in CAR-based immunotherapy for cardiac fibrosis, focusing on disease pathobiology, validated and emerging target antigens, diverse cellular platforms, preclinical evidence, and the key barriers to safe and effective clinical translation.
Brain regions are organized into large-scale networks through dynamic functional connections that support sensorimotor and cognitive processes across the lifespan. Age-related disruptions of these functional systems are associated with cognitive and motor decline and increased risk of neurocognitive disorders. A growing body of evidence suggests that structured physical training can modulate resting-state functional connectivity within these networks, offering a potential neuroprotective strategy. However, the relative efficacy of different training modalities, and the mechanisms by which simultaneous cognitive loading during motor training may confer neuroplastic benefits, remain incompletely characterized. This narrative review critically integrates evidence on network-level changes following cardiorespiratory, resistance and balance training, cognitive stimulation, and combined motor-cognitive interventions (with exergames (i.e., interactive physical and/or motor-cognitive exercises to control traditional or extended reality games) and mind-body practices) in older adults. We critically appraise evidence strength across three methodological tiers: direct neuroimaging (i.e., rs-fMRI), indirect measures (i.e., EEG and fNIRS), and conceptual frameworks, and apply this hierarchy to critically evaluate the guided-plasticity facilitation framework, a working hypothesis proposing synergistic neuroplastic effects when motor and cognitive demands overlap, for which direct neuroimaging support in humans remains limited. Key methodological gaps are identified: scarcity of direct comparison trials, inadequate dose-matching, limited long-term data, and near-absence of dynamic functional connectivity analyses. We outline research priorities to advance a mechanistic, individualized understanding of experience-dependent brain network plasticity in aging and neurocognitive disorders and propose network-level biomarkers as a candidate direction for future personalized training prescriptions. We also outline a prospective precision-medicine framework for exercise prescription in neurocognitive disorders, noting that prospective validation studies are needed before network-level biomarkers can inform clinical decision-making.
Cognitive impairment (CI) refers to impairment of cognitive domains that comprise memory, attention, language, and processing speed that exceed normal age-related changes and interfere with daily functions. Its pathophysiology includes neuronal dysfunction of synaptic activity, cerebral hypoperfusion, microglial inflammatory response, oxidative stress, mitochondrial dysregulation, impairment of the blood-brain barrier (BBB), and lipopolysaccharide (LPS). These interconnected mechanisms promote neuroinflammatory responses, impair neuronal connectivity, and gut-brain axis (GBA) balance, thereby contributing to the development and progression of CI. Postbiotics are non-viable microbial cells or structural components with therapeutic potential without live colonisation. They promote synaptic plasticity, reduce oxidative stress and neuroinflammation, enhance BBB integrity, improve mitochondrial activity, and regulate neurotransmitter levels, including serotonin, dopamine, and γ-aminobutyric acid (GABA). Postbiotics can be utilised in CI for their ability to generate bioactive metabolites that enhance gut-brain axis communication, immune modulation, and neuronal and BBB activity. Emerging preclinical evidence indicates that postbiotics modulate key pathological processes, including synaptic plasticity, oxidative stress, neuroinflammation, and BBB integrity; however, the majority of these findings are derived from in vitro and animal models, with limited clinical validation. This review aims to provide a systematic evaluation of the role of postbiotics in the prevention and management of CI across different neurological and metabolic disorders, and to summarise the available preclinical findings with potential therapeutic implications and future directions.
With accelerating population aging, age-related bone loss, osteoporosis, and delayed bone defect repair have become major challenges in regenerative medicine. Bone aging is not caused by the decline of a single cell type, but is a multilevel pathological process driven by the continuous coupling and mutual reinforcement of intracellular damage accumulation, senescence signal propagation, and microenvironmental deterioration. Based on established aging theories, this review integrates regenerative impairment in aged bone into three interconnected pathological cycles from the perspectives of dynamic feedback and regenerative intervention. Intracellular damage and homeostatic imbalance promote cellular senescence; senescent cells spread senescence signals through SASP and immune dysregulation, inducing abnormalities in metabolism, extracellular matrix (ECM) structure, and intercellular communication; the deteriorated microenvironment then further aggravates intracellular damage and homeostatic disruption, forming a self-reinforcing pathological loop. Within this framework, we summarize biomaterial strategies targeting intracellular damage, senescent cells and SASP-mediated propagation, and the aged microenvironment, and discuss multifunctional and responsive materials for staged or multi-level intervention. This framework organizes dispersed aging mechanisms into a dynamic network of feedback relationships and actionable nodes, providing guidance for mechanism-oriented biomaterial design and strategy selection in aged bone regeneration.
Cardiovascular ageing is accompanied by progressive impairment of redox buffering, mitochondrial quality control, proteostasis and metal homeostasis. Iron and copper homeostasis, together with cystine-glutathione and thiol/disulfide redox metabolism, are increasingly recognized as interconnected determinants of metabolic vulnerability and regulated cell death (RCD) in age-related cardiovascular diseases. Ferroptosis, defined by iron-dependent lipid peroxidation and impaired anti-peroxidative defence, has a substantial evidence base in myocardial ischaemia/reperfusion injury, atherosclerosis, heart failure and cardiac fibrosis. By contrast, cuproptosis is supported by emerging but still limited cardiovascular mechanistic evidence, whereas disulfidptosis in cardiovascular tissues is supported mainly by cross-system mechanistic extrapolation and pathway-associated transcriptomic signatures rather than demonstration of canonical cell-death execution. This review integrates iron-, copper-, and sulfur-metabolism-related RCD programmes across shared pathological interfaces, disease-specific contexts, and translational opportunities. We highlight circulating metal and thiol/disulfide indices, transcriptomic signatures, lesion-responsive nanomedicine, and imaging platforms as candidate routes for risk stratification and intervention. A layered interpretation of evidence is essential for translating iron-, copper-, and sulfur-metabolism-related RCD mechanisms into ageing-focused cardiovascular medicine. Here, "metal-sulfur metabolic derangement" is used as an evidence-stratified conceptual framework for partially intersecting stress programmes, not as a unitary mechanism or evidence that the three death modes have equivalent cardiovascular importance.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression, including oxidative phosphorylation impairment, mitochondrial DNA (mtDNA) mutations and genetic defects, excessive reactive oxygen species (ROS) production, mitochondrial dynamics imbalance, mitophagy dysfunction, calcium homeostasis dysregulation, mitochondrial transport defects, and the bidirectional regulatory pathway of tau pathology, and elucidates the pathological network featured by cascade amplification and reciprocal regulation among these abnormal mechanisms. It also comprehensively summarizes mitochondria-targeted intervention strategies for AD, analyzes the research limitations in this field such as model heterogeneity, lack of specific biomarkers and inefficient drug delivery, and prospects future research directions by integrating cutting-edge technologies including cell reprogramming and artificial intelligence (AI). This study provides a novel interpretation of the aging-related pathogenic mechanisms of AD from a mitochondrial perspective, lays a theoretical foundation for the development of precise and efficient mitochondria-targeted therapeutic strategies for AD, and offers a new paradigm for breaking through the bottlenecks of clinical diagnosis and treatment of AD.
As the body’s primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual Protein homeostasis (proteostasis) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component of cellular defense against superoxide radicals, is itself vulnerable to oxidative modification. ROS-mediated post-translational oxidation of SOD1 may promote its misfolding and the formation of toxic protein species, potentially establishing a self-amplifying cycle of superoxide accumulation, further protein damage, and impaired cellular homeostasis. In cutaneous cell types, including dermal fibroblasts and epidermal cells, these processes may be especially relevant to age-associated declines in proteostatic capacity and skin aging. This review distinguishes established skin-specific evidence from hypotheses extrapolated from other systems and synthesizes current evidence on the interplay among ROS-induced protein damage, proteostasis failure, SOD1 dysfunction, and cutaneous aging. We highlight the bidirectional relationship between proteostasis collapse and mitochondrial dysfunction, which may establish a self-reinforcing cycle of oxidative stress, cellular senescence, and chronic low-grade inflammation. These interconnected processes may converge to promote extracellular-matrix remodeling and tissue dysfunction, contributing to wrinkles, reduced elasticity, and impaired barrier function. By positioning SOD1 oxidation as a potential contributor to cutaneous proteostatic dysfunction, this review provides a framework for evaluating whether the SOD1 proteotoxic axis represents a candidate therapeutic target for skin aging.
Asymptomatic infections are traditionally considered harmless, reflecting effective immune control and the absence of clinical disease. Yet growing evidence shows that these silent encounters with microbes are far from being immunologically neutral. Throughout life, humans are challenged by a remarkably broad spectrum of viruses and bacteria, including latent pathogens that persist, fluctuate, or periodically reactivate without producing significant symptoms. From an evolutionary standpoint, this represents a fundamental trade-off. Long-lived hosts benefit from maintaining diverse commensal, latent, and low-grade persistent microbes that enhance immune readiness, promote cross-protective immunity, and reduce vulnerability to severe infections. However, this adaptive advantage is counterbalanced by the continuous burden of chronic, almost undetectable immune activation and inflammation, and by the energetic cost of sustaining such mechanisms of surveillance. In this regard, retroviral integrations provide a striking illustration of how persistent viral presence has shaped the evolution of complex organisms by introducing new regulatory elements, immune modulators, and developmental programs. These ancient viral imprints demonstrate that clinically-silent host-microbe interactions can exert long-term selective pressures and influence species-specific biological trajectories. At the individual level, repeated asymptomatic infections trigger transient waves of immune activation, endothelial perturbation, mitochondrial stress, and complement engagement. Although each episode is mild and self-limited, their cumulative burden generates micro-damage that accelerates immunosenescence, perturbs metabolic and vascular homeostasis, and contributes to the progressive rise in systemic inflammation characteristic of aging. Notably, in the context of the recent pandemics of SARS-CoV-2 infection, the emergence of Long COVID has highlighted how even clinically mild or initially asymptomatic infections can leave durable immunological, metabolic, and neurological traces, reinforcing the concept that "silent" infections may have lasting consequences.
Central nervous system (CNS) diseases remain a major challenge in neuroscience research due to their complex pathophysiology and the limited effectiveness of current therapies. Mesenchymal stem cells (MSCs), adult multipotent stem cells, have attracted growing interest for CNS disorders because of their homing-related trafficking, paracrine effects, and immunomodulatory capabilities. Evidence from experimental studies suggests that peripherally administered MSCs can respond to lesion-associated inflammatory cues and exert neuroprotective and reparative effects through the release of extracellular vesicles and other bioactive factors. In addition, MSCs can modulate inflammatory responses and immune cell functions, thereby improving the microenvironment relevant to tissue repair. Although preclinical studies support the therapeutic potential of MSCs, their mechanisms of action remain incompletely defined, and multiple obstacles hinder clinical translation. Therefore, this review summarizes three synergistic mechanisms by which peripherally administered MSCs may influence CNS disease outcomes, including homing, paracrine signaling, and immunomodulation. By integrating recent advances, we discuss mechanistic rationales and translational considerations that may help explain how peripheral MSC delivery contributes to CNS repair.
Age-related decline in muscle health is commonly defined using cut-offs for strength, muscle quantity or quality, and physical performance. These measures are essential for diagnosis, but prevention and recovery require an understanding of how muscle responds to stress over time. A central question is when recovery remains possible and why older adults with similar clinical measurements follow different trajectories. Clinical cohorts, animal studies and static cell models each address part of this problem. None readily combines human-tissue relevance with controlled perturbation, repeated functional measurement and experimentally testable recovery cues. We propose a clinically anchored workflow that treats sarcopenia as a model problem for studying age-related muscle change as a dynamic process. The sequence begins with a clinical or biological question, applies a standardised perturbation, uses repeated functional readouts, matches analysis to the question and data structure, and validates the resulting interpretation against independent evidence. Human muscle organ chips, particularly when integrated with adipose, immune, vascular or neuromuscular modules, can expose engineered muscle to defined inflammatory, metabolic, unloading or denervation-like stress while tracking functional and molecular responses. Current evidence remains largely proof of concept and does not support prediction of patient-specific recovery windows, responder status or long-term sarcopenia progression. AI should support this experimental sequence by organising time-course data, quantifying donor-, platform- and measurement-related uncertainty, prioritising informative readouts, and suggesting follow-up experiments. Within these limits, AI-assisted organ-chip studies could help investigate reversible decline, tissue crosstalk and divergent recovery in ageing.
Ageing research has undergone a paradigm shift from descriptive theories to a mechanistic understanding grounded in the interconnected biological processes. This work synthesizes the current landscape of ageing research, emphasizing the critical role of biomarkers in translating mechanistic insights into clinical application. Biomarkers, ranging from molecular and cellular markers to functional and imaging parameters, serve as essential tools for quantifying biological age, assessing the efficacy of therapeutic interventions, and predicting age-related disease risk. However, rather than offering another catalogue of hallmarks or isolated biomarker classes, this work structures the field through a translational decision framework that connects mechanistically grounded, organ-specific biomarkers to therapeutic evidence levels, participant stratification, longitudinal response tracking, and safety evaluation. Within this framework, we distinguish interventions targeting ageing biology from those directed at established age-related diseases, critically assess insights from inconclusive or negative human trials, and delineate essential prerequisites for biomarker qualification and clinical adoption. Despite significant challenges, such as the lack of a universal gold standard biomarker and discrepancies between preclinical models and human biology, the continued development and validation of robust biomarker systems are imperative. As the field moves toward next-generation composite biomarkers and multi-target combination therapies, biomarkers will be indispensable for driving the paradigm shift from treating age-related diseases to proactively managing the ageing process itself, ultimately paving the way for clinical-grade anti-ageing interventions.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose pathological course involves amyloid-β (Aβ) deposition, tau abnormalities, neuroinflammation, and neurovascular dysfunction. Interest in the microbiota-gut-brain axis does not arise because gut dysbiosis has been established as an independent initiating cause of sporadic AD, but because this axis connects modifiable peripheral factors-including diet, medication, ageing, and intestinal physiology-with barrier homeostasis, immunometabolic state, neural afferent signaling, and the brain's response to pathology. Human studies have detected microbiota differences in biomarker-positive preclinical AD and suggest that barrier abnormalities may be associated with subsequent cognitive change; patient-derived microbiota transfer, APOE-dependent tau models, and immune-vagal circuit studies further support phenotype modifiability under defined experimental conditions. This review therefore integrates barrier, immune, metabolic, and neural pathways and emphasizes that diverse microbial alterations may converge on a limited set of measurable functional nodes that could be more informative than individual genera for mechanistic validation, risk stratification, and treatment monitoring. Although clinical intervention evidence remains at an early stage, the peripheral accessibility and modifiability of the microbiota provide a rationale for investigating it as an adjunctive target alongside standard AD therapy. Future work should concurrently evaluate the microbiome, metabolites, both barriers, and immune and neural readouts in longitudinal cohorts and stratified randomized trials to determine which patients, disease stages, and intervention modalities are most likely to benefit.
Sarcopenia has consensus criteria on three continents and an all-cause mortality hazard ratio near 1.6, yet no drug is approved for the primary age-related condition and agents that reliably enlarge muscle have not improved the strength and gait-speed endpoints that define it. We approach this translational failure from the biology rather than the pipeline. Ageing degrades four properties of skeletal muscle that jointly determine force production and are each druggable in principle: innervation, through motor-unit loss and failed compensatory reinnervation; metabolic competence, through declining mitochondrial content and respiratory capacity; regenerative capacity, through satellite-cell drift into senescence within an inflamed niche; and intramuscular lipid, through fibro-adipogenic progenitor-derived adipogenesis. Mapping every therapeutic class onto these axes shows that anabolic agents engage none of them, that classes engaging a quality axis engage exactly one, and that no sarcopenia programme has been designed around innervation or intramuscular lipid. Two experiments make the innervation gap concrete: soluble activin receptor IIB failed to protect denervated muscle, and follistatin overexpression, added to voluntary exercise, rescued neither motor-unit loss nor neuromuscular junction transmission beyond exercise alone. The clinical record remains compatible with three explanations no completed trial can separate: a mismeasured exposure, since dual-energy X-ray absorptiometry lean mass is not muscle; a mismeasured outcome, since the minimal detectable change of gait speed and the Short Physical Performance Battery exceeds their own consensus thresholds for substantial clinical change; and genuinely uncoupled biology. We appraise 15-PGDH inhibition, now in early clinical development, together with its counter-case, and propose a mass-matched trial design capable of separating the three.
