Digital cytopathology links specimen preparation, staining, imaging, quality control, and artificial intelligence (AI)-assisted interpretation. This narrative review compares how equipment conditions, annotation levels, and aggregation mechanisms affect model performance and its clinical interpretation. Recent studies cover cervical screening as well as thyroid, urinary, pancreatic, and effusion cytology, but differences in specimen types, reference standards, and validation designs limit direct comparisons. We explain detection and segmentation, weakly supervised aggregation, self-supervised adaptation, and multimodal fusion, distinguishing technical endpoints from reader performance and patient benefit. Preparation-dependent morphology, sparse abnormal cells, overlapping groups, and focal-plane selection constrain transfer between laboratories. An equipment–quality control–AI–human review framework can organize error-specific corrective actions, but its overall safety and cost-effectiveness require prospective evaluation. Deployment must match the validated specimen, population, and assistive or autonomous role.

Aging is a major risk factor for chronic diseases, and reliable biomarkers are urgently needed to improve healthspan. Nuclear condensates (NCs), membraneless organelles formed via liquid-liquid phase separation (LLPS), regulate essential nuclear functions including transcription, DNA repair, and RNA processing. This review summarizes recent advances in NC biology, focusing on their dynamic changes during cellular senescence and their dysregulation in major aging-related diseases, including neurodegeneration, cancer, progeroid syndromes, and cardiovascular diseases. Canonical NCs such as nucleoli, Cajal bodies, PML-NBs, nuclear speckles, paraspeckles, and heterochromatin domains undergo structural and functional remodeling with aging, and their dysregulation, manifested as morphological alterations, aberrant phase transitions, or mislocalization of components, contributes to disease pathogenesis. We also discuss the emerging, though still largely exploratory, potential of NCs as diagnostic biomarkers, highlighting both imaging and molecular strategies for clinical translation as well as the substantial challenges that remain. Finally, we outline key unanswered questions and future directions, with an emphasis on the need for standardized methodologies, causal mechanistic studies, and validated clinical assays. Collectively, this review suggests that NCs may offer new conceptual and therapeutic angles on aging-related diseases.

Relapsed and refractory paediatric brain tumors—including high-grade gliomas (HGG) such as diffuse hemispheric glioma, diffuse midline glioma (DMG), diffuse intrinsic pontine glioma (DIPG), and atypical teratoid rhabdoid tumors (AT/RT), medulloblastoma (MB) and ependymoma (EPN)—remain among the most treatment-resistant childhood malignancies. Despite multimodal therapy combining maximal safe resection, radiotherapy, and chemotherapy, long-term survival after relapse is exceedingly rare. The limitations of conventional cytotoxic regimens and the largely immune-silent nature of these tumors have driven interest in therapeutic vaccination as a strategy to induce durable, antigen-specific immune responses. Advances in molecular profiling and immunopeptidomics have enabled the identification of tumor-exclusive peptides, even within the low-mutational landscape typical of paediatric gliomas. Preclinical investigations demonstrate that dendritic-cell- (DC), peptide-, or mRNA-based vaccines can elicit tumor-specific cytotoxic T-cell responses and modify the tumor microenvironment. Early clinical experiences in relapsed paediatric HGG and DMG indicate safety and feasibility, with emerging evidence of immune activation and prolongation of survival. Features of paediatric immunity render children particularly responsive to cancer vaccines and insights from paediatric trials may prove valuable for the design of immunotherapeutic strategies in aging-related cancers. This review summarizes current preclinical and clinical developments in paediatric brain-tumor vaccination, focusing on antigen discovery, immunologic mechanisms, vaccine platforms, and translational challenges that define this evolving frontier in paediatric neuro-oncology.

C-N chiral axes are prevalent in natural products, bioactive molecules, and chiral ligands. The development of synthetic methodologies for constructing C-N chiral axes has attracted considerable interest among chemists. Herein, we review advances in the construction of C-N axial chirality via asymmetric C-H activation, a strategy with high atom- and step-economy. This review covers the literatures from 2019 to 2026, categorizing the transformations into annulation, alkynylation, alkenylation, alkylation, arylation, borylation and imidoylation. The representative products, reaction mechanisms, and the application of products are demonstrated. We hope this review will serve as a useful guide for chemists interested in this field and stimulate further progress in this area.

The transcription factor p53, widely known as the “guardian of the genome”, is a central tumour suppressor that coordinates cellular responses to stress. Upon DNA damage and other perturbations, p53 activates transcriptional programs that promote cell-cycle arrest, senescence, and apoptosis. However, it has become increasingly clear that these canonical pathways alone do not fully account for the tumour-suppressive functions of p53. A growing body of evidence instead highlights metabolic regulation as a major component of the p53 network. p53 coordinates cellular metabolism to preserve genomic and redox homeostasis, regulate adaptation to metabolic stress, and influence cell-fate decisions through multiple forms of regulated cell death. Beyond cell-intrinsic effects, p53-dependent metabolic programs also shape the tumour microenvironment by modulating nutrient availability, immune-cell function, and intercellular signalling. In this review, we discuss how p53 regulates metabolism at both cell-intrinsic and cell-extrinsic levels and how these functions contribute to tumour suppression. We further examine how distinct p53 mutations reprogram metabolic pathways and alter the tumour-suppressive activities of wild-type p53, emphasizing the context dependence and functional heterogeneity of mutant p53. Together, these findings position metabolic regulation as a central and multifaceted component of p53 biology with important implications for understanding tumour development and therapeutic vulnerability.

As a precious traditional Chinese medicine, Asini Corii Colla (ACO) has long been used for hematopoiesis, hemostasis, and wound repair, yet its mechanisms in wound healing remain incompletely elucidated. Using human skin fibroblasts (HSF) and a murine macrophage-like cell line (RAW 264.7), along with a rat full-thickness skin defect model, the biocompatibility, cell proliferation and migration-promoting ability, and wound healing acceleration efficacy of ACO were investigated. HSF cells were used to assess proliferation and migration, whereas RAW 264.7 cells were used for cytocompatibility and macrophage polarization studies. The potential mechanisms were further explored by transcriptomic analysis. In vitro cytotoxicity assays revealed that ACO exhibited no obvious cytotoxicity at concentrations up to 100 mg/mL. Accordingly, further functional assays demonstrated that within the safe concentration range of 10-40 mg/mL, ACO significantly promoted acute wound healing. H&E and Masson’s trichrome histological staining, IL-1β and IL-10 immunohistochemistry, and CD31/α-SMA immunofluorescence staining revealed that ACO enhanced epithelial regeneration, increased collagen deposition, improved collagen fiber arrangement, effectively downregulated the pro-inflammatory cytokine IL-1β, upregulated the anti-inflammatory cytokine IL-10, and significantly increased CD31-positive vessel density. Transcriptomic analysis further revealed temporally distinct associations of ACO: at early stages, ACO treatment was associated with gene signatures related to cell migration, inflammatory regulation, and matrix synthesis, whereas at later stages it was associated with signatures related to tissue contraction, vascular maturation, and metabolic reprogramming. These findings provide preliminary evidence that ACO may be a promising bioactive ingredient for functional skin repair, warranting exploration of its synergistic potential for advanced wound management.

Aims: Ferroptosis is driven by iron-dependent lipid peroxidation, but whether cholesterol undergoes radical-mediated oxidation during this process remains incompletely understood. We examined the temporal relationship between lipid peroxidation, cell death, and C7 cholesterol oxidation during erastin-induced ferroptosis.

Methods: Human SH-SY5Y cells were treated with erastin. Cell viability, lipid hydroperoxides, and lipid radicals were assessed using Alamar Blue, Liperfluo, and LipiRADICAL, respectively. Total 7α-hydroxycholesterol (t7α-OHCh), total 7β-hydroxycholesterol (t7β-OHCh), and 7-ketocholesterol (7-ketoCh) were quantified by GC–MS after triphenylphosphine reduction and saponification.

Results: Erastin-induced cell death was suppressed by deferoxamine, ferrostatin-1, and α-tocopherol. Liperfluo fluorescence increased before detectable LipiRADICAL fluorescence and loss of cell viability. t7α-OHCh increased during the early phase, whereas t7β-OHCh increased later; no statistically significant change in 7-ketoCh was detected. Because t7α-OHCh and t7β-OHCh represent composite pools of pre-existing free and esterified hydroxycholesterols and hydroperoxide-derived products, the early t7α-OHCh signal cannot distinguish enzymatic hydroxylation from a 7α-hydroperoxycholesterol (7α-OOHCh)-derived product. The increase in t7β-OHCh together with the overall C7 stereochemical profile is consistent with radical-mediated C7 cholesterol oxidation.

Conclusion: These findings support radical-mediated C7 cholesterol oxidation as an early component of erastin-induced ferroptotic lipid damage. The biological activity and extracellular transfer of these products remain to be established.

Periodontitis, a bacteria-induced chronic inflammatory disease, is characterized by progressive destruction of periodontal tissues, thereby severely affecting aesthetics, mastication, and quality of life. A critical mechanism of periodontitis is mitochondrial dysfunction, therefore, various mitochondria-regulating biomaterials have been designed to restore mitochondrial homeostasis, and further enhance antibacterial defense, modulate immune responses, and promote osteogenesis and angiogenesis. In this review, the pathogenic mechanisms derived from mitochondrial dysfunction of various cell types and their effect on the periodontal regeneration are comprehensively summarized. Furthermore, mitochondria-regulating biomaterials for periodontitis treatment along with the challenges and future perspectives for clinical translation are discussed.

Aim: To determine whether menopausal status, menopausal hormone therapy (MHT), or oral contraceptive (OCP) use modifies the association between elevated Lp(a) and prevalent coronary artery disease (CAD).

Aim: To determine whether menopausal status, menopausal hormone therapy (MHT), or oral contraceptive (OCP) use modifies the association between elevated Lp(a) and prevalent coronary artery disease (CAD).

Methods: We conducted a cross-sectional study of 6,314 U.S. Women Veterans with Lp(a) testing from 1999-2025 to evaluate whether menopausal status, MHT use, or OCP use modify the association between elevated Lp(a) (≥ 125 nmol/L) and prevalent CAD. Logistic regression was used to estimate adjusted odds ratios (aOR), with interaction terms evaluated by likelihood ratio tests. Restricted cubic splines were used to model the continuous association between Lp(a) and prevalent CAD.

Results: Elevated Lp(a) was present in 31.6% of Women Veterans and was independently associated with increased odds of prevalent CAD (aOR 1.24, 95% confidence interval 1.06-1.44, p = 0.0079). We observed a continuous increase in prevalent CAD with rising Lp(a) levels (aOR 1.023 per 25 nmol/L increase, 95% confidence interval 1.010-1.040, p = 0.0033). No effect modification was detected for menopausal status (p-value for interaction = 1.0), MHT use in postmenopausal women (p-value for interaction = 0.20), or OCP use in premenopausal women (p-value for interaction = 0.32).

Conclusion: Elevated Lp(a) is common and associated with prevalent CAD in Women Veterans. We did not detect modification of the association between elevated Lp(a) and prevalent CAD based on menopausal status or hormonal therapy. These findings support systematic Lp(a) screening across the full female reproductive spectrum.

The global human population is aging rapidly, and the prevalence of aging-related diseases is increasing. Thus, understanding the molecular pathways involved in the hallmarks of aging is essential for the development of therapies that promote healthy aging and extend lifespan. Fibroblast growth factor (FGF) 21 has emerged as a promising therapeutic candidate due to its pleiotropic beneficial roles in metabolism, stress response, and tissue repair through pathways that regulate oxidative stress and cellular senescence. Preclinical studies have associated FGF21 with beneficial effects against metabolic syndrome, liver steatosis, kidney injury, and neurodegenerative disorders that occur in aged individuals. Conversely, FGF21 has also been linked to skeletal muscle loss and concentric cardiac hypertrophy. This review summarizes current evidence on FGF21 signaling and its effects on either healthy aging or aging-related diseases, highlighting its tissue-, time-, origin- and stress- dependent effects.

Chiral organosilicon compounds are widely applied in frontier fields including synthetic chemistry, materials science, and pharmaceutical research. Thus, the design of green, operationally simple, and chemoselective strategies for the assembly of structurally sophisticated organosilicon frameworks is of paramount significance and continues to attract considerable attention. Silacyclobutanes (SCBs), a class of small-ring compounds with unique structural features, exhibit excellent reactivity due to their inherent ring strain. During the past decade, the transition-metal-catalyzed (Rh, Pd, Ni) regio- and enantioselective C–Si bond cleavage of silacyclobutanes has emerged as a powerful and complementary synthetic tool for accessing structurally diverse, functionalized chiral organosilanes. This review systematically surveys recent advances in transition-metal-catalyzed asymmetric cleavage of C–Si bonds in silacyclobutanes with various coupling partners, such as alkenes, alkynes, allenes, and carbonyls, for the construction of chiral functionalized organosilanes featuring carbon-centered, silicon-centered, or axially chiral stereogenic units. We also briefly discuss the associated reaction mechanisms, strategic modulation of reactivity and enantioselectivity, and prospective developments.

Exceptional points (EPs) in non-Hermitian systems can produce nonlinear responses to weak perturbations, but maintaining these responses at a stable operating frequency remains challenging. Here, we develop a hyperbolic photonic metacrystal that combines dispersion and loss engineering. By exploiting the opposite angular dispersions of the hyperbolic and dielectric layers, we achieve first-order phase compensation that suppresses angular variations in the accumulated optical phase and keeps the localized resonances nearly unchanged with incident angle. We first consider a parity-time (PT)-symmetric system with balanced effective gain and loss, where a Hamiltonian EP coincides with a scattering-matrix (S-matrix) EP. Although this operating point exhibits square-root scattering-eigenvalue splitting, refractive-index perturbations also shift the Hamiltonian eigenfrequencies, limiting the stability of the operating frequency. By breaking the effective gain-loss balance, we obtain a PT-asymmetric state in which the squared coupling strength equals the product of effective gain and loss. Under this condition, a bound-state-in-the-continuum (BIC)-associated real-frequency solution emerges, and the S-matrix remains at an EP while the effective Hamiltonian no longer exhibits an EP. The scattering eigenvalue splitting therefore retains its square-root dependence on refractive-index perturbations, while the resonance-frequency drift is substantially reduced. Together with hyperbolic phase compensation, this response is maintained over incident angles from 0° to 60°, offering a route to EP-based sensing that combines angular robustness with spectral stability without sacrificing the square-root scattering response.

Ferroptosis is a dependent and controlled form of cell death, which is characterized by lipid peroxidation and impaired antioxidant defense, and has become an important mechanism of myocardial damage. It promotes myocardial ischemia-reperfusion injury (MIRI), chemotherapy-induced cardiotoxicity, septic cardiomyopathy, and pathological remodeling, making it a potential therapeutic target. A nanozyme is a nanomaterial with enzyme mimicking catalytic activity, which provides a multifunctional method for oxidative stress regulation, iron metabolism, lipid peroxidation, and inflammation. In this mini-review, we summarize the participation of ferroptosis in myocardial lesions and its main treatment goals, as well as the recent use of nanozymes to reduce cardiac inflammation, myocardial cell death, fibrosis, and adverse remodeling. Although some studies provide direct evidence of ferroptosis regulation, the nanozyme-mediated heart protection mechanism has not been fully defined. Problems such as cardiac targeting, biosafety, pharmacokinetics, biodegradability, and clinical verification also limit translation. Subsequently, the development of nanozymes that are targeted to the heart and mechanically determined can promote clinical research on the regulation of ferroptosis during myocardial lesions.

Chiral sulfur(IV) and sulfur(VI) compounds bearing S=N bonds are important structural units in drug discovery, materials science, and asymmetric catalysis. The presence of a stereogenic sulfur atom increases the three-dimensional complexity of molecules, allowing for the precise tuning of their physicochemical properties and biological target-binding affinities. However, the highly stereoselective construction of these high-valent sulfur centers has long been a significant synthetic challenge. This review summarizes recent progress, primarily covering literature from 2020 to 2026, in the catalytic asymmetric synthesis of chiral sulfur compounds bearing S=N bonds. For S(IV) motifs including sulfilimines, sulfinamidines, and sulfinimidate esters, we examine advances in transition-metal catalysis and organocatalysis, highlighting recent breakthroughs in radical cross-coupling and direct asymmetric amination. For S(VI) frameworks including sulfoximines, sulfonimidamides, sulfonimidate esters, and sulfonimidoyl fluorides, the discussion covers asymmetric C–H functionalization, dynamic kinetic asymmetric transformations (DyKAT), and stereospecific oxidative transfers from enantioenriched S(IV) precursors. We highlight stereocontrol strategies, reaction mechanisms, and substrate scopes. We also discuss current limitations and suggest possible directions for future work, with an emphasis on more sustainable catalytic methods and modular strategies for building new functional molecules.

Janus and core-shell structures are among the most fundamental dual-chamber architectures for advanced functional materials. However, compared to electrospun core-shell nanofibers, electrospun Janus nanofibers have been extremely limited over the past three decades. This commentary examines the evolution of side-by-side electrospinning and Janus nanofibers. This limitation stems from the electrostatic repulsion between working fluids, posing a significant challenge to the formation of integrated Janus nanofibers. As increasing efforts have been devoted to this issue, new insights have emerged for resolving it through rational spinneret design and modifications to electrospinning processes. To bridge this gap in Janus-nanofiber-based devices and products, several key directions are proposed: (i) designing novel spinneret structures as templates for Janus nanofibers; (ii) scaled-up production via the newly developed "needle-in-hole" electrospinning technique; (iii) strategies for large-scale manufacturing of potential commercial products; and (iv) novel complex tri-chamber architectures.

Multi-object tracking (MOT) provides an effective approach for occupant monitoring in intelligent built environments. Real-time MOT is challenging on resource-constrained edge devices. This study establishes a systematic evaluation framework for lightweight head-based MOT, examining structured channel pruning and quantization across the complete detection-tracking pipeline. Experiments on Cchead use five detectors and multiple trackers. We comprehensively compare different pruning criteria and pruning strategies, showing that layer-wise pruning with fine-tuning reduces complexity while preserving tracking performance. We further compare post-training quantization (PTQ) and quantization-aware training (QAT) in terms of accuracy preservation, tracking stability, and deployment efficiency; QAT improves AP_50:95 by up to 13.33% for PPYOLOE-S. Practical deployment on Jetson Nano, Jetson TX2, and Intel Neural Compute Stick 2 achieves latency reductions exceeding 48%. Robustness tests under Gaussian noise show up to 158.41% relative improvement with QAT. These results characterize trade-offs among efficiency, tracking performance, and resilience for edge MOT deployment.

How is it possible to double the lifespan of an organism already close to death? Many biological theories of aging fail to explain this phenomenon. At the Physics of Aging workshop, we used late-life lifespan extension in Caenorhabditis elegans to illustrate how a simple stochastic dynamical-systems model can naturally account for dramatic geriatric interventions. We build on a Langevin-type framework in which aging can occur in stable or unstable dynamical regimes, depending on whether slow, lifespan-determining modes are initially restoring or non-restoring. We argue that C. elegans operates in the unstable regime, a view supported independently by temporal scaling of survival curves, late-life mortality deceleration, and persistent lifespan effects following transient interventions. In the unstable regime, stochastic fluctuations are amplified over time until a failure threshold is reached as a first-passage event. The instability rate α sets the speed of this divergence, while the nonlinear feedback strength g, together with α, sets the failure boundary z_max = α/g. Auxin-induced degradation of DAF-2 in very old animals is interpreted as a late shift in dynamical parameters, and the model naturally accounts for the resulting lifespan extension without requiring reversal of accumulated structural damage. This reconciles persistent senescent pathologies with restored proteostasis and stress resilience, and suggests that altering regulatory instability, rather than reversing damage, can strongly reshape survival trajectories. More broadly, this work illustrates how low-dimensional, physics-inspired stochastic models can capture key features of aging and motivate new collaborations on late-life interventions.

Chiral carbon-rich molecules have attracted increasing attention because they integrate extended π-conjugation with stereochemical complexity, thereby giving rise to circularly polarized luminescence, chiral charge/spin transport, molecular recognition and unconventional open-shell electronic structures. Among the structural elements available for their construction, five-membered carbon rings occupy a particularly important position. This review provides an overview of recent progress in chiral carbon-rich molecules incorporating five-membered carbocyclic motifs, including chiral fullerenes, nonbenzenoid and bowl-shaped nanographenes, helically distorted open-shell systems, and chiral PAHs with interrupted π-conjugation. We emphasize the dual and complementary roles of five-membered carbocycles. In fully conjugated frameworks, pentagons introduce curvature, non-benzenoid topology, perturbed aromaticity and unusual spin/electronic distributions, thereby enabling diverse chiral fullerene and nanographene architectures with distinctive optical, magnetic and supramolecular properties. In frameworks with interrupted π-conjugation, five-membered rings incorporated into spiro-, indane-, or cyclophane-type motifs can rigidify three-dimensional architectures, mediate chirality transfer, attenuate through-bond π-conjugation, and enhance through-space electronic coupling, thereby offering effective design strategies for high-performance chiroptical and optoelectronic systems. By comparing these two regimes, we highlight how five-membered carbocycles have emerged since 2019 as versatile design elements for modulating chirality, topology, and function in carbon-rich molecules, and we discuss current synthetic limitations, unresolved mechanistic questions, and potential future opportunities in photonic, spintronic, and molecular electronic applications.

During aging, modifiable lifestyle factors, such as physical activity, play an increasingly important role. Specifically, it is known that physical fitness declines relatively predictably with age and that resistance training can be a highly effective strategy for preventing this decline, both at muscular and cognitive levels. Several studies have described that one of the mechanisms mediating some of the beneficial effects of physical exercise during aging is the regulation of miRNAs, and in particular, the miR-29 family appears to play a relevant role. In this review, we analyse, firstly, the relevance of the miR-29 family in aging and, secondly, the protective effects of resistance exercise in delaying age-related dysfunction through the regulation of miR-29.

Redox-active ligands, metal complexes, and larger coordination frameworks are chemically precise, responsive building blocks for smart materials, molecular electronics, energy storage, and neuromorphic device concepts. However, their redox behavior depends strongly on the experimental regime in which it is probed. Bulk electrochemistry, confined nanodroplet methods, electrochemical scanning probe microscopy, tunneling spectroscopy, and synchrotron-coupled nanospectroscopy often probe the same molecular event through fundamentally different physical observables. In this mini-review, we use polyoxometalates as a guiding molecular class to compare redox behavior across three length-scale regimes: bulk ensembles, confined nanoscale assemblies, and single-molecule or few-molecule junctions. We discuss cyclic voltammetry, scanning electrochemical probe methods, electrochemical scanning tunneling microscopy, scanning tunneling spectroscopy, electron-spin-resonance scanning tunneling microscopy (ESR-STM), scattering-type near-field optical microscopy, and synchrotron nanospectroscopic methods. We argue that advanced scanning probe microscopy provides the missing conceptual and experimental bridge between classical electrochemical redox potentials and nanoscale electronic charge and spin structure, enabling a regime-aware design language for redox-programmable molecular materials.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is intricately linked with oxidative stress through shared regulatory nodes and reciprocal amplification loops. Although ferroptosis and oxidative stress have each been extensively investigated, their bidirectional crosstalk, together with its consequences for the tumor microenvironment, has yet to be systematically elucidated. On this basis, this review proposes and systematically dissects a “ferroptosis-oxidative stress-tumor microenvironment” triad, focusing on its bidirectional interaction network and therapeutic translational value. We analyze the driving mechanisms underlying the mutually amplifying loop between the two processes, including iron metabolism, lipid peroxidation cascades, antioxidant defense, and organelle function. Within the tumor microenvironment, this interplay drives context-dependent remodeling of immune cell function, cancer-associated fibroblast activity, angiogenesis, and tumor heterogeneity. Furthermore, this review evaluates emerging therapeutic strategies that target ferroptosis and oxidative stress within the TME, and outlines the obstacles hindering clinical translation and future directions. A deep understanding of the “ferroptosis-oxidative stress-tumor microenvironment” triad will advance our fundamental understanding of the execution and regulatory mechanisms of ferroptosis, and lay a theoretical foundation for the future development of precision therapeutic strategies centered on ferroptosis.

Lipoprotein(a) [Lp(a)] is a major, independent determinant of atherosclerotic cardiovascular disease and calcific aortic valve disease, yet its integration into routine clinical practice remains fragmented. Persistent uncertainties regarding when to measure Lp(a), how to interpret assay results, and how to manage elevated Lp(a) levels in the absence of approved Lp(a)-lowering therapies continue to hinder its adoption. Meanwhile, targeted therapies, including antisense oligonucleotides, siRNA agents, and small molecules, are advancing through phase 3 trials and may soon provide evidence regarding the clinical impact of pharmacological reduction of Lp(a). This evolving landscape demands a transition from passive awareness to active implementation. Early identification of individuals with elevated Lp(a), transparent communication of its clinical implications, and structured referral pathways between general practitioners and lipid clinics for the optimization of cardiovascular prevention and preparation for future therapeutic options are crucial steps for bridging the existing Lp(a) gap. This perspective proposes a pragmatic framework for integrating Lp(a) into cardiovascular risk assessment and management across primary and specialist care, addressing operational challenges in measurement, interpretation, and treatment to support an actionable and coordinated Lp(a) clinical pathway. To this end, it formulates practical advice to orient Lp(a) management in primary care.

Aims: To identify plasma proteins associated with all-cause mortality and determine their relationships with chronic disease burden and biological aging at both the organismal and organ-specific levels, thereby providing insights into the biological mechanisms underlying healthy aging and longevity.

Methods: We conducted a prospective cohort study of 1,025 older adults from the LonGenity study, analyzing 4,265 plasma proteins. Associations between protein levels and all-cause mortality were evaluated using Cox proportional hazards regression over a mean follow-up of 8.05 years. Mortality-associated proteins were further examined for their relationships with chronic disease burden and proteome-derived measures of organismal and organ-specific biological aging. Findings were independently validated in 1,124 participants from the Baltimore Longitudinal Study of Aging (BLSA).

Results: Seventeen plasma proteins were significantly associated with all-cause mortality. Higher levels of epidermal growth factor receptor (ERBB1) and anthrax toxin receptor 2 (ANTXR2) were associated with lower mortality risk and younger biological age across multiple organ systems. Conversely, higher levels of macrophage inhibitory cytokine 1 (MIC-1) (growth differentiation factor 15 (GDF15)), human epididymis protein 4 (HE4), and insulin-like growth factor-binding protein 2 (IGFBP-2) were associated with increased mortality and older biological age across multiple organ systems. Specifically, elevated MIC-1 was associated with older organismal biological age, whereas ERBB1 was associated with younger liver biological age. These associations were independently replicated in the BLSA cohort.

Conclusion: Mortality-associated plasma proteins reflect key biological pathways involved in biological aging, physiological homeostasis, and systemic stress. These biomarkers may have potential utility for identifying individuals at increased mortality risk and advancing the development of biomarkers for healthy aging and longevity.