Biology and Life Sciences

Abstract: Maximum lifespan varies widely among mammals and is strongly correlated with adult body mass, but molecular correlates of longevity beyond body size remain incompletely understood. I tested whether liver expression of a predefined 16-gene chromatin-maintenance module was associated with mammalian maximum longevity after accounting for adult mass and phylogeny. Across 936 mammal species, adult mass was positively associated with maximum longevity in phylogenetic generalized least-squares (PGLS) analysis (β=0.126, P<0.001; λ=0.974). In a matched set of 19 species with liver RNA-seq data, chromatin-module expression showed a negative, marginal association with longevity after adjustment for mass and phylogenetic covariance (β=−0.137, SE = 0.069, P=0.067). Adding the module modestly improved model fit relative to mass alone (ΔAIC = 1.81). However, the association was highly sensitive to Sciurus carolinensis; excluding this species reduced the module effect to near zero (β=−0.0096, P=0.953). Thus, liver chromatin-maintenance expression may contain longevity-related information not captured by body mass, but the present evidence is preliminary and leverage-sensitive. Larger comparative datasets and direct measures of chromatin state are needed to evaluate this hypothesis.

Abstract: The process by which fascial membranes emerge during fetal development remains incompletely understood. Recent developmental anatomical studies suggest that recognizable fascial lamination appears as a late fetal event coinciding with extracellular matrix maturation, skeletal stiffening, and the emergence of a body-wide tension network. Within this developmental framework, Poisson-compression-driven syneresis may transform hydrated loose mesenchyme into dense fascial membranes through mechanical phase separation.We propose that aging represents the reverse rotation of this developmental process. In development, increasing tension fields generate orthogonal compression, fluid expulsion, collagen densification, and membrane formation. In aging, progressive decline of tension fields reduces Poisson compression, allowing Donnan osmotic swelling pressure to predominate. This shift promotes rehydration, re-expansion, loss of structural density, ligamentous creep, and eventual membrane failure.This framework provides a unified biomechanical explanation for several age-related disorders characterized by failure of tension-dependent supporting membranes, including pelvic organ prolapse, abdominal wall and inguinal hernia, and age-related spinal kyphosis. Rather than interpreting these conditions as isolated local diseases, we suggest they represent different anatomical manifestations of a common biomechanical cascade:

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Tension field decay

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Loss of Poisson compression

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Loss of syneresis

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Re-expansion

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Creep

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Membrane failure

We further propose a Two-Hit Framework in which systemic fascial decompression establishes vulnerability, while local trauma or shear loading determines the anatomical site of failure. This model connects developmental morphogenesis and age-related structural collapse through a single physical principle and offers a conceptual foundation for future investigation of connective tissue aging.

Abstract: Fast, high-threshold motor units translate rapidly organized neural activity into explosive muscular force. Their deterioration may therefore have consequences that precede obvious muscle wasting or frailty. This paper develops the First to Fall hypothesis: the fast/high-threshold motor-unit system, particularly its Type IIx-associated elements, is an exceptionally vulnerable functional reserve whose early deterioration may initiate or amplify a broader cascade of human aging. The proposed process includes impaired activation and synaptic connectivity in surviving motor neurons, altered intrinsic excitability and discharge, neuromuscular-junction dysfunction, denervation, compensatory remodeling, and eventual structural loss. These stages need not occur in a fixed order in every muscle or person. Human longitudinal power data, rapid-force studies, disuse experiments, motor-unit recordings, and Masters-athlete observations are considered alongside anatomical and animal evidence. Together they support investigation of an early neurogenic contribution to declining explosive capacity, while leaving preferential lifelong loss of identified human Type IIx motor units and causation of systemic aging incompletely resolved. Persistent inward currents and synaptic-input changes deepen the proposed mechanism rather than replace the fast-motor-unit hypothesis. The paper distinguishes preservation of muscle fibers from preservation of their original motor-unit architecture, functional improvement from neuronal replacement, and general physical activity from exposure sufficient to maintain rapid neuromuscular demands. It further proposes that loss of fast neuromuscular reserve can reduce movement, loading, and muscle–organ signaling, creating feedback that accelerates downstream deterioration. Cellular aging mechanisms remain relevant within this account; the central challenge is whether they adequately explain the functional chronology without measuring neural control. Longitudinal and interventional tests are specified to determine whether early fast-system dysfunction predicts, mediates, and can modify subsequent systemic decline.

Abstract: Longevity clinics need more than predictions: they need to translate a person's measurements into reviewable biological states, trace the evidence, and decide what to reassess. We introduce the Virtual Longevity Clinic (VLC), a clinic-oriented AI-agent research prototype that makes this interpretive lens explicit as a versioned, auditable State Map—the state-representation layer of a biomedical world model. An observation mapper records how measurements enter the map, while the knowledge base that supplies evidence and the map's inference boundaries remain distinct layers alongside it. The architecture is designed to connect map-grounded findings to person-level option review and planned follow-up. In a targeted survey of research systems and public clinic-product materials, VLC is the first research prototype we identified in person-level longevity medicine to make the State Map explicit, versioned, and auditable and connect it to option review and planned follow-up. We evaluated one aging-hallmark module workflow in 11 prepared cases (10 de-identified public profiles and one synthetic). Across five reruns per case (55 total), the top-ranked module remained unchanged. In a separate option-list replay, 29/32 suggestions were traceable to supplied options. Single-model blinded judging did not favor deliberation over a no-peeking control (14/33 versus 17/33; two ties); deliberation used 2.2 times as many tokens. A five-role round averaged 8,916 tokens and 137 seconds; its token-equivalent list-price estimate was approximately RMB 0.01 under stated assumptions. These results demonstrate repeatable software behavior and partial option traceability—not clinical benefit, safety, or calibrated confidence. Map selection and cross-Map comparisons, clinician review, and real follow-up remain untested. A paired fixed-input State Map v1/v2 replay is the next direct test before prospective clinician-reviewed studies.

Abstract: An older athlete can retain exceptional performance in a practiced task without demonstrating preservation of a young-adult neuromuscular system. Building on the previously proposed Dual-Barrier Model of motor specificity and biological aging, this review provides a mechanistic expansion of Barrier 2, Biological Aging (Ruggia, 2026). It examines central motor organization, predictive control, sensory integration, descending input, spinal neuromodulation, motor-unit organization, neuromuscular transmission, muscle composition, and contractile function. Human evidence supports age-associated differences at multiple levels, but does not establish a universal sequence of failure or a single dominant lesion. Lower indirect estimates of persistent inward currents, altered rapid motor-unit discharge, and impaired muscle contractile properties provide complementary explanations for reduced force-time performance. Important counterevidence includes preserved implicit motor adaptation, retained modulation of spinal excitability, training-associated improvements, and successful functional reinnervation. Regeneration of a downstream component therefore cannot be presumed either sufficient for integrated rejuvenation or incapable of useful recovery. The expanded model proposes that the expression of age-associated limitations depends on interactions among biological capacity, compensation, task-specific expertise, and movement demands. Its principal prediction is that constrained preparation time and multidirectional reactive demands will reveal differences that successful performance alone may obscure. This prediction remains untested as an integrated mechanistic model in Masters sprinters. A research agenda combines matched movement tasks with sensory, electrophysiological, force-time, and tissue measurements, while specifying outcomes that would weaken the model. The contribution is a testable systems framework, not evidence that training is ineffective, regeneration must fail, or an immutable biological ceiling has been established.

Abstract: Fruits of Sonneratia apetala (S. apetala) are widely consumed as food and employed in traditional medicine across tropical coastal communities. Nevertheless, their pharmacological potential remains insufficiently explored. Our previous study identified a series of structurally diverse chromone derivatives from the fruits of S. apetala, termed sonnerachromones A–G (SCA–SCG), all of which extended lifespan in Caenorhabditis elegans (C. elegans). In the present study, we further evaluated their anti-aging activities and investigated their underlying molecular mechanisms. Treatment with SCA–SCG significantly enhanced heat stress resistance, reduced lipofuscin accumulation and intracellular reactive oxygen species (ROS) levels. In addition, lipid deposition was significantly decreased by SCA–SCD. Importantly, these beneficial effects were achieved without detectable adverse effects on reproductive capacity. Among the tested compounds, SCA–SCC exhibited the strongst senescence-delaying effect. Mechanistic investigations suggested that these chromone derivatives may potentially bind to telomere-associated proteins POT-1 and POT-2 and thereby influence telomere-related regulatory processes. This was associated with altered expression of telomere-related factors and increased telomerase activity, ultimately correlating with a modest attenuation of telomere shortening. Chromone derivatives from S. apetala, particularly SCA–SCC, exhibit promising anti-aging activity in C. elegans and are associated with coordinated modulation of telomere–telomerase-related processes, including changes in POT-1/POT-2-associated regulation, telomerase activity, and telomere length dynamics. These findings provide new insights into the anti-aging mechanisms of mangrove-derived chromone derivatives and support their potential as lead compounds for the development of natural anti-aging agents.

Abstract: Longevity medicine needs ways to identify a small number of candidate intervention targets that might affect several functions at once. Protein–protein interaction (PPI) networks help map molecular connections and rank candidate drugs, but they do not show which maintenance states are associated with age-related patterns in particular organs. We introduce RootMap, a blood DNA-methylation framework for mapping these conditional dependencies, and apply it to 656 discovery and 1,394 replication participants. Each of 332 gene modules is scored as a module-level intrinsic capability (mIC). We define a conditional dependency as a difference in an organ module’s association with age between participants with higher versus lower age-adjusted mIC for a hallmark module. Twenty-two hallmark–organ pairs passed four artifact checks; 17 of 20 pairs on the replication list kept their direction in the second cohort, including all 10 testable organ-line pairs. The pattern was asymmetric: hallmark modules more often marked differences in organ–age associations than organs marked differences in hallmark–age associations. Stem-cell maintenance was the broadest marker in the discovery cohort, relating to 12 organ modules; senescence regulation was broadest in the replication cohort. The meaning of dependency is illustrated by bone marrow: among people with higher age-adjusted stem-cell-maintenance mIC, bone-marrow mIC was negatively associated with age (r = −0.241), while among those with lower mIC the association was close to zero (r = +0.005). The map also distinguishes organs by their patterns of dependencies: for example, the liver had several hallmark associations, including associations in opposite directions. These are patterns in blood-based scores, not proof of biological control. The map may help drug screening by adding information about biological layer and dependency to molecular proximity. In a benchmark, filtering a protein-interaction (PPI)-ranked anti-aging candidate list by functional-layer labels made the list 2.8 times more compact and increased hit enrichment from 3.19-fold to 8.87-fold. This gain was not distinguishable from draws matched for the number of drug targets (p = 0.18), and the filter used layer labels rather than learned dependency edges. Thus, the result supports testing layer information alongside PPI—not claiming that dependency edges have already improved drug discovery. Separately, discovery dependency effect sizes were associated with replication dependencies (ρ = +0.153, p = 0.005), whereas the tested PPI-proximity measures were not. Functional modules also showed intervention-associated changes more often than hallmark modules (25.4% versus 14.4% of tests); this measures response in the studied intervention series, not clinical benefit. Traditional Chinese medicine (TCM) concepts were analyzed separately within the same framework. Essence was the largest hub, contributing 5 of 10 significant fundamental-substance pairs. The TCM concept “liver” corresponded more strongly to lymph and immune modules than to the anatomical liver (r = −0.15), illustrating that a traditional concept need not map onto the organ with the same name. RootMap offers longevity medicine a framework for connecting foundational maintenance states with organ-aging patterns. By distinguishing capabilities associated with broad reach from functions that showed more frequent score changes in the intervention series, it gives researchers a practical basis for deciding what to measure, which candidate targets to investigate, and which functions to follow in longitudinal and N-of-1 studies. The dependency measures carried modest but reproducible information across cohorts beyond the PPI-proximity measures tested here, while layer-label filtering compacted a PPI-ranked candidate list in the screening benchmark. Together, these findings position RootMap as an evidence-graded map for prioritizing hypotheses in longevity research and as a foundation for future individual-level biomedical world models. Learned dependency edges and absolute mIC values remain priorities for further validation and calibration.

Abstract: Human skin aging comprises compartment and exposure-dependent changes in extracellular matrix, epidermal differentiation, barrier function, redox and proteostasis, inflammation, and senescence. This study used targeted, non-exhaustive PubMed searches and citation checking through 25 August 2026 to conduct a structured secondary analysis of published adult human in vivo, human ex vivo, and primary adult skin-cell proteomic evidence. Forty selected core reports represented 36 distinct evidence units; one antibody-based targeted panel study was retained as adjacent evidence. Findings were synthesized descriptively by biological domain while preserving specimen, exposure, analytical platform, comparator, and molecular level. Qualitative convergence was strongest for extracellular matrix remodeling, epidermal and barrier biology, oxidative stress and proteostasis, inflammaging, and senescence-associated programs. Protein-level agreement was constrained by small cohorts, heterogeneous sampling, variable protein-inference rules and statistical reporting, scarce external validation, and frequent commercial involvement. Most bottom-up studies resolved protein groups rather than intact proteoforms; peptide-location and cleavage-susceptibility studies demonstrated that abundance, processing, modification, and structural accessibility are not interchangeable. Direct in vivo topical-intervention evidence was sparse and formulation-specific. Current evidence supports contextual pathway interpretation and candidate prioritization, but not universal skin-age biomarkers, individualized product matching, or clinical efficacy inferred from proteomic shifts alone.

Abstract: Biomedical world models are usually built to predict the next state. For deciding interventions, however, a prediction matters only when it improves selection: which action to take, for this person, now. We therefore argue for predictability before prediction - learn where prediction works before predicting. This perspective proposes the route; two published studies anchor it, and the rest is scheduled work. Step one: build a state map. Health is represented as 332 named gene modules, each with an interpretable capability score - a compressed, readable map of where a person stands. Step two: learn the dependency structure, which modules regulate which. An open 332 x 1,916 drug-module matrix already records what each intervention is expected to move; an initial hallmark-to-organ dependency map is under construction. Step three: test the map against paired before-and-after data, the data type the Cell Perspective names as the field's binding constraint. Each response will be read through two lenses: a single-score clock and the module map. Which lens can read intervention response is exactly what the agenda will decide. The negative results will mark where prediction is not supported. Selection then has a working definition: act where the map and the data agree, and stay out where they do not. The deliverable is not a bigger predictor but a harness for state evolution. It is the biological counterpart of what turns a raw language model into a useful, bounded system; this is what the program's term steerability has always meant. In one line: prediction is the means, selection is the end. The contribution is not a validated clinical decision system. It is a proposed, falsifiable route to intervention-oriented biomedical world models before longitudinal data are abundant.

Abstract: Aging is an extensive biological process characterized by morphological and functional alterations at different biological scales, resulting in a systematic decline in biological functions ultimately leading to death. Overall, two main types of theories have been proposed: damage-based theories and programmatic theories. We propose a third option, framed in the cognitive perspective on multiscale biological systems. Here, we review the different theories of aging, organize them in a conceptual hierarchy, and integrate our new model within the existing frameworks: aging as a consequence of loss of goal-directedness (in anatomical space). In this model, aging is driven by a dynamical systems-level disruption of homeostatic alignment within cellular collectives that build and repair a healthy body during development and maturation. In this model, morphogenesis is a homeostatic (goal-seeking) process; left with no goals after the developmental phase has been completed, aging can occur in the absence of damage via the functional disbanding of body components from their original aligned goal state. We suggest a roadmap with important implications for regenerative medicine and aging.

Abstract: Masters sprinters can retain remarkable straight-line speed into older age, creating the appearance of youthful movement despite continued biological aging. This hypothesis paper distinguishes outstanding task performance from restoration of the integrated neuromuscular system. The Dual-Barrier Model combines motor specificity with biological neuromuscular aging. First, improved straight-line speed does not automatically transfer to increasingly demanding change-of-direction tasks. Second, competitive Masters athletes can retain substantial muscle and sporting expertise while exhibiting age-associated differences in body composition, muscle quality, motor-unit organization, and power production. Human studies of rapid force development provide a further measurement window into function that maximal strength and visual observation may not capture. The model introduces whole-body reactive force-time capacity: the ability to organize, generate, absorb, redirect, and stabilize force across body segments when the required response is incompletely known in advance. It predicts that Masters sprinters will show larger age-associated differences relative to appropriately characterized young athletes as movement demands increase in multidirectional control and reactive uncertainty. Successful task completion need not preclude differences in force-time behavior, coordination, or stabilization. Existing evidence supports the component distinctions, but does not establish the proposed age-by-demand interaction in Masters sprinters. Body composition is one contributor, not a sufficient explanation, and residual impairment cannot automatically be assigned to neural degeneration. No evidence reviewed here demonstrates that training restores the integrated neuromuscular system of an older adult to its young-adult biological state. A preregistered, within-participant comparison of sprinting, planned change of direction, and matched reactive tasks is proposed to test or falsify the central prediction.

Abstract: Longevity-medicine services are expanding rapidly, yet the field still lacks the quality infrastructure that mature health disciplines take for granted. The first gap is practical: practitioners have no public consensus on what competent service looks like, from inquiry to intervention review. The second is evidential: because typical clients are multi-morbid individuals receiving many interventions at once, the population-average evidence of conventional medicine answers their questions poorly, leaving individualized reasoning unregulated. We propose a working draft of Good Healthspan Practice (GHP), an open, product-neutral good-practice guide that addresses both gaps in one design. The draft is modular: five process guides cover the full service cycle (inquiry, multi-omics measurement, root-cause attribution, intervention and contribution review), with root-cause attribution as the hard requirement on which the others depend, anchoring individualized reasoning in the hallmarks of aging, the small set of mechanisms the whole field shares. A sixth guide, GHP-600, runs across all five and makes individualized causal inference itself checkable: causal claims must be registered, falsifiable and honestly reviewed, using tools regulators have already developed for N-of-1 trials, real-world evidence and learning health systems. Adoption is voluntary and by self-declaration, module by module, with no conformity assessment. Each adopted client loop yields a prediction–validation record that, aggregated across adopters, calibrates the guide itself over time. In the longer run, these records feed biomedical world models that predict how one person responds to one intervention; the guide is built to grow with them. GHP is not a standard under any national standardization law, not a certification and not an association; it is a public working document whose aim is to make competent practice definable, individualized reasoning verifiable, and the field's evidence base cumulative. The draft text (v0.2) is public at ghp-ai.com, offered as a starting point for community discussion and iteration rather than a finished code for adoption.

Abstract: Neuromuscular aging involves changes in motor-unit number, recruitment, discharge behavior, sensory feedback, muscle properties, and the coordination of movement. Preserved performance in selected muscles does not establish preservation of the entire movement system. I propose the Systemic Motor Unit Integrity Hypothesis: maintaining neuromuscular function across the body may protect integrated movement capacity, whereas deterioration in an inadequately maintained region may impair the wider system through altered feedback, compensatory control, biomechanical redistribution, and secondary disuse. The accompanying Network Degradation Model distinguishes local impairment, compensatory reorganization, cross-regional functional consequences, and possible progressive loss of reserve. The pelvic floor, neck, shoulder, hands, and feet are illustrative regions, not an exhaustive list or a demonstrated hierarchy of initiating sites. This revision integrates human motor-unit studies, shared-input and intermuscular-coherence research, disuse experiments, and evidence of training-related neural adaptation. It distinguishes structural neuron loss from altered excitability, synaptic disconnection, junctional dysfunction, and muscle-fiber phenotype. Published findings support the relevance of distributed control and regional heterogeneity, but do not yet establish the proposed causal propagation or the superiority of lifelong whole-body training for preserving motor-unit number. A prospective measurement framework and a controlled intervention are proposed to distinguish propagation from shared aging and local compensation. The model concerns movement longevity and functional reserve; it does not establish that neuromuscular decline initiates all biological aging or determines a universal lifespan limit.

Abstract: Background/Objectives: Fractional blood pressure (FBP), calculated as FBP (%) = (pulse pressure/systolic pressure) × 100 and expressed as a percentage, may provide a proportional measure of vascular function, but its behavior across childhood remains unclear. This study characterized age-related FBP patterns in children and adolescents. Methods: FBP was calculated from published pediatric blood pressure reference data for children aged 1–17 years and analyzed by age group, sex, and blood-pressure categories. Severe hypertension was defined as systolic blood pressure at or above the 95th percentile plus 12 mm Hg. Results: FBP declined in early childhood, from 52% to 40% in boys and from 50% to 40% in girls. At blood pressure values corresponding to the severe-hypertension threshold, FBP declined from 42% to 31% in boys and from 37% to 31% in girls. From later childhood through adolescence, FBP remained relatively stable, approximately 40%–42% in boys and 39%–41% in girls, while calculated values in adolescents at the severe-hypertension threshold were consistently lower, at approximately 34% in boys and 33% in girls. Conclusions: FBP declines during early childhood and subsequently stabilizes despite increasing absolute blood pressure. FBP at the severe-hypertension threshold remained consistently lower than normotensive values. These findings suggest that FBP may be influenced by age-dependent vascular properties, including arterial compliance and impedance.

Abstract: Hair follicle function depends on the coordinated interaction of endocrine regulation, structural integrity, inflammatory-redox homeostasis, mitochondrial function, vascular support, and regenerative signaling. Oxidative stress is closely interconnected with chronic inflammation, mitochondrial dysfunction, cellular senescence, and impaired tissue regeneration, suggesting that redox imbalance may represent an important biological interface in the progressive loss of follicular resilience. Nutraceuticals may influence these interconnected processes through pleiotropic rather than isolated molecular mechanisms. This review critically integrates mechanistic, translational, and clinical evidence on nutraceutical compounds relevant to hair health, with particular emphasis on redox-sensitive pathways and their interaction with broader physiological networks. Polyphenols, oligomeric proanthocyanidins, vitamins, trace elements, structural nutrients, hormonal modulators, and mitochondrial-supportive compounds may influence complementary processes involving oxidative defense, inflammatory signaling, KEAP1–NRF2 regulation, mitochondrial homeostasis, androgen signaling, keratin synthesis, microvascular function, and regenerative signaling. To organize this biological complexity, we propose a systems-oriented framework comprising four complementary domains: endocrine regulation, structural integrity, inflammatory-redox homeostasis, and metabolic-regenerative competence. Within this framework, follicular resilience is conceptualized as an emergent property of interacting biological networks rather than the consequence of a single dominant pathway. Available clinical studies suggest that selected nutraceutical interventions may improve hair density, growth, shaft characteristics, shedding, or overall hair quality. However, the strength of evidence varies considerably among compounds, and mechanistic plausibility should not be equated with demonstrated clinical efficacy. Collectively, current evidence supports a transition from reductionist interpretations of nutraceutical action toward a systems-oriented model of hair follicle biology. Prospective studies integrating standardized clinical outcomes with validated biological biomarkers are required to determine whether this framework can improve patient stratification, treatment selection, and monitoring of nutraceutical interventions for long-term hair health.

Abstract: Somatostatin receptor subtype 2 (SSTR2), a class A G protein-coupled receptor encoded at chromosome 17q25.1, is overexpressed in high-risk stage 4 neuroblastoma with 17q gain, yet no non-peptide small-molecule ligand has been developed for this indication. We applied an AI-assisted computational workflow to identify and prioritise candidate SSTR2 ligands using the non-peptide agonist L-054,522 as the structural template. BROOD generated 5,507 analogues, of which 293 drug-like candidates were docked to SSTR2 (PDB 7XN9) with FRED, HYBRID and POSIT. The shape-based query was validated against a purpose-built benchmark of known SSTR2 ligands and property-matched decoys, achieving a ROC AUC of 0.798 with enrichment factors of 45.7 and 11.0 at the top 1% and 5%. Compounds achieving GREAT pose confidence were re-docked with AutoDock Vina Extended, FITTED and Flare, and against a second SSTR2 structure (7WIG). ADMET properties were predicted using the QSAR and deep-learning platforms T.E.S.T., DEEP-PK and SwissADME, and synthetic accessibility was assessed using the neural retrosynthesis platforms ChemAIRS and Spaya. Eight compounds achieved GREAT pose confidence. Re-docking of the crystallographic ligand recovered the experimental pose with Flare (heavy-atom RMSD 0.94 Å) and POSIT (1.79 Å) but not with the remaining platforms, and Flare scores were therefore given the greatest weight. Compound 8 ranked first among the eight candidates in three of seven receptor–program combinations, reproduced interactions with Asp122, Gln126, Thr194 and the aromatic pocket, showed no predicted developmental toxicity, was moderately rather than poorly soluble, and alone received a Spaya RScore of 1.0 indicating a fully precedented synthetic route. Because docking cannot distinguish agonism from antagonism, this work delivers a ranked, synthesisable hypothesis set for experimental testing rather than a characterised pharmacological agent.

Abstract: Oxidative stress and mitochondrial dysfunction are hallmarks of aging and major contributors to age-related disease. Yet the structural and functional determinants within respiratory Complex I that maycontribute to species-specific differences in longevity remain poorly understood. Using comparativegenomic, evolutionary, and structural analyses, I identified a conserved primate ubiquinonegatekeeper signature (Met17/Met21/Met225) within mitochondrially encoded NADH dehydrogenasesubunit 1 (MT-ND1), positioned at the entrance to the respiratory Complex I ubiquinone accesschannel. Remarkably, multiple exceptionally long-lived vertebrate lineages, including bats,cetaceans, birds, marsupials, monotremes, and coelacanth, independently evolved a sharedVal17/Thr21/Leu225 gatekeeper signature at this site. Cartilaginous fishes exhibit a closely relatedThr17/Thr21/Leu225 gatekeeper signature. Structural mapping places these residues within the MT-ND1 ubiquinone access pathway, where oxidative modification could influence ubiquinone access,electron transfer, and reactive oxygen species (ROS) generation. This region overlaps with thepharmacologically important ubiquinone-binding site targeted by numerous Complex I inhibitors.Their recurrent replacement in evolutionarily distant, exceptionally long-lived vertebrates isconsistent with reduced oxidative vulnerability of Complex I. Together, these observations support amodel in which oxidation-prone MT-ND1 methionines contribute to mitochondrial oxidativevulnerability, whereas their recurrent evolutionary replacement may promote mitochondrial redoxhomeostasis. These findings identify the MT-ND1 ubiquinone gatekeeper signature as a previouslyunrecognized molecular nexus linking respiratory chain architecture, therapeutic response, andvertebrate longevity.

Abstract: Objective: Molecular measures are increasingly proposed as surrogate endpoints for evaluating gerontological interventions. Their appeal rests on two assumptions: that effects on functional outcomes are small or slow to emerge, and that molecular measures can provide valid and more detectable substitutes. Here, these assumptions are examined using simulations and empirical data. Results: Intervention effects need not occur on the timescale of the deterioration they counteract. Even when effects are small or gradual, surrogate endpoints are only one of several ways to improve detectability. Study design can do so without changing the endpoint. Even if surrogates are preferred, their validity requires that the candidate molecular measure respond to the intervention, causally influence the primary outcome under that intervention, and fully mediate the intervention’s effect on that outcome. For outcomes that are weakly constrained by selection, late-life, failure-defined, or aggregate, a small and manageable molecular surrogate set is unlikely, and one that generalizes across interventions still less so.

Abstract: Human motricity operates within a continuous balance between biological organization and disorder. This focused scientific review synthesizes evidence linking movement entropy, lifespan neuromuscular decline, motor-unit remodeling, rapid force production, denervation, mitochondrial dysfunction, and high-velocity training. Longitudinal cohorts show that physical capacity and muscle power peak in early adulthood and decline progressively thereafter. Motor-unit number estimates indicate substantial loss with aging, while surviving units enlarge through collateral reinnervation. Meta-analytic evidence also shows lower motor-unit discharge rates and modestly reduced voluntary activation in older adults. Mechanistic human data identify the first 50 ms of explosive force production as especially dependent on neural excitation; in active octogenarians, normalized 0-50 ms RFD is selectively impaired. Disuse can alter motor-unit properties and neuromuscular-junction transmission within 21 days, while persistent sporadic denervation in very old muscle is linked mechanistically to mitochondrial dysfunction. Histological muscle entropy is independently associated with lower power, mobility, and mitochondrial energetics. Together, these findings support an integrative neuromuscular-aging framework in which neural, motor-unit, tissue, and bioenergetic changes interact across the lifespan. High-velocity power training is presented as a targeted countermeasure for preserving rapid force and function, while several causal links remain to be tested longitudinally.

Abstract: Aging is associated with systemic changes in circulating plasma proteins that influence tissue function. Heterochronic parabiosis and plasma transfer experiments in mice have established that exposure to young or old blood is sufficient to modulate neurogenesis, synaptic plasticity, and cognition, indicating that age-regulated plasma proteins contribute causally to brain aging phenotypes. In parallel, the most recent proteome-wide studies of poly(ADP-ribose) (PAR) signaling have identified hundreds of candidate proteins that interact with PAR through non-covalent PAR binding motifs, including proteins involved in DNA repair, stress responses, inflammation, and metabolism, which are known as key ageing-associated factors. Multiple plasma proteomic studies in humans have defined sets of proteins whose abundance differs between young and older adults, and cross-referencing these datasets suggests that a subset of age-regulated plasma proteins may have experimental and/or predicted PAR-binding capacity. This review integrates evidence from heterochronic parabiosis, PAR-binding proteome (PARome) studies and age-stratified plasma proteomics to examine whether PAR-binding plasma proteins can form a mechanistically relevant subset of circulating age-dependent factors. Here we review how altered levels of these proteins with age may interface with intracellular PAR signaling networks to influence brain plasticity, inflammatory tone, and metabolic resilience, providing a potential explanation for the beneficial effects of young plasma and the detrimental effects of old plasma observed in parabiosis.