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

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

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

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

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

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

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

Abstract: This review explores the modulation of the host cellular flexibility “kinome" (protein kinases) and "phosphatome" (protein phosphatases) by dietary nutrients and gut microbiota metabolites, proposing a potential paradigm in the strategies for healthy aging and metabolic disease prevention. While mainstream nutrition approaches focus on population-wide guidelines, precision nutrition exploits the innovations in personal molecular networks and systems medicine, integrating genomics and metabolomics to address "metabolic rigidity"—the cell inability to switch between fuel sources. The review examines how master molecular regulators like AMPK and mTOR, and "metabolic brakes" like PTP1B and PTEN, are affected by single nucleotide polymorphisms (SNPs) and microbial signals (SCFAs, secondary bile acids, indoles). Specifically, the "microbial kinomic interference" hypothesis is discussed, where gut metabolites act as remote ligands for host signaling enzymes. Finally, the potential role of a personalized phosphoproteomics strategy is highlighted as an effective functional readout to guide nutritional interventions, aiming to restore metabolic plasticity through a gut microbiota/multi-omics approach.

Abstract: Background: Aging is shaped by interdependent molecular processes captured by the hallmarks framework, in which epigenetic alterations stand out as a potentially modifiable regulatory layer. DNA methylation (DNAm) patterns change with age and can be summarized by epigenetic clocks that estimate biological age, pace of aging, and risk-related phenotypes. Yet, the extent to which interventions reproducibly modulate DNAm-based biomarkers across tissues and species remains uncertain. Methods: A systematized review of longitudinal intervention studies (2010–2025; English/Spanish) was conducted in PubMed, Scopus, and Cochrane CENTRAL, with selection documented using PRISMA. Human eligibility included randomized controlled trials (RCTs), non-randomized controlled studies, and pre–post designs (n≥10; adults ≥18 years). Preclinical eligibility included longitudinal mammalian studies (n≥5 per group). Outcomes were changes in DNAm-based epigenetic age (years) and/or pace of aging (e.g., DunedinPACE). Data were extracted into a standardized matrix (clock, tissue, effect direction/magnitude, safety, RoB_overall) and synthesized narratively; meta-analysis was not performed due to heterogeneity. Results: Thirty-five longitudinal studies were included (29 human, 6 preclinical). Lifestyle interventions in humans generally showed modest effects, with more consistent signals when exposure was sustained and accompanied by plausible physiological changes (e.g., prolonged calorie restriction affecting DunedinPACE, with effect sizes up to d=−0.43 at 12 months and d=−0.40 at 24 months in higher-adherence participants). Exogenous compounds showed higher heterogeneity and mixed evidence, including robust null epigenetic findings in some trials (e.g., metformin adjusted ITT differences ranging from −0.91 to +0.82 years across clocks, all p≥0.18) alongside favorable signals in smaller analytic subsets or open-label settings (e.g., bezisterim sub-study with reductions of −3.68 years in SkinBloodAge, −5.00 in Hannum, and −4.77 in InflammAge). Blood/circulation-derived interventions produced some of the largest reported effect sizes but also raised interpretation challenges: therapeutic plasma exchange with a sham arm reported epigenetic age decreases of ~1.3–2.6 years depending on the clock and regimen, with pronounced shifts in immune/inflammation-sensitive clocks; the apparent benefits waned after treatment cessation. Unexpectedly, repeated plasmapheresis in donors was associated with increases in several clocks and DunedinPACE per procedure (~+0.16–0.26 years per session across GrimAge-family clocks and ~0.003±0.001 DunedinPACE units per session). In rodents, plasma fractions/exosome-rich preparations and heterochronic parabiosis reported large percentage reductions across tissues, with strong dependence on exposure duration and concerns about translational uncertainty (up to ~77.6% in liver and ~68.2% in blood in one plasma-fraction study). Evidence for partial reprogramming (OSKM) was limited to a single rat study with small, near-significant trends in hippocampus-based clocks (two-sided p=0.064–0.088 across three clocks). Conclusions: DNAm-based epigenetic biomarkers are modifiable by interventions in mammals, but effects are heterogeneous and depend on the intervention, clock construct (age vs pace/risk signatures), biological matrix, tissue, follow-up duration, and study design. A single notion of “epigenetic rejuvenation” is not supported; instead, intervention effects appear domain-specific and must be interpreted in relation to what each clock measures.

Abstract: Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled, protein depleted CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels. Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Mechanistically, stromal-derived Gln promotes cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further supports chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness, and a potential therapeutic vulnerability in the context of TIS.

Abstract: Aging remains one of the most complex phenomena in biology, giving rise to a diverse range of theoretical frameworks aimed at elucidating its mechanisms. These theories often overlap, exhibiting both consistencies and contradictions, making it challenging to systematically categorize them. In this review, we revisit prominent aging theories from multiple perspectives. First, from the classical viewpoints of “wear-and-tear” and “programmed” aging, we introduce several foundational theories, including the oxidative damage family theories and information theory. We then examine these theories from an evolutionary perspective, which leads to the antagonistic pleiotropy (AP) theory and the hyperfunction theory. Following the mechanistic discussion, we consider several inclusive theories, including the “np” theory. Analogies are used throughout, and each section concludes with a philosophical reflection on the essence of aging. All discussions are centered on a fundamental question: “Is lifespan constrained by what nature does not pursue, or by what it fundamentally cannot achieve?” At least according to the “np” theory, an ultimate restriction stems from the information entropy. Finally, we highlight emerging rejuvenation strategies, which provide alternative lens to view aging theories. This review aims to inspire readers to think critically about current theories and to explore novel conceptual frameworks in the biology of aging.

Abstract: Extremophilic bacteria survive salt, temperature, and pH extremes by coordinating stress-induced protein networks that preserve macromolecules, sustain energetics, and repair damage. This review integrates recent proteomics with functional genomics to resolve both network state and causality across halophiles, thermophiles, acidophiles, and alkaliphiles, with targeted contrasts from psychrophiles and radiation-resistant bacteria. Quantitative proteomics maps condition-specific induction of chaperones, proteases, ion transporters, osmolyte pathways, DNA repair proteins, antioxidants, and envelope remodelling enzymes. Complementary perturbation genetics/functional genomics and transcriptomics help identify essential nodes and regulatory circuits underlying stress tolerance. In halophiles, compatible solute synthesis and Na+/H+ exchange couple to protein quality control and central metabolism. Thermophiles rely on heat-shock systems, ATP-dependent proteolysis, membrane adjustments, and redox balancing. Acidophiles maintain near-neutral cytosol via proton export and low-permeability membranes while linking iron handling to oxidative defence. Alkaliphiles use Na+-based bioenergetics, multi-subunit antiporters, and cell wall modifications to retain protons. Psychrophiles emphasize cold-shock RNA chaperones, flexible enzymes, and cryoprotectants, whereas radiophiles combine exceptional DNA repair with strong antioxidant capacity. Across clades, oxidative stress forms a cross-cutting axis that explains extensive regulon overlap and cross-protection. We synthesize network architecture, highlight conserved modules and lineage-specific solutions, and outline open questions in stress sensing, multi-stress integration, and functions of uncharacterized proteins. These insights provide a framework for engineering robust biocatalysts and organisms for biotechnology and environmental applications.

Abstract: Aging is a fundamental biological process characterized by morphological and functional decline ultimately leading to death. Current research in aging is directed toward extending both healthspan and lifespan by elucidating the molecular and cellular mechanisms that drive aging and by developing interventions capable of delaying, preventing, or reversing age-associated physiological decline and multimorbidity. In this chapter, we take a broader view beyond the healthspan and lifespan of individuals, to consider deep issues impacting the duration and nature of our embodiment, including the nature of change, the meaning of personal persistence, and the future of humanity at multiple scales. If you don’t change, you die out (or become irrelevant); but if you change, are you still present? We argue that aging, like traumatic injury and cancer, is a fundamental challenge to an embodied mind seeking to maintain its distinct nature, differentiated from the environment. Understanding aging thus must take place within the context of a broader story of how biological individuals come to exist, how they continue to exist despite continual challenge, and how their plasticity can be leveraged for transformative change beyond mere persistence. Here, we will present our aging framework grounded in the collective intelligence of cells, then we will discuss the implication for the human- and the species-level aspects of artificial chimerism and its corollary - multiscale (non-Darwinian) evolution. We conclude with some important open questions for humanity with respect to the implications of rejuvenation and longevity technologies.

Abstract: Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we outline a unified model suggesting that αSyn‑driven disease emerges within specific neural circuits through the combined effects of cell‑type‑specific roles, subcellular environments, and post‑translational modifications. These interacting and additive dimensions generate strain diversity within regions of co-pathology and, collectively, rather than αSyn alone, shape whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia, its compartment-dependent functions, and the molecular transitions that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective can inform the development of next-generation biomarkers and precision therapies tailored to αSyn biology across distinct disorders.

Abstract: Biological ageing is accompanied by progressive alterations in mitochondrial metabolism, microvascular function, and thermoregulation, which together shape tissue heat production and dissipation, with underlying molecular-level processes that may include quantum-scale phenomena. Passive microwave radiometry (MWR) provides a non-invasive, radiation-free detecting of deep-tissue bioenergy emissions, complementing surface infrared thermography. Here, we evaluate a thermophysiological Bioenergetic Index (BEI) derived from deep-tissue microwave emission, surface temperature, and their spatial and deep–surface relationships as a proxy for biological ageing. We analysed breast thermophysiology measurements from 36,391 women aged 20–80 years collected during routine clinical assessments. Supervised machine-learning models trained exclusively on thermal features (with chronological age used only as the target) predicted age at the individual level with MAE ≈ 3.5 years and RMSE ≈ 5.4 years (R² ≈ 0.76). Aggregation into 5-year age bins revealed a robust non-linear ageing trajectory (R² = 0.984), characterised by mid-life decline and late-life stabilisation. These findings demonstrate a strong ageing signal in female breast thermophysiology, while highlighting the need for longitudinal and cross-population validation.

Abstract: Age-related muscle decline is associated with impaired mitochondrial bioenergetics, altered redox signaling, and reduced myogenic capacity, yet how photobiomodulation (PBM) source characteristics shape these processes under replicative aging remains unclear. Here, we investigated source-specific PBM responses in C2C12 myoblasts using a 660 nm light-emitting diode (LED) and an 830 nm near-infrared (NIR) laser across fluence ranges and replicative stages. Single-cell screening performed at passage 25 identified 5 J/cm² as the optimal fluence for both sources, producing biphasic increases in mitochondrial membrane potential and ROS. Population-level assays in young (≤5 passages) and old (≥30 passages) cells revealed divergent downstream outcomes. LED irradiation elicited stronger metabolic activation and ATP production, particularly in aged cells, whereas NIR irradiation robustly enhanced myogenic fusion in both age groups and partially rescued differentiation deficits in aged myoblasts. Bulk ROS increased significantly after PBM independent of source, while extracellular vesicle release displayed age-dependent source sensitivity, with NIR favoring canonical small EV populations in young cells and LED inducing greater particle release in aged cells. Together, these findings demonstrate that PBM engages conserved mitochondrial signaling while source-specific delivery and wavelength differentially directs metabolic, paracrine, and myogenic outputs under replicative aging conditions.

Abstract: Primary sarcopenia is an age-associated degenerative disorder marked by progressive loss of skeletal muscle mass, strength, and function, representing a major driver of frailty and morbidity after midlife. Convergent evidence from human muscle biopsies, aged rodents, Drosophila, and myogenic cell models identifies mitochondrial dysfunction as the proximal cause of this decline, with impaired mitophagy emerging as the central mechanistic failure. Aging muscle exhibits reduced mitochondrial content, compromised oxidative phosphorylation, dysregulated dynamics favoring excessive fission, and accumulation of oxidized, depolarized mitochondria. These defects closely associate with a collapse in mitophagy flux, characterized by coordinated downregulation of PINK1–PARKIN signaling, receptor-mediated pathways (BNIP3, NIX, FUNDC1), autophagosome formation, and lysosomal clearance, resulting in defective mitochondrial turnover and bioenergetic insufficiency. Genetic or pharmacological restoration of mitophagy reverses these phenotypes, preserving muscle mass, respiratory capacity, and functional performance while extending lifespan in multiple model organisms. Notably, the natural compounds urolithin A and spermidine consistently activate mitophagy, improve mitochondrial quality control, and enhance muscle strength and endurance in aged animals and sedentary middle-aged humans. Collectively, these data position age-related mitophagy suppression as the pivotal driver of skeletal muscle aging and define mitochondrial quality control as a tractable, mechanistic therapeutic target to delay or reverse primary sarcopenia.

Abstract: Mitochondrial dysfunction is increasingly recognized as a central, integrative driver of biological aging and a convergent mechanism underlying multiple age-associated pathologies. This review synthesizes current evidence identifying a coordinated network of mitochondrial “drivers of aging” that collectively erode cellular homeostasis and organismal resilience. Core processes include decline in ATP production, impaired electron transport chain efficiency and supercomplex assembly, excessive reactive oxygen species generation, accumulation of mitochondrial DNA damage and mutations, rising heteroplasmy, reduced DNA repair capacity, and progressive loss of mitochondrial DNA copy number. These genomic and bioenergetic failures are compounded by dysregulated mitochondrial dynamics, diminished biogenesis, and defective mitophagy, leading to the persistence of dysfunctional organelles and amplification of inflammatory and senescence-associated signaling. We propose a conceptual mitochondrial lifespan clock model in which the cumulative imbalance among these interdependent mechanisms accelerates functional decline across tissues, particularly in post-mitotic systems such as muscle, heart, and brain. Importantly, multiple drivers remain plastic and responsive to metabolic, genetic, and pharmacological interventions, highlighting mitochondria not only as biomarkers but as actionable targets for extending healthspan. Understanding the hierarchy, interaction, and reversibility of these mitochondrial determinants provides a unifying framework for translational strategies aimed at delaying aging and mitigating age-related disease.

Abstract: Skeletal muscle regeneration declines with age despite the persistence of satellite cells, indicating that regenerative impairment reflects functional dysregulation rather than stem cell loss. Increasing evidence identifies early satellite cell activation as a stress-sensitive, rate-limiting checkpoint that is preferentially disrupted in aged muscle. Integrative analyses indicate that aged satellite cells exhibit elevated stress programs and reduced membrane remodeling capacity, accompanied by weakened activa-tion-associated transcriptional signatures, while proliferative and differentiation pro-grams remain relatively accessible in successfully activated cells. This imbalance is consistent with impaired activation fidelity, in which early instability drives compen-satory downstream responses at the expense of long-term self-renewal. Within this framework, MG53 (TRIM72) is positioned beyond its canonical role in myofiber mem-brane repair as a permissive, stress-responsive regulator that stabilizes the early acti-vation environment. Rather than directly specifying cell fate, MG53 is proposed to support early activation by limiting stress-associated membrane disruption and main-taining coordination of the activation program under age-related constraints. These ob-servations suggest that restoring activation quality, rather than amplifying proliferation, may represent a more durable strategy to preserve regenerative capacity in aging skeletal muscle.

Abstract: The extracellular matrix (ECM) is a dynamic and complex three-dimensional network that provides structural support and mechanical stability to tissues. The complete repertoire of ECM and associated proteins has recently been cataloged as matrisome, which encompasses both core structural components and ECM-associated proteins. Advances in ECM biology have overturned the traditional view of the ECM as a purely passive scaffold, revealing its active involvement in a wide range of biological processes. Among these, the ECM plays a critical regulatory role in inflammation. This review examines the bidirectional interplay between the matrisome and inflammatory processes, highlighting how matrisome components shape inflammatory responses and how inflammation, in turn, drives matrisome remodeling. A deeper understanding of matrisome–inflammation in-teractions will provide important insights into immunopathology and may inform the development of novel therapeutic strategies.