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.

Abstract: Cellular senescence is typically driven by DNA damage, telomere attrition, and metabolic/mitochondrial stress, resulting in a state of durable proliferative arrest accompanied by a senescence-associated secretory phenotype (SASP) that amplifies inflammation and paracrine remodeling across tissues, thereby accelerating functional decline and age-related pathologies. This review examines the molecular mechanisms and in vivo activities of procyanidin C1 (PCC1), a natural dualmode geroprotector. This dual behavior ostensibly allows PCC1 to function in an early or lowdose phase wherein PCC1 attenuates selected NFκB–driven SASP components while stabilizing redox and bioenergetic homeostasis; under high senescent burden or tumor-associated stress, elevated doses of PCC1 enable the selective reduction of refractory senescent cells and mitigation of pro-tumorigenic SASP outputs, concomitant with modulation of immune infiltration and metabolic reprogramming. PCC1 further exhibits pronounced anti-inflammatory and anti-tumor potential by reshaping inflammatory and chemotactic gradients within the tumor microenvironment. Reflecting broad multi-organ geroprotective potential, PCC1 can exert antioxidative, mitochondrial-supportive, and anti-fibrotic modulation in cardiovascular/metabolic tissues, skin, liver, kidney, and neural niches. Compared with BCL-2 inhibitors or multi-kinase senolytics, PCC1 shows lower cytotoxicity toward normal proliferating cells and fewer indications of platelet or hematopoietic suppression, with its staged regulatory profile and natural scaffold suggesting a wider therapeutic window. Future priorities include quantifying dose–timing transition thresholds, establishing integrated biomarker panels, and optimizing delivery strategies to define its translational potential in precision, phase-adapted geroprotective interventions.

Abstract: Endurance performance is influenced by age- and sex-specific physiological determinants, while emerging evidence indicates an increasing prevalence of Relative Energy Deficiency in Sport (REDs) among both young and master endurance runners. Despite its clinical relevance, limited data exist on how long-term endurance training modulates REDs risk, skeletal muscle characteristics, and physiological ageing in comparison with inactive individuals. Methods: This cross-sectional study protocol will examine 112 participants stratified by sex, age (20–35 vs. 65–80 years), and training status (endurance runners vs. inactive controls). Cardiorespiratory fitness (VO₂max) is defined as the primary outcome. Secondary outcomes include body composition, musculoskeletal function, biochemical and hormonal markers, and REDs–related screening variables. Assessments will comprise cardiorespiratory testing, DXA-based bone and body composition analysis, isometric knee dynamometry, mobility testing, validated REDs screening tools (LEAF-Q, LEAM-Q, and IOC REDs CAT2), seven-day dietary and training monitoring, venous blood sampling, and skeletal muscle biopsies from the vastus lateralis. Results: The study is designed to generate an integrated overview of physiological, nutritional, metabolic, and muscle-cell characteristics across sex-, age-, and training-specific subgroups. Conclusions: This protocol provides comprehensive insight into how ageing and sex influence endurance physiology and REDs susceptibility, and whether long-term endurance training preserves functional capacity across the lifespan. The findings aim to support evidence-based screening, prevention, and targeted interventions for REDs in endurance athletes.

Abstract: We have previously demonstrated that the endocannabinoid system is dysregulated at synaptic terminals in the cerebral cortex of aged rats, characterized by reduced availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) as a result of im-paired metabolic enzyme activity. This deficit was only partially compensated by canna-binoid receptor (CBR) ligand binding. Given that Δ9-tetrahydrocannabinol (THC) func-tions as a CBR ligand, the present study was designed to determine whether a full-spectrum cannabis extract with high THC content, its THC-free fraction, or pure THC could modulate the age-related dysregulation of 2-AG. Synaptosomes isolated from the cerebral cortex of adult and aged rats were incubated with a full-spectrum extract, a THC-free fraction, or pure THC, together with the corre-sponding radiolabeled substrates to assess 2-AG-metabolizing enzyme activity. Our re-sults demonstrate that the age-related decline in 2-AG bioavailability (a) is exacerbated by either the THC-free fraction or pure THC, primarily due to a significant reduction in 2-AG synthesis, and (b) is partially attenuated through inhibition of 2-AG hydrolysis when the extract contains THC. Consequently, a high-THC full-spectrum extract regulates 2-AG metabolism more effectively than THC alone. These findings support the concept that cannabis phytochemicals act synergistically (the entourage effect) and highlight the therapeutic potential of high-THC extracts for restoring reduced 2-AG levels in the aging brain.

Abstract: Alzheimer's disease is manifested by a pattern of asymmetric neurofunctional decline, with initial impairment in the consolidation of recent memories and relative preservation of remote information. This dissociation is related to the topography of synaptic degeneration and the biochemical selectivity of structures such as the hippocampus, entorhinal cortex, anterior cingulate cortex and dorsolateral prefrontal cortex. The reduction in the synthesis and transmission of neurotransmitters, especially acetylcholine and dopamine, is associated with loss of efficiency in episodic memory, executive functions and sustained attention. The loss of functional connectivity, measured by diffusion and functional imaging, shows that Alzheimer's failure is not only morphological, but also functional. Understanding this complex dynamic is fundamental for the development of preventive approaches and early interventions based on applied neuroscience.

Abstract: D-galactose (D-gal) induced accelerated aging is a popular and widely used experimental method in the field of aging and aging-related degenerative disorders. It has been shown that the major characteristics of D-gal induced aging process are increased oxidative stress, decreased antioxidant enzymes, elevated cell death, increased tissue fibrosis and accumulation of inflammatory mediators. This review focuses on D-gal induced kidney aging in mice and rats with discussions on both kidney aging mechanisms and anti-kidney aging regimens using this model. It is our belief that D-gal induction of accelerated kidney aging will continue to be used as a convenient platform for elucidating kidney aging mechanisms and exploring novel anti-kidney aging targets that may slow down kidney aging and retard the development of aging related renal disorders.

Abstract: Cognitive aging is characterized by declines in executive functions, yet the molecular mechanisms underlying the dissociation between cortical control and emotional reactivity remain unclear. This article proposes a conceptual model based on divergent transcriptomic erosion in the prefrontal cortex (PFC) compared to the relative resilience of the limbic system. We summarize data showing that the PFC exhibits marked reductions in the expression of genes critical for synaptic integrity and layer II/III glutamatergic signaling, such as PTGS2, DRD4, SST, and CREB1. Furthermore, we propose that postnatal attenuation of human-specific developmental factors, including ARHGAP11B, may limit "cortical reserve," increasing the vulnerability of the neocortex to mitochondrial and oxidative stress. In contrast, phylogenetically older limbic structures, such as the amygdala, exhibit a more conserved expression profile, with relative retention of early response genes (ARC, FOS). FAT4 gene expression in subcortical limbic structures (such as the amygdala) remains relatively constant after brain development is complete. It is less sensitive to momentary neurotransmitter fluctuations, resulting in a flatter expression profile. We posit that this "transcriptomic mismatch" leads to a disruption of descending disinhibition, in which stable limbic reactivity is no longer modulated by weakening prefrontal cortex activity. This evolutionary tradeoff provides a molecular basis for age-related increases in impulsivity and emotional lability, suggesting that more recently evolved brain regions are the first to succumb to the molecular pressures of aging, compared to the more conservative and stable limbic system. This confirms and illustrates how the brain has evolved over the course of evolution and how new cortical areas often become unstable or incompletely developed as they develop further.

Abstract: In this work, we analyze the reasons for the absence of immortality from the perspective of “genetic information metabolism.” All living organisms synthesize and release genes, including novel and previously unknown genes, into the external environment through the process of genetic information metabolism. As a result, new genes become available for inclusion in the unified complex of genetic information represented by all living and non-living carriers, which has been termed the “Pangenome,” ensuring the maintenance of life on Earth under changing biotic and abiotic conditions. Part of the newly created genetic information remains inaccessible to spreading to other members of the Pangenome during the lifetime of an organism and can only be released after its death. We hypothesize, to our knowledge for the first time, that the absence of immortality is associated with the necessity of releasing novel genes for spread within the Pangenome, which can happen efficiently only after an organism’s death. We define the spread of genes and their integration into the genomes of other organisms as “gene reincarnation.” Within the Pangenome, genes are redistributed, ensuring the further evolution of life. We formulate a new definition of death as “a stage in the metabolism of genetic information during which all genes of an organism become available for reincarnation.” This understanding for the first time views death as a crucial part of the genetic cycle of life. Based on above novel concepts, we propose certain properties that immortal organisms should possess.

Abstract: Melanogenesis is a highly complex process regulated by multiple signaling pathways that control melanin synthesis in melanocytes and its subsequent transfer to keratinocytes. This process is further influenced by an intricate network of interactions among various skin cell populations, including inflammatory cells, which release paracrine factors in response to internal and external stimuli, such as UV radiation. The aim of this study was to evaluate effectiveness a new cosmetic formulation Skin Glow Complex designed for the topical treatment of skin dyschromia. We investigated the potential benefits of the for-mulation in two major resident skin cell types, keratinocytes and fibroblasts subjected to UV irradiation. Additionally, its effects were tested in 3D human melanocyte spheroid model, that better mimics the skin's environment. Treatment with the new formulation prevented UV-induced reactive oxygen species (ROS) formation in keratinocytes. In dermal fibroblasts, the formulation decreased the expression of matrix metalloproteinases while simultaneously promoting cell proliferation and collagen synthesis. Finally, results obtained from the melanocyte spheroid model confirmed the formulation’s ability to reduce melanin production, reinforcing its potential use in the treatment of skin dyschromia. Overall, these findings indicate that the new product represents a promising natural option to support skin repair and counteract aging and UV-induced damage.

Abstract: Background: Immunosenescence, the age-related decline in immune function, represents a critical challenge in geriatric medicine. Traditional modeling approaches fail to capture the spatial heterogeneity and compositional complexity of the aging immune system.Methods: We developed a quantum-inspired tensor product Hilbert space framework integrating 11 immune cell types across 8 tissue compartments (dimension: 88). Two cohorts—young adults (<50 years) and elderly individuals (>65 years)—were simulated using empirically derived distributions from recent immune cell census studies. State evolution was governed by a spatial Hamiltonian incorporating intratissue dynamics, cellular trafficking, and cytokine-mediated coupling.Results: The elderly cohort exhibited hallmark immunosenescence signatures: 30% reduction in naive T lymphocytes (p<0.001), 25% expansion of NK cells (p<0.001), and 33% impairment in migration capacity. Tissue-specific Shannon entropy decreased by 8-12% across major compartments (lymph nodes: -11%, bone marrow: -8%, peripheral blood: -9%), providing a quantitative metric for immune aging. Enhanced intertissue coupling (1.5-fold increase) captured inflammaging signatures. Multivariate analysis yielded a composite aging index with 89% discrimination accuracy (AUC=0.89, 95% CI: 0.83-0.94).Conclusions: Information-theoretic diversity metrics derived from spatially resolved models provide quantifiable biomarkers of immunological aging with strong clinical correlations. This framework enables personalized immune age assessment, vaccine responsiveness prediction, and rational design of immune rejuvenation strategies.