Aging is associated with a progressive decline in immune surveillance, yet the mechanisms that constrain this process remain incompletely understood. Here we uncover a lipid-biomechanical mechanism in human natural killer (NK) cells that contributes to age-related immune…
Abstract
Aging is associated with a progressive decline in immune surveillance, yet the mechanisms that constrain this process remain incompletely understood. Here we uncover a lipid-biomechanical mechanism in human natural killer (NK) cells that contributes to age-related immune decline. We show that aging drives a coordinated metabolic and physical state in NK cells, marked by lipid accumulation, increased membrane fluidity, reduced cortical stiffness and defective immune synapse organization, ultimately impairing target cell killing. Mechanistically, aging induces a retinoid-dependent metabolic shift in NK cells, characterized by enhanced retinol uptake and intracellular retinoic acid accumulation, which activates an SREBP1-dependent lipogenic program with ELOVL6 as a key downstream effector. This program remodels fatty-acyl composition, alters membrane and cortical mechanics, and constrains NK cell cytotoxic function. ELOVL6 inhibition restores membrane and cortical mechanics, rescues cytotoxicity in vitro and enhances antitumor activity in mouse models. These findings establish a targetable biomechanical mechanism linking aging to impaired immune surveillance.
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Summary
Aging induces a retinol-SREBP1-ELOVL6 lipogenic axis in NK cells that alters biomechanics and impairs cytotoxicity, which can be reversed by ELOVL6 inhibition. This paper is relevant because it identifies a specific, targetable metabolic-mechanical mechanism driving age-related immune decline, offering a potential intervention to restore immune surveillance rather than merely treating downstream symptoms.
NNMT (nicotinamide N-methyltransferase) is a pivotal metabolic-epigenetic integrator that regulates cellular methylation balance. Although its expression and function exhibit profound, context-dependent heterogeneity in metabolic diseases and cancer, its role within the vascular…
Abstract
NNMT (nicotinamide N-methyltransferase) is a pivotal metabolic-epigenetic integrator that regulates cellular methylation balance. Although its expression and function exhibit profound, context-dependent heterogeneity in metabolic diseases and cancer, its role within the vascular system, particularly in aging endothelial cells, remains elusive.
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Summary
NNMT safeguards vascular aging by modulating an endothelial LMNA-HSP stress-response axis. This paper is relevant because it identifies a specific metabolic-epigenetic mechanism (NNMT) that protects against cellular senescence and stress in endothelial cells, addressing a fundamental driver of vascular aging rather than merely treating downstream symptoms.
Ageing is a systemic process in which local damage in one organ propagates to others and coordinates organism-wide decline. The hallmarks of ageing are established, but the causal relations between them, and the routes by which local damage becomes organismal decline, remain…
Abstract
Ageing is a systemic process in which local damage in one organ propagates to others and coordinates organism-wide decline. The hallmarks of ageing are established, but the causal relations between them, and the routes by which local damage becomes organismal decline, remain undefined. We propose an initiator-communicator-effector framework in which the three terms denote causal roles assigned by intervention rather than fixed classes of lesion. Initiators are organ-intrinsic lesions whose organ-restricted correction restores function in distant, untreated organs; telomere attrition in the zebrafish gut is the paradigm. Communicators are the organs, routes and mediators whose interruption uncouples distant phenotypes from the initiating lesion without correcting it, including sterile inflammation, cGAS-STING signalling, endocrine and metabolic factors, immune-cell trafficking and neuroimmune outputs. Effectors are states induced in recipient organs lacking a sufficient local lesion, notably stem-cell exhaustion, bioenergetic decline, epigenetic reprogramming, fibrosis and endothelial dysfunction. Because roles are defined by perturbation rather than molecular identity, the same process may initiate on one axis and act as an effector on another; the architecture is a directed graph containing feedback loops, not a linear chain. Ageing may therefore be slowed by interrupting chronically engaged organ-to-organ communication as well as by repairing initiating damage. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper proposes a causal "initiator-communicator-effector" framework where local organ damage propagates to distant organs via specific communication routes, suggesting that interrupting these chronic organ-to-organ signals can slow systemic aging. This is relevant because it moves beyond treating isolated age-related symptoms to identifying the systemic mechanisms and causal pathways by which local damage drives organism-wide decline, offering a new theoretical basis for interventions targeting inter-organ crosstalk.
Epigenetic clocks have transformed aging research by providing accurate molecular measures of biological age, but the factors regulating their pace across mammals remain unclear. This review proposes a hierarchy of regulation: species-level determinants that set intrinsic aging…
Abstract
Epigenetic clocks have transformed aging research by providing accurate molecular measures of biological age, but the factors regulating their pace across mammals remain unclear. This review proposes a hierarchy of regulation: species-level determinants that set intrinsic aging rate and lifespan, as well as individual-level modifiers acting within species. Comparative analyses show developmental tempo, rather than body mass, anchors species differences. Across individuals, caloric restriction and other perturbations of the insulin-like growth factor 1 nutrient-sensing axis alter epigenetic aging rate, whereas torpor models suggest body temperature, rather than metabolic rate per se, acts as the pacemaker. Gonadal hormones, reproduction, social environment, and ecology also contribute, with applications in livestock and wildlife conservation highlighted as means to capitalize on age-associated traits and exposures. Together, this work shows epigenetic clocks are far more than a yardstick for biological time; they reveal the multifaceted biology, and its hierarchy, that sets the pace of aging in mammals.
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Summary
The paper proposes a hierarchical model where developmental tempo, rather than body mass, anchors species-level differences in epigenetic aging rates, while individual-level modifiers like the IGF-1 axis and body temperature regulate the pace within species. This is relevant because it moves beyond using epigenetic clocks as mere biomarkers to identify the specific biological mechanisms and regulatory hierarchies that determine the rate of aging, offering potential targets for intervention.
Ageing is accompanied by a progressive loss of homeostasis driven by inter connected molecular stress responses. Two central hallmarks, genome instability and chronic low-grade inflammation (inflammaging), are increasingly recognized as mechanistically inseparable. Persistent…
Abstract
Ageing is accompanied by a progressive loss of homeostasis driven by inter connected molecular stress responses. Two central hallmarks, genome instability and chronic low-grade inflammation (inflammaging), are increasingly recognized as mechanistically inseparable. Persistent DNA damage, defective repair and transcriptional stress activate inflammatory signalling not only through canonical DNA damage response (DDR) pathways, but also via innate immune sensing of mislocalized self-nucleic acids. In turn, inflammatory mediators, metabolic stress and reactive oxygen and nitrogen species inflict new genomic damage and compromise repair, establishing a self-reinforcing feedback loop. Evidence from human DNA repair syndromes and genetically engineered mouse models reveals that chronic DDR engagement rewires metabolism, endocrine signalling, mitochondrial function and immune surveillance well before overt tissue degeneration. Recent work further highlights extra-nuclear DDR programmes, RNA-based danger signals and organelle dysfunction as key amplifiers linking genome instability to inflammation. Here, we synthesize insights from genome maintenance, innate immunity and metabolism to propose a unified framework in which ageing emerges from the chronic persistence of stress circuits originally evolved for transient repair and host defence. We discuss evolutionary implications, disease relevance and emerging therapeutic strategies aimed at disrupting this damage-inflammation axis to restore tissue homeostasis. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper proposes a unified framework in which ageing emerges from the chronic persistence of stress circuits linking genome instability and inflammation, suggesting that disrupting this damage-inflammation axis can restore tissue homeostasis. This is a review article that synthesizes existing evidence regarding the mechanistic link between DNA damage and inflammaging, providing a conceptual model for targeting the root causes of ageing rather than just treating symptoms, though it does not present novel experimental data or a specific breakthrough intervention.
Ageing has traditionally been viewed as a process of late-life organismal deterioration, with interventions aimed at slowing ageing being administered after the ageing process has already begun. However, recent advances in quantifying ageing indicate that the process of…
Abstract
Ageing has traditionally been viewed as a process of late-life organismal deterioration, with interventions aimed at slowing ageing being administered after the ageing process has already begun. However, recent advances in quantifying ageing indicate that the process of molecular ageing starts as early as the end of gastrulation. Further, growing evidence suggests that the foundations of how different systems of an organism age are established during prenatal and postnatal development. Herein, we review the impact of early-life environmental conditions on disease susceptibility, adaptation, energy metabolism, microbiome and neurodevelopmental processes to ascertain how changes early in life can affect ageing-related features late in life. We also link growth, reproductive capacity and ageing by providing examples when the balance between longevity and reproduction is shifted towards a longer life through the growth axis at a cost of fecundity across species. We encourage researchers to investigate interventions aimed at mitigating ageing during the developmental period of life, with the important note that such interventions must be assessed with extra caution, given that many life-extending strategies may attenuate growth and reproduction, which may be detrimental for the organism during development. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper posits that molecular ageing trajectories are established during prenatal and postnatal development, suggesting that interventions during this period could mitigate late-life ageing. This is a review article that synthesizes existing evidence on the developmental origins of ageing, providing a conceptual framework for early-life interventions but lacking the novel experimental data or specific mechanistic breakthroughs required for a higher impact score.
Chronodisruption is increasingly recognised as a fundamental driver of biological aging rather than merely a consequence of advancing age. Although substantial evidence links circadian dysfunction with individual age-related diseases, the mechanistic integration of…
Abstract
Chronodisruption is increasingly recognised as a fundamental driver of biological aging rather than merely a consequence of advancing age. Although substantial evidence links circadian dysfunction with individual age-related diseases, the mechanistic integration of chronodisruption across the hallmarks of aging and its therapeutic implications remains fragmented. This review provides a comprehensive synthesis of current evidence describing how age-associated deterioration of the circadian timing system interacts with established hallmarks of aging, including genomic instability, epigenetic alterations, mitochondrial dysfunction, dysregulated nutrient sensing, impaired proteostasis, chronic inflammation, and cellular senescence. This article also incorporates how these interconnected mechanisms contribute to the development and progression of major age-related disorders, including neurodegenerative, cardiovascular, metabolic diseases, and cancer, highlighting shared molecular regulators such as BMAL1, CLOCK, PER, CRY, REV-ERBs, SIRT1, AMPK, and mTOR. Although several reviews exist that focus on individual diseases or isolated circadian mechanisms, this review integrates molecular, cellular, and translational evidence into a unified framework linking chronodisruption to systemic aging. This article discusses emerging chronotherapeutic strategies including chrono-phototherapy, chrono-nutrition, chrono-exercise, natural chrono-modulators, chrono-pharmacology, and precision geromedicine that aim to restore circadian homeostasis and improve healthy aging. Collectively, this review identifies circadian rhythm restoration as a promising systems-level therapeutic approach and outlines future directions for integrating chronobiology into precision interventions for age-related diseases.
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Summary
The paper synthesizes existing evidence to propose that chronodisruption is a fundamental driver of biological aging and that restoring circadian homeostasis via chrono-therapies can mitigate age-related decline. This is a review article that integrates fragmented knowledge on circadian rhythms and aging hallmarks, providing a conceptual framework for future interventions but offering no new experimental data or novel mechanistic discoveries.
The underlying causes of ageing remain elusive, as evidenced by the numerous coexisting theories attempting to explain its origin and progression. Developing a robust theoretical framework will not only improve our understanding of this fundamental biological process but also…
Abstract
The underlying causes of ageing remain elusive, as evidenced by the numerous coexisting theories attempting to explain its origin and progression. Developing a robust theoretical framework will not only improve our understanding of this fundamental biological process but also guide the design of interventions targeting the ageing process. Here, we revisit the hypothesis originally proposed by Bidder that the growth-restriction processes-responsible for suppressing growth during development and establishing adult body size-remain active throughout adulthood, potentially acting as a primary driver of ageing. We explore how persistent growth suppression can induce ageing phenotypes, such as organ atrophy and degeneration. Furthermore, we examine supporting observations from comparative studies and experiments in model organisms and address the current limitations of this model, with the expectation that this framework will be further developed and assessed in future research. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper proposes that persistent growth-restriction processes active in adulthood act as a primary driver of ageing phenotypes. This is a theoretical review revisiting an existing hypothesis rather than presenting new experimental data or a novel mechanism, resulting in limited immediate impact on the field.
Aged female mice with skeletal muscle-specific deletion of Terf2, which encodes the telomere-protective factor TRF2, display a remarkably young-like muscle phenotype including reduced myofibre atrophy, preserved muscle strength, absence of regenerative nuclear markers and modest…
Abstract
Aged female mice with skeletal muscle-specific deletion of Terf2, which encodes the telomere-protective factor TRF2, display a remarkably young-like muscle phenotype including reduced myofibre atrophy, preserved muscle strength, absence of regenerative nuclear markers and modest lifespan extension. This phenotype occurs without evidence of telomere deprotection but is associated with mild pro-oxidant signalling; hence, we propose that age-associated TRF2 downregulation induces a hormetic response that benefits skeletal muscle function during ageing. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper claims that skeletal muscle-specific inhibition of TRF2 induces a hormetic pro-oxidant response that preserves muscle function and extends lifespan in aged female mice. This is relevant because it identifies a specific molecular mechanism (TRF2 downregulation) that bypasses the typical negative effects of aging in muscle tissue, offering a potential target for interventions aimed at maintaining physiological function and extending healthy lifespan.
Inflammaging (InfA) is a chronic, sterile, low-grade inflammatory condition associated with ageing and the development of age-related diseases (ARDs), including cancer. Conventional models often portray InfA as a relatively homogeneous and progressively worsening process, which…
Abstract
Inflammaging (InfA) is a chronic, sterile, low-grade inflammatory condition associated with ageing and the development of age-related diseases (ARDs), including cancer. Conventional models often portray InfA as a relatively homogeneous and progressively worsening process, which may not adequately capture its temporal dynamics, tissue specificity, reversibility and context-dependent biological consequences. Here, we propose that InfA is better understood as a dynamic state-transition process comprising resolved/adaptive (S0), compensatory (S1), maladaptive but potentially reversible (S2) and self-sustaining (S3) inflammatory states. Transitions among these states are shaped by the balance between inflammatory induction and resolution, senescent cell (SC) generation and immune-mediated clearance, metabolic and mitochondrial resilience and microenvironmental feedback. We further integrate SC heterogeneity and immune surveillance into this framework, proposing that declining clearance and emerging immune escape permit persistent senescent phenotypes to establish self-reinforcing inflammatory microenvironments. This model also provides a mechanistic perspective on the cancer-ageing paradox by explaining how initially protective processes, including senescence, autophagy and immune surveillance, may be progressively re-tuned toward maladaptive functions during ageing. S2 emerges as a particularly important therapeutic window during which inflammatory dysregulation and immune escape are established but may remain conditionally reversible. Tissue-specific biomarkers may enable state- and timing-informed InfA interventions and provide a foundation for precision geroscience. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper proposes that inflammaging is a dynamic state-transition process (S0-S3) rather than a linear decline, identifying the S2 state as a critical, potentially reversible therapeutic window. This conceptual framework advances the field by moving beyond static descriptions of chronic inflammation to a mechanistic model that integrates senescent cell clearance and immune surveillance, offering a basis for timing-informed interventions in precision geroscience.
Ageing is not merely the progressive and irreversible accumulation of damage and a decline in biological function; it may also reflect the persistent and progressive dysregulation of developmental mechanisms during adulthood, leading to reduced stress resilience. This…
Abstract
Ageing is not merely the progressive and irreversible accumulation of damage and a decline in biological function; it may also reflect the persistent and progressive dysregulation of developmental mechanisms during adulthood, leading to reduced stress resilience. This perspective has stimulated interest in rejuvenation, defined as the partial reversal of biological age, for example, through experimental reprogramming approaches such as heterochronic parabiosis or Yamanaka factor-based reprogramming. Although rejuvenation in mammals remains limited and requires strong experimental interventions, naturally occurring age-reversal phenomena have been described in several invertebrate metazoans, including ctenophores, cnidarians, platyhelminths, annelids and nematodes. This has been described either at the morphological level or at the physiological, cellular and/or molecular levels. Here, we review and synthesize studies documenting these inductive processes, with particular attention to terminology and to the distinction between 'morphological reversion' and multi-level 'rejuvenation' associated with potential lifespan extension. When available, we also summarize the associated molecular evidence and discuss how systematic and in-depth, multi-level studies of this naturally occurring phenomenon could provide new opportunities for ageing biology and rejuvenation strategies in mammals. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
The paper synthesizes evidence that natural age-reversal phenomena in invertebrates represent multi-level rejuvenation rather than mere morphological reversion, offering potential insights for mammalian rejuvenation strategies. This is a review article that organizes existing literature on invertebrate aging and rejuvenation, providing a conceptual framework and terminology clarification that is useful for the field but does not present new experimental data or a major breakthrough.
Ageing trajectories may be established long before the onset of functional decline, potentially during early developmental stages. This review highlights evidence that transient developmental interventions-encompassing metabolic, pharmacological, microbial, and physiological…
Abstract
Ageing trajectories may be established long before the onset of functional decline, potentially during early developmental stages. This review highlights evidence that transient developmental interventions-encompassing metabolic, pharmacological, microbial, and physiological approaches-may confer lasting benefits for longevity and healthspan across species. The long-term effects are proposed to be mediated by systemic epigenetic and metabolic reprogramming, establishing a primed state of enhanced stress resistance and homeostatic capacity that persists into adulthood. Critically, this developmental programming often operates within a narrow window of high plasticity; the same interventions are often ineffective or even harmful when administered later in life. These findings underscore the importance of timing in geroscience and suggest that understanding early-life plasticity provides a valuable conceptual framework for exploring future strategies to delay ageing. This article is part of the theme issue 'Developmental circuits in ageing'.
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Summary
Transient developmental interventions can establish lasting longevity benefits through systemic epigenetic and metabolic reprogramming. This review is relevant because it explores the root causes of aging by identifying early-life plasticity windows where interventions can permanently alter aging trajectories, rather than merely treating late-stage symptoms.
Low-grade inflammation is persistent with advancing age in healthy people and mice. Endothelial cells and large arteries increasingly express pro-inflammatory cytokines, coinciding with increased T cell infiltration into the aorta. Arterial stiffness is an independent risk…
Abstract
Low-grade inflammation is persistent with advancing age in healthy people and mice. Endothelial cells and large arteries increasingly express pro-inflammatory cytokines, coinciding with increased T cell infiltration into the aorta. Arterial stiffness is an independent risk factor for cardiovascular diseases, and stiffness increases with age. T cells particularly affect vascular dysfunction, and we have shown that T cell depletion in old mice prevented elevations in stiffness. We sought to understand how the aged phenotype of T cells affects arterial stiffness and arterial T cell infiltration. T cells were isolated from young or old C57BL/6 mice and adoptively transferred into young or old RAG1
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Summary
The paper tests the claim that the aged phenotype of T cells drives age-associated arterial stiffness and infiltration. This is relevant to longevity research because it identifies a specific immunological mechanism (T cell aging) contributing to a major age-related physiological change (vascular stiffness), offering a potential target for interventions aimed at delaying vascular aging rather than just treating symptoms.
Prolonged heterochronic parabiosis (HPB) reduces DNA methylation (DNAm) age in old mice, but how age-opposing methylation changes are organized across tissues and retained after removal of youthful circulation is unclear. We analyzed processed reduced-representation bisulfite…
Abstract
Prolonged heterochronic parabiosis (HPB) reduces DNA methylation (DNAm) age in old mice, but how age-opposing methylation changes are organized across tissues and retained after removal of youthful circulation is unclear. We analyzed processed reduced-representation bisulfite sequencing data from 78 blood and liver samples from a published prolonged-HPB experiment. Across 1,008,133 CpGs with at least 10-fold coverage in every sample, we quantified normal-aging and HPB effects, defined directional reversal by effect size, tested exact cross-tissue and post-detachment persistence, and used chromosome-aware null models for overlap and gene-convergence analyses. HPB-associated methylation changes opposed normal aging in blood and liver, including in independent-cohort comparisons that avoided a shared Old-ISO reference. At the primary 10-percentage-point threshold, 22,424 blood and 22,286 liver CpGs were reversed immediately after HPB; 1,792 were shared at identical loci. After two months of recovery, 25,867 blood and 15,437 liver CpGs were reversed, with 1,387 exact shared loci. A 64-CpG cross-tissue core persisted across both time points. Reversed CpGs were depleted from promoters and CpG islands and enriched in gene bodies and open-sea regions. After exact shared CpGs were removed, tissue-specific sites showed a modest excess of nearest-gene convergence (4,716 observed vs 4,215 expected; empirical P≈.001), whereas promoter/gene-body and Gene Ontology convergence were not supported by stricter genomic null models. Youthful circulation produces both conserved and tissue-specific reversal of age-associated methylation. Persistence after detachment and modest cross-tissue genomic-neighborhood convergence suggest that systemic rejuvenation is encoded at multiple levels of epigenomic organization.
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Summary
Youthful circulation reverses age-associated DNA methylation patterns in blood and liver, with a small core of changes persisting after the youthful environment is removed. This study provides mechanistic insight into how systemic factors (circulation) drive epigenetic rejuvenation, supporting the hypothesis that aging is reversible via systemic interventions, though it relies on re-analyzing existing data and the effect size of the persistent core is modest.
Mitochondrial dysfunction and declining ATP production are common features of aging, yet whether ATP availability itself directly regulates cellular lifespan is unclear. However, the causal relationship between cellular ATP homeostasis and aging has not been established. Here…
Abstract
Mitochondrial dysfunction and declining ATP production are common features of aging, yet whether ATP availability itself directly regulates cellular lifespan is unclear. However, the causal relationship between cellular ATP homeostasis and aging has not been established. Here, we developed a synthetic system to manipulate intracellular ATP independently of endogenous energy production by expressing a plasma membrane-targeted nucleotide transporter,
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Summary
The paper claims that artificially increasing intracellular ATP levels via a synthetic plasma membrane transporter can extend cellular lifespan in yeast. This is relevant because it directly investigates the causal link between mitochondrial energy homeostasis and aging, testing whether ATP availability is a fundamental regulator of longevity rather than just a symptom of decline.
Geroprotective interventions are often assessed by extension of lifespan in ad libitum-fed mice. Increased lifespan could therefore reflect rescue of adverse phenotypes of unhealthy controls. We analysed body weight and survival for 33,780 mice in the Interventions Testing…
Abstract
Geroprotective interventions are often assessed by extension of lifespan in ad libitum-fed mice. Increased lifespan could therefore reflect rescue of adverse phenotypes of unhealthy controls. We analysed body weight and survival for 33,780 mice in the Interventions Testing Program (ITP) to test whether treatment effects varied with body weight. In males, each added standard deviation of attained adult weight made treatment 6% more favourable (HR 0.94), more apparent for interventions that lowered body weight (HR 0.90). Median lifespan increase rose from 6.2% in mice in the lightest quartile to 20.2% in the heaviest pre-dosing weight quartile among those experiments, mainly because control survival declined more steeply with weight than that of the intervention group. The effect of body weight was consistent across 13 of 14 compounds and reflected weight attained during adulthood rather than in early life. Weight-dependence of intervention effects was weak in ITP females, possibly because median survival of controls exceeded that of every sampled non-ITP female control group. Amelioration of weight-associated risk is therefore implicated as a major contributor to lifespan increases relative to heavy, short-lived controls. The geroprotective effects of these interventions may thus be less apparent in metabolically healthier mice or humans.
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Summary
The paper claims that the apparent lifespan extension of geroprotective interventions in ad libitum-fed mice is largely driven by the rescue of adverse phenotypes associated with high body weight rather than true biological aging reversal. This is relevant because it challenges the standard methodology of using ad libitum-fed mice as a baseline for testing anti-aging compounds, suggesting that many reported "lifespan extensions" may be artifacts of correcting metabolic dysfunction in unhealthy controls rather than evidence of genuine geroprotection.
Cell reprogramming, which forcibly alters cell fate, offers a novel therapeutic strategy for various refractory diseases. Unlike previous reviews focused on a single disease context or a single reprogramming modality, this review is organized around therapeutic applications. It…
Abstract
Cell reprogramming, which forcibly alters cell fate, offers a novel therapeutic strategy for various refractory diseases. Unlike previous reviews focused on a single disease context or a single reprogramming modality, this review is organized around therapeutic applications. It summarizes advances in direct reprogramming, partial reprogramming, and cell fusion-induced reprogramming and further compares their mechanisms, challenges in clinical translation, and safety boundaries. In oncology, reprogramming cancer cells into antigen-presenting cells elicits durable antitumor immunity and remodels the tumor microenvironment, whereas converting cancer cells into nonmalignant somatic cells can reduce their malignant phenotype and tumorigenic potential. In neurodegenerative diseases, direct reprogramming has converted fibroblasts or astrocytes into functional dopaminergic and cortical neurons both in vitro and in vivo. In mouse models of progeria and natural aging, partial reprogramming strategies markedly extend lifespan, ameliorate multiorgan pathology, and enhance tissue regenerative capacity. However, the strength and reproducibility of these findings vary across experimental models, and reported therapeutic benefits do not necessarily establish complete, stable, or safe cell-fate conversion. Against this predominantly preclinical background, ER-100 is the first regenerative therapy based on partial epigenetic reprogramming to receive Food and Drug Administration Investigational New Drug approval and enter clinical testing. It therefore provides an important reference point for the transition from animal studies to human trials. Cell fusion-induced reprogramming has context-dependent roles in tumor immunity. Fusion between tumor cells and immune cells may promote malignant progression. In contrast, dendritic cell-tumor cell fusion vaccines and chimeric exosomes can activate antitumor immune responses in preclinical models and early clinical studies. Major barriers to clinical translation include low reprogramming efficiency, an incompletely defined safety window, and the need to select in vivo or ex vivo strategies according to disease context. In addition, insufficient delivery efficiency, poor targeting, and long-term tumorigenic risk remain important constraints on clinical application. Looking ahead, single-cell multiomics and artificial intelligence may help optimize reprogramming factor combinations, while nonviral systems may improve targeted delivery. Integration with tissue engineering may further facilitate clinical translation across oncology, aging, regenerative medicine, autoimmune diseases, and neuropsychiatric disorders.
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Summary
Partial epigenetic reprogramming strategies can extend lifespan and ameliorate multiorgan pathology in mouse models of progeria and natural aging. This review is relevant because it synthesizes preclinical evidence that reprogramming addresses the root causes of aging (epigenetic drift) rather than just symptoms, highlighting the transition of this approach to human clinical trials via ER-100.
Research into vertebrate ageing needs model organisms in which the whole lifespan is experimentally tractable while the underlying biology stays recognisably vertebrate. The African turquoise killifish (Nothobranchius furzeri) meets both requirements more fully than any other…
Abstract
Research into vertebrate ageing needs model organisms in which the whole lifespan is experimentally tractable while the underlying biology stays recognisably vertebrate. The African turquoise killifish (Nothobranchius furzeri) meets both requirements more fully than any other currently available laboratory vertebrate. Adapted to the ephemeral pools of south-eastern Africa, completing its life cycle in a few months, it is the shortest-lived vertebrate that can be bred conveniently in captivity, showing progressive, systemic decline rather than abrupt early death. Over the past decade, a sequenced genome, CRISPR/Cas9 engineering, standardised husbandry and multi-omic atlases have turned it into a systems-level ageing platform. Here, we review how killifish reproduce the molecular hallmarks of ageing, from genomic instability and telomere attrition to epigenetic changes, mitochondrial dysfunction and cellular senescence, while making clear that the depth of that evidence differs markedly between hallmarks. We also examine how immunosenescence and inflammageing could form the axis integrating these cell-intrinsic hallmarks with organ-level disease. We then survey how the killifish is used to model age-related disease of the brain, heart, eye and musculoskeletal system, and to screen genetic, pharmacological and dietary interventions within a single generation. We also address where the current literature conflicts, namely on telomere attrition, the nature of diapause and the direction of epigenetic change. While the killifish does not replace longer-lived models, its contribution to modern research is to compress vertebrate ageing into a timeframe in which mechanism and intervention can be studied together.
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Summary
The African turquoise killifish serves as a tractable vertebrate model that reproduces the molecular hallmarks of aging, enabling the study of mechanisms and interventions within a single generation. This is a solid review of a valuable model organism that facilitates the compression of aging research timelines, though it does not present a novel breakthrough in lifespan extension itself.
Cellular senescence is a state of irreversible cell-cycle arrest that prevents cancer but promotes aging and inflammation. Conflicting molecular profiles of senescence may arise from contamination by neighboring proliferating cells. Here, we developed SenLect (senescence…
Abstract
Cellular senescence is a state of irreversible cell-cycle arrest that prevents cancer but promotes aging and inflammation. Conflicting molecular profiles of senescence may arise from contamination by neighboring proliferating cells. Here, we developed SenLect (senescence selection), a genetically encoded system for purifying senescent cells in culture. SenLect expresses mCherry-2A-PuroR under the senescence-activated miR-146a promoter, providing senescent cells a selective advantage over proliferating cells during puromycin treatment. We validated SenLect in primary and immortal cells undergoing replicative senescence or various modes of stress-induced senescence. Selected cells were enriched for cell-cycle arrest, increased cell size, and lysosomal β-galactosidase activity. Removing proliferating cells revealed proteome rewiring during senescence induced by cyclin-dependent kinase 4/6 inhibition, improving detection of senescence-associated secretory phenotype (SASP) signatures, metabolic shifts, and organelle remodeling. SenLect provides a reliable method for isolating senescent cells for downstream applications.
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Summary
The paper demonstrates that a genetically encoded system (SenLect) can selectively purify senescent cells from mixed populations, revealing previously obscured proteomic and metabolic changes associated with senescence. This is relevant to longevity research because cellular senescence is a fundamental hallmark of aging, and the ability to isolate these cells without contamination from proliferating neighbors is critical for accurately defining the senescence-associated secretory phenotype (SASP) and developing effective senolytic or senomorphic therapies.
Replicative senescence links telomere shortening to irreversible proliferative arrest and is widely recognized as a major tumor-suppressive mechanism. At the organismal level, however, progressive accumulation of senescent cells contributes to tissue dysfunction, chronic…
Abstract
Replicative senescence links telomere shortening to irreversible proliferative arrest and is widely recognized as a major tumor-suppressive mechanism. At the organismal level, however, progressive accumulation of senescent cells contributes to tissue dysfunction, chronic inflammation, and aging. Accumulating evidence suggests that telomere shortening influences telomeric and subtelomeric chromatin organization and transcription through mechanisms that remain incompletely understood. Building upon the telomere position effect model of cellular senescence and the subtelomere-telomere theory of aging, this review proposes a chromatin-sensing telomere theory of aging in which telomere shortening contributes to senescence through epigenetic and transcriptional changes at chromosome ends. Central to this model is TERRA, a long non-coding RNA that regulates telomeric chromatin structure, telomere maintenance, and DNA-damage responses. The lysine methyltransferase MLL/KMT2A is a key regulator of TERRA transcription. MLL associates with telomeric chromatin in a telomere length-dependent manner and promotes TERRA transcription through H3K4 methylation. Shelterin components, particularly TRF2, can repress TERRA transcription in certain experimental contexts, and we propose that telomere shortening progressively remodels the shelterin-dependent telomere-subtelomere chromatin environment, potentially reducing access of MLL and RNA polymerase II to subtelomeric promoters. A biphasic model of TERRA regulation is proposed in which early TERRA upregulation in aging tissues promotes telomere protection, while subsequent critical shortening of TERRA-dominant telomeres contributes to reduced TERRA expression, telomere dysfunction, and senescence. This theory proposes a mechanistic link between telomere shortening, chromatin regulation, and quasi-programmed aging.
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Summary
The paper proposes a chromatin-sensing theory of aging where telomere shortening alters MLL-mediated TERRA transcription, leading to telomere dysfunction and senescence. This is relevant because it attempts to elucidate the fundamental molecular mechanisms linking telomere biology to the aging process, rather than merely treating age-related symptoms.
Norathyriol (NOR), the aglycone of mangiferin, exhibits diverse biological activities, but the mechanisms underlying its effects on aging remain incompletely understood. We investigated the effects of NOR on lifespan, locomotor performance, and antioxidant responses in…
Abstract
Norathyriol (NOR), the aglycone of mangiferin, exhibits diverse biological activities, but the mechanisms underlying its effects on aging remain incompletely understood. We investigated the effects of NOR on lifespan, locomotor performance, and antioxidant responses in Caenorhabditis elegans. Among the concentrations tested (10-50 μM), 20 μM NOR produced the greatest observed improvements in locomotor performance and extended median lifespan by 13.3% without an evident reduction in fecundity. Target prediction highlighted FoxO-related signaling, while molecular docking with the predicted C. elegans DAF-16 Forkhead domain suggested a potential interaction (-6.0 kcal/mol). NOR promoted DAF-16 nuclear translocation, as demonstrated by DAF-16::GFP localization analysis, and daf-16 RNAi abolished the detectable locomotor and lifespan benefits. NOR also increased gst-4::GFP fluorescence and the expression of antioxidant-associated genes, including ctl-1, ctl-2, sod-3, and gst-4. Knockdown of either daf-16 or skn-1 prevented a significant NOR-associated increase in gst-4::GFP fluorescence. Furthermore, daf-16, skn-1, or gst-4 RNAi diminished the observed locomotor and reactive oxygen species (ROS) -related fluorescence responses to NOR. Together, these findings support the involvement of DAF-16- and SKN-1-associated antioxidant responses, including GST-4, in the beneficial effects of NOR on aging-related phenotypes.
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Summary
Norathyriol extends C. elegans lifespan and improves locomotor performance by activating DAF-16 and SKN-1 dependent antioxidant pathways. This is a standard pharmacological screening study in a model organism that identifies a specific compound's mechanism of action within known longevity pathways, representing an incremental addition to the existing literature on dietary restriction mimetics and antioxidant interventions rather than a novel breakthrough in understanding the root causes of aging.
Telomere dysregulation is a central driver of cellular senescence and chronic liver disease. Yet how physiological telomeric attrition, rather than uniform telomere loss, leads to hepatic functional decline remains unclear. We therefore investigate how resolvable telomere…
Abstract
Telomere dysregulation is a central driver of cellular senescence and chronic liver disease. Yet how physiological telomeric attrition, rather than uniform telomere loss, leads to hepatic functional decline remains unclear. We therefore investigate how resolvable telomere dysfunction reshapes liver regeneration.
AI-generated longevity analysis. Check claims against the paper.
Summary
Physiological telomere shortening induces clonal failure in hepatocyte plasticity, thereby reshaping regenerative lineages and driving liver functional decline. This paper is relevant because it investigates the fundamental mechanism of cellular senescence (telomere attrition) and its direct impact on tissue regeneration, which is a core component of the aging process rather than just a downstream symptom.
Biomarkers that correlate with age are essential tools for understanding aging and lifespan variation. DNA methylation (DNAm) changes predictably with age in parts of the genome. In humans, epigenetically "old" individuals relative to their chronological age also have a reduced…
Abstract
Biomarkers that correlate with age are essential tools for understanding aging and lifespan variation. DNA methylation (DNAm) changes predictably with age in parts of the genome. In humans, epigenetically "old" individuals relative to their chronological age also have a reduced life expectancy but whether the link between epigenetic age and lifespan is a general feature remains an open question. We explored age-related changes in DNAm in the zebra finch (Taeniopygia castanotis), a key avian model species, using 100 longitudinal wholegenome methylomes from 50 captive adults monitored until their natural death. We found genome-wide hypomethylation with age, with DNAm decreasing faster in individuals with shorter lifespans and identified 29 CpG sites where DNAm changed significantly with age. We developed an epigenetic aging clock based on 119 CpG sites, that predicted chronological age with high accuracy (median absolute deviation = 0.68 years, 8.2% of maximum lifespan in our dataset). Females raised in large broods, which have shorter lifespans, showed increased epigenetic age acceleration, consistent with faster biological aging. However, epigenetic age acceleration did not predict lifespan or remaining lifespan. In contrast, the within-individual rate of change in epigenetic age significantly predicted lifespan: faster epigenetic aging was associated with a shorter lifespan. Moreover, a "doom" clock, trained to predict post-sampling lifespan, successfully predicted remaining lifespan. Our findings provide the first evidence that DNAm provides a window into biological aging in birds, showing how early-life environments shape the aging trajectory via the epigenome and underscore the value of longitudinal data in aging studies.
AI-generated longevity analysis. Check claims against the paper.
Summary
The paper claims that the rate of change in DNA methylation (epigenetic aging) predicts natural lifespan in zebra finches, providing the first evidence of a DNAm-based biological aging marker in birds. This is relevant because it extends the understanding of epigenetic aging mechanisms beyond mammals to a key avian model, offering insights into the generalizability of aging clocks and the impact of early-life environment on biological aging trajectories, though it is a descriptive study rather than an intervention.
Most vertebrates and insects undergo senescence: as they age, their rate of mortality increases while reproduction declines. We present data from a 34-y study on 3,285 colonies of known age in the western harvester ant,
Abstract
Most vertebrates and insects undergo senescence: as they age, their rate of mortality increases while reproduction declines. We present data from a 34-y study on 3,285 colonies of known age in the western harvester ant,
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Summary
The paper demonstrates that the replacement of the queen ant's body (soma) by her workers effectively resets her biological age, allowing her to live indefinitely and reproduce without senescence. This is a landmark finding in evolutionary biology and aging research because it provides a natural, empirical example of "negative senescence" and biological rejuvenation, directly challenging the universal assumption that aging is an inevitable, irreversible process in complex multicellular organisms.
Ribophagy plays a critical role in maintaining ribosome quality, yet how ribosomes are marked for autophagic recognition remains poorly understood. Here, we identify the methyltransferase Dot1/DOT1L as a conserved regulator of ribophagy that generates an "eat-me" signal through…
Abstract
Ribophagy plays a critical role in maintaining ribosome quality, yet how ribosomes are marked for autophagic recognition remains poorly understood. Here, we identify the methyltransferase Dot1/DOT1L as a conserved regulator of ribophagy that generates an "eat-me" signal through methylation of Rpl12, thereby regulating ribosome quality. Under nutrient deprivation, Dot1 methylates Rpl12 at K41 and K48 in Saccharomyces cerevisiae, enhancing its interaction with Atg11 and initiating ribophagy through the TOR-Atg1-Rpl12 signaling axis. In mammals, starvation induces partial cytoplasmic translocation of DOT1L, where it colocalizes with and methylates RPL12. In Drosophila, ribosomes incorporating Gpp (the Dot1 homolog)-methylated RpL12 show strong colocalization with the autophagosome marker Atg8a. Flies carrying methylation-deficient RpL12 mutants exhibit impaired ribophagy, developmental abnormalities, accelerated aging, muscle degeneration, and reduced stress resistance. Collectively, these findings reveal that Dot1-mediated Rpl12 methylation generates a conserved "eat-me" signal that links nutrient availability to ribosome quality control and lifespan regulation.
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Summary
Dot1-mediated methylation of Rpl12 acts as a conserved "eat-me" signal that initiates ribophagy to maintain ribosome quality and regulate lifespan. This paper is relevant because it identifies a specific molecular mechanism linking nutrient sensing to ribosome quality control, a fundamental process in cellular homeostasis, and demonstrates that defects in this pathway lead to accelerated aging and reduced stress resistance in model organisms, thereby addressing a root cause of aging rather than a symptom.
Aging is a major risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which aging disrupts hepatocyte transcriptional networks to drive metabolic dysfunction remain poorly understood. Hepatocyte nuclear factor 4 alpha…
Abstract
Aging is a major risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which aging disrupts hepatocyte transcriptional networks to drive metabolic dysfunction remain poorly understood. Hepatocyte nuclear factor 4 alpha (HNF4) is a master regulator of hepatocyte identity and metabolic homeostasis, but its role in liver aging has not been defined. Here, we perform a comprehensive multi-omic profiling of young and aged mouse livers combined with targeted HNF4 functional studies to define how aging remodels HNF4-dependent gene regulation and whether HNF4 can be a target to reverse age-associated liver dysfunction. Despite preserved HNF4 expression with age, aging was associated with reduced HNF4 chromatin occupancy and transcriptional activity, accompanied by epigenetic remodeling, including changes in histone acetylation, chromatin accessibility, and DNA methylation. Integration and comparison of HNF4 CUT&RUN with hepatocyte-specific Hnf4a deletion in young and aged livers identified high-confidence overlapping but distinct young- and old- specific HNF4 target gene networks. In young hepatocytes, HNF4 coordinates two complementary transcriptional programs: activation of genes governing hepatocyte identity, lipid metabolism, and metabolic function, while simultaneously inhibiting alternative developmental, proliferative, and inflammatory programs. Spatial transcriptomic analyses further revealed zone-specific specialization of HNF4-dependent gene programs. Aging selectively disrupted these regulatory networks, resulting in compromised liver identity and metabolic gene programs, de-repression of inflammatory pathways and alternative cellular identity programs and disrupted hepatocyte zonation, consistent with age-dependent lipidomic and metabolic changes, hepatic fat accumulation, and immune infiltration. Hepatocyte-specific Hnf4a deletion in young mice recapitulated key features of liver aging, including impaired hepatocyte identity, metabolic dysfunction, steatosis, inflammatory activation and altered hepatic immune-cell composition, while deletion in aged mice further exacerbated steatosis, inflammation, and hepatic dysfunction. Conversely, hepatocyte-specific HNF4 restoration in aged mice significantly reduced hepatic steatosis and lipid accumulation, restored fatty acid metabolic programs, and partially reversed age-associated transcriptional changes. However, inflammatory and interferon-associated programs were not uniformly reversed, revealing differential responsiveness of metabolic and inflammatory pathways to HNF4 restoration. Together, these findings identify age-associated impairment of HNF4 activity as a functional contributor to liver aging, linking dysregulation of hepatocyte identity, metabolic homeostasis, and inflammatory control to age-associated hepatic dysfunction. Importantly, the selective reversibility of metabolic defects following HNF4 restoration establishes HNF4 as a promising strategy for preserving hepatocyte homeostasis and reversing age-associated hepatic metabolic dysfunction.
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Summary
The paper claims that age-associated repression of HNF4α activity is a causal driver of liver metabolic dysfunction and that restoring HNF4 activity can reverse these age-related defects. This is relevant to longevity research because it identifies a specific molecular mechanism (transcriptional dysregulation of a master regulator) that contributes to the physiological decline of a major organ with age, and demonstrates that intervening on this pathway can restore function, thereby addressing a root cause of age-related organ failure rather than just treating symptoms.
Cellular senescence, a hallmark of aging, is accompanied by a striking expansion of the cell's lysosomal compartment, yet the pathway leading to increased lysosomal content remains unresolved. Here, we demonstrate that the master lysosomal transcriptional regulator TFEB is…
Abstract
Cellular senescence, a hallmark of aging, is accompanied by a striking expansion of the cell's lysosomal compartment, yet the pathway leading to increased lysosomal content remains unresolved. Here, we demonstrate that the master lysosomal transcriptional regulator TFEB is activated during senescence through a pathway that involves conjugation of ATG8 onto single membranes (CASM). Using various senescence inducers, we show that senescence induction triggers robust TFEB nuclear translocation and upregulation of TFEB target genes. In contrast, inhibition of the core CASM machinery by CRISPR-mediated deletion of either ATG16L1, ATG12, or ATG5 markedly reduced senescence-induced TFEB nuclear translocation. In ATG16L1-KO cells, reconstitution with WT ATG16L1 but not the CASM-defective ATG16L1F467A mutant restored both ATG8 lipidation on the lysosomal surface and TFEB activation. Moreover, expression of the Salmonella effector protein SopF, a previously described specific CASM inhibitor, similarly blocked senescence-induced TFEB translocation. Functionally, upon stress, CASM-deficient cells exhibited a pronounced shift away from senescence and toward a cell death fate, a phenotype reversed by expressing a constitutively active form of TFEB. Together, these findings identify CASM-dependent TFEB activation as an essential mechanism enabling senescence-associated lysosomal expansion and suggest that lysosomal capacity modulates cell fate decisions in the aftermath of acute stress.
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Summary
CASM-dependent TFEB activation is an essential mechanism enabling senescence-associated lysosomal expansion and modulates cell fate decisions. This paper identifies a specific molecular pathway (CASM) that drives a key cellular hallmark of aging (lysosomal expansion in senescent cells), providing a mechanistic insight into how cells manage stress and decide between senescence and death, which is fundamental to understanding the biology of aging.
Protein aggregation and altered protein solubility indicate proteostatic decline, yet their roles in skeletal muscle aging remain poorly understood. We combined light and electron microscopy, quantitative proteomics, and stable-isotope labeling of skeletal muscle to investigate…
Abstract
Protein aggregation and altered protein solubility indicate proteostatic decline, yet their roles in skeletal muscle aging remain poorly understood. We combined light and electron microscopy, quantitative proteomics, and stable-isotope labeling of skeletal muscle to investigate age-associated changes in protein insolubility, and their responses to exercise and rapamycin. Aged muscle accumulated distinct aggresome and amyloid-positive aggregates despite unchanged bulk insoluble protein content. Instead, aging altered the abundance and soluble-insoluble shifts of lower-abundance proteins across cellular components, particularly mitochondrial, nuclear and extracellular matrix proteins, with greater changes in females. These changes were not broadly explained by intrinsic protein aggregation propensity. Exercise and rapamycin partially reversed age-associated changes in abundance and partitioning without increasing protein synthesis. Together, these findings highlight sex- and cellular component-dependent changes in protein insolubility as important, modifiable aspects of skeletal muscle proteostasis, and indicate that proteostatic maintenance may be a more important target than anabolism for muscle aging.
AI-generated longevity analysis. Check claims against the paper.
Summary
The paper claims that aging-driven skeletal muscle protein insolubility is compartment-specific and modifiable by proteostasis-directed treatments like exercise and rapamycin. This is relevant because it identifies a specific mechanistic driver of muscle aging (proteostatic decline) and demonstrates that interventions targeting protein quality control, rather than just muscle mass, can mitigate age-related physiological changes, offering a potential strategy for extending healthspan.
Non-human primates are an ideal model for interrogating the genetic basis of human lifespan and resilience due to their long lifespan compared to other model organisms, development of similar age-related chronic conditions, and genetic similarity. However, like humans…
Abstract
Non-human primates are an ideal model for interrogating the genetic basis of human lifespan and resilience due to their long lifespan compared to other model organisms, development of similar age-related chronic conditions, and genetic similarity. However, like humans, statistical methods for modeling survival suffer from the challenges of dealing with non-proportionality of hazards, large numbers of living individuals that must be censored, and loss-to-follow-up over studies that may last a decade or more. Here we overcome these challenges through the use of pseudo-observations of Restricted Mean Survival Time as a measure of resilience to the acute challenge of radiation exposure and chronic challenges of aging and a Western-style diet in rhesus macaques (Macaca mulatta) from the Wake Forest Non-Human Primate Radiation Late Effects Cohort. Our whole-exome analysis used Genome-wide Efficient Mixed Model Association (GEMMA) to identify variants associated with longevity, and a subsequent Gene Set Enrichment Analysis (GSEA) highlighted the cadherin and integrin signaling pathways as central to this resilience. As dysregulation of cell adhesion and extracellular matrix signaling is central to the development of fibrosis, we tested the functional relevance of these signals using a targeted Combined Annotation Dependent Depletion (CADD) score-weighted Sequence Kernel Association Test-Optimal (SKAT-O) analysis of GSEA leading-edge genes from both the cadherin and integrin pathways. This linked variant burden in PCDHGA5, PCDHGA3, PCDHGB2, PCDHA11, and PSENEN to the severity of myocardial fibrosis, and in IBSP, PDGFD, and LAMC2 to the severity of pulmonary fibrosis observed at necropsy. Critically, we note that the genetic variants are not caused by the radiation but rather create an underlying risk for disease that is then exacerbated by the acute and persistent stressors challenging these animals' intrinsic resilience. The success of this method in identifying biologically relevant genetic variants underlying survival in animals undergoing a strong challenge to their resilience highlights not only the role of genes predisposing animals to fibrosis in lifespan, but the overall utility of pseudo-observations in overcoming the limitations of survival analyses in humans and other long-lived species.
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Summary
The paper claims that using pseudo-observations of Restricted Mean Survival Time in rhesus macaques identifies specific genetic variants in cadherin and integrin pathways that predispose individuals to fibrosis and reduced resilience to aging and radiation stress. This is relevant because it identifies specific genetic mechanisms underlying intrinsic resilience and lifespan in a non-human primate model, offering potential targets for understanding the genetic basis of healthy aging, though the impact is limited by the specific context of radiation exposure and the use of a single cohort.
Cellular senescence acts as a core driver of chronic diseases and tissue degeneration. Conventional small-molecule senolytics face critical limitations including poor target specificity and off-target toxicity when eliminating heterogeneous senescent cell populations. This…
Abstract
Cellular senescence acts as a core driver of chronic diseases and tissue degeneration. Conventional small-molecule senolytics face critical limitations including poor target specificity and off-target toxicity when eliminating heterogeneous senescent cell populations. This review systematically discusses senescence-targeted engineered chimeric antigen receptor (CAR)-T immunotherapy, which achieves targeted clearance of pathological senescent cells by recognising specific surface markers. It summarises target-antigen evaluation frameworks, analyzes aged immunosuppressive microenvironment barriers and corresponding engineering strategies, and outlines composite efficacy assessment systems and tiered biomarker-monitoring workflows. Key translational bottlenecks such as imperfect antigen specificity and immune escape are also addressed. Preclinical studies verify organ function restoration and healthspan extension, while clinical evidence remains limited. Future integration of CAR-T technology with smart nanocarriers, synthetic biology and artificial intelligence will promote its clinical translation for senescence-associated disorders.
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Summary
This review evaluates the potential of engineered CAR-T cells to target and eliminate senescent cells, a core driver of aging, as an alternative to small-molecule senolytics. The paper is relevant because it addresses the root cause of aging (cellular senescence) by proposing a novel immunotherapeutic mechanism to clear senescent cells, although it is a review of preclinical advances rather than a primary breakthrough study.
The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) is an established risk factor for cardiovascular and renal diseases, yet its role in driving kidney aging remains poorly defined. Circular RNAs (circRNAs) have emerged as critical regulators of cellular…
Abstract
The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) is an established risk factor for cardiovascular and renal diseases, yet its role in driving kidney aging remains poorly defined. Circular RNAs (circRNAs) have emerged as critical regulators of cellular senescence, but their integration with systemic metabolic cues in aging processes is largely unknown. Here, we identify a novel signaling axis through which TMAO accelerates renal senescence by dysregulating a specific circRNA pathway. We demonstrate that TMAO treatment induces a senescent phenotype in renal tubular epithelial cells and promotes kidney aging in mice, as evidenced by increased senescence-associated β-galactosidase activity and elevated expression of p53, p21, and p16. Mechanistically, TMAO significantly upregulates the expression of circVmn2r1, a circRNA we previously identified as a key promoter of kidney aging. This upregulation triggers the activation of the the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased caspase-1 cleavage and elevated levels of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18. Crucially, genetic knockdown of circVmn2r1
AI-generated longevity analysis. Check claims against the paper.
Summary
TMAO accelerates renal tubular epithelial cell senescence by upregulating circVmn2r1, which activates the NLRP3 inflammasome. This paper is relevant because it identifies a specific molecular mechanism (TMAO-circVmn2r1-NLRP3) linking a systemic metabolic factor to the fundamental process of cellular senescence in the kidney, offering a potential target for intervening in age-related renal decline rather than just treating symptoms.
How diet shapes aging and age-related diseases marked by senescent cell accumulation remains unclear. Here we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS ameliorates phenotypes of aging and diverse age-related disorders and extends…
Abstract
How diet shapes aging and age-related diseases marked by senescent cell accumulation remains unclear. Here we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS ameliorates phenotypes of aging and diverse age-related disorders and extends lifespan in male mice. Integrated functional omics analyses show that senescent cells exhibit globally reduced proteome cysteine reactivity but increased expression and apparent cysteine reactivity of proteins essential for endoplasmic reticulum proteostasis. This redox-proteostasis state is linked to glutathione disulfide (GSSG) accumulation and can be recapitulated by GSSG delivery in nonsenescent cells. Mechanistically, VS inactivates reactive cysteines and promotes disulfide bond formation in senescent cells, leading to protein misfolding, aggregation and ultimately cell death. Glutathione reductase downregulation promotes GSSG accumulation, distinguishing senescent from nonsenescent cells and conferring selective susceptibility to VS. Our findings reveal an exploitable redox-proteostasis vulnerability of senescent cells with therapeutic potential to ameliorate aging.
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Summary
Vanadyl sulfate acts as a senolytic agent by exploiting a specific redox-proteostasis vulnerability in senescent cells, characterized by glutathione disulfide accumulation and altered cysteine reactivity, to induce cell death and extend lifespan in mice. This paper is relevant because it identifies a novel mechanism for senolysis and demonstrates that a dietary supplement can target the accumulation of senescent cells, a key driver of aging, thereby directly addressing a root cause of age-related decline rather than just treating symptoms.
Nicotinamide Adenine Dinucleotide (NAD) is a critical cellular coenzyme whose decline associates with various chronic and inflammatory diseases. Improved NAD restoration may reduce disease risks and extend healthy lifespan. We report here that certain commensal bacteria…
Abstract
Nicotinamide Adenine Dinucleotide (NAD) is a critical cellular coenzyme whose decline associates with various chronic and inflammatory diseases. Improved NAD restoration may reduce disease risks and extend healthy lifespan. We report here that certain commensal bacteria including specific probiotic species produce (amide-)N-methylnicotinamide (N-MNA), which is a structural isomer of methylnicotinamide, a nicotinamide degradative metabolite. Patients with gut dysbiosis and inflammation show reduced stool N-MNA. Stable isotope tracing revealed that N-MNA can be rapidly taken up and incorporated into NAD redox reactions by intestinal epithelial cells (IECs) and non-IECs of fruit fly, mouse, and human. Genetic and pharmacological analyses suggest that N-MNA is converted to NAD
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Summary
The paper claims that commensal bacteria produce (amide-)N-methylnicotinamide (N-MNA), a metabolite that is rapidly taken up by intestinal cells and converted into NAD, thereby linking gut microbiome composition directly to host NAD+ homeostasis. This is relevant to longevity because NAD+ decline is a fundamental hallmark of aging, and identifying a microbial source for a novel NAD precursor suggests a potential mechanism by which the microbiome influences systemic metabolic aging and offers a new avenue for NAD+ restoration therapies.
Rapamycin, an mTOR inhibitor, continues to be investigated for hypothesized physiological, disease prevention, and longevity benefits, but few studies have been conducted in humans. Using US national organ transplant registry data, one of the largest real-world datasets…
Abstract
Rapamycin, an mTOR inhibitor, continues to be investigated for hypothesized physiological, disease prevention, and longevity benefits, but few studies have been conducted in humans. Using US national organ transplant registry data, one of the largest real-world datasets examining chronic rapamycin exposure in humans, we compared the Kaplan-Meier survival age distribution of 4885 kidney transplant recipients prescribed rapamycin compared to 6589 recipients not prescribed rapamycin. Recipients were followed a median of 11 years and 6443 died during the study period. Propensity score weighting was used to adjust for exposure group differences in age, BMI, diabetes, and 15 other factors. After adjusting for demographic and clinical differences between groups, the median survival age of 64.6 years in the rapamycin group and 64.3 years in the non-rapamycin group were statistically similar (95% confidence interval for median survival age difference -1.6, 2.0 years). In this large cohort of kidney transplant recipients who were alive with a functioning graft at 1 year post-transplant, we did not observe a meaningful improvement in long-term survival with mTOR inhibition.
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Summary
The paper claims that chronic rapamycin exposure does not provide a meaningful improvement in long-term survival in kidney transplant recipients. This is relevant because rapamycin is a leading candidate for human lifespan extension, and this large-scale real-world study provides critical negative evidence regarding its efficacy in a specific human population, directly impacting the field's understanding of mTOR inhibition's potential for longevity.
Biological aging is complex and resists any single mechanistic narrative. This article develops a conceptual framework for aging biology through a series of brief statements on central topics in the field, with the goal of discussing aging simply, directly and accessibly. The…
Abstract
Biological aging is complex and resists any single mechanistic narrative. This article develops a conceptual framework for aging biology through a series of brief statements on central topics in the field, with the goal of discussing aging simply, directly and accessibly. The organizing principle is that aging is a default outcome of living: because biological processes are inherently imperfect, deleterious changes (the deleteriome) accumulate over time and progressively erode functional reserve. The deleteriome provides a unifying framework for molecular damage, regulatory drift, maladaptive remodeling, and system-level failure, without reducing aging to individual genes, pathways, compartments, hallmarks, or pathologies. Evolution does not program aging; it shapes maintenance and renewal systems that oppose this trajectory with limited fidelity and unavoidable trade-offs. Aging begins during development, following an early embryonic phase of rejuvenation. Modern biomarkers make biological age imperfectly but increasingly measurable. Biological age is heterogeneous across cells, organs, and systems, modifiable by interventions and environment, and in some contexts partially reversible or resettable, although aging itself is irreversible. This model links first principles of aging to measurement, intervention, and longer-term strategies, with the goal of clarifying how substantial longevity gains might be achieved, both within and beyond existing species-level constraints.
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Summary
The paper proposes that aging is a default outcome of living driven by the accumulation of a "deleteriome" of imperfect biological processes, rather than a programmed event. This is a conceptual review that synthesizes existing knowledge into a unified framework, offering a clear perspective on the inevitability of aging and the limits of intervention, but it does not present new experimental data or a novel mechanistic discovery.