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.
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.
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.
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.
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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.
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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.
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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
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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.
Gut microbiota dysbiosis caused by a high-fat diet disrupts hematopoietic stem cell (HSC) homeostasis; however, the underlying mechanisms remain unclear. Here, we identify gut microbial secondary bile acid deoxycholic acid (DCA) as a key mediator of HSC dysfunction in mice…
Abstract
Gut microbiota dysbiosis caused by a high-fat diet disrupts hematopoietic stem cell (HSC) homeostasis; however, the underlying mechanisms remain unclear. Here, we identify gut microbial secondary bile acid deoxycholic acid (DCA) as a key mediator of HSC dysfunction in mice. Plasma DCA levels were elevated during aging, consistent with previously reported increases in high-fat diet-fed mice. Chronic DCA administration upregulated Spred1 in mouse HSCs, as also observed during aging, contributing to HSC loss. DCA treatment in Spred1-deficient mice triggered myeloproliferative neoplasm-like disease, highlighting Spred1's role in mediating a trade-off between HSC aging and tumor suppression. Unexpectedly, DCA-counteracting ursodeoxycholic acid also promoted age-associated expansion of myeloid-biased mouse HSCs. In contrast, a high-fiber diet lowered plasma DCA levels and mitigated aging-associated HSC decline. Our findings reveal that systemic gut microbial metabolites, particularly secondary bile acids, critically affect HSC fate, and suggest that dietary interventions targeting the gut microbiota can regulate hematopoietic homeostasis.
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Summary
The paper claims that gut microbial secondary bile acid deoxycholic acid (DCA) disrupts hematopoietic stem cell homeostasis by upregulating Spred1, linking dietary interventions to the mitigation of age-associated HSC decline. This is relevant to longevity because it identifies a specific, modifiable systemic mechanism (dietary fiber affecting gut metabolites) that directly influences a fundamental aspect of biological aging (stem cell exhaustion and immune aging), rather than merely treating a downstream symptom.
Hematopoietic aging is marked by declining regenerative capacity and a shift from lymphoid to myeloid output. Previous studies have focused primarily on hematopoietic stem cells (HSCs), yet whether aging uniformly remodels the hematopoietic stem and progenitor cell (HSPC)…
Abstract
Hematopoietic aging is marked by declining regenerative capacity and a shift from lymphoid to myeloid output. Previous studies have focused primarily on hematopoietic stem cells (HSCs), yet whether aging uniformly remodels the hematopoietic stem and progenitor cell (HSPC) compartment, or selectively affects distinct populations, remains largely unknown. To address this, we profile HSCs and multipotent progenitors MPP1-6 from young and aged mice across transcriptomic, epigenomic, metabolomic and lipidomic layers, together with single-cell division and in vivo serial transplantation assays. We identify young MPP6 (negative for CD150, CD34, CD48 and CD135) as an HSC-like, lymphoid-biased population with long-term reconstitution capacity, positioned within the top-tier of the differentiation hierarchy and marked by low global chromatin accessibility and metabolic activity. Upon aging, MPP6 preserved long-term lymphoid reconstitution, underwent limited transcriptional and regulatory remodeling, and did not accumulate polyunsaturated phospholipids or show mitochondrial oxidation. By contrast, most HSPCs, and particularly HSCs, underwent pronounced age-associated changes, including myeloid-biased expansion, metabolic rewiring, extensive distal regulatory alteration and accumulation of long-chain polyunsaturated phospholipids linked to increased oxidative stress. Pseudotime analysis further resolved the aged MPP6 compartment into two subsets, including a dormant, lymphoid-biased Dlk1-expressing population characterized by reduced mitochondrial activity, which was distinctly affected by inflammatory challenge in vivo. Together, these findings establish MPP6 as a comparatively resilient population within the aged HSPC compartment and suggest that it may represent a potential target for restoring hematopoietic balance.
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Summary
The paper claims that the MPP6 multipotent progenitor population is uniquely resilient to age-associated remodeling compared to HSCs, preserving lymphoid reconstitution capacity. This is relevant to longevity research because it identifies a specific cellular compartment that retains regenerative potential in aged hematopoiesis, offering a mechanistic insight into why aging is not uniform across stem cell lineages and suggesting a potential target for restoring hematopoietic balance, though it remains a descriptive study in mice without direct interventions to extend lifespan.
The Mexican cavefish, Astyanax mexicanus, is a powerful evolutionary model for investigating how adaptation to extreme environments reshapes vertebrate physiology. Multiple cave populations have independently evolved under subterranean conditions, acquiring traits including…
Abstract
The Mexican cavefish, Astyanax mexicanus, is a powerful evolutionary model for investigating how adaptation to extreme environments reshapes vertebrate physiology. Multiple cave populations have independently evolved under subterranean conditions, acquiring traits including insulin resistance, persistent hyperglycaemia, increased adiposity, altered sleep patterns, hypoxia tolerance and extensive metabolic reprogramming. Despite these differences, cavefish exhibit lifespans comparable to those of surface fish, while selected traits, including fertility and locomotor performance, appear to be better preserved with age. These observations challenge the assumption that persistent metabolic dysfunction necessarily entails accelerated functional decline and raise the possibility that cavefish have evolved mechanisms of ageing resilience. This narrative review examines evidence linking cave adaptation to biological processes relevant to ageing, focusing on nutrient sensing, lipid metabolism, mitochondrial function, redox homeostasis and immune regulation. Rather than eliminating metabolic stress, cave-associated adaptations may buffer some of its downstream consequences, preserving selected physiological functions. Evidence is evaluated within the framework of the hallmarks of ageing, considering genomic instability, telomere dynamics, deregulated nutrient sensing, mitochondrial dysfunction and chronic inflammation, while identifying major knowledge gaps regarding epigenetic alterations, loss of proteostasis, macroautophagy, cellular senescence, stem-cell exhaustion, altered intercellular communication and dysbiosis. The available evidence supports A. mexicanus as a comparative model for investigating how chronic environmental and metabolic stress can be uncoupled from selected aspects of functional decline. Distinguishing delayed ageing from enhanced tolerance or compensation in response to accumulated damage will be essential to establish the extent and mechanisms of ageing resilience in this species.
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Summary
The paper proposes that cavefish have evolved mechanisms of ageing resilience that buffer the downstream consequences of chronic metabolic stress, thereby preserving selected physiological functions despite persistent metabolic dysfunction. This is a narrative review that synthesizes existing evidence on a comparative model organism to explore the uncoupling of metabolic stress from functional decline, offering a conceptual framework for understanding ageing resilience rather than presenting new experimental data or a direct intervention strategy.