Teresa R Kee, Brianna M Masters, Khoi D Tran ...
· Mitochondria
· Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
· pubmed
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson's disease (PD)-linked CHCHD2
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson's disease (PD)-linked CHCHD2
Longevity Relevance Analysis
(4)
CHCHD2 mutations cause age-associated proteostatic collapse by disrupting the mitochondria-lysosome axis, and maintaining this homeostasis mitigates the resulting cellular dysfunction. This paper is relevant because it identifies a specific molecular mechanism (the mitochondria-lysosome axis) underlying proteostatic failure, a core hallmark of aging, and links it to a known genetic risk factor for neurodegeneration, offering a potential target for interventions aimed at preserving cellular health during aging.
Yongjian He, Julia Hanna Haddad Guez, Xu-Wen Wang ...
· q-bio.MN
· Not available
· arxiv
A central hypothesis in aging biology proposes that the gradual accumulation of stochastic molecular damage drives transcriptional deregulation (TD), ultimately leading to functional decline. However, existing single-cell analyses largely rely on static expression measurements an...
A central hypothesis in aging biology proposes that the gradual accumulation of stochastic molecular damage drives transcriptional deregulation (TD), ultimately leading to functional decline. However, existing single-cell analyses largely rely on static expression measurements and provide limited resolution of how regulatory responses change at the level of individual cells. Here, we leverage DKO, a deep learning framework that predicts cell-specific virtual gene perturbation effects from unperturbed transcriptomes, capturing cell-to-cell differences in regulatory context without requiring a reconstructed gene regulatory network or matched perturbation data. Applying DKO to single-cell transcriptomic datasets from humans, mice, Drosophila, and C. elegans revealed that the transcriptional consequences of perturbing the same gene became increasingly heterogeneous across cells with age, indicating that gene regulatory responses become less consistent and more dependent on cellular context. Furthermore, we find that cells with higher somatic mutation burdens have greater knockout-response variability, linking accumulated molecular damage to regulatory inconsistency. Within the same cellular populations, higher impact variability was also associated with higher senescence scores, linking transcriptional dysregulation to senescence-associated states. Our findings identify a progressive loss of regulatory robustness at both the gene and cell levels as a conserved feature of aging, linking stochastic molecular damage to increasing heterogeneity in cellular regulatory responses.
Longevity Relevance Analysis
(4)
The paper claims that aging is characterized by a progressive loss of regulatory robustness, where the transcriptional consequences of gene perturbations become increasingly heterogeneous across cells due to accumulated stochastic molecular damage. This is relevant to longevity research as it provides a mechanistic link between the accumulation of stochastic damage (a root cause of aging) and the resulting functional decline via transcriptional deregulation, offering a new perspective on how cellular context influences aging trajectories.
Iqbal, S., Gladyshev, V. N.
· cell biology
· Brigham and Women's Hospital, Harvard Medical School
· biorxiv
Aging and regeneration are fundamental biological processes, but the relationship between them is poorly understood. During intestinal regeneration, adult epithelial cells reactivate developmental programs that support repair. To investigate if this plasticity alters tissue biolo...
Aging and regeneration are fundamental biological processes, but the relationship between them is poorly understood. During intestinal regeneration, adult epithelial cells reactivate developmental programs that support repair. To investigate if this plasticity alters tissue biological age, we developed and validated intestinal tissue and epithelium-specific transcriptomic aging clocks. Across various regeneration models, epithelial states were predicted by these clocks to be younger than controls. Their expression changes were also negatively associated with intestinal aging signatures. The resulting younger state was characterized by YAP-associated regeneration and reduced mature enterocyte identity. In a separate irradiation model, the predicted epithelial age first increased, then fell at the peak of regeneration and later increased again during recovery. The pace of this response differed with host age. In a chemotherapy-induced injury model, epithelium in young animals also entered this younger state earlier and then returned to its preinjury state during recovery. Old epithelium responded later, but also reversibly transitioned through a rejuvenated state. Further spatial transcriptomic analyses linked lower epithelial age with regeneration in selected injured and tumor-associated regions. In addition, liver regeneration after partial hepatectomy in old animals also led to a decreased transcriptomic age, accompanied by pathway changes negatively associated with aging signatures. Overall, these findings suggest that mammalian regeneration is associated with a transient reduction in biological age, whose timing and persistence depend on tissue, host age and the course of repair.
Longevity Relevance Analysis
(4)
Mammalian tissue regeneration is associated with a transient reduction in transcriptomic biological age, with the timing and magnitude of this rejuvenation depending on host age and tissue type. This is relevant because it provides mechanistic evidence that regenerative processes can temporarily reverse molecular aging signatures, offering a potential biological basis for understanding how tissue repair might be leveraged to extend functional lifespan or mitigate age-related decline.
Mengnan Li, Zheming Chen, Lu Wang ...
· Exploration (Beijing, China)
· State Key Laboratory For Innovation and Transformation of Luobing Theory Shijiazhuang China.
· pubmed
Chronic stress potentially accelerates aging and increases age-related disease risk. However, the underlying mechanisms and organ specificity remain unclear. Utilizing a 12-month unpredictable chronic mild stress (UCMS) mouse model, we revealed chronic stress significantly exacer...
Chronic stress potentially accelerates aging and increases age-related disease risk. However, the underlying mechanisms and organ specificity remain unclear. Utilizing a 12-month unpredictable chronic mild stress (UCMS) mouse model, we revealed chronic stress significantly exacerbates systemic inflammation, causing widespread tissue damage and lifespan shortening. Integrated single-cell RNA sequencing analysis of multiple tissues suggests a common feature of lymphocyte reduction and myeloid cell expansion. The lungs and kidneys exhibited pronounced stress responses, including epigenetic dysregulation and mitochondrial dysfunction. Both β-nicotinamide mononucleotide (NMN) and compound medicine Bazi Bushen (BZBS) effectively alleviate the UCMS-induced aging phenotypes. BZBS restores immune system homeostasis and reduces stress/inflammation levels in various tissues. Bioactive compounds from BZBS constituents
Longevity Relevance Analysis
(3)
Bazi Bushen Formula reverses chronic stress-induced inflammaging and extends lifespan by activating the AMPK-Sirtuins axis and resetting myeloid cells. The paper is relevant because it investigates the mechanistic pathways (AMPK/Sirtuins) underlying stress-accelerated aging and demonstrates that a specific intervention can reverse these aging phenotypes and extend lifespan in a chronic stress model, addressing the root causes of accelerated aging rather than just treating symptoms.
Song, X., Cai, X., Hegarty, S. ...
· neuroscience
· Harvard Medical School
· biorxiv
Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerati...
Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.
Longevity Relevance Analysis
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The paper claims that the onset of breathing at birth triggers CO2 exhalation, which activates SNRK to suppress mTOR signaling, thereby permanently switching off regenerative capacity in mammalian tissues. This is highly relevant to longevity research because it identifies a fundamental, conserved physiological mechanism that limits tissue repair and regeneration in adulthood, suggesting that modulating CO2 levels or the SNRK/mTOR pathway could restore regenerative potential and mitigate age-related tissue degeneration.
Hidenori Tani
· Ageing research reviews
· Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano, Totsuka, Yokohama 245-0066, Kanagawa, Japan. Electronic address: [email protected].
· pubmed
Transcriptomic surveys of aging tissues routinely report hundreds to thousands of differentially expressed long non-coding RNAs (lncRNAs), and the field has no agreed way of separating causal drivers from passengers that merely track the aging phenotype. I translate Sir Austin Br...
Transcriptomic surveys of aging tissues routinely report hundreds to thousands of differentially expressed long non-coding RNAs (lncRNAs), and the field has no agreed way of separating causal drivers from passengers that merely track the aging phenotype. I translate Sir Austin Bradford Hill's nine criteria for causal inference, formulated in 1965, into operational tests for aging-associated lncRNAs. Each criterion is recorded as 0, 1 or 2, and the per-criterion profile is the result: no sum or band decides a category. Hill offered viewpoints, not independent quantities to be added; here half of the cited studies support two or more criteria, so a total counts some evidence twice. Two axes are reported separately - molecular causal evidence, and organism-level validation (criterion 8), recorded as supportive, not evaluated, or in vivo at a non-aging endpoint - so that an animal experiment on development, reproduction, cancer or injury is not read as a negative test of aging. Applied to ten worked examples chosen to illustrate rather than to sample the field - NEAT1, MEG3, lincRNA-p21, MALAT1, MIR31HG, SALNR, TERRA, PANDAR, HOTAIR, TUG1 - the profiles separate candidates awaiting an animal experiment from those whose animal experiments addressed something else. MALAT1 is instructive: of six in-vivo perturbation studies, one assays a senescence endpoint. No candidate has an aging experiment that returned a negative result, and none reaches the top of criterion 8, which requires conditional deletion or a titrated antisense regimen with rescue. Organism-level evidence, not literature volume, is the structural bottleneck.
Longevity Relevance Analysis
(3)
The paper proposes a standardized framework using Bradford Hill criteria to distinguish causal drivers of aging from passenger lncRNAs, identifying organism-level validation as the primary bottleneck. This is relevant because it addresses the fundamental challenge of identifying true causal mechanisms of aging in transcriptomic data, which is essential for developing effective longevity interventions rather than targeting non-causal biomarkers.
Dwight A L Mattocks, Naidu B Ommi, András K Ponti ...
· Caloric Restriction
· Animal Science Laboratory, Orentreich Foundation for the Advancement of Science Inc., Cold Spring-on-Hudson, NY, USA.
· pubmed
To discover novel mechanisms, we compared changes in redox metabolism markers induced by caloric restriction (CR) and sulfur amino acid restriction (SAAR).
To discover novel mechanisms, we compared changes in redox metabolism markers induced by caloric restriction (CR) and sulfur amino acid restriction (SAAR).
Longevity Relevance Analysis
(3)
The paper claims that caloric restriction and sulfur amino acid restriction induce distinct, divergent adaptations in redox metabolism markers in male rats. This is relevant because it investigates the specific metabolic and redox mechanisms underlying two established interventions known to extend lifespan, helping to distinguish the pathways by which different dietary restrictions influence aging biology.
Armstrong, J. O., Kwan, E. X., Alvino, G. M. ...
· genetics
· University of Washington School of Medicine
· biorxiv
Single-celled organisms grown in identical conditions have variable life spans. Identifying the factors that drive the inherent variability in life span is crucial for our understanding of aging at a fundamental level. Here, we revisit the role of chromosome XII instability as a ...
Single-celled organisms grown in identical conditions have variable life spans. Identifying the factors that drive the inherent variability in life span is crucial for our understanding of aging at a fundamental level. Here, we revisit the role of chromosome XII instability as a source of life span variability in aging populations of the budding yeast, Saccharomyces cerevisiae. We followed populations of mother cells as they aged and quantified changes in karyotype, DNA content, and aberrant structures within the rDNA. We quantified the kinetics of rDNA amplification both as extrachromosomal rDNA circles (ERCs) and as structural forms that are not resolved on CHEF gels. We propose mechanistic models of rDNA instability that describe how both ERCS and other aberrant structures are generated and the unique affects they have on life span. One of the models, which we call Catastrophic IntraChromosomal Repair (CICR), follows the fate of a broken replication fork in the rDNA locus when the template used for repair has already been replicated. At the completion of replication, when all other replication forks have successfully terminated, single, unopposed replication forks remain in the rDNA generating branched DNA molecules that have profound consequences during mitosis and/or subsequent cycles. In addition to ERCs, CICR and related events are additional forms of rDNA instability that contribute to the life span variability in isogenic populations of aging yeast.
Longevity Relevance Analysis
(3)
The paper proposes that a specific mechanism called Catastrophic IntraChromosomal Repair (CICR) generates branched DNA structures in the rDNA locus, contributing to lifespan variability in yeast. This is relevant because it identifies a novel, non-ERC source of genomic instability that drives aging in a model organism, offering a potential target for understanding the fundamental mechanisms of replicative senescence.
Salvatore Nesci, Cristina Algieri
· GeroScience
· Department of Veterinary Medical Sciences, University of Bologna, 40064, Ozzano Emilia, Italy. [email protected].
· pubmed
Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial...
Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial dysfunction as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, two central features of biological ageing. We discuss how impaired oxidative phosphorylation, loss of mitochondrial membrane potential, increased electron leak, and excessive reactive oxygen species progressively damage mitochondrial DNA, proteins, and lipids, thereby amplifying organelle dysfunction and compromising cellular homeostasis. Particular emphasis is placed on the threshold effect of mitochondrial DNA mutations, whose age-dependent clonal expansion can drive respiratory chain deficiency in vulnerable tissues. We further analyze mitochondria as signalling platforms that integrate regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and as sources of mitochondrial damage-associated molecular patterns promoting sterile inflammation. Finally, we highlight mitochondrial dysfunction-associated senescence as a central process through which persistent mitochondrial stress reshapes the senescence-associated secretory phenotype and reinforces inflammaging. Overall, the evidence supports a model in which dysfunctional mitochondria act as both initiators and amplifiers of senescence and inflammation, contributing to tissue degeneration and age-related functional decline. Understanding these interconnected mechanisms may help identify therapeutic strategies targeting mitochondrial bioenergetics, inflammatory signalling, and senescent cell burden in ageing.
Longevity Relevance Analysis
(3)
The paper posits that mitochondrial dysfunction acts as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, thereby driving age-related functional decline. This is a review article that synthesizes existing knowledge on mitochondrial mechanisms in aging rather than presenting novel experimental data or a breakthrough discovery, resulting in a limited incremental impact on the field.
Meijuan Chen, Min Zhang, Hanyi Mei ...
· Hematopoietic Stem Cells
· Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
· pubmed
Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms un...
Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms underlying HSPC aging is essential for developing strategies to alleviate age-related dysfunction. Here, we identify angiopoietin-like 8 (ANGPTL8), a secreted glycoprotein known for its role in glucose and lipid metabolism, as a novel regulator of HSPC aging. Systemic ANGPTL8 knockout significantly attenuated senescence-associated phenotypes in multiple murine tissues. In vitro and in vivo analyses of proliferation, colony-forming capacity, mitochondrial membrane potential, senescence-associated secretory phenotype (SASP) expression, reactive oxygen species (ROS) accumulation, myeloid skewing, and early hematopoietic regeneration further demonstrated that ANGPTL8 promotes HSPC aging. Mechanistically, ANGPTL8 deficiency activated the PI3K/AKT signaling pathway, whereas a PI3K activator rescued the senescence effects induced by recombinant ANGPTL8 (rANGPTL8). Furthermore, co-immunoprecipitation (Co-IP) confirmed that rANGPTL8 directly interacts with the transmembrane receptor PirB. Recombinant PirB (rPirB) reduced the phosphorylation of PI3K/AKT, whereas PirB knockdown effectively blocked the inhibitory effect of rANGPTL8 on PI3K/AKT phosphorylation. Collectively, our findings suggest that ANGPTL8 drives HSPC aging primarily by suppressing the PI3K/AKT pathway via its receptor PirB, providing a new potential target to alleviate the aging of HSPCs.
Longevity Relevance Analysis
(4)
ANGPTL8 drives hematopoietic stem/progenitor cell aging by suppressing the PI3K/AKT pathway via its receptor PirB. This paper is relevant because it identifies a specific molecular mechanism and secreted factor responsible for the functional decline of stem cells during aging, offering a potential target for interventions aimed at rejuvenating the hematopoietic system rather than merely treating downstream symptoms.
Jeffrey M Melin, Nancy A Young, Joseph Camardo
· Journal of Alzheimer's disease : JAD
· TOR Therapeutics Inc., Meadowbrook, PA, USA.
· pubmed
Rapamycin, a potent mTORC1 inhibitor, is a leading candidate for treating age-related neurodegenerative disease. Numerous studies demonstrate beneficial effects in a variety of diseases that affect the brain. Yet a persistent belief among researchers is that rapamycin cannot pene...
Rapamycin, a potent mTORC1 inhibitor, is a leading candidate for treating age-related neurodegenerative disease. Numerous studies demonstrate beneficial effects in a variety of diseases that affect the brain. Yet a persistent belief among researchers is that rapamycin cannot penetrate brain tissue, citing as evidence its absence of detection in cerebrospinal fluid (CSF). This narrative review synthesizes clinical and preclinical evidence challenging this "CSF misconception." In humans, direct tissue sampling in glioblastoma detects rapamycin in brain at mTORC1-inhibitory concentrations, while functional measures-tumor regression and seizure control in tuberous sclerosis complex, cerebral metabolic preservation on PET in Alzheimer's disease, increased cerebral blood flow in
Longevity Relevance Analysis
(4)
The paper claims that oral rapamycin effectively penetrates brain tissue and exerts functional mTORC1-inhibitory activity, refuting the common belief that it is excluded from the central nervous system due to its absence in cerebrospinal fluid. This is relevant to longevity research because rapamycin is a leading candidate for extending healthspan and lifespan via mTOR inhibition, and clarifying its bioavailability in the brain is critical for understanding its efficacy in preventing age-related neurodegeneration.
Lev Salnikov, Saveli Goldberg, Eugene Pinsky
· GeroScience
· InterceptAge LLC, San Diego, CA, 92121, USA. [email protected].
· pubmed
Aging biology still lacks a fully mechanistic explanation for why functional decline accelerates after sexual maturity in the absence of a single initiating pathology. Here, we integrate cross-species epigenetic, transcriptomic, and proteomic datasets to test whether aging is ass...
Aging biology still lacks a fully mechanistic explanation for why functional decline accelerates after sexual maturity in the absence of a single initiating pathology. Here, we integrate cross-species epigenetic, transcriptomic, and proteomic datasets to test whether aging is associated with a post-maturity imbalance between two genome partitions: housekeeping genes (HG), which encode the cellular maintenance infrastructure, and integrative genes (IntG), which support specialized tissue functions. We emphasize HG because this compartment defines the basal capacity for repair, proteostasis, biosynthesis, and cell-autonomous survival; changes in HG output may therefore help distinguish candidate upstream regulatory changes from downstream damage signatures. Across datasets, we observe a consistent divergence after sexual maturity: the HG compartment loses transcriptional share in low-renewal tissues, whereas IntG promoter methylation becomes progressively more dispersed, with methylation-mRNA Spearman correlations of rho = -0.15 to -0.28 (five tissues, p < 0.05 FDR) and modest mRNA-protein concordance (rho = 0.204, p < 0.001, n = 6,449), indicating partial post-transcriptional decoupling. These associations are compatible with the continued action of an ontogenetic regulatory program that shifts genome activity toward specialized function at the expense of maintenance. This interpretation is consistent with hyperfunction/developmental theories, while reframing the hyperfunctional state as a possible downstream consequence of asymmetric developmental regulation. Although causality remains to be tested experimentally, the convergence of multi-omics evidence supports a testable model in which restoring HG/IntG regulatory balance may represent a future experimental direction for modulating age-related decline, rather than a translational implication supported by the current data.
Longevity Relevance Analysis
(3)
The paper proposes that aging is driven by a conserved post-maturity imbalance where housekeeping gene activity declines relative to integrative gene activity, suggesting that restoring this balance could modulate age-related decline. This is relevant to longevity research as it attempts to identify a fundamental, upstream regulatory mechanism (the shift from maintenance to specialization) rather than treating downstream symptoms, although the evidence is largely correlative and the effect sizes are modest.
Aina M Llabrés-Mas, Antonio Merino-Navarro, Marta Menéndez-García ...
· Extracellular Vesicles
· Epigenetics and Cellular Senescence Group, Spanish National Research Council (CSIC), Biological Research Centre (CIB), Madrid 28040, Spain.
· pubmed
Senescent cells accumulate during both physiological and pathological processes, including aging. They are characterized by the expression of the cell cycle inhibitor p16
Senescent cells accumulate during both physiological and pathological processes, including aging. They are characterized by the expression of the cell cycle inhibitor p16
Longevity Relevance Analysis
(3)
Small extracellular vesicles mediate the paracrine effects of senescent cells in aging models. This paper is relevant because it investigates the mechanisms of cellular senescence, a fundamental driver of biological aging, rather than merely treating downstream symptoms of age-related diseases.
Le Liu, Haoran Hu, Kexin Chai ...
· Ecotoxicology and environmental safety
· Department of Geriatrics, Second Hospital of Tianjin Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, 300211, China.
· pubmed
Arsenic is a naturally occurring metalloid, and its pollution poses a global threat to humanity. Studies have shown that arsenic exposure accelerates aging, but the effects and mechanisms of sodium arsenite exposure on aging across both parental and offspring remain unclear. In t...
Arsenic is a naturally occurring metalloid, and its pollution poses a global threat to humanity. Studies have shown that arsenic exposure accelerates aging, but the effects and mechanisms of sodium arsenite exposure on aging across both parental and offspring remain unclear. In this study, we investigated the effects of sodium arsenite on lifespan, locomotion, heat tolerance, antioxidant defense systems, autophagy, and the insulin/IGF-1 signaling (IIS) pathway in Caenorhabditis elegans (C. elegans). Initially, exposure from the L1 to L4 larval stage to 100 μM or 200 μM sodium arsenite significantly shortened the lifespan of C. elegans. Sodium arsenite also reduced body length, body width, head-swing frequency, and heat-stress resistance. It also reduced superoxide dismutase (SOD) activity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation in C. elegans parents and offspring. qRT-PCR analysis showed that sodium arsenite exposure activated the IIS pathway in C. elegans parents and offspring by upregulating the upstream genes age-1 and daf-2 and downregulating the downstream transcription factor daf-16. Concurrently, it reduced the mRNA levels of bec-1, lgg-1, and sod-3, indicating impaired autophagy and reduced DAF-16 activity. Furthermore, sodium arsenite exposure diminished the fluorescence intensity of LGG-1::GFP in the DA2123 strain and SOD-3::GFP in the CF1553 strain across both generations, consistent with the qRT-PCR results. To further investigate the role of autophagy, we treated worms with rapamycin, which alleviated the pro-aging effects of arsenite in both generations. Therefore, our results show that sodium arsenite exposure accelerates aging in both parental and offspring C. elegans, a process linked to the IIS pathway, oxidative stress, and autophagy.
Longevity Relevance Analysis
(2)
Sodium arsenite exposure accelerates aging in C. elegans parents and offspring by activating the insulin/IGF-1 signaling pathway, inducing oxidative stress, and impairing autophagy. This study provides mechanistic insight into how environmental toxins accelerate aging via conserved pathways (IIS/autophagy), but it is an incremental toxicological study in a model organism that does not offer novel interventions or significant breakthroughs in extending lifespan.
Romeo Guitart, D., Tirani, T., Milunov, D. ...
· neuroscience
· Institut Necker Enfants Malades
· biorxiv
Body-brain communication is crucial for optimal neuronal performance across the lifespan, yet whether peripheral organs regulate spinal cord motoneuron (MN) function through circulating molecules remains unknown. The expression of hormone receptors by spinal MNs raises the possib...
Body-brain communication is crucial for optimal neuronal performance across the lifespan, yet whether peripheral organs regulate spinal cord motoneuron (MN) function through circulating molecules remains unknown. The expression of hormone receptors by spinal MNs raises the possibility that circulating cues allow the spinal cord to sense the body's energetic state and sustain motor activity. Here, we show that the bone-derived hormones osteocalcin (OCN) signals on spinal MNs via its receptor GPR158. GPR158 is selectively enriched in spinal cholinergic MNs, and its loss, globally or specifically in spinal MNs, or the one of OCN, impairs locomotor function and reduces choline acetyltransferase (ChAT) levels. Mechanistically, OCN signaling through GPR158 fine-tunes autophagy, mitophagy and mitochondrial activity in spinal MNs. Restoring any of these processes, by pharmacologically inducing mitophagy or chemogenetically activating mitochondria, is sufficient to rescue the locomotor deficits of Gpr158-deficient mice. Finally, OCN restoration in aged mice reverses age-related locomotor decline through a mechanism that requires MN autophagy and mitophagy. This study reveals that through OCN, the skeleton influences motor functions by fine-tuning motoneuronal mitochondria, and suggests that age-related motor decline is, at least in part, reversible.
Longevity Relevance Analysis
(6)
Bone-derived osteocalcin signals to spinal motoneurons via GPR158 to sustain mitochondrial function, and restoring this pathway reverses age-related locomotor decline. This is relevant because it identifies a specific, reversible molecular mechanism (bone-to-brain signaling) that maintains neuronal health and mitigates a core aspect of physiological aging (motor decline), rather than merely treating a downstream symptom.
Goyal, G., Palanisamy, P., Paul, A. ...
· neuroscience
· Penn State University College of Medicine
· biorxiv
Postmitotic neurons must preserve genome integrity for decades despite continuous oxidative, transcription-associated, and environmental DNA damage. Although recent studies have established ongoing repair-associated DNA synthesis in mature neurons, the polymerases that execute th...
Postmitotic neurons must preserve genome integrity for decades despite continuous oxidative, transcription-associated, and environmental DNA damage. Although recent studies have established ongoing repair-associated DNA synthesis in mature neurons, the polymerases that execute this synthesis remain incompletely defined. DNA polymerase kappa (POLK), a Y-family translesion synthesis polymerase, is highly expressed in neurons and undergoes an age-associated redistribution from the nucleus to the cytoplasm, suggesting that loss of nuclear POLK may compromise neuronal genome maintenance. Here, we investigated the consequences of POLK loss and augmentation in primary mouse cortical neurons and human induced pluripotent stem cell-derived forebrain neurons, including APOE e4/e4 backgrounds.
Partial POLK depletion reduced neuronal arbor complexity, enlarged neuronal nuclei, increased LAMIN A/C and nuclear-envelope abnormalities, and induced a multidimensional senescence-like stress phenotype characterized by increased senescence-associated {beta}-galactosidase, p21, nuclear p38 MAPK, inflammatory signaling, lysosomal remodeling, and reduced mitochondrial-associated staining. POLK localized in proximity to EdU-labeled DNA in mature neurons, and POLK depletion reproducibly reduced EdU incorporation across independent human neuronal backgrounds and maturation stages. Exploratory nuclear POLK immunoprecipitation-mass spectrometry, together with proximity ligation assays, placed POLK near proteins involved in nucleotide excision repair, base-excision/single-strand break repair, DNA-end repair, checkpoint signaling, and specialized polymerase regulation, including PCNA-Ub and RAD18.
POLK loss also produced Alzheimer disease-relevant cellular phenotypes. In wild-type neurons, POLK depletion increased 6E10 immunoreactivity and was accompanied by remodeling of APP/endosomal, lipid/cholesterol, and lysosomal pathways. In APOE e4/e4 neurons, POLK depletion increased cytoplasmic dsDNA and phospho-tau. Conversely, neuron-directed POLK augmentation increased EdU incorporation while reducing 53BP1 and {gamma}H2AX signals, p38 MAPK, cytoplasmic dsDNA, 6E10 immunoreactivity, and phospho-tau.
Together, these findings identify POLK as a component of repair-associated DNA synthesis in mature neurons and support a model in which neuronal POLK availability contributes to genome maintenance, stress resilience, and vulnerability in aging and Alzheimer disease-relevant states.
Longevity Relevance Analysis
(4)
The paper claims that DNA polymerase kappa (POLK) is essential for repair-associated DNA synthesis in postmitotic neurons, and that its age-associated loss contributes to genomic instability, senescence, and Alzheimer's disease pathology. This is relevant to longevity research because it identifies a specific molecular mechanism (translesion synthesis polymerase activity) that maintains genome integrity in long-lived postmitotic cells, suggesting that preserving or augmenting POLK function could mitigate age-related neuronal decline and neurodegeneration.
Blaise L Mariner, Brianah M McCoy, Ashlee Greenier, ★ Matt Kaeberlein ...
· DNA Transposable Elements
· School of Life Sciences, Arizona State University, Tempe, AZ, USA.
· pubmed
The extraordinary lifespan variation in domestic dogs provides a natural experiment for testing how intrinsic rates of biological aging shape lifespan. Using 1640 methylomes from 894 dogs, we developed an epigenetic clock that predicted mortality and demonstrated that epigenetic ...
The extraordinary lifespan variation in domestic dogs provides a natural experiment for testing how intrinsic rates of biological aging shape lifespan. Using 1640 methylomes from 894 dogs, we developed an epigenetic clock that predicted mortality and demonstrated that epigenetic aging is fastest early in life. At orthologs of human age-associated genes, dogs exhibited concordant age effects on promoter methylation, highlighting conserved remodeling of immune pathways. We found that larger and male dogs, which are shorter lived, exhibit accelerated molecular aging. Distinct epigenetic architectures mediated these effects: Sex-dependent methylation changes were concentrated on the X chromosome, whereas size-associated methylation was especially pronounced at transposable elements (TEs). These findings show that epigenetics reflects lifespan differences in dogs and identifies TEs as potential mediators of size-associated lifespan.
Longevity Relevance Analysis
(4)
The paper claims that transposable element (TE) dysregulation mediates the accelerated epigenetic aging and lifespan compression observed in larger dog breeds. This is relevant because it identifies a specific molecular mechanism (TEs) linking intrinsic biological aging rates to lifespan variation, providing a testable target for understanding how to slow the rate of aging.
Alba Iglesias-Fente, Junquera López-Seijas, María C Arufe ...
· Liposomes
· CICA - Centro Interdisciplinar de Química e Bioloxía, Universidade da Coruña, A Coruña, Spain.
· pubmed
The potential of senescent cell clearance to extend healthspan and delay the onset of age-related diseases has driven the development of innovative senotherapeutics. Thus, niosome-based gene therapy has emerged as a promising strategy to overcome the off-target limitations of fir...
The potential of senescent cell clearance to extend healthspan and delay the onset of age-related diseases has driven the development of innovative senotherapeutics. Thus, niosome-based gene therapy has emerged as a promising strategy to overcome the off-target limitations of first-generation senolytics, senomorphics, and senoreverts. In the present study, we investigated two new niosome formulations for genetically modifying primary umbilical cord stroma senescent MSCs (UC-MSCs) in a Palbociclib-induced senescent model, using non-senescent UC-MSCs as a control. These niosomes were formulated by fixing the cationic lipid composition (1,2-di-O-octadecenyl-3 trimethylammonium propane, DOTMA, D) and varying the non-ionic surfactants (polysorbate 20, P20, or polysorbate 80, P80) and the helper lipids (chloroquine, CQ, or cholesterol, CH) (DP20CQ and DP80CH, respectively) at two mole ratios (1:2:1 and 1:2:2 for DP20CQ; 1:2:2 and 1:2:4 for DP80CH). Results on transfection revealed that the DP20CQ formulations outperformed those with DP80CH in both UC-MSCs phenotypes from four different donors. Notably, DP20CQ niosomes prepared at 10/1 and 15/1 DOTMA/DNA ratios achieved the highest transgene expression levels in senescent UC-MSCs, surpassing even the commercial reagent Lipofectamine. Further, DP20CQ formulations exhibited adequate physicochemical properties for transfection and promoted a marked endosomal escape, particularly at the DOTMA/DNA ratio 10/1, without compromising cell viability. These findings underscore the value of niosomes as robust gene delivery vehicles for senescent cells in therapeutic antiaging strategies.
Longevity Relevance Analysis
(3)
The paper claims that specific niosome formulations (DP20CQ) can efficiently deliver genes to senescent mesenchymal stem cells with higher efficacy than commercial reagents. This is relevant to longevity research because it addresses a critical technical bottleneck in developing senotherapeutics and gene-based interventions for cellular senescence, a core driver of aging, though the study is limited to in vitro cell models and represents an incremental advance in delivery vehicle optimization rather than a fundamental breakthrough in aging biology.
Zeng-Yang Wang, Xin-Jie Zhao, Shuo Gao ...
· Free radical biology & medicine
· State Key Laboratory of Natural Medicines, Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
· pubmed
Aging is driven by multiple factors such as mitochondrial dysfunction and oxidative stress, leading to various age-related diseases. Phosphodiesterase-4 (PDE4) is a subfamily of phosphodiesterases and specifically hydrolyzes cAMP. PDE4 inhibitors have been approved for the treatm...
Aging is driven by multiple factors such as mitochondrial dysfunction and oxidative stress, leading to various age-related diseases. Phosphodiesterase-4 (PDE4) is a subfamily of phosphodiesterases and specifically hydrolyzes cAMP. PDE4 inhibitors have been approved for the treatment of several diseases and shown to improve aging-related conditions. However, the precise effects and underlying mechanisms of PDE4 inhibitors on lifespan and cellular senescence remain unclear. Here, we report that two PDE4 inhibitors (roflumilast and rolipram) extend C. elegans lifespan and that roflumilast attenuates passage-induced cellular senescence in mouse embryonic fibroblasts (MEFs). We further demonstrate that protein kinase A (PKA) activation mediates PDE4 inhibitors' anti-aging effects by improving mitochondrial function and alleviating oxidative stress, and that the mechanism is conserved in C. elegans and MEFs. Our findings provide evidence that PDE4 inhibitors possess anti-aging potential.
Longevity Relevance Analysis
(3)
PDE4 inhibitors extend C. elegans lifespan and attenuate cellular senescence in MEFs via PKA-mediated improvement of mitochondrial function and reduction of oxidative stress. This paper provides mechanistic evidence for the anti-aging potential of a clinically approved drug class, linking cAMP signaling to mitochondrial health, which is a core driver of aging, though the findings are largely incremental given the known effects of PDE4 inhibitors on metabolic pathways.