Cinzia Vicidomini, Travis D Goode, Ruilin Yu ...
· Nature neuroscience
· Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
· pubmed
Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase,...
Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.
Longevity Relevance Analysis
(6)
The paper claims that the secreted phospholipase PLA2G2F acts as a compensatory neuroprotective signal that maintains lipid homeostasis to prevent aging-associated cognitive decline. This is relevant to longevity research because it identifies a specific molecular mechanism (lipid homeostasis via a secreted factor) that can be manipulated to bypass age-related neurodegeneration and extend cognitive healthspan, rather than merely treating downstream symptoms of Alzheimer's disease.
Masashi Sato, Keiko Hirata, Hiromu Takagishi ...
· Bioscience, biotechnology, and biochemistry
· Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Miki, Kagawa, Japan.
· pubmed
Advanced glycation end products (AGEs) accumulate with age and contribute to age-related disease. Using an autofluorescence assay in Caenorhabditis elegans, we screened all eight ketohexose stereoisomers. The response was highly stereoselective: only d-allulose significantly supp...
Advanced glycation end products (AGEs) accumulate with age and contribute to age-related disease. Using an autofluorescence assay in Caenorhabditis elegans, we screened all eight ketohexose stereoisomers. The response was highly stereoselective: only d-allulose significantly suppressed autofluorescence (∼22% at 10 mM and ∼20% at 25 mM; corrected p < 0.01), while its enantiomer l-allulose, assayed alongside it, had no detectable effect. The suppression was undetectable at 5 mM and did not deepen between 10 and 25 mM, and suppression was also detected at 25 mM with killed bacteria. Despite this in vivo suppression, d-allulose generated substantial glycation-associated fluorescence in a cell-free bovine serum albumin system at 60 °C, indicating that it is not chemically inert. These results establish a stereochemical activity map of ketohexoses toward AGE-related autofluorescence.
Longevity Relevance Analysis
(3)
The paper claims that d-allulose stereoselectively suppresses AGE-related autofluorescence in C. elegans without being chemically inert in cell-free systems. This is relevant because it investigates a specific molecular mechanism of aging (glycation) and identifies a potential dietary intervention that may mitigate a root cause of age-related damage, although the effect size is modest and the mechanism remains unclear given the contradictory in vitro results.
Hyun-Jin Na, Min-Sun Kim, Mi Jeong Sung
· GeroScience
· Aging Research Group, Food Functionality Research, Korea Food Research Institute, 245 Nongsaenmyeong-Ro, Iseo-Myeon, Wanju-Gun, 55365, Jeollabuk-do, Republic of Korea. [email protected].
· pubmed
Aging-associated intestinal dysfunction is characterized by impaired epithelial homeostasis, excessive intestinal stem cell (ISC) proliferation, and progressive barrier deterioration. Although oxidative stress is widely recognized as a major driver of intestinal aging, the mechan...
Aging-associated intestinal dysfunction is characterized by impaired epithelial homeostasis, excessive intestinal stem cell (ISC) proliferation, and progressive barrier deterioration. Although oxidative stress is widely recognized as a major driver of intestinal aging, the mechanisms linking redox imbalance to ISC dysregulation remain incompletely understood. In this study, we investigated the effects of dietary chlorogenic acid (CGA) treatment using Drosophila models of physiological aging, H₂O₂-induced oxidative stress, and high-sucrose feeding. CGA treatment was associated with reduced ROS accumulation, DNA damage response, and aberrant ISC proliferation under stress conditions. Genetic analysis further demonstrated that CncC, the Drosophila ortholog of NRF2, is required for these protective effects, although our data do not establish direct activation of CncC by the parent CGA molecule or its metabolites. Transcriptomic analysis revealed CGA-associated changes in pathways related to antioxidant defense, genome maintenance, and cell cycle regulation. CGA treatment improved intestinal barrier integrity and reduced stress-associated autophagic responses. Collectively, our findings demonstrate that the intestinal protective effects observed following CGA treatment are associated with attenuation of oxidative stress and require CncC-dependent capacity. These findings extend the redox-protective effects observed following dietary CGA treatment to aging-associated ISC and epithelial homeostasis and provide a framework for further investigation of dietary bioactive compounds in aging.
Longevity Relevance Analysis
(3)
Chlorogenic acid attenuates oxidative stress-associated intestinal stem cell dysfunction and barrier deterioration in Drosophila via a CncC-dependent mechanism. This study provides mechanistic insight into how a dietary bioactive compound may mitigate specific hallmarks of aging (oxidative stress and stem cell dysregulation) in the gut, offering a potential avenue for dietary interventions to preserve tissue homeostasis during aging, though the findings are limited to an invertebrate model and do not establish direct molecular activation of the pathway.
Zhichao Li, Kuanhui Gao, Mengjie Wang ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Center For Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
· pubmed
Reversing the destructive remodeling of the bone marrow microenvironment during aging remains a major challenge. Here, we reveal an age-dependent dual role of bone marrow macrophage (BMM) STING signaling during skeletal aging. While BMM STING deficiency is detrimental during earl...
Reversing the destructive remodeling of the bone marrow microenvironment during aging remains a major challenge. Here, we reveal an age-dependent dual role of bone marrow macrophage (BMM) STING signaling during skeletal aging. While BMM STING deficiency is detrimental during early bone development and maturation, it paradoxically confers protection against age-related bone loss from middle age onward. Mechanistically, accumulating bone marrow adipocytes secrete substantial soluble dipeptidyl peptidase 4 (sDPP4). This sDPP4 functions as an extracellular ligand for Toll-like receptor 4 on BMMs, thereby collaborating with endogenous mitochondrial DNA to activate STING signaling. This STING activation concurrently induces a CD38-dependent salvage synthesis pathway. Importantly, this STING-driven upregulation of CD38 not only amplifies bone marrow inflammation but also, through its ecto-nicotinamide adenine dinucleotide (NAD
Longevity Relevance Analysis
(6)
The paper claims that inhibiting STING signaling in bone marrow macrophages prevents age-related bone loss by blocking a CD38-dependent NAD depletion pathway triggered by marrow adipose expansion. This is relevant because it identifies a specific molecular mechanism (STING-CD38-NAD axis) driving the deterioration of the bone marrow microenvironment during aging, offering a potential target for reversing skeletal aging rather than just treating osteoporosis symptoms.
Kaushik, D., Dugam, P., Sarkar, G. ...
· neuroscience
· Neuroscience and Ageing Biology Division, CSIR-Central Drug Research Institute, Lucknow, U.P. (226031), India. Academy of Scientific and Innovative Research (Ac
· biorxiv
Ageing locks hippocampal neural stem cells (NSCs) into deeper quiescence and inflammation-driven senescence, which are also associated with impaired cognition. The bile-acid receptor TGR5, a member class I G-protein coupled receptors (GPCRs), is expressed in cultured hippocampal ...
Ageing locks hippocampal neural stem cells (NSCs) into deeper quiescence and inflammation-driven senescence, which are also associated with impaired cognition. The bile-acid receptor TGR5, a member class I G-protein coupled receptors (GPCRs), is expressed in cultured hippocampal NSCs and in SOX2-positive cells of the adult sub granular zone, yet its role in NSC homeostasis is unknown. In this study we show that TGR5 selective agonist, TC-G 1005, expanded the NSC pool without forcing neuronal differentiation. Primary NSCs treatment with TC-G 1005 increased BrdU incorporation and PCNA in a concentration-dependent manner, and both responses were lost after TGR5 knockdown. TGR5 agonism in differentiating cultures increased nestin, left doublecortin (DCX) unchanged and suppressed MAP2 expression, preserving stemness rather than neuronal commitment. The agonist also released BMP4-imposed quiescence, lowering FOXO3a and restoring phospho-EGFR and ASCL1, and reopened autophagic flux, with less p62 and LC3-II, fewer LAMP2 puncta and more Beclin-1. Furthermore, activation of TGR5 suppressed IL-6 induced p53 and p16 expression, restored proliferation and contracted the inflammatory transcriptome by more than 90%, including Cdkn2a, Cdkn2b and Cdk6. In 18-month-old mice, brain-penetrant TC-G 1005 (5 mg/kg, subcutaneously, twice daily for 28 days) expanded SOX2-positive and proliferating NSCs, reduced p16, recovered ASCL1 and improved spatial memory, without changing locomotion or generating DCX-positive neurons. Dentate gyrus-restricted TGR5 knockdown abolished these cellular effects and the rescue of spatial and social discrimination. Hippocampal proteomic analysis revealed that TC-G 1005 treated aged mice occupied an intermediate, partially rejuvenated position between young and aged proteomes, with 86 proteins shared between ageing- and treatment-responsive sets, and mitochondrial and complement C1q modules shifted toward youthful levels. TGR5 activation therefore relieves both quiescence and senescence in the aged neurogenic niche without driving neuronal differentiation. Collectively, these results suggest that TGR5 could be targeted to preserve cognition in ageing by rejuvenating the hippocampal stem-cell niche.
Longevity Relevance Analysis
(4)
The paper claims that activation of the TGR5 receptor reverses age-induced quiescence and senescence in hippocampal neural stem cells, thereby improving spatial memory in aged mice. This is relevant to longevity research as it identifies a specific molecular target (TGR5) that can rejuvenate the neurogenic niche and mitigate age-related cognitive decline, addressing a key aspect of healthy aging rather than just treating a specific disease symptom.
Xuehui Li, Wenjing Ding, Xuechun Yang ...
· Molecular & cellular proteomics : MCP
· Department of Geriatric Medicine, Laboratory of Gerontology and Anti-aging Research, Jinan Clinical Research Center for Geriatric Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China.
· pubmed
Cardiac aging is characterized by progressive functional decline and metabolic remodeling. We previously found that lysine β-hydroxybutyrylation (Kbhb) is altered in wild-type (WT) aged and AMP-activated protein kinase alpha 2 (AMPKα2)-knockout (AK) young hearts, but whether this...
Cardiac aging is characterized by progressive functional decline and metabolic remodeling. We previously found that lysine β-hydroxybutyrylation (Kbhb) is altered in wild-type (WT) aged and AMP-activated protein kinase alpha 2 (AMPKα2)-knockout (AK) young hearts, but whether this landscape can be reversed therapeutically remains unknown. We evaluated the therapeutic potential of human umbilical cord mesenchymal stromal cell-derived exosomes (hUCMSC-exos) in WT and AK aged mice, using young and aged untreated cohorts as controls. Quantitative proteomics across six experimental groups identified 1,755 Kbhb sites on 652 proteins, mapping the dynamic cardiac Kbhb landscape under aging, AMPKα2 deficiency, and exosome intervention. In wild-type aged (WTA) mice, hUCMSC-exos improved systolic and diastolic function, enhanced grip strength, reduced fibrosis, and restored ATP levels, accompanied by predominant downregulation of Kbhb on enzymes of glycolysis/gluconeogenesis, fatty acid oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. In AMPKα2-knockout aged (AKA) mice, exosomes partially improved mitochondrial ultrastructure and diastolic indices but did not rescue systolic function or fibrosis. Site-level analysis revealed that exosomes selectively normalized Kbhb sites elevated during aging, whereas AMPKα2 deficiency caused nonselective global depletion. The candidate AMPKα2-SIRT3 pathway, supported by SIRT5, may underlie this Kbhb reprogramming. We validated carnitine acetyltransferase (CRAT) K141bhb as an age-accumulated modification reversed by exosomes in an AMPKα2- associated manner. Molecular modeling indicated that K141bhb neutralizes the positive charge of K141, disrupting the local salt bridge between K141 and E144 and destabilizing the α-helical structure, suggesting that K141bhb may serve as a metabolic brake on CRAT activity. These findings map the cardiac Kbhb landscape and show that hUCMSC-exos ameliorate cardiac aging through AMPKα2- associated Kbhb modulation.
Longevity Relevance Analysis
(3)
The paper claims that human umbilical cord mesenchymal stromal cell-derived exosomes ameliorate cardiac aging by modulating lysine β-hydroxybutyrylation (Kbhb) levels in an AMPKα2-associated manner, specifically reversing age-accumulated modifications on metabolic enzymes like CRAT. This is relevant to longevity research as it investigates the reversal of molecular hallmarks of aging (metabolic remodeling and post-translational modification landscapes) in a major age-related organ system, providing mechanistic insight into how exosome therapy might restore youthful metabolic states rather than just treating symptoms.
Chunli Dong, Fang Liu, Xiaocong Li ...
· GeroScience
· The Key Lab of Guizhou Provincial Department of Education for Medical Prevention and Treatment of Tumor, Zunyi Medical University, Zunyi, 563003, Guizhou, China.
· pubmed
Aging is closely associated with dysregulation of lipid metabolism, making the modulation of lipid metabolism a promising strategy for promoting healthspan. Streptococcus thermophilus, a widely utilized probiotic, has shown potential in regulating host metabolism. However, whethe...
Aging is closely associated with dysregulation of lipid metabolism, making the modulation of lipid metabolism a promising strategy for promoting healthspan. Streptococcus thermophilus, a widely utilized probiotic, has shown potential in regulating host metabolism. However, whether and how it can promote healthspan by modulating specific lipid metabolic pathways remains unclear. Using the Caenorhabditis elegans model, this study investigated the effects of Streptococcus thermophilus on healthspan and the underlying molecular mechanisms. We found that Streptococcus thermophilus supplementation significantly extended the healthspan of worms, improving multiple health indicators including enhanced motility and reduced accumulation of age pigments. Furthermore, we found that Streptococcus thermophilus remodeled the host fatty acid profile, markedly increasing the proportion of monounsaturated fatty acids (MUFAs). Mechanistically, Streptococcus thermophilus specifically upregulated the nuclear hormone receptor NHR-49 (a functional ortholog of mammalian PPARα), which in turn activated the expression of downstream delta-9 desaturase genes, including fat-5, fat-6 and fat-7, resulting in increased levels of MUFAs thereby extending healthspan. Intriguingly, exogenous supplementation of 1 mM oleic acid (OA) and palmitoleic acid (POA) restored nhr-49, fat-5, fat-6 and fat-7 mutants-induced shortened lifespan phenotype. In summary, our study demonstrates that Streptococcus thermophilus promotes healthspan by activating the NHR-49/Delta-9 desaturase axis, leading to a systemic reprogramming of lipid metabolism. This finding provides a novel mechanistic basis for developing precise probiotic-based anti-aging strategies targeting the lipid metabolic network.
Longevity Relevance Analysis
(3)
Streptococcus thermophilus extends healthspan in C. elegans by upregulating the NHR-49/Delta-9 desaturase axis to increase monounsaturated fatty acid levels. This study provides a specific mechanistic link between a common probiotic and lipid-mediated longevity pathways, offering a testable hypothesis for how dietary microbiome components might modulate host aging via metabolic reprogramming, though the findings are limited to a simple invertebrate model and represent an incremental addition to the known role of PPARα/omega-3 signaling in aging.
Na Liang, Jia He, Xiangji Guo ...
· Cell metabolism
· State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
· pubmed
Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotid...
Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotide (NAD
Longevity Relevance Analysis
(6)
Serpina3n is an adipose-derived adipokine that mediates the protective effects of NAD+ supplementation on skeletal muscle integrity. This paper is relevant because it identifies a specific systemic metabolic mechanism (an adipokine) through which NAD+ precursors, a major class of longevity interventions, prevent age-related muscle loss (sarcopenia), thereby addressing a root cause of frailty rather than just treating symptoms.
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
(8)
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.