Rui Feng, Sarah F Rosen, Irshad Ansari ...
· Aging
· Department of Neuroscience, Washington University School of Medicine, St Louis, United States.
· pubmed
Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many disea...
Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron soma residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo in DRG explant cultures improves axon growth in both adult and aged conditions. In vivo, treatment with the FDA-approved compound, Bosentan, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment. These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies.
Longevity Relevance Analysis
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Inhibition of endothelin B receptor function enhances axon regeneration and reverses age-dependent decline in regenerative capacity. This research addresses a mechanism underlying the decline in regenerative ability with age, which is a critical aspect of longevity and age-related functional decline.
Yonghe Ding, Xueling Ma, Feixiang Yan ...
· Aging cell
· Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
· pubmed
While BAG3 has been identified as a causative gene for dilated cardiomyopathy, the major pathological events in BAG3-related cardiomyopathy that could be targeted for therapeutic benefit remain to be discovered. Here, we aim to uncover novel pathological events through genetic st...
While BAG3 has been identified as a causative gene for dilated cardiomyopathy, the major pathological events in BAG3-related cardiomyopathy that could be targeted for therapeutic benefit remain to be discovered. Here, we aim to uncover novel pathological events through genetic studies in a zebrafish bag3 cardiomyopathy model. Given the known cardioprotective effects of mtor inhibition and the fact that transcription factor EB (tfeb) encodes a direct downstream phosphorylation target of mTOR signaling, we generated a cardiomyocyte-specific transgenic line overexpressing tfeb (Tg[cmlc2:tfeb]). This overexpression was sufficient to restore defective proteostasis and rescue cardiac dysfunction in the bag3 cardiomyopathy model. Importantly, we detected accelerated cardiac senescence in the bag3 cardiomyopathy model, which can be mitigated by Tg(cmlc2:tfeb). We compared cardiac transcriptomes between the Tg(cmlc2:tfeb) transgenic fish and the mtor
Longevity Relevance Analysis
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The paper claims that overexpression of tfeb can restore proteostasis and mitigate cardiac senescence in a bag3 cardiomyopathy model. This research is relevant as it explores mechanisms that could potentially target the aging process in cardiac tissue, addressing root causes of age-related cardiac dysfunction rather than merely treating symptoms.
Jiang, W. I., Vale, G. D. d., Pearce, Q. ...
· physiology
· UCSF
· biorxiv
The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unk...
The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.
Longevity Relevance Analysis
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The paper claims that downregulation of triglyceride lipids and upregulation of malonic acid in neural stem cells confer resilience to hypoxia and aging. This research is relevant as it explores metabolic adaptations that may address underlying mechanisms of aging and resilience, potentially offering insights into strategies for combating age-related pathologies.
Habib Joukhdar, Sunny Shinchen Lee, Thomas R Cox ...
· Advanced materials (Deerfield Beach, Fla.)
· School of Medical Sciences, University of Sydney, Sydney, NSW, 2006, Australia.
· pubmed
The disparity between the global increase in life expectancy and the steady decline in health outcomes with age has been a major driver for developing new ways to research aging. Although this current tools for studying aging outside of the human body-such as animal models and ce...
The disparity between the global increase in life expectancy and the steady decline in health outcomes with age has been a major driver for developing new ways to research aging. Although this current tools for studying aging outside of the human body-such as animal models and cells in a dish-have improved this fundamental understanding of the markers and key mechanisms underlying this process, several limitations remain. Animal models are poor biological representations of humans and have a weak track record of translating pre-clinical results into successful clinical applications. Similarly, current 2D cellular models do not recapitulate the dynamic 3D environment of human tissue. This gap between the need for accurate biological mimicry and the limitations of current aging models presents an exciting opportunity for the field of biofabrication. Over the past decade, the combination of biofabrication and advanced biomaterials has shown potential to engineer high-resolution features that change over time or respond to specific stimuli. In this perspective, the current state of in vitro aging models is reflected, identify the key features that new models must emulate, discuss the technologies available to meet these complex specifications, and consider some of the potential challenges facing the field.
Longevity Relevance Analysis
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The paper discusses the limitations of current aging models and proposes the potential of biofabrication to create more accurate in vitro models of aging. This research is relevant as it addresses the need for improved methodologies to study the biological mechanisms of aging, which is crucial for developing interventions that could extend lifespan and improve health outcomes.
Maanya Vittal, Manlio Vinciguerra
· Withania
· School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK. [email protected].
· pubmed
Ashwagandha (Withania somnifera), a revered herb in Ayurvedic medicine, has gained significant scientific recognition for its potential to promote healthy aging. Traditionally used as a Rasayana or rejuvenator, this potent adaptogen helps the body manage stress and enhance vitali...
Ashwagandha (Withania somnifera), a revered herb in Ayurvedic medicine, has gained significant scientific recognition for its potential to promote healthy aging. Traditionally used as a Rasayana or rejuvenator, this potent adaptogen helps the body manage stress and enhance vitality. This review synthesises extensive evidence for its multifaceted anti-aging capabilities, which target key hallmarks of the aging process. The mechanisms underpinning its effects include enhancing telomerase activity to support cellular longevity, combating systemic oxidative stress, and powerfully countering inflammaging by modulating immune responses and lowering inflammatory markers like C-reactive protein. Robust clinical evidence demonstrates its efficacy in improving crucial physiological parameters, including significant gains in muscle strength and size, enhanced cardiorespiratory fitness, hormonal balance, skin health, and improved sleep quality in older adults. Furthermore, trials have consistently shown its ability to improve cognitive function, including memory and information-processing speed, particularly in adults with mild cognitive impairment. Promising preclinical data also highlight its neuroprotective potential in models of Alzheimer's and Parkinson's disease. Here, we review the current evidence supports Ashwagandha's therapeutic potential in extending healthspan and enhancing quality of life. Large-scale, long-term clinical trials using standardized extracts are essential to fully confirm its role in healthy aging within the global population.
Longevity Relevance Analysis
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Ashwagandha has multifaceted geroprotective benefits that may enhance healthspan by targeting key hallmarks of aging. The paper discusses mechanisms that could potentially address the root causes of aging rather than merely treating age-related symptoms.
Zachary J Fennel, Negar Kosari, Paul-Emile Bourrant ...
· JCI insight
· Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America.
· pubmed
Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized t...
Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls. Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.
Longevity Relevance Analysis
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Transient hypoxia enhances pro-inflammatory macrophage function, improving muscle cellular remodeling and recovery in aged mice. The paper addresses the metabolic and inflammatory mechanisms underlying muscle regrowth in aging, which is a critical aspect of longevity research focused on improving age-related functional decline.
Yina Lan, Xiaole Liang, Guotao Kuang ...
· Aging cell
· Department of Pediatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
· pubmed
The CST (CTC1-STN1-TEN1) complex, a single-stranded DNA (ssDNA) binding complex, is essential for telomere maintenance and genome stability. Depletion of either CTC1 or STN1 results in cellular senescence, while mutations in these components are associated with severe hereditary ...
The CST (CTC1-STN1-TEN1) complex, a single-stranded DNA (ssDNA) binding complex, is essential for telomere maintenance and genome stability. Depletion of either CTC1 or STN1 results in cellular senescence, while mutations in these components are associated with severe hereditary disorders. In this study, we demonstrate that the direct STN1-CTC1 interaction stabilizes CTC1 by preventing its degradation via TRIM32 mediated ubiquitination. Functional assays indicate that TRIM32 and the CTC1/STN1 complex exert opposing effects on cellular proliferation. Additionally, transcriptomic analysis of large-scale RNA sequencing data from the Genotype-Tissue Expression (GTEx) reveals inverse expression patterns of TRIM32 and CTC1/STN1 during somatic cell aging. Structural modeling using AlphaFold3 predicts that the TRIM32-CTC1 interaction occurs at the OB-G domain of CTC1, with the binding interface positioned near the STN1-interacting region, termed the "cleft" motif. Mechanistically, STN1 likely associates with the OB-G domain of CTC1, competing with TRIM32 for binding sites and thereby interfering with TRIM32-mediated ubiquitination of CTC1. Collectively, our findings identify STN1 as a critical regulator of CST complex integrity and cellular aging by safeguarding CTC1 from TRIM32-driven ubiquitin-proteasome degradation.
Longevity Relevance Analysis
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STN1 prevents TRIM32-mediated ubiquitination of CTC1, thereby protecting against cellular aging. The paper addresses a mechanism related to telomere maintenance and cellular senescence, which are critical factors in the aging process.
Angela D Mazza
· Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
· Endocrinology, Metabolic Center for Wellness, Oviedo, United States.
· pubmed
Thyroid hormones (TH), primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevit...
Thyroid hormones (TH), primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevity through modulation of key cellular pathways. Objective: This review explores the role of thyroid hormones in aging biology, with a focus on their interaction with longevity-associated signaling pathways and the hallmarks of aging. Both physiological and subclinical thyroid states in the context of healthspan, cognitive preservation, metabolic resilience, and mitochondrial integrity are explored. A narrative synthesis of human and animal studies was conducted, including mechanistic, epidemiologic, and clinical data, to evaluate how thyroid hormone levels affect aging pathways such as mTOR, AMPK, IGF-1, sirtuins, FOXO transcription factors, and mitochondrial biogenesis. Thyroid hormones modulate several hallmarks of aging, including mitochondrial dysfunction, genomic instability, epigenetic drift, and deregulated nutrient sensing. T3 enhances mitochondrial respiration and autophagy while interacting with mTOR and AMPK to regulate energy balance. Altered thyroid function-particularly subclinical hypothyroidism, has been paradoxically associated with increased longevity in some centenarian cohorts, possibly due to reduced oxidative metabolism. However, overt thyroid dysfunction is linked to increased metabolic risk in aging populations. Thyroid hormones serve as metabolic gatekeepers that influence both cellular aging and organismal longevity. A deeper understanding of their role in aging pathways may inform novel strategies for promoting healthy aging, including thyroid hormone modulation, and personalized endocrine optimization.
Longevity Relevance Analysis
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Thyroid hormones influence aging pathways and may modulate longevity through their effects on mitochondrial health and metabolic flexibility. This paper is relevant as it explores the role of thyroid hormones in the context of aging biology and longevity, addressing potential mechanisms that could contribute to healthy aging.
Hariharan Easwaran, Ashani T Weeraratna
· Nature reviews. Cancer
· The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. [email protected].
· pubmed
Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer r...
Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50-60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.
Longevity Relevance Analysis
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The paper claims that epigenetic changes in the ageing tumour microenvironment enhance the effects of cancer driver mutations, promoting cancer development in aged individuals. This research addresses the underlying mechanisms of ageing that contribute to cancer, which is relevant to longevity and age-related diseases.
Groves, J. W., Bot, V. A., Ding, D. Y. ...
· epidemiology
· Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK
· medrxiv
The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited and age-related diseases are leading causes of morbidity and mortality. Proteomic ...
The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited and age-related diseases are leading causes of morbidity and mortality. Proteomic clocks allow organ ageing to be estimated from blood sampling, facilitating study of how life course exposures shape biological ageing heterogeneity. Here, we leverage the unique design of the MRC National Survey of Health and Development (NSHD), the world's oldest continuously followed birth cohort, to track 1,803 individuals across eight decades since birth in 1946. At mean age 63.2 years, we estimated proteomic ageing in seven organs. Despite near identical chronological ages, participants' proteomes revealed biological ageing disparities spanning decades. Extreme ageing in multiple organs was a strong prognostic indicator for all-cause mortality over the following 15 years (HR=6.62 for [≥]4 extremely aged organs). Adversity and being overweight in adolescence associated with accelerated ageing decades later in life. Completing secondary school education and maintaining physical activity linked to relative biological youth. Mediation analyses indicated liver, kidney and immune ageing linked life course exposures to mortality. Across 10,776 plasma protein targets, we identified 143 predictors of longevity, including MED9, strongly linked to diverse socio-behavioural exposures. These findings provide unique insights into which factors are likely to shape how we age, when in life they may be influential, and how biological effects emerge, informing healthy ageing promotion.
Longevity Relevance Analysis
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The paper identifies life course exposures that influence biological ageing and longevity through proteomic analysis. This research is relevant as it explores the underlying factors affecting the biological processes of aging, which is central to understanding longevity and promoting healthy aging.
Meneses-Plascencia, J., Moreno-Mendez, E., Ascencio, D. ...
· cell biology
· Cinvestav, Centro de Investigacion sobre el Envejecimiento, 14330 Tlalpan, Cd.Mx., Mexico
· biorxiv
The widely used antidiabetic drug metformin extends lifespan across diverse model organisms, from yeast to primates. However, the cellular mechanisms underlying its anti-aging effects remain only partially understood. Here, we combined large-scale genetic screening and high-resol...
The widely used antidiabetic drug metformin extends lifespan across diverse model organisms, from yeast to primates. However, the cellular mechanisms underlying its anti-aging effects remain only partially understood. Here, we combined large-scale genetic screening and high-resolution lifespan phenotyping with transcriptomic and proteomic analyses to provide a systems view of metformin\'s impact on the chronological lifespan of Saccharomyces cerevisiae. Unexpectedly, we uncovered pronounced gene-drug interactions between metformin and chromatin-modifying factors. Specifically, deletions of Set3C histone deacetylation complex subunits phenocopied the longevity effect of metformin, with no additive benefit when combined, suggesting convergence on shared pathways. Transcriptome profiling further revealed that metformin reprogrammed stationary-phase gene expression, with Ty1-copia retrotransposons emerging as a consistently induced signature, thereby suggesting a possible mechanism for the observed interactions with Set3C regulation. Paradoxically, TYA Gag-like protein levels and retrotransposition frequency were modestly reduced, indicating an uncoupling between transcriptional activation and retromobility. Proteome analysis revealed increased abundance of mitochondrial and stress-response proteins as primary outcomes of metformin exposure, both known modulators of Ty1 dynamics in yeast. Together, our findings position chromatin regulation and retrotransposon expression as integral components of metformin\'s pro-longevity mechanisms, expanding its influence beyond signaling, metabolism, and stress response.
Longevity Relevance Analysis
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The paper claims that metformin's longevity effects in yeast are linked to chromatin regulation and retrotransposon dynamics. This research is relevant as it explores potential mechanisms underlying lifespan extension, contributing to the understanding of aging processes.
Sen Zhang, Charles E Ayemoba, Anna M Di Staulo ...
· Blood
· University of Illinois at Chicago, Chicago, Illinois, United States.
· pubmed
Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the me...
Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
Longevity Relevance Analysis
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The paper claims that Platelet Factor 4 (PF4) can rejuvenate aged hematopoietic stem cells (HSCs) by restoring their youthful functional phenotypes. This research addresses mechanisms of HSC aging and suggests potential therapeutic strategies to reverse age-related decline, aligning with longevity research goals.
Sruthi Sivakumar, Ryan William LeFebre, Giulia Menichetti ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Department of Physical Medicine and Rehabilitation, University of Pittsburgh (U. Pitt.); Pittsburgh, USA.
· pubmed
Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middl...
Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; 'input message') and corresponding target genes (TG; 'output message'). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (ie, channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.
Longevity Relevance Analysis
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The paper claims that aging leads to a decline in communication efficiency between transcription factors and target genes in muscle cells. This research is relevant as it addresses the underlying mechanisms of aging at the cellular level, focusing on biomolecular communication, which could inform strategies for lifespan extension and understanding age-related cellular dysfunction.
Gebremeskel, S., Embile, I. B., Bazhanov, N. ...
· immunology
· Fibrobiologics Inc
· biorxiv
Thymic function can decline due to age-related involution, congenital disorders, acute infections or chemo/radiation therapy. Decline in thymic function leads to decreased T cell production and weakened immunity. To address these thymic insufficiencies, we sought to develop a tra...
Thymic function can decline due to age-related involution, congenital disorders, acute infections or chemo/radiation therapy. Decline in thymic function leads to decreased T cell production and weakened immunity. To address these thymic insufficiencies, we sought to develop a transplantable and scalable micro-organoid system using fibroblasts and thymic cells. We have developed a reliable and rapid method to generate thymic micro-organoids using selectively screened fibroblasts and murine thymic cells. The thymic micro-organoids are cryo-preservable, injectable, and give rise to T cells both in vitro and in vivo. Thymic organoids expressed key genes required to sustain T cell development and maturation: ccl25, dll-1, dll-4, foxn-1, il-7, scf. When injected into T cell-deficient Prkdcscid mice, the organoids gave rise to functional {beta}, {gamma}{delta}, natural killer T (NKT) cells, and FoxP3+ regulatory T cells. Organoid-derived T cells expressed a diverse T cell receptor (TCR) repertoire in vivo and respond to stimulation with anti-CD3/28, Concanavalin-A, or Phytohemagglutinin. Thymic organoids derived from pmel-1 thymocytes gave rise to V{beta}13+ T cells that delayed the growth of B16 melanoma and enhanced activation of T and NK cells. This approach presents a valuable tool for mechanistic studies and addressing current therapeutic gaps in diseases associated with thymic decline and insufficiencies.
Longevity Relevance Analysis
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The paper claims that a scalable micro-organoid system can generate functional T cells to address thymic insufficiencies. This research is relevant as it targets the decline in thymic function, which is a root cause of weakened immunity associated with aging.
Bari, K. A., Librais, G. N., Duennwald, M. L. ...
· cell biology
· The University of Western Ontario
· biorxiv
Impaired proteostasis is a hallmark of aging and is associated with several neurodegenerative diseases, including Huntington\'s Disease (HD) where the polyglutamine (polyQ) expanded Huntingtin aggregates to form insoluble inclusions bodies (IBs) associated with neurotoxicity. Chr...
Impaired proteostasis is a hallmark of aging and is associated with several neurodegenerative diseases, including Huntington\'s Disease (HD) where the polyglutamine (polyQ) expanded Huntingtin aggregates to form insoluble inclusions bodies (IBs) associated with neurotoxicity. Chronological lifespan (CLS) in yeast resembles many aspects of aging of non-dividing cells such as neurons. During chronological aging, acidification of the culture media due accumulation of acetic acid is one of the major cell-extrinsic factors contributing to age-related cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansion proteins display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and promotes longevity. We also found that growth at alkaline pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Our study thus provides new insight into how pH can promote proteotoxic stress resistance and longevity by modulating the HSR.
Longevity Relevance Analysis
(4)
Buffering media pH promotes proteostasis and extends lifespan in yeast models of polyglutamine toxicity. The study addresses the root cause of aging by exploring how extracellular pH influences proteostasis and longevity, which is directly relevant to aging research.
Watts, T., Johnston, H. E., Al-Mufti, Y. ...
· cell biology
· Signalling Programme, The Babraham Institute, Cambridge, UK
· biorxiv
Healthy protein homeostasis (\'proteostasis\') relies on tightly-regulated protein quality-control (PQC) circuits that co-ordinate sequestration and clearance of potentially toxic aggregation-prone proteins, arising from various internal or external stress throughout an organism\...
Healthy protein homeostasis (\'proteostasis\') relies on tightly-regulated protein quality-control (PQC) circuits that co-ordinate sequestration and clearance of potentially toxic aggregation-prone proteins, arising from various internal or external stress throughout an organism\'s lifespan. At the protein level, proteotoxic stress responses typically involve extensive poly-ubiquitylation and sequestration of aggregation-prone proteins and PQC factors into various protective cytoplasmic and nuclear granules. However, much of our current understanding regarding this aspect of stress responses in humans stems from research in proliferating cells--despite growing evidence that stress responses vary considerably at the transcriptional level across cell proliferation states. Here, we show that the senescent cellular state--considered a major contributor to ageing-associated degeneration due to a chronic inflammatory phenotype--re-wires PQC and expels the misfolded protein load to mitigate proteotoxic stresses. Starting with a multi-dimensional transcriptomics and proteomics approach for measuring levels of total, poly-ubiquitylated, and granule-forming proteins, we have discovered a clear point of divergence between senescent and proliferating or quiescent human cell states in their responses to proteotoxic stress. Although the proteins that were poly-ubiquitylated and degraded during stress were largely conserved across states, the stress-induced sedimentation of a large number of disease-associated RNA-binding proteins (including TDP-43) was impaired only in the senescent state. Strikingly, TDP-43, as well as several other misfolded proteins, were actively secreted through the endo-lysosomal system by a diverse range of senescent cells during acute or chronic stress, through a process that requires the vesicle-associated HSP70 co-chaperone DNAJC5--an established risk factor for several neurodegenerative diseases. Misfolded protein secretion could be rescued by increasing intracellular HSP levels in \'shallow\' but not \'deep\' senescence, suggesting that secretion is a proteostatic adaptation that becomes less reversible over time. Our findings reveal an unappreciated aspect of the senescent-cell secretory phenotype, which may have important consequences for the non-cell-autonomous impact of senescence at the level of tissue resilience and frailty.
Longevity Relevance Analysis
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The paper claims that senescent cells expel misfolded proteins to mitigate proteotoxic stress, revealing a novel aspect of the senescent-cell secretory phenotype. This research addresses the mechanisms underlying cellular senescence, which is a significant contributor to aging and age-related degeneration, thus providing insights into potential interventions for longevity.
Eun-Sun Yang, Se-Yun Cheon, Ji Yeong Park ...
· BMB reports
· Research Institute for Korean Medicine, Pusan National University, Yangsan 50612, Korea.
· pubmed
Lipid metabolism plays an important role in aging and longevity, and lipophagy-a specialized form of autophagy that targets lipid vesicles-regulates lipid homeostasis and alleviates metabolic diseases such as metabolic dysfunctionassociated steatotic liver disease (MASLD). Ilimaq...
Lipid metabolism plays an important role in aging and longevity, and lipophagy-a specialized form of autophagy that targets lipid vesicles-regulates lipid homeostasis and alleviates metabolic diseases such as metabolic dysfunctionassociated steatotic liver disease (MASLD). Ilimaquinone (IQ), a sesquiterpene extracted from the sea, is well-known for its various biological effects; however, its effects on lipid metabolism and longevity have not yet been elucidated. In this study, IQ acted in a dose-dependent manner, extending the lifespan of Caenorhabditis elegans (C. elegans) by up to 50%, causing transcriptional changes in 1,878 genes related to fatty acid degradation and longevity pathways. Additionally, IQ reduced lipid accumulation in C. elegans and mouse AML12 cells, as confirmed by Oil Red O staining. RNA sequencing and quantitative reverse transcription polymerase chain reaction validation showed that the expression of key lipid metabolism genes, such as lipl-4 in worms and Lipa in mammalian cells, increased with IQ treatment. Lipophagy has been identified as the key mechanism underlying the lipid-lowering effects of IQ. The inhibition of autophagy by Bafilomycin A1 reversed the reduction in lipid accumulation in both C. elegans and AML12 cells, indicating the involvement of autophagic flux. Western blot analysis demonstrated that IQ activates AMPK, a key regulator of autophagy and lipid metabolism, and inhibits mTOR. IQ increased the turnover of LC3-II and decreased p62 levels, confirming autophagosome formations and increased lysosomal degradation. These findings suggest that IQ promotes autophagy, alleviates lipid accumulation, and has a therapeutic potential for metabolic diseases. In addition, AMPK activation and mTOR inhibition pathways may have contributed to the extension of C. elegans lifespan. Future studies should investigate the potential of IQ in lipid metabolism regulation and lifespan extension.
Longevity Relevance Analysis
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Ilimaquinone promotes lipophagy and extends lifespan in C. elegans through AMPK activation. The study addresses mechanisms of lipid metabolism and autophagy that are directly linked to aging and longevity, making it relevant to the field of longevity research.
Kehan Zhang, Xiangyao Wang, Yuxiao Zhang ...
· Journal of clinical periodontology
· Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
· pubmed
To investigate the functional significance of mitophagy in age-related osteogenic decline and the underlying mechanisms using in vivo and in vitro models.
To investigate the functional significance of mitophagy in age-related osteogenic decline and the underlying mechanisms using in vivo and in vitro models.
Longevity Relevance Analysis
(4)
The paper claims that Parkin acetylation-mediated mitophagy plays a crucial role in osteogenesis and bone regeneration during aging. This research addresses mechanisms related to age-related decline in osteogenesis, which is pertinent to understanding and potentially mitigating aspects of aging.
Cassandra Malecki, Giovanni Guglielmi, Benjamin Hunter ...
· Aging cell
· School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
· pubmed
Ageing is one of the most significant risk factors for heart disease; however, it is still not clear how the human heart changes with age. Taking advantage of a unique set of pre-mortem, cryopreserved, non-diseased human hearts, we performed omics analyses (transcriptomics, prote...
Ageing is one of the most significant risk factors for heart disease; however, it is still not clear how the human heart changes with age. Taking advantage of a unique set of pre-mortem, cryopreserved, non-diseased human hearts, we performed omics analyses (transcriptomics, proteomics, metabolomics, and lipidomics), coupled with biologically informed computational modelling in younger (≤ 25 years old) and older hearts (≥ 50 years old) to describe the molecular landscape of human cardiac ageing. In older hearts, we observed a downregulation of proteins involved in calcium signalling and the contractile apparatus. Furthermore, we found a potential dysregulation of central carbon generation of fuel, glycolysis, and fatty acids oxidation, along with an increase in long-chain fatty acids. This study presents and analyses the first molecular data set of normal human cardiac ageing, which has relevant implications for understanding the human cardiac ageing process and the development of age-related heart disease.
Longevity Relevance Analysis
(4)
The study identifies age-specific molecular changes in the human heart that contribute to understanding cardiac aging. This research is relevant as it explores the underlying molecular mechanisms of aging in the heart, which could inform strategies for addressing age-related heart disease.
Gizowski, C., Popova, G., Shin, H. ...
· neuroscience
· Calico Life Sciences
· biorxiv
Aging, the key risk factor for cognitive decline, impacts the brain in a region-specific manner, with microglia among the most affected cell types. However, it remains unclear whether this is intrinsically mediated or driven by age-related changes in neighboring cells. Here, we d...
Aging, the key risk factor for cognitive decline, impacts the brain in a region-specific manner, with microglia among the most affected cell types. However, it remains unclear whether this is intrinsically mediated or driven by age-related changes in neighboring cells. Here, we describe a scalable, genetically modifiable system for in vivo heterochronic myeloid cell replacement. We find reconstituted myeloid cells adopt region-specific transcriptional, morphological and tiling profiles characteristic of resident microglia. Young donor cells in aged brains rapidly acquired aging phenotypes, particularly in the cerebellum, while old cells in young brains adopted youthful profiles. We identified STAT1-mediated signaling as one axis controlling microglia aging, as STAT1-loss prevented aging trajectories in reconstituted cells. Spatial transcriptomics combined with cell ablation models identified rare natural killer cells as necessary drivers of interferon signaling in aged microglia. These findings establish the local environment, rather than cell-autonomous programming, as a primary driver of microglia aging phenotypes.
Longevity Relevance Analysis
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The paper claims that the local brain environment is a primary driver of microglia aging phenotypes rather than intrinsic cellular programming. This research is relevant as it addresses the mechanisms of aging at the cellular level, specifically focusing on microglia, which are crucial for brain health and cognitive function in the context of aging.
Catlin, J. P., Fraher, S., Alexander, J. J. ...
· neuroscience
· State University of New York at Buffalo
· biorxiv
It is widely thought that age-related damage is the single biggest contributing factor to neurodegenerative diseases. However, recent studies are beginning to indicate that many of these diseases may have developmental origins that become unmasked overtime. It has been difficult ...
It is widely thought that age-related damage is the single biggest contributing factor to neurodegenerative diseases. However, recent studies are beginning to indicate that many of these diseases may have developmental origins that become unmasked overtime. It has been difficult to prove these developmental origins, as there are still few known links between defective embryonic neurogenesis and progressive neurodegeneration. We have created a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 (Nrmt1-/- mice). Nrmt1-/- mice display phenotypes associated with premature aging. Specifically in the brain, they exhibit age-related striatal and hippocampal degeneration, which is accompanied by impaired short and long-term memory. These phenotypes are preceded by depletion of the postnatal neural stem cell (NSC) pools, which appears to be driven by their premature differentiation and migration. However, this differentiation is often incomplete, as many resulting neurons cannot permanently exit the cell cycle and ultimately undergo apoptosis. Here, we show that the onset of apoptosis corresponds to increased cleavage of p35 into the CDK5 activator p25, which can promote neuroinflammation. Accordingly, Nrmt1-/- brains exhibit an increase in pro-inflammatory cytokine signaling, astrogliosis, complement activation, microgliosis, and markers of a compromised blood brain barrier, all of which indicate an activated neuroimmune response. We also find Nrmt1-/- mice do not activate a corresponding anti-inflammatory response. These data indicate that abnormal neurogenesis can trigger neuroinflammation, which in the absence of compensatory anti-inflammatory signaling, could lead to neuronal apoptosis and progressive neurodegeneration.
Longevity Relevance Analysis
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Abnormal neurogenesis in Nrmt1-/- mice triggers neuroinflammation, leading to neuronal apoptosis and progressive neurodegeneration. This paper is relevant as it explores the developmental origins of neurodegeneration and links neuroinflammation to aging-related processes, addressing potential root causes of age-related diseases.
Fernandez Ugidos, I., Calvo Iglesias, J., Milanes, S. ...
· neuroscience
· Tulane University
· biorxiv
Healthy aging is accompanied by a gradual decline in higher-order cognitive functions, including working memory, attention, and cognitive flexibility, processes that critically rely on intact frontal cortical circuits. While neuronal loss is minimal during aging, whether there ar...
Healthy aging is accompanied by a gradual decline in higher-order cognitive functions, including working memory, attention, and cognitive flexibility, processes that critically rely on intact frontal cortical circuits. While neuronal loss is minimal during aging, whether there are changes in functional plasticity in this region remains unexplored. In this regard, dendritic spines, the primary postsynaptic structures of excitatory synapses, act as key hubs for experience-dependent synaptic remodeling. Using longitudinal in vivo two-photon imaging in Thy1-eGFP-M mice, we examined age-related changes in dendritic spine density and dynamics in layer 5 pyramidal neurons of the secondary motor area (MOs), a frontal cortical region essential for strategy switching and cognitive flexibility, and that was assessed using an operant conditioning paradigm. We found that aged mice (18 to 22 months) exhibited significant impairments in cognitive flexibility relative to young mice (3 to 5 months) in the four-odor choice discrimination and reversal task. Analysis of dendritic spine plasticity revealed that baseline spine density, turnover, and morphology were largely preserved in aged mice. Sex differences were evident, with females displaying higher spine density and a greater fraction of stable spines, a feature maintained across aging. Importantly, despite preserved baseline architecture, aged mice showed impaired ketamine-induced spinogenesis and reduced stabilization of newly formed spines, in contrast to the robust structural plasticity observed in young mice. These results indicate that healthy aging selectively impairs activity-dependent synaptic remodeling without affecting steady-state spine architecture in frontal cortical circuits. By linking deficits in induced synaptic plasticity to age-related impairments in cognitive flexibility, our study highlights the critical need to target plasticity mechanisms as a therapeutic strategy to restore executive function and cognitive adaptability in the aging brain.
Longevity Relevance Analysis
(4)
Healthy aging impairs ketamine-induced synaptic plasticity in layer 5 pyramidal neurons, affecting cognitive flexibility. The study addresses the mechanisms of synaptic plasticity in the aging brain, which is crucial for understanding and potentially mitigating age-related cognitive decline.
Tartrate-resistant acid phosphatase (TRAP/ACP5), primarily known as an osteoclast marker, has emerged as a critical regulator of skeletal integrity, regulating sex-specific bone growth, and bones response to mechanical load in young adult male mice. In this study, we investigated...
Tartrate-resistant acid phosphatase (TRAP/ACP5), primarily known as an osteoclast marker, has emerged as a critical regulator of skeletal integrity, regulating sex-specific bone growth, and bones response to mechanical load in young adult male mice. In this study, we investigated the sex-specific roles of TRAP in bone structure and response to mechanical stimuli in old (19-month-old) wild-type (WT) and TRAP-deficient (TRAP-/-) mice using micro-computed tomography, serum bone turnover markers, in vivo axial mechanical loading, and in vitro mechanotransduction assays. Our findings revealed that TRAP-/- mice of both sexes maintained shorter tibiae than WT mice independent of sex. Notably, male, but not female, TRAP-/- mice have increased trabecular bone volume fraction and cortical bone area compared to WT, indicative of disrupted bone remodelling processes in male mice. Interestingly, TRAP-deficiency substantially impaired the anabolic bone response to mechanical loading, affecting both trabecular and cortical compartments in both sexes, indicating that when challenged, TRAP is important for bone formation also in female mice. Mechanical stimulation in vitro of hematopoietic progenitor cells from WT and TRAP-/- mice revealed that the increased ATP-release in response to mechanical stimulation was only disrupted in male mice, while mechanically induced increase in osteoclast formation was inhibited in TRAP-/- mice of both sexes. These results highlight the importance of TRAP in maintaining trabecular architecture and cortical bone in male mice and underscore its critical function in mediating adaptive responses to mechanical loading of both sexes, during aging. Future investigations should focus on elucidation of TRAP-dependent pathways as potential therapeutic targets to counteract age-related deficits in bone adaptation and remodelling.
Longevity Relevance Analysis
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The study claims that TRAP is crucial for maintaining bone structure and mediating responses to mechanical loading in aging mice. This research is relevant as it explores the role of TRAP in bone maintenance, which is a critical aspect of age-related skeletal integrity and could inform therapeutic strategies for age-related bone loss.
Daisy Sproviero, César Payán-Gómez, Chiara Milanese ...
· Nature aging
· IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
· pubmed
Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to in...
Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression.
Longevity Relevance Analysis
(4)
The paper claims that a blood-based DNA damage signature can predict disease severity in Parkinson's disease. This research is relevant as it explores an aging-related mechanism in the pathogenesis of Parkinson's disease, linking DNA damage to disease progression and potentially offering insights into age-related diseases.
Ibrahim, R., Froschauer, C., Broschk, S. ...
· genetics
· University of Glasgow
· biorxiv
The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signal...
The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is leading example, which can extend healthy lifespan in a range of animals; but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess "mito-nuclear" epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as gatekeeper.
Longevity Relevance Analysis
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Reduced insulin signaling can have varying effects on lifespan depending on the genetic combination of mitochondrial and nuclear DNA. This study is relevant as it explores the genetic factors influencing lifespan extension through insulin signaling, a key mechanism in aging research.
Holthusen, H., Trinkaus, V. A., Fernandez Gonzalez, C. ...
· cell biology
· Max Planck Institute for Biochemistry
· biorxiv
Protein aggregation in various cellular compartments is a hallmark of proteostasis impairment linked to aging and numerous pathologies. Mitochondrial function depends on a balanced interplay of proteins imported from the cytosol as well as those synthesized on mitochondrial ribos...
Protein aggregation in various cellular compartments is a hallmark of proteostasis impairment linked to aging and numerous pathologies. Mitochondrial function depends on a balanced interplay of proteins imported from the cytosol as well as those synthesized on mitochondrial ribosomes (mitoribosomes). Here, we reveal an unexpected susceptibility of mitoribosome biogenesis to organellar proteostatic stress. Importing aggregation-prone proteins into yeast and human mitochondria triggered a chain of detrimental events involving extensive co-aggregation of newly-imported mitoribosome subunits and other RNA-binding proteins, as well as local disruption of mitochondrial cristae morphology. As a result, mitoribosome assembly and mitochondrial translation were severely impaired, leading to respiratory deficiency and, ultimately, loss of mitochondrial DNA. Surprisingly, dysfunction of mitochondrial HSP60 phenocopied the ribosome biogenesis defect and inhibition of translation, indicating a pronounced chaperone dependence of mitoribosome proteins. Declining mitochondrial translation likely contributes to aging and diseases associated with deficiencies in mitochondrial protein quality control machinery.
Longevity Relevance Analysis
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Mitochondrial proteostatic stress disrupts mitoribosome biogenesis and translation. The study addresses the underlying mechanisms of mitochondrial dysfunction, which is a critical factor in aging and age-related diseases, suggesting that improving mitochondrial protein quality control could have implications for longevity.
A O Esemezie, D J Lizotte, G Tsakos ...
· Journal of dental research
· Dentistry, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
· pubmed
The fundamental cause theory posits social factors as causes of disease as they encompass access to important resources such as knowledge, wealth, and social networks. While these social factors have been consistently associated with oral and systemic diseases, causality remains ...
The fundamental cause theory posits social factors as causes of disease as they encompass access to important resources such as knowledge, wealth, and social networks. While these social factors have been consistently associated with oral and systemic diseases, causality remains unestablished. Here, we estimated the causal effect of social adversity, comprising low economic and social capital, on the development of (1) oral conditions (OC) and (2) multimorbidity including oral conditions (MIOC) in a cohort of middle-aged and older adults over a 7-y period and assessed whether effects varied by age or gender. We analyzed 2 waves from the Canadian Longitudinal Study on Aging (CLSA) (2011 and 2018). Social adversity comprised low economic (income) and social capital (community participation, social relationships). OC was defined as having 1 or more of poor self-reported oral health, lack of functional dentition (<20 natural teeth), or edentulism. Participants with an OC at baseline were excluded. MIOC was defined as having 2 or more chronic diseases and an OC. Logistic marginal structural models with inverse probability weighting estimated the causal odds ratio (OR) of developing both outcomes, controlling for sociodemographic and behavioral factors. In a total of 23,366 participants, 14% experienced social adversity at baseline, with a prevalence of 17% OC and 7% MIOC at follow-up. Social adversity significantly increased the odds of developing OC (OR = 1.9, 95% confidence interval [CI] 1.7, 2.2) and MIOC (OR = 1.7, 95% CI 1.5, 2.0) at follow-up. The observed effects were strongest in the middle-aged group, with similar odds observed in both men and women. Our findings indicate that social and economic capital are causally linked to the development of OC and MIOC over time. We suggest that policies for healthy aging should prioritize action on social and living conditions.
Longevity Relevance Analysis
(4)
Social adversity causally increases the odds of developing oral conditions and multimorbidity in middle-aged and older adults. The paper is relevant as it addresses social determinants of health, which are critical factors influencing aging and longevity outcomes.
Itai, S., Usami, R., Korekata, M. ...
· bioengineering
· Tohoku University
· biorxiv
Vascular aging contributes to multisystem diseases and limits health span. Although various animal models have contributed to aging research, their vasculatures poorly recapitulate human physiology. Even existing tissue-engineered blood vessels fail to mimic human vascular functi...
Vascular aging contributes to multisystem diseases and limits health span. Although various animal models have contributed to aging research, their vasculatures poorly recapitulate human physiology. Even existing tissue-engineered blood vessels fail to mimic human vascular function and pathology, hindering translational advances in vascular aging studies. Here, we present a novel human physiological vascular model fabricated via the unique molding-induced circumferential alignment of human induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells with luminally seeded endothelial cells. This architecture enabled dynamic vasodiameter changes in response to vasoactive stimuli, including hormones and intraluminal pressure. Using iPSCs from a patient with Werner syndrome, the model recapitulated aging-associated phenotypes, such as hypercontractility and increased vascular compliance, possibly due to impaired nitric oxide bioavailability. Transcriptomic and metabolomic analyses revealed age-related dysregulation consistent with vascular senescence. As a key advantage of the vasculature, spatial transcriptomic analysis demonstrated upregulation of the aging marker CDKN1A near the lumen and downregulation of COL6A1 and TPM1 throughout the vessel. Treatment with mitochonic acid 5, a mitochondria-targeted compound, significantly reversed the aging phenotypes. These findings demonstrate that our engineered vascular model recapitulates key aspects of human vascular properties and provides a platform for mechanistic studies of vascular aging and drug discovery aimed at extending health span.
Longevity Relevance Analysis
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The paper presents a novel human physiological vascular model that recapitulates aging-associated phenotypes and provides a platform for studying vascular aging and drug discovery. This research is relevant as it addresses the mechanisms of vascular aging, which is a root cause of age-related diseases and health span limitations.
Gao-Hong Zhu, Rui He, Zhi-Yu Yang ...
· Brain : a journal of neurology
· Department of Nuclear Medicine, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.
· pubmed
The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) along...
The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioral assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HC aging and these glycosyltransferases as therapeutic targets against cognitive decline.
Longevity Relevance Analysis
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The paper claims that STT3A and ALG5 play critical roles in maintaining glucose metabolism in the aged hippocampus, which is essential for cognitive function. The research addresses mechanisms underlying metabolic resilience in aging, contributing to our understanding of age-related cognitive decline and potential therapeutic targets.
Jian Liu, Mingjie Rong, Chen Liu ...
· ACS nano
· State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.
· pubmed
Cellular senescence is a critical factor in organismal aging and age-related diseases. Nicotinamide adenine dinucleotide (NAD
Cellular senescence is a critical factor in organismal aging and age-related diseases. Nicotinamide adenine dinucleotide (NAD
Longevity Relevance Analysis
(4)
The paper claims that targeting senescence and recycling NAD can attenuate senescence-associated phenotypes. This research is relevant as it addresses cellular senescence, a fundamental mechanism of aging, and explores potential interventions that could mitigate age-related decline.
Sarah Al-Dulaimi, Ross Thomas, Sheila Matta ...
· Telomerase
· Centre for Genome Engineering and Maintenance, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK.
· pubmed
Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between telomere length and aging-related di...
Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between telomere length and aging-related diseases. Therefore, telomeres are considered to be one of the biomarkers of aging, and increasing or maintaining telomere length may contribute to healthy aging and longevity. Epitalon has been the subject of several anti-aging studies however, quantitative data on the biomolecular pathway leading to telomere length increase, hTERT mRNA expression, telomerase enzyme activity, and ALT activation have not been extensively studied in different cell types. In this article, the breast cancer cell lines 21NT, BT474, and normal epithelial and fibroblast cells were treated with epitalon then DNA, RNA, and proteins were extracted. qPCR and Immunofluorescence analysis demonstrated dose-dependent telomere length extension in normal cells through hTERT and telomerase upregulation. In cancer cells, significant telomere length extension also occurred through ALT (Alternative Lengthening of Telomeres) activation. Only a minor increase in ALT activity was observed in Normal cells, thereby showing that it was specific to cancer cells. Our data suggests that epitalon can extend telomere length in normal healthy mammalian cells through the upregulation of hTERT mRNA expression and telomerase enzyme activity.
Longevity Relevance Analysis
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Epitalon can extend telomere length in normal healthy mammalian cells through the upregulation of hTERT mRNA expression and telomerase enzyme activity. The paper addresses the potential of a compound to influence telomere length, which is directly linked to aging and longevity, making it relevant to the study of aging and lifespan extension.
Xin Shen, Xianzhi Gao, Lie Wang
· Acta biochimica et biophysica Sinica
· Co-Facility Center, Zhejiang University School of Medicine, Hangzhou 310058, China.
· pubmed
Intestinal immunosenescence, a hallmark of organismal aging, has emerged as a critical biological process impacting the health of elderly individuals. This review systematically examines the core mechanisms underlying intestinal immunosenescence, including immune cell dysfunction...
Intestinal immunosenescence, a hallmark of organismal aging, has emerged as a critical biological process impacting the health of elderly individuals. This review systematically examines the core mechanisms underlying intestinal immunosenescence, including immune cell dysfunction, imbalances in immune-microbiota interactions, and impaired barrier function. We analyze its associations with infectious diseases, chronic inflammation, and neurodegenerative disorders, summarizing recent advances in dietary interventions, microecological therapy, and other emerging strategies. By integrating cutting-edge technologies, we prospect the development of precision interventions aimed at delaying intestinal immunosenescence, thereby providing a theoretical basis for improving the healthspan of the aging population.
Longevity Relevance Analysis
(4)
The paper claims that understanding and intervening in intestinal immunosenescence can improve healthspan in the aging population. This research is relevant as it addresses the underlying mechanisms of aging and seeks to develop interventions that could potentially mitigate age-related decline rather than merely treating symptoms.
Sarah M Chang, Latisha P Franklin, Sampurna Sattar ...
· Genetics
· Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
· pubmed
Mitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remain unclear. Here, we uncover a physiological role for the C. elegans mitochondri...
Mitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remain unclear. Here, we uncover a physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using genetic alleles with deletions that destroy catalytic activity, we demonstrate that sir-2.2 and sir-2.3 mutants live an average of 25% longer than controls when fed the normal lab diet of live E. coli OP50. While decreased consumption of food is a known mechanism for lifespan extension, we did not find evidence of reduced pharyngeal pumping. Interestingly, lifespan extension effected by loss of sir-2.2 or sir-2.3 is sensitive to the diet. The lifespan extension of the sir-2.2 mutants is eliminated and that of sir-2.3 mutants is attenuated when the animals are fed the E. coli strain HT115, which is typically used for RNAi experiments. We used growth ability of the food source and a virulent pathogenic strain to ask if differences in pathogenicity are related to the mechanisms for lifespan extension. sir-2.3 deletion results in lifespan extension in all conditions. However, removing the ability of the food source to grow eliminated the sir-2-mediated effect. We also examine the response of the mutants to oxidative stress, and our results suggest that a hormetic response contributes to lifespan extension in both mutants. Our data suggest that sir-2.2 and sir-2.3 use overlapping yet distinct mechanisms for regulating lifespan.
Longevity Relevance Analysis
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The paper claims that mitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans through distinct mechanisms. This research is relevant as it investigates the physiological role of specific genes in lifespan regulation, contributing to our understanding of the biological mechanisms underlying aging.
Anam Naseer, Pranoy Toppo, Mahmood Akbar ...
· Disease models & mechanisms
· Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
· pubmed
Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology...
Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavored to study the functional implications of mitochondrial sirtuin, sir-2.2 (ortholog of human SIRT4), in regulating neuroprotection employing Caenorhabditis elegans model. We observed that upon sir-2.2 knockdown, the alpha-synuclein aggregation was increased and expression of dopamine transporter, dat-1, was reduced. Also, the levels of marker proteins for innate immunity, oxidative stress, mitophagy, UPRmt, and autophagy, were decreased, suggesting an important function of sir-2.2 in maintaining mitochondrial homeostasis, regulating protein clearance and ameliorating the disease condition. Because of their crucial role in regulating oxidative stress and mitochondrial quality control, studying mitochondrial sirtuin will provide therapeutic insights into the metabolic regulation of ageing and neurodegeneration.
Longevity Relevance Analysis
(4)
The paper claims that knockdown of mitochondrial sirtuin sir-2.2 leads to increased alpha-synuclein aggregation and impaired energy homeostasis in C. elegans. This research is relevant as it explores the role of sirtuins in mitochondrial function and their potential implications for aging and neurodegenerative diseases, addressing mechanisms that could underlie age-related decline.
Yunqi Xing, Junfeng Zhu
· International journal of molecular medicine
· Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China.
· pubmed
Cellular senescence, a hallmark of aging, is characterized by irreversible, permanent cell cycle arrest accompanied by halted proliferation triggered by endogenous or exogenous stimuli. The accumulation of senescent cells in tissues or organs elicits detrimental effects on adjace...
Cellular senescence, a hallmark of aging, is characterized by irreversible, permanent cell cycle arrest accompanied by halted proliferation triggered by endogenous or exogenous stimuli. The accumulation of senescent cells in tissues or organs elicits detrimental effects on adjacent normal cells through their pathogenic senescence‑associated secretory phenotype (SASP), driving secondary senescence, disrupting tissue homeostasis and ultimately exacerbating age‑related pathologies such as types of cancer and neurodegenerative disorders. Hepatic disorders constitute a leading cause of global mortality, imposing considerable healthcare burdens. Robust clinical evidence has now demonstrated a strong correlation between cellular senescence and poor clinical outcomes in various hepatopathies. This intricate yet critical signaling network is dynamically regulated in both physiological homeostasis and chronic hepatic inflammatory conditions. Notably, recent years have witnessed extensive research into pharmacological strategies to deplete senescent cells, inhibit SASP, and target other senescence markers across diverse contexts, thereby establishing the field of senotherapeutics. The present review systematically summarized key molecular pathways and biomarkers of hepatic senescence, while outlining the emerging role of cellular senescence in inflammatory liver disorders. It also discussed the therapeutic potential of senescence‑regulating drugs for liver disease, which could alleviate hepatic inflammation and enhance clinical outcomes.
Longevity Relevance Analysis
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The paper discusses the role of cellular senescence in hepatic diseases and the potential of senotherapeutics to improve clinical outcomes. This research is relevant as it addresses the underlying mechanisms of aging-related pathologies and explores therapeutic strategies that could mitigate age-related liver diseases.
Antoine M Dujon, Klara Asselin, Jean François Lemaître ...
· Aging cell
· CREEC/CANECEV, MIVEGEC (CREES) Department, University of Montpellier, CNRS, IRD, Montpellier, France.
· pubmed
Aging, and by extension age-related diseases, has traditionally been understood through classical evolutionary genetic models, such as the mutation accumulation and antagonistic pleiotropy theories. However, these frameworks primarily focus on the declining efficacy of organismal...
Aging, and by extension age-related diseases, has traditionally been understood through classical evolutionary genetic models, such as the mutation accumulation and antagonistic pleiotropy theories. However, these frameworks primarily focus on the declining efficacy of organismal-level selection against mutations with deleterious effects in late life. Here, we propose a novel hypothesis: many chronic diseases associated with aging may emerge, at least in part, as a result of selection acting at lower organizational levels, including non-replicative biological entities, enabled by the relaxation of selective pressures that constrained within-organism evolutionary processes in early life. This hypothesis is built on the recently proposed concept of selection for function that extends the evolutionary process to non-replicative entities. While Darwinian selection acting at the organismal level strongly constrains within-organism evolution during an organism's reproductive lifespan, these constraints weaken with age. As a consequence, lower-level non-replicative entities, such as benign and malignant tumors, atherosclerotic plaques, and neurodegenerative aggregates, may experience a form of selection that favors those with increased stability, organization, and long-term persistence, sometimes at the cost to host fitness. These entities do not evolve via long-term differential reproduction, but rather certain configurations of their structure persist preferentially over others due to environmental constraints, microenvironmental selection, and internal stabilization mechanisms. Understanding aging through the lens of selection for function at the level of internal non-replicative entities provides new insights into the evolution of chronic diseases and opens novel therapeutic avenues aimed at disrupting internal functional organization, rather than merely targeting cellular proliferation/abnormalities or disease symptoms.
Longevity Relevance Analysis
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The paper proposes that chronic diseases associated with aging may arise from selection acting at lower organizational levels, such as non-replicative biological entities. This perspective offers insights into the underlying mechanisms of aging and chronic diseases, potentially guiding novel therapeutic approaches that address root causes rather than just symptoms.
Zhihua Huang, Xinxin Liu, Xiaojia Zhou ...
· Aging cell
· Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, China.
· pubmed
The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS...
The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy significantly reduced SNC burden in diverse tissues, improved physiological function, and attenuated progression of age-related conditions including osteoporosis, atherosclerosis, and non-alcoholic fatty liver disease. Our findings establish concurrent targeting of extracellular and intracellular Asn supplies as a potent, selective senolytic strategy with broad therapeutic potential for age-related disorders.
Longevity Relevance Analysis
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The paper claims that a combination of L-asparaginase and autophagy inhibitors can selectively eliminate senescent cells by targeting their unique dependence on asparagine. This research is relevant as it addresses a root cause of aging by proposing a novel senolytic strategy that could potentially mitigate age-related diseases through the removal of senescent cells.
Zhou, Y., Ahsan, F., Li, S. ...
· molecular biology
· Massachusetts General Hospital and Harvard Medical School
· biorxiv
Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon horm...
Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. In this study, we identified histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. The increase in H3K27ac, mediated by pioneer factor PHA-4/FOXA and cooperating transcription factor NHR-49/HNF4, is crucial for lifespan extension under hermetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch that bridges nutrient status with transcriptomic reprogramming, underpinning the pro-longevity effects of hormetic fasting through orchestrating lipid catabolism and antioxidative defenses.
Longevity Relevance Analysis
(5)
The paper claims that histone H3K27ac mediates the effects of hormetic nutrient stress on lifespan extension through enhanced lipid catabolism and antioxidant defenses. This research is relevant as it explores the underlying mechanisms of aging and longevity, specifically how nutrient stress can influence gene expression to promote healthier aging.
Herzog, C. M. S., Vavourakis, C. D., Theeuwes, B. ...
· systems biology
· Universitaet Innsbruck
· biorxiv
Smoking is one of the single most important preventable risk factors for cancer and other adverse health outcomes [1,2]. Smoking cessation represents a key public health intervention with the potential to reduce its negative health outcomes [2-4]. While epidemiological, cross-sec...
Smoking is one of the single most important preventable risk factors for cancer and other adverse health outcomes [1,2]. Smoking cessation represents a key public health intervention with the potential to reduce its negative health outcomes [2-4]. While epidemiological, cross-sectional, and individual longitudinal \'omic\' or biomarker studies have evaluated the impact of smoking cessation, no study to date has systematically profiled molecular and clinical changes in several organ systems or tissues longitudinally over the course of smoking cessation that could allow for more detailed assessment of response biomarkers and the identification of interindividual differences in the recovery of physiological functions. Here, we report the first human longitudinal multi-omic study of smoking cessation, evaluating 2,501 unique single or composite features from 1,094 longitudinal samples. Our comprehensive analysis, leveraging over half a million longitudinal data points, revealed a profound effect of smoking cessation on epigenetic biomarkers and microbiome features across multiple organ systems within 6 months of smoking cessation, alongside shifts in the immune and blood oxygenation system. Moreover, our multi-omic analysis provided unprecedented granularity that allows for identification of new cross-ome associations for mechanistic discovery. We anticipate that data and an interactive app from the Tyrol Lifestyle Atlas (eutops.github.io/lifestyle-atlas), comprising the current study and a parallel study arm evaluating the impact of diet on biomarkers of health and disease, will provide the basis for future discovery, biomarker benchmarking in their responsiveness to health-promoting interventions, and study of individualised response group, representing a major advance for personalised health monitoring using biomarkers.
Longevity Relevance Analysis
(5)
The paper claims that smoking cessation leads to significant molecular and clinical changes across multiple organ systems within six months. This research is relevant as it explores the biological mechanisms of recovery and health improvement following smoking cessation, which can contribute to understanding aging processes and promoting longevity.
Herzog, C. M. S., Vavourakis, C. D., Theeuwes, B. ...
· systems biology
· Universitaet Innsbruck
· biorxiv
While intermittent fasting (IF) promotes longevity in animal models, its systemic effects in humans remain poorly understood. Here, we present a six-month longitudinal IF intervention in 114 women (BMI 25-35) with deep clinical, molecular, and microbiome profiling across >3,400 b...
While intermittent fasting (IF) promotes longevity in animal models, its systemic effects in humans remain poorly understood. Here, we present a six-month longitudinal IF intervention in 114 women (BMI 25-35) with deep clinical, molecular, and microbiome profiling across >3,400 biospecimens from six tissues. Analyses spanning >2,200 multi-omic features and 11,000 microbial function predictions demonstrate coordinated clinical benefits, including improvements in body composition and cardiorespiratory fitness, and reveal coordinated molecular responses across tissues. Iron metabolism emerged as a central axis: transferrin increased while ferritin, haemoglobin, and erythrocytes decreased, changes that opposed ageing trajectories yet remained within physiological limits. Epithelial DNA methylation biomarkers (cervical, buccal) of cancer risk reduced, while blood clocks were largely unresponsive, underscoring tissue-specificity of the epigenome. Immune profiling uncovered dynamic, partially reversible shifts. Notably, we derived a new immunophenotyping-based ImmuneAge score that increased during fasting and tracked with inflammatory function, while the pro-inflammatory cytokine IL-17A declined selectively in postmenopausal women. Oral microbiota showed rapid restructuring, whereas gut microbiota shifted more subtly toward enhanced metabolic capacity. Together, these data provide unprecedented insight into the systemic and tissue-specific responses to IF in humans and identify iron homeostasis and immune remodelling as candidate mechanisms. Our findings are available through the Lifestyle Atlas (https://eutops.github.io/lifestyle-atlas).
Longevity Relevance Analysis
(5)
The paper claims that intermittent fasting induces systemic multi-omic remodelling that promotes health benefits and opposes aging trajectories. This research is relevant as it explores the mechanisms by which intermittent fasting may influence biological processes associated with aging and longevity, rather than merely addressing age-related diseases.
Seda Koyuncu, Yaiza Dominguez-Canterla, Rafael Alis ...
· Nature aging
· Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. [email protected].
· pubmed
Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link t...
Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington's disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.
Longevity Relevance Analysis
(5)
The paper claims that targeting EPS8 and its regulatory mechanisms can prevent protein aggregation and extend longevity. This research is relevant as it addresses the underlying mechanisms of aging and their connection to neurodegenerative diseases, suggesting potential therapeutic strategies for age-related conditions.
Bridge, J. E., Xia, C., Zheng, C. ...
· genomics
· University of Minnesota
· biorxiv
Accurate detection of somatic mutations in noncancerous cells is critical for studying somatic mosaicism, a process implicated in aging and multiple chronic diseases. However, single-cell and single-molecule DNA sequencing platforms differ in their error profiles, coverage biases...
Accurate detection of somatic mutations in noncancerous cells is critical for studying somatic mosaicism, a process implicated in aging and multiple chronic diseases. However, single-cell and single-molecule DNA sequencing platforms differ in their error profiles, coverage biases, and sensitivity to specific mutation types, complicating cross-platform comparisons. Here, we present in vitro and in silico benchmarks to quantify true-positive and false-positive rates in single-cell whole-genome sequencing using Single-Cell Multiple Displacement Amplification, and in single-molecule sequencing using Nanorate Sequencing (NS) and whole-genome NS (WGNS). Using standard cell lines, we show that all three methods detect single-nucleotide variants (sSNVs) and small insertions and deletions (sINDELs) with high accuracy, but differ in genomic coverage and susceptibility to artifacts. Method-specific biases influence mutational signatures and hotspot detection. Applying results of the benchmark to IMR-90 fibroblasts, we estimate higher in vitro mutation rates using NS than expected from in vivo data, consistent with potential replication stress and culture-associated DNA damage. Overall, our study highlights the substantial impact of sequencing platform-specific biases on somatic mutation detection and interpretation, and lays the foundation for standardized, cross-platform-comparable analyses of somatic mosaicism in normal human tissues.
Longevity Relevance Analysis
(4)
The paper benchmarks the accuracy of different sequencing methods for detecting somatic mutations, which are implicated in aging and chronic diseases. The study addresses the complexities of somatic mosaicism, a process that may contribute to the aging process, thus providing insights that could be relevant for understanding the root causes of aging.
Stefan M M Goetz, Todd Lucas, Eric Finegood ...
· Psychoneuroendocrinology
· Wayne State University, USA.
· pubmed
Age related diseases present disproportionately among African Americans and have been tied to broad social inequalities and accompanying stress. Yet, there is considerable variability among African Americans in susceptibility, highlighting potential connections to both intersecti...
Age related diseases present disproportionately among African Americans and have been tied to broad social inequalities and accompanying stress. Yet, there is considerable variability among African Americans in susceptibility, highlighting potential connections to both intersectionality and stress-related biological processes. A growing body of research links exposure to racism and discrimination to telomere length (TL)-an indicator of biological aging that is increasingly implicated in explaining stress-related racial health disparities. However, few studies have examined links to accompanying stress processes that may precede TL shortening. This includes examining Uric Acid (UA), which growing evidence suggests may comprise a unique biological aspect of the acute stress response, with implications for both racial health disparities and within-race heterogeneity. In a secondary analysis of a sample of healthy African Americans (N = 103, 33 men; M age = 31.41 years), we assessed the relationship between salivary UA (sUA) and TL. With an eye towards within-group heterogeneity, we also considered the moderating role of age and gender. Our findings revealed a negative association between UA and TL that was most pronounced in African American men and among younger African Americans. We apply an intersectional lens to interpret these results, revealing that different intersections of identity operate through distinct mechanisms. Among men, UA consistently predicted shorter telomeres regardless of discrimination exposure, suggesting biological pathways may be primary. However, among women, the UA/TL relationship was moderated by discrimination-with UA positively predicting TL under low discrimination but showing negative associations under high discrimination conditions. These findings demonstrate that intersectionality operates through multiple pathways simultaneously, with some intersections characterized by biological vulnerabilities while others are defined by social moderation effects. Future research directions should consider the multifaceted influences of UA on TL, recognizing that different intersectional positions may require examination of distinct biological and social mechanisms including potential interventions targeting UA levels to mitigate age-related illnesses and address health disparities among African Americans. Additionally, future studies should examine how additional intersecting systems of oppression might moderate the relationship between UA and TL.
Longevity Relevance Analysis
(4)
Salivary uric acid is negatively associated with telomere length in younger African American men, suggesting biological pathways that may contribute to age-related health disparities. The paper explores the intersectionality of age and gender in relation to biological aging markers, which is pertinent to understanding the root causes of aging and health disparities in a specific population.
Safina, K. R., Kotliar, D. A., Curtis, M. ...
· cell biology
· Brigham and Women\'s Hospital
· biorxiv
Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by ...
Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NF{kappa}B, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.
Longevity Relevance Analysis
(4)
The paper identifies a gene expression program linking inflammatory pathway activation and quiescence in aging hematopoietic stem cells. This research is relevant as it explores the underlying mechanisms of aging at the cellular level, potentially informing strategies for interventions that target the root causes of aging.
Ya Zhao, Jia-Yu Qiu, Fang Wu ...
· Aging cell
· Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease, Nanchang, Jiangxi, China.
· pubmed
Vascular aging increases the susceptibility to cardio-cerebrovascular conditions, such as atherosclerotic diseases and hypertension, the leading causes of global disability and mortality. Dietary citrate extends the lifespan of Drosophila melanogaster and Caenorhabditis elegans a...
Vascular aging increases the susceptibility to cardio-cerebrovascular conditions, such as atherosclerotic diseases and hypertension, the leading causes of global disability and mortality. Dietary citrate extends the lifespan of Drosophila melanogaster and Caenorhabditis elegans as well as improves the memory of mice injured by a high-fat diet (HFD); whether it alleviates vascular aging and age-related vascular diseases; however, remains unknown. Here, we showed that dietary supplementation of citrate delayed vascular aging, as evidenced by maintaining the integrity of elastic fibers and decreasing the level of the aging-related marker, CDKN1A (p21). Functionally, citrate improved the sensitivity to endothelial-dependent vasodilators and lowered blood pressure, and in HFD-fed ApoE
Longevity Relevance Analysis
(4)
Dietary citrate supplementation improves endothelial cell function and alleviates age-related vascular dysfunction. The paper addresses a potential intervention for vascular aging, which is a root cause of age-related diseases, thus contributing to longevity research.
Qifeng Song, Shi Sun, Yuxiu Song ...
· Neural regeneration research
· Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
· pubmed
Ferroptosis is a newly recognized form of programmed cell death characterized by iron overload-dependent lipid peroxidation. These pathological phenomena are often observed in neurodegenerative diseases. Aging is an irreversible process characterized by the deterioration of tissu...
Ferroptosis is a newly recognized form of programmed cell death characterized by iron overload-dependent lipid peroxidation. These pathological phenomena are often observed in neurodegenerative diseases. Aging is an irreversible process characterized by the deterioration of tissue and cell function. It has been shown to contribute to neurodegenerative diseases and increase susceptibility to ferroptosis. Therefore, ferroptosis may be involved in the progression of neurodegenerative diseases as a pathogenic factor, and aging is the common catalyst of both processes. The purpose of this review is to elucidate the latest progress on the mechanisms related to ferroptosis in neurodegenerative diseases, including iron overload, lipid peroxidation, antioxidant defense, cell membrane repair, and the regulation of autophagy and transcription factors. We also explored the relationship between ferroptosis and aging and reported that aging can induce ferroptosis by increasing iron overload, enhancing lipid peroxidation, and exacerbating autophagy disorders. Since ferroptosis is a pathogenic factor in neurodegenerative diseases, we screened gene bank databases and found that many genes associated with ferroptosis and neurodegenerative diseases overlap. Additionally, genes related to both the peroxidation pathway and ferroptosis are enriched. Ferroptosis occurs under conditions of age-related iron accumulation and lipid enrichment, as well as due to disorders in autophagy levels and transcription factors. Furthermore, in various neurodegenerative diseases, specific pathological changes or products can also contribute to the occurrence of ferroptosis. Finally, based on animal studies and clinical trials involving ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies in neurodegenerative diseases, it has been found that inhibiting ferroptosis can effectively reverse neurological dysfunction and cognitive impairment associated with these conditions. However, given various limitations, the conclusions of some animal studies and clinical trials have not been ideal, indicating that further large-scale research is necessary. Taken together, ferroptosis induces aging-related neurodegenerative diseases and neuronal cell death, triggering disease onset and progression. Ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies show great potential for inhibiting ferroptosis in neurodegenerative disease.
Longevity Relevance Analysis
(4)
Ferroptosis is implicated as a pathogenic factor in neurodegenerative diseases, with aging acting as a catalyst for this process. The paper discusses mechanisms linking ferroptosis and aging, which are central to understanding and potentially addressing the root causes of age-related neurodegenerative diseases.
Brandon T Tran, Vidthiya Jeyanathan, Ruoqiong Cao ...
· Hematopoietic Stem Cells
· Department of Pediatrics, Division of Infectious Diseases, and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine and Texas Children's Hospital, Houston, United States.
· pubmed
Human and murine studies reveal that innate immune cells are able to mount enhanced responses to pathogens after primary inflammatory exposure. Innate immune memory has been shown to last for months to years, longer than the lifespan of most innate immune cells. Indeed, long-live...
Human and murine studies reveal that innate immune cells are able to mount enhanced responses to pathogens after primary inflammatory exposure. Innate immune memory has been shown to last for months to years, longer than the lifespan of most innate immune cells. Indeed, long-lived hematopoietic stem and progenitor cells (HSPCs) serve as a cellular reservoir for innate immune memory. In this review, we summarize the evidence that innate immune memory is epigenetically encoded in HSPCs, and we consider whether HSPC subpopulations with differentiation bias, cell autonomous epigenetic reprogramming, or both features underlie the phenomenon of central trained immunity. We further profile the significant implications of central trained immunity in stem cell transplant, aging, inflammatory diseases, and vaccination strategies for the future.
Longevity Relevance Analysis
(4)
Hematopoietic stem and progenitor cells (HSPCs) serve as a reservoir for innate immune memory, which has implications for aging and inflammatory diseases. The paper discusses mechanisms that could influence longevity through the understanding of immune memory and its epigenetic encoding in HSPCs, which is relevant to the root causes of aging and age-related diseases.
Feng, G., Ruark, E. M., Mulligan, A. G. ...
· physiology
· Vanderbilt University
· biorxiv
While certain forms of mitochondrial impairment confer longevity, disease-associated mutations trigger dysfunction and severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex...
While certain forms of mitochondrial impairment confer longevity, disease-associated mutations trigger dysfunction and severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. We find that the InsP3R promotes mitochondrial respiration, but the mitochondrial calcium uniporter is dispensable for both respiration and lifespan extension in Complex I mutants, suggesting InsP3R action is independent of matrix Ca2+ flux. Transcriptomic profiling and imaging reveal a previously unrecognized role for the InsP3R in regulating mitochondrial scaling, where InsP3R impairment results in maladaptive hyper-expansion of dysfunctional mitochondrial networks. We reveal a conserved InsP3R signaling axis through which calmodulin and actomyosin remodeling machineries, including Arp2/3, formin FHOD-1, and MLCK, constrain mitochondrial expansion and promote longevity. Disruption of actin remodeling or autophagy mimics InsP3R loss. Conversely, driving fragmentation ameliorates mitochondrial expansion and rescues longevity, supporting a model in which InsP3R-dependent actin remodeling sustains mitochondrial turnover. These findings establish an inter-organelle signaling axis by which ER calcium release orchestrates mitochondrial-based longevity through cytoskeletal effectors.
Longevity Relevance Analysis
(4)
The paper claims that InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics. This research is relevant as it explores the mechanisms underlying longevity and mitochondrial function, addressing potential pathways that could influence aging and lifespan extension.
Calubag, M. F., Ademi, I., Green, C. L. ...
· physiology
· University of Wisconsin-Madison
· biorxiv
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient ...
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
Longevity Relevance Analysis
(4)
Lifelong restriction of dietary valine improves metabolic health and extends lifespan in male mice. The study addresses dietary interventions that may influence the aging process and healthspan, focusing on mechanisms that could be relevant for longevity research.
A Ibáñez de Opakua, R Conde, A de Diego ...
· npj metabolic health and disease
· ATLAS Molecular Pharma, Parque Tecnológico de Bizkaia, Ed. 800, 48160, Derio, Spain.
· pubmed
Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-th...
Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-throughput platform to assess metabolic health. We summarize key NMR-based models and present a new approach that combines high predictive accuracy with clinical interpretability, identifying disease-specific metabolic distortions and supporting risk stratification and early detection of accelerated aging.
Longevity Relevance Analysis
(4)
The paper presents a novel NMR-based metabolomic approach for estimating biological age and identifying metabolic distortions related to aging. This research is relevant as it aims to improve the understanding of biological aging processes and offers potential for early detection and risk stratification, which are crucial for addressing the root causes of aging.
Ailsa M Jeffries, Tianxiong Yu, Jennifer S Ziegenfuss ...
· Nature
· Department of Molecular, Cell and Cancer Biology, Genome Integrity Program, University of Massachusetts Chan Medical School, Worcester, MA, USA.
· pubmed
Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process
Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process
Longevity Relevance Analysis
(4)
The paper investigates single-cell transcriptomic and genomic changes in the ageing human brain. This research is relevant as it explores the biological mechanisms underlying aging, which could contribute to understanding and potentially addressing the root causes of age-related decline.
Lars Thielecke, Kalpana Nattamai, Aishlin Hassan ...
· Stem cells (Dayton, Ohio)
· Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.
· pubmed
The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans...
The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.
Longevity Relevance Analysis
(4)
The paper claims that aged hematopoietic stem cells maintain clonal diversity similar to young HSCs under certain transplantation conditions. This research is relevant as it explores the complex interactions between aging and stem cell transplantation, which could have implications for understanding and potentially mitigating age-related decline in hematopoiesis.
Jiaxin Shi, Jason M Fletcher
· Population studies
· The Hong Kong University of Science and Technology.
· pubmed
Research indicates a significant slowdown in life expectancy growth in the United States (US) post 2010, marking a departure from the consistent progress in longevity throughout the twentieth century. We extend this understanding, tracing the deceleration of US life expectancy ba...
Research indicates a significant slowdown in life expectancy growth in the United States (US) post 2010, marking a departure from the consistent progress in longevity throughout the twentieth century. We extend this understanding, tracing the deceleration of US life expectancy back to the 1950s, after which average decadal change dropped from 3.80 to 1.61 years. Surprisingly, these mid-twentieth-century shifts were consistent across race and sex in the US and also in other high-income countries. Using a simple approach of quantifying potential life expectancy gains by eliminating mortality at specific ages, we find that the potential gains in life expectancy from reducing midlife mortality have been larger in the US than in other countries since 1900. The findings suggest that US life expectancy is unlikely to progress at the high speed observed between 1900 and the 1950s, with future advancements hinging on the reduction of old-age mortality, particularly from cardiovascular diseases and mental and nervous system diseases.
Longevity Relevance Analysis
(4)
The paper claims that potential life expectancy gains in the US from reducing midlife mortality have been larger than in other countries since 1900. This research is relevant as it addresses trends in life expectancy and explores factors that could influence future longevity advancements, focusing on mortality reduction rather than merely treating age-related diseases.
Bnaya Gross, Joseph Ehlert, Vadim N. Gladyshev ...
· q-bio.MN
· Not available
· arxiv
Despite the thousands of genes implicated in age-related phenotypes,
effective interventions for aging remain elusive, a lack of advance rooted in
the multifactorial nature of longevity and the functional interconnectedness of
the molecular components implicated in aging. Here, w...
Despite the thousands of genes implicated in age-related phenotypes,
effective interventions for aging remain elusive, a lack of advance rooted in
the multifactorial nature of longevity and the functional interconnectedness of
the molecular components implicated in aging. Here, we introduce a network
medicine framework that integrates 2,358 longevity-associated genes onto the
human interactome to identify existing drugs that can modulate aging processes.
We find that genes associated with each hallmark of aging form a connected
subgraph, or hallmark module, a discovery enabling us to measure the proximity
of 6,442 clinically approved or experimental compounds to each hallmark. We
then introduce a transcription-based metric, $pAGE$, which evaluates whether
the drug-induced expression shifts reinforce or counteract known age-related
expression changes. By integrating network proximity and $pAGE$, we identify
multiple drug repurposing candidate that not only target specific hallmarks but
act to reverse their aging-associated transcriptional changes. Our findings are
interpretable, revealing for each drug the molecular mechanisms through which
it modulates the hallmark, offering an experimentally falsifiable framework to
leverage genomic discoveries to accelerate drug repurposing for longevity.
Longevity Relevance Analysis
(5)
The paper claims to identify existing drugs that can modulate aging processes by leveraging a network medicine framework. This research is relevant as it addresses the root causes of aging by exploring drug repurposing to target hallmarks of aging, rather than merely treating age-related diseases.
Xie, G.
· bioinformatics
· Nantong University
· biorxiv
Aging Clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneit...
Aging Clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneities remain underdeveloped. This study introduces scAgeClock, a novel gated multi-head attention (GMA) neural network-based single-cell aging clock model. Leveraging a large-scale dataset of over 16 million single-cell transcriptome profiles from more than 40 human tissues and 400 cell types, scAgeClock demonstrates improved age prediction accuracy compared to baseline methods. Notably, the mean absolute error for the best-performing cell type is remarkably low at 2 years. Feature importance analysis reveals enrichment of aging clock genes related to ribosome, translation, defense response, viral life cycle, programmed cell death, and COVID-19 disease. A novel metric, the Aging Deviation Index (ADI) proposed by this study, revealed deceleration of ages in cells with higher differentiation potencies and tumor cells in higher phases or under metastasis, while acceleration of ages was observed in skin cells. Furthermore, scAgeClock is publicly available to facilitate future research and potential implementations.
Longevity Relevance Analysis
(5)
The paper claims to introduce scAgeClock, a single-cell aging clock model that improves age prediction accuracy and reveals insights into cellular aging dynamics. This research is relevant as it addresses the biological mechanisms of aging at a single-cell level, which could contribute to understanding and potentially mitigating the root causes of aging.
Fuentes-Ramos, M., Alaiz-Noya, M., Miozzo, F. ...
· neuroscience
· Instituto de Neurociencias (UMH-CSIC)
· biorxiv
While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. To address this, we used TRAP2 activity-reporter mice, nuclear tagging, and FOS-based activity mapping to track neurons activated during contextual fear memory encod...
While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. To address this, we used TRAP2 activity-reporter mice, nuclear tagging, and FOS-based activity mapping to track neurons activated during contextual fear memory encoding and reactivated during recall in young and aged mice. Across 378 brain regions, we quantified engram size, spatial distribution, and reactivation stability. We further applied fluorescence-activated nuclear sorting (FANS) combined with single-nucleus RNA sequencing (snRNA-seq) to characterize gene expression changes associated with memory encoding and recall across diverse cell types. In addition, we compared the transcriptional profiles of first-time versus second-time neuronal responder cells in the dentate gyrus. Aged brains exhibited altered engram allocation, reduced reactivation stability, and distinct gene expression patterns during memory retrieval. These findings reveal age-related changes in the organization and molecular identity of memory traces, providing mechanistic insight into cognitive decline and highlighting potential targets for intervention.
Longevity Relevance Analysis
(4)
Aging alters the distribution, stability, and transcriptional signature of engram cells in the brain. This study provides insights into the mechanisms of cognitive decline associated with aging, which is directly relevant to understanding and potentially addressing the root causes of aging and age-related cognitive impairments.
Juan Long, Meng Ma, Yuting Chen ...
· eLife
· Department of Health Management and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal ...
The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this study, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate in
Longevity Relevance Analysis
(4)
Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake. The study explores a mechanism that could influence lifespan extension through metabolic regulation, which is directly related to the biology of aging.
Foley, J., McPherson, J., Roger, M. ...
· evolutionary biology
· University of Bristol
· biorxiv
Evolution has given rise to lifespans in extant species ranging from days to centuries. Given that mechanisms of ageing are highly conserved, studying long-lived lineages across the animal kingdom could yield insights relevant for healthy ageing in humans. However, typical models...
Evolution has given rise to lifespans in extant species ranging from days to centuries. Given that mechanisms of ageing are highly conserved, studying long-lived lineages across the animal kingdom could yield insights relevant for healthy ageing in humans. However, typical models of extended lifespan often live for decades, making them impractical for longitudinal studies. Ideal model systems would be organisms that are naturally long-lived compared to their close relatives, but have lifespans on experimentally tractable scales. Here, we present the Neotropical butterfly genus Heliconius as a novel model system for the evolution of extended longevity. We collate data from 27 species across the Heliconiini tribe to reveal a 25-fold variation in lifespan within the group, with our 348-day maximum for Heliconius hewitsoni longer than any butterfly species previously recorded in the scientific literature. While previous work has attributed this lifespan extension to a plastic response to enhanced nutrition, we conduct detailed survival and functional senescence analyses on two species representative of shorter- and longer-lived clades to show evidence of evolved, heritable mechanisms of slowed ageing in Heliconius. Our results add a new case study to the canon of noteworthy agers, and provide valuable insights into the evolution of increased longevity.
Longevity Relevance Analysis
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The paper claims that the Heliconius butterfly genus exhibits evolved, heritable mechanisms of slowed ageing. This research is relevant as it explores the evolutionary basis of increased longevity and ageing mechanisms, which could provide insights into the biology of ageing and potential applications for lifespan extension.
Luciano, A., Robinson, L., Schott, W. H. ...
· genetics
· The Jackson Laboratory
· biorxiv
Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models...
Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models. However, inter-individual variation in physiological responses to these interventions, which affects their safety and efficacy when translated to humans, remains poorly understood despite being observed in multiple studies. In this study, we implemented intermittent fasting (IF) for two days per week in 10 inbred strains (n = 800 mice) from the Collaborative Cross (CC). The CC is a multiparent recombinant inbred strain panel that offers a diverse collection of reproducible models to study the genetic control of heterogeneous intervention responses. We conducted longitudinal phenotyping to characterize hundreds of traits, including lifespan, in the CC mice. We demonstrate that sex and genetic background induce variable responses to intermittent fasting across multiple physiological outcomes, including metabolic, hematologic, and immunologic health. Effects of IF on lifespan were sex-specific and variable across genetic backgrounds. Thus we establish that response to IF is genetically determined in an animal model with physiological features similar to humans. We compared our findings in the CC with those from a parallel study of Diversity Outbred (DO) mice, highlighting common predictors of health and lifespan, as well as key differences between the genetically diverse inbred and outbred models. These findings underscore the importance of genetic factors in dietary intervention responses, offering valuable insights for translating intermittent fasting benefits to human health and longevity.
Longevity Relevance Analysis
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The paper claims that genetic background and sex influence the physiological responses to intermittent fasting, affecting lifespan outcomes. This research is relevant as it investigates the genetic regulation of dietary interventions that may enhance longevity and metabolic health, addressing fundamental aspects of aging biology.
Kun Zhang, Yehua Li, Yi Ren ...
· Aging cell
· Department of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
· pubmed
Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have ide...
Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have identified the proton-sensing receptor GPR65, which is specifically expressed in osteoclasts and is significantly down-expressed in osteoclast differentiation, aging, ovariectomy (OVX)-, and tail suspension (TS)-induced osteoporotic bone tissue. In vivo experiments confirmed that knockout of GPR65 exacerbates bone loss and OP induced by TS, OVX, and aging. In vitro experiments demonstrated that silencing GPR65 or application of either endogenous or exogenous antagonist of GPR65 promotes osteoclast differentiation, whereas overexpression of GPR65 or application of either endogenous or exogenous agonist inhibits osteoclast differentiation, and knockout of Gpr65 mitigates this effect. Mechanistic studies revealed that GPR65 inhibits osteoclast differentiation by binding to Gαq, activating GSK3β, and suppressing its phosphorylation, thereby inhibiting the nuclear translocation of NFATc1 that mediates osteoclast differentiation. Furthermore, application of GPR65 agonist alleviated OVX-induced OP in vivo, indicating GPR65 as a novel therapeutic target for bone aging and OP.
Longevity Relevance Analysis
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GPR65 functions as a key factor in osteoclast differentiation and bone aging, presenting it as a novel therapeutic target for osteoporosis. The study addresses a mechanism related to bone aging, which is a significant aspect of longevity research.
Jiale Cai, Deng Wu, Dahua Xu ...
· Cancer science
· College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
· pubmed
Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular s...
Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.
Longevity Relevance Analysis
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The study claims that aging and cancer exhibit directionally opposite transcriptional profiles at the single-cell level, suggesting that cellular senescence may act as a barrier to tumor formation. This paper is relevant as it explores the interplay between aging and cancer at a mechanistic level, addressing potential root causes of age-related diseases rather than merely treating symptoms.
Gutierrez, I., Edgar, C., Tyler, J. K.
· cell biology
· Weill Cornell Medicine
· biorxiv
Overexpression of the mRNA binding protein Ssd1 extends the yeast replicative lifespan. Using microfluidics to trap and image single cells throughout their lifespans, we find that lifespan extension by Ssd1 overexpression is accompanied by formation of cytoplasmic Ssd1 foci. The ...
Overexpression of the mRNA binding protein Ssd1 extends the yeast replicative lifespan. Using microfluidics to trap and image single cells throughout their lifespans, we find that lifespan extension by Ssd1 overexpression is accompanied by formation of cytoplasmic Ssd1 foci. The age-dependent Ssd1 foci are condensates that appear dynamically in a cell cycle-dependent manner and their failure to resolve during mitosis coincided with the end of lifespan. Ssd1 overexpression was epistatic with calorie restriction (CR) for lifespan extension and yeast overexpressing Ssd1 or undergoing CR were resistant to iron supplementation-induced lifespan shortening while their lifespans were reduced by iron chelation. The nuclear translocation of the Aft1 transcriptional regulator of the iron regulon occurred during aging in a manner that predicted remaining lifespan, but was prevented by CR. Accordingly, age-dependent induction of the Fit2 and Arn1 high-affinity iron transporters within the iron regulon was reduced by CR and Ssd1 overexpression. Consistent with age-dependent activation of the iron regulon, intracellular iron accumulated during aging but was prevented by CR and Ssd1 overexpression. Moreover, lifespan extension by Ssd1 overexpression or CR was epistatic to inactivation of the iron regulon. These studies reveal that CR and Ssd1 overexpression extend the yeast replicative lifespan by blocking deleterious age-dependent iron uptake, identifying novel therapeutic targets for lifespan extension.
Longevity Relevance Analysis
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Overexpression of Ssd1 and calorie restriction extend yeast replicative lifespan by preventing deleterious age-dependent iron uptake. The study addresses mechanisms of lifespan extension and identifies potential therapeutic targets related to aging processes, making it relevant to longevity research.
Ziyou Yuan, Eugenie Nepovimova, Qinghua Wu ...
· Biogerontology
· College of Life Science, Yangtze University, Jingzhou, 434025, China.
· pubmed
The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadi...
The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadian regulation is the CLOCK protein, which controls gene transcription related to tissue homeostasis, cellular senescence, and DNA repair. Research reveals CLOCK's dual role: in normal cells, it supports rejuvenation by activating DNA repair factors like XPA and modulating metabolism; in tumor cells, CLOCK signaling is often hijacked by oncogenic drivers like c-MYC and Pdia3, which inhibit telomere shortening / cellular senescence, thereby fostering uncontrolled proliferation and tumorigenesis. Additionally, gut microbiota-derived aryl hydrocarbon receptor (AhR) signals can disrupt the CLOCK-BMAL1 complex, affecting circadian rhythms. CLOCK also interacts with mTOR and NF-κB pathways to regulate autophagy and mitigate harmful secretions impacting tissue function. This review examines the molecular links between CLOCK and cellular senescence, drawing from animal and human studies, to highlight CLOCK's role in aging and its potential as a target for anti-aging therapies.
Longevity Relevance Analysis
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The paper claims that CLOCK signaling plays a dual role in cellular senescence, influencing both rejuvenation in normal cells and tumorigenesis in cancer cells. This research is relevant as it explores the molecular mechanisms linking circadian rhythms to aging processes and cellular senescence, potentially identifying targets for anti-aging therapies.
Vijayraghavan Seshadri, Charmaine Chng, Joel Tyler ...
· Aging cell
· Monash Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
· pubmed
Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU in...
Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU incorporation, p21 and p16, are used to identify senescent cells, no single biomarker universally defines cellular senescence and current methods often fail to address heterogeneity in biomarker expression levels. This study leverages single-cell fluorescence imaging to assess multiple senescence markers including SA-βgal enzymatic activity, p21 and IL-6 expression and nuclear and cell area in chemotherapy-induced (mitomycin C) and oxidative stress-induced (D-galactose) senescence models in human fibroblasts. Our findings reveal significant heterogeneity in SA-βgal activity and distinct sub-populations within senescent cells. Nuclear and cell area measurements emerged as robust indicators of cellular senescence, displaying similar variability across individual cells. Importantly, we identified specific nuclear area sub-populations that strongly correlate with IL-6 expression levels, demonstrating a relationship between the heterogeneous expression of senescence biomarkers and the SASP. To address this heterogeneity, we introduced an induction threshold method to more accurately quantify the percentage of cells expressing senescence biomarkers. Furthermore, in both senescence models, we observed that rapamycin, a well-known senomorphic agent, selectively targets specific biomarker-expressing sub-populations. This study underscores the value of assessing cellular heterogeneity in senescence research and provides an improved approach for analysing senescence markers in diverse cellular contexts.
Longevity Relevance Analysis
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The study identifies heterogeneity in senescence biomarkers and demonstrates that rapamycin selectively targets specific sub-populations of senescent cells. This research is relevant as it addresses cellular senescence, a fundamental process associated with aging, and explores potential interventions that could influence longevity.
Chin, R., Zhang, X.-H., Anderson, K. M. ...
· neuroscience
· Yale University
· biorxiv
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be e...
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.
Longevity Relevance Analysis
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The paper claims that genetic factors and glial cell-related transcripts influence age-related changes in white matter microstructure. This research is relevant as it explores the genetic and cellular mechanisms underlying structural changes in the brain associated with aging, which could contribute to understanding the biological processes of aging and potential interventions.
Zhouwei Wu, Shu Yang, Zhichen Jiang ...
· Autophagy
· Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
· pubmed
Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucle...
Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its "KFERQ" motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering
Longevity Relevance Analysis
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UCHL1 mitigates nucleus pulposus cell senescence by activating chaperone-mediated autophagy. The study addresses a mechanism related to cellular senescence and intervertebral disc degeneration, which are important aspects of aging and age-related degeneration.