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
(4)
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.
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
(5)
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
(4)
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
(4)
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
(4)
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
(4)
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
(4)
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
(4)
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
(4)
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
(4)
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
(4)
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.
Kim, Y. L., Jo, Y.-W., Yoo, T. ...
· developmental biology
· Seoul National University
· biorxiv
Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC ...
Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC population, raising questions about the underlying mechanisms of age-associated dysfunction. Here, we used Pax7CreERT2;RosaYFP mice (MuSCYFP) to label Pax7-expressing MuSCs and chronologically traced MusCs until geriatric age. Genetic labeling and chronological tracing revealed that the number of YFP+ MuSC remained comparable between young, middle and geriatric ages. At geriatric age, YFP+ MuSCs exhibited reduced expression of traditional MuSC markers such as VCAM1 and PAX7. A previously unrecognized subpopulation emerged, characterized by loss of VCAM1 and low or absent PAX7. Despite their altered marker profile, these cells retained transcriptional signatures of quiescence and myogenic potential, but displayed significantly reduced proliferative and regenerative capacities. They displayed gene expression patterns indicative of senescence-like state and were selectively ablated by senolytic treatment. DHT restored regenerative function in aged mice and re-induced VCAM1 expression in YFP+/Pax7-/low/VCAM1- cells, indicating responsiveness to rejuvenation. Based on their emergence with aging, functional impairment and responsiveness to rejuvenation, we termed this population GERI-MuSCs (Geriatric Emerging Rejuvenation-responsive and Impaired MuSCs). CD63 and CD200 were identified as novel surface markers that together with VCAM1, reliably detect GERI-MuSCs as well as classical Pax7+/VCAM1High MuSCs, providing a tool for comprehensive isolation of MuSCs from aged wild-type mice. Together, our findings provide a refined framework for studying MuSC aging and offer new tools for isolating functionally distinct MuSC subsets from aged skeletal muscle.
Longevity Relevance Analysis
(5)
The paper identifies a novel subpopulation of muscle stem cells (GERI-MuSCs) that exhibit age-related functional impairments and responsiveness to rejuvenation treatments. This research is relevant as it addresses the mechanisms of muscle stem cell aging, which is a root cause of age-related decline in muscle regeneration and function.
Shaokai Tang, Yuanwen Geng, Qinqin Lin
· Lipids in health and disease
· College of Sports Science, Jishou University, Jishou, 416000, China.
· pubmed
Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adip...
Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adipose tissue is among the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of adipose progenitor and stem cells, accumulation of senescent cells, and immunosenescence. These alterations may act synergistically and play a role in abnormalities in metabolic organs including the cardiovascular, liver, skeletal muscle, and brain. Studies have demonstrated that exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing the accumulation of ectopic lipids, enhancing the browning of white adipose tissue and thermogenesis in brown adipose tissue, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence. This review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.
Longevity Relevance Analysis
(4)
Exercise interventions can mitigate the effects of adipose tissue aging on metabolic organ abnormalities. The paper addresses the mechanisms of adipose tissue aging and its impact on metabolic health, which are central to understanding and potentially reversing aspects of aging.
Lauren M Hablitz, Maiken Nedergaard
· The Journal of clinical investigation
· Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.
· pubmed
Cerebrospinal fluid dynamics play an important role in maintaining brain health and clearing metabolic waste from the brain. In this issue of the JCI, Gursky et al. investigate how CSF distribution is affected when its primary efflux pathway - the deep cervical lymph nodes - is d...
Cerebrospinal fluid dynamics play an important role in maintaining brain health and clearing metabolic waste from the brain. In this issue of the JCI, Gursky et al. investigate how CSF distribution is affected when its primary efflux pathway - the deep cervical lymph nodes - is disrupted by cauterization. This timely study reveals compensatory fluid drainage routes from the skull, age-dependent adaptations in CSF homeostasis, and the emergence of neuroinflammation when an efflux pathway is occluded. The findings underscore the need to better understand the physiological mechanisms governing CSF clearance, how these pathways evolve with aging, and whether CSF influx and efflux exhibit region-specific dynamics shaped by neuroanatomy. Additionally, the study raises important questions about whether peripheral injury can influence central nervous system states. A more complete understanding of CSF flow regulation may offer new perspectives on the origins of neuropathology.
Longevity Relevance Analysis
(4)
Disruption of cerebrospinal fluid efflux pathways leads to compensatory drainage routes and neuroinflammation, highlighting the importance of CSF dynamics in brain health. The study addresses physiological mechanisms that could influence aging and age-related neurodegenerative processes, making it relevant to longevity research.
Andrew Patton, Jörn Davidsen
· PLoS computational biology
· Department of Physics and Astronomy, University of Calgary, Calgary, Alberta, Canada.
· pubmed
Although the brain's structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased sync...
Although the brain's structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased synchronization between brain regions are taken as enhanced cognitive integration, while decreased synchronization is indicative of cognitive segregation. The ability to dynamically switch between different levels of integration and segregation across different cognitive systems is believed to be crucial for overall cognitive performance. Building on a recently proposed cognitively informed, synchronization-based framework, we study here age-related variations in dynamical flexibility between segregation and integration, as captured by changes in the variable patterns of partial synchronization or chimera states. Leveraging personalized brain network models based on large-scale, multisite datasets of cross-sectional healthy cohorts, we systematically show how regional brain stimulation produces distinct patterns of synchronization. We find that chimera states play a crucial role in regulating the balance between cognitive integration and segregation as the brain ages, providing new insights into the mechanisms underlying cognitive decline and preservation in aging. Whereas the emergent synchronization behavior of brain regions belonging to the same cognitive system often show the same aging trends, different cognitive systems can demonstrate distinct trends. This supports the idea that aging affects cognitive systems differently and that understanding this variability is essential for a more comprehensive view of neuro-cognitive aging. At the same time, dynamical flexibility increases in the oldest age groups across most cognitive systems. This may reflect compensatory mechanisms to counteract age-related cognitive declines and points towards a phenomenon of dedifferentiation. Yet, the multiplicity of behaviors highlights that whereas dedifferentiation emerges in certain cognitive systems, differentiation can also occur in others. This illustrates that these processes, though seemingly oppositional, can coexist and unfold in parallel across different cognitive systems.
Longevity Relevance Analysis
(4)
The paper claims that age-related variations in brain network synchronization patterns influence cognitive integration and segregation. This research is relevant as it explores the underlying mechanisms of cognitive decline and preservation in aging, contributing to a deeper understanding of neuro-cognitive aging processes.
Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes ...
· NLR Family, Pyrin Domain-Containing 3 Protein
· BioAge Labs , Emeryville, CA, USA.
· pubmed
The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously perform...
The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.
Longevity Relevance Analysis
(4)
The paper claims that BAL-0028 and its derivative BAL-0598 are potent inhibitors of the NLRP3 inflammasome, which is implicated in age-related inflammatory diseases. The relevance lies in its focus on a novel mechanism to inhibit NLRP3, potentially addressing a root cause of inflammation associated with aging and age-related diseases.
Emma B Hasselholm, Jesper Just, Simon Chang ...
· Klinefelter Syndrome
· Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. [email protected].
· pubmed
The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological functi...
The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological function rather than chronological age, is increased in both syndromes. To investigate whether DNA methylation patterns linked to physiological decline could contribute to the comorbidity patterns and reduced lifespan in TS and KS, we applied so-called epigenetic clocks to DNA methylation data from cohorts of TS (n = 57) compared to female controls (n = 33) and KS (n = 65) compared to male controls (n = 63). Additionally, we evaluated correlations between epigenetic age and clinical variables, aiming to identify clinical aging markers in TS and KS.
Longevity Relevance Analysis
(4)
The paper investigates the relationship between epigenetic age acceleration and clinical aging markers in Turner and Klinefelter syndromes. This research is relevant as it explores biological aging mechanisms and their implications for lifespan and health in specific genetic conditions, contributing to the understanding of aging processes.
Levy, T., Anselmi, C., Ishizuka, K. J. ...
· cell biology
· Stanford University
· biorxiv
Germline stem cells (GSCs), the source of gametes, are the only stem cells capable of passing genes to future generations and are therefore considered units of natural selection. Yet, the factors that influence GSC fitness, and thus govern GSC competition, which exist in both pro...
Germline stem cells (GSCs), the source of gametes, are the only stem cells capable of passing genes to future generations and are therefore considered units of natural selection. Yet, the factors that influence GSC fitness, and thus govern GSC competition, which exist in both protochordates and mammals, remain poorly understood. We studied how aging affects GSC fitness in the protochordate Botryllus schlosseri, an evolutionary crosspoint between invertebrates and vertebrates. GSCs were isolated and distinguished from developing and mature gametes using flow cytometry and scRNA-Seq, facilitated by a new PacBio genome assembly. Moreover, their function was validated through a novel lineage tracing approach that combines membrane-labeled GSC transplantation with scRNA-Seq. Leveraging our method to isolate them, single-cell transcriptomics showed significant age-related changes between young and old GSCs. Spermatids and sperm, however, showed minimal changes, suggesting that reproductive aging is governed by GSCs rather than by gametes. Reduced expressions of markers like DDX4 and PIWIL1 in aged GSCs mirrored trends in mammalian datasets, pointing to a conserved GSC-driven aging mechanism across chordate evolution. This study provides new techniques that lay the foundation to investigate further drivers of GSC fitness and highlights fertility-related genes as promising targets for therapies to preserve reproductive health.
Longevity Relevance Analysis
(4)
Aging negatively impacts germline stem cell fitness, which may influence reproductive aging mechanisms. The study investigates the fundamental biological processes underlying aging in germline stem cells, which is crucial for understanding longevity and potential interventions in reproductive health.
Wei-Li Wang, Yu-Tsung Shih, Shu-Yi Wei ...
· Atherosclerosis
· Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
· pubmed
Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction...
Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction, marked by impaired barrier function, inflammation, and metabolic dysregulation, constitutes an early and pivotal event in atherogenesis. As key sensors of hemodynamic forces, ECs are constantly exposed to blood flow-induced shear stress, which exert divergent effects on metabolism depending on the flow pattern. Laminar flow with relatively high shear stress (LS), as a critical atheroprotective factor, maintains EC quiescence and promotes anti-inflammatory responses and antioxidant defense, whereas disturbed flow with low and oscillatory shear stress (OS), induces the athero-susceptible signaling network to activate glycolysis and inflammation in ECs. While genetic, epigenetic, and molecular signaling mechanisms in EC physiology and pathophysiology have been extensively explored, the crucial role of EC metabolism in EC dysfunction and atherogenesis remains largely understudied. By serving as precursors, intermediates, and end products of cellular processes, metabolites offer a dynamic snapshot of endothelial metabolic states under both physiological and pathophysiological conditions. With aging, ECs undergo profound metabolic reprogramming, including disrupted glycolysis, mitochondrial dysfunction, and altered redox homeostasis. In healthy vasculature, ECs maintain quiescence and metabolic homeostasis, primarily relying on glycolysis for energy. With aging, the gradual accumulation of atherosclerotic risk factors, including oxidative stress, inflammation, dyslipidemia, and hyperglycemia, drives metabolic reprogramming in ECs, particularly in regions exposed to disturbed flow with OS, ultimately leading to EC dysfunction and atherosclerosis. This review summarizes recent advances in age-related metabolic reprogramming in ECs and its contribution to atherosclerosis, particularly focusing on the dysregulation of glycolysis, fatty acid metabolism, amino acid metabolism, and mitochondrial respiration induced by age and fluid shear stress. This review also outlines recent methodologies for profiling EC metabolism, and discusses potential therapeutic applications of targeting EC metabolism to prevent or delay the development of atherosclerosis.
Longevity Relevance Analysis
(4)
The paper claims that aging induces metabolic reprogramming in vascular endothelial cells, contributing to atherosclerosis development. This research addresses the underlying metabolic changes associated with aging, which are crucial for understanding and potentially mitigating age-related diseases.
Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li ...
· Nature aging
· Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
· pubmed
Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specifi...
Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38
Longevity Relevance Analysis
(4)
The paper claims that nerve-associated macrophages play a crucial role in regulating adipose homeostasis and controlling age-related inflammation. This research is relevant as it addresses mechanisms underlying inflammaging, which is a significant factor in aging and age-related diseases.
Xiao-Ting Yu, Nan Zhao, Yu-Tao Ma ...
· Acta pharmacologica Sinica
· Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China.
· pubmed
Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for ma...
Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.
Longevity Relevance Analysis
(4)
SIRT6 plays a protective role against thoracic aortic aneurysm development by maintaining mitochondrial homeostasis in vascular smooth muscle cells. The study addresses a mechanism related to cellular aging and dysfunction, which is pertinent to longevity research.
Stefania Lucia, Silvia Fornaro, Massimo Federici ...
· Acta diabetologica
· Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. [email protected].
· pubmed
The growing prevalence of type 2 diabetes (T2D) among older adults represents a major public health concern, given its association with accelerated cognitive decline and increased risk of neurodegenerative diseases. Several diabetes-related mechanisms, including chronic hyperglyc...
The growing prevalence of type 2 diabetes (T2D) among older adults represents a major public health concern, given its association with accelerated cognitive decline and increased risk of neurodegenerative diseases. Several diabetes-related mechanisms, including chronic hyperglycaemia, oxidative stress, vascular dysfunction, and insulin resistance in the brain, negatively impact key cognitive domains, including memory and executive functions. These neuropathophysiological alterations are also linked to structural brain changes, contributing to vulnerability to dementia. This narrative review examines both established and emerging strategies aimed at counteracting the cognitive impact of T2D in aging populations. Traditional interventions, especially structured physical activity programs, have consistently demonstrated benefits for global cognitive functioning. In parallel, new pharmacological treatments, such as GLP-1 receptor agonists (e.g., semaglutide), not only improve glycemic control but may also exert neuroprotective effects. Multidomain approaches integrating metabolic management, nutritional optimization, physical exercise, and social engagement, such as those tested in the J-MIND-Diabetes study, have yielded promising outcomes in preserving cognitive functions. We argue that combining pharmacological and behavioral strategies holds significant potential for supporting cognitive health in elderly individuals with T2D. Such multimodal interventions may enhance resilience to cognitive decline, improve quality of life, and promote healthy brain aging in this at-risk population.
Longevity Relevance Analysis
(4)
Combining pharmacological and behavioral strategies may enhance cognitive health in elderly individuals with type 2 diabetes. The paper addresses the cognitive decline associated with type 2 diabetes in aging populations and explores multidimensional approaches to mitigate this decline, which is relevant to longevity and age-related cognitive health.
Fernandes, S. A., Pan, J., Terziyska, D. S. ...
· cell biology
· Max Planck Institute for Biology of Ageing (MPI-AGE)
· biorxiv
Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPas...
Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPases to regulate its localization and activity. Interestingly, although mTOR is a heavily ubiquitinated protein, the role of this post-translational modification (PTM) in regulating its activation status remains poorly understood. Here, through an unbiased RNAi screen, we identified the tumor suppressor CYLD deubiquitinase (DUB) as a direct negative regulator of both mTORC1 and mTORC2 activities. Mechanistically, CYLD interacts with mTOR and removes non-degradative, K63-linked ubiquitin (Ub) chains from multiple of its residues. Consequently, CYLD loss-of-function cells are characterized by mTORC1/2 hyperactivation, elevated rates of protein synthesis, increased cell size, and resistance to serum-starvation-induced activation of cell death pathways. Moreover, silencing of cyld-1, the C. elegans CYLD ortholog, fully reverses the extended lifespan of low-TORC1-activity mutant worms. Finally, we find that inactivation of CYLD is associated with hyperactivation of mTORC1 also in skin biopsies from CYLD cutaneous syndrome (CCS) patients. In sum, our findings highlight CYLD as a sentinel of mTOR hyperactivation via direct control of its ubiquitination, and suggest that dysregulated mTOR activity may contribute to the development and progression of CCS tumors.
Longevity Relevance Analysis
(4)
The paper claims that the tumor suppressor CYLD acts as a deubiquitinase for mTOR, negatively regulating its activity and influencing lifespan in C. elegans. The findings suggest a mechanism by which mTOR hyperactivation can be controlled, linking it to longevity and age-related processes.
Lopez-Pernas, G., Murga, M., Ahmed, W. ...
· cancer biology
· CNIO
· biorxiv
The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxi...
The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxic for cells with an activated DNA damage response (DDR). This screen identified the tyrosine kinase inhibitor GNF-7 as a top hit. Subsequent work revealed that GNF-7 is a potent senolytic, even when senescence is triggered by therapies that do not activate the DDR. Consistently, GNF-7 is highly efficacious to kill cancer cells previously treated with CDK4/6 inhibitors, including in patient-derived organoids and mouse xenografts. Surprisingly, the senolytic effect of GNF-7 is not mediated by the inhibition of a tyrosine kinase (TK), but rather by the activation of GCN2, an effect previously reported for other TK inhibitors. Together, our study reports the discovery of a novel senolytic agent that strongly synergizes with CDK4/6 inhibitors when applied sequentially and expands our understanding of the mechanisms behind the anticancer effects of TK inhibitors.
Longevity Relevance Analysis
(4)
GNF-7 is identified as a novel senolytic agent that targets senescent cells through the activation of GCN2. The paper is relevant as it explores a potential therapeutic approach to eliminate senescent cells, which are implicated in aging and age-related diseases, thereby addressing a root cause of aging rather than merely treating symptoms.
Mingzhuang Hou, Yifan Ma, Yaoge Deng ...
· Proceedings of the National Academy of Sciences of the United States of America
· Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
· pubmed
Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondr...
Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.
Longevity Relevance Analysis
(4)
The paper claims that targeting mitofusin-2 (MFN2) can restore mitochondrial function and prevent cartilage degeneration in osteoarthritis. This research addresses mitochondrial dysfunction, a key aspect of aging, and proposes a potential therapeutic strategy that could mitigate age-related degeneration in joint health.
Herzog, C. M. S., Vavourakis, C. D., Redl, E. ...
· systems biology
· Universitaet Innsbruck
· biorxiv
Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (ag...
Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (aged 30-60 years) undergoing 6-month intermittent fasting (n=114) or smoking cessation (n=42) interventions. Participants were sampled up to four times across seven tissues and fluids, generating >3,450 biospecimens with harmonised DNA methylation, metabolomics, microbiome, and immune profiling, alongside skin histology, barrier measurements, and rich clinical metadata. We demonstrate the utility of this dataset through: (i) multi-omics-wide association studies linking traits to molecular features; (ii) integrative factor modelling revealing coordinated cross-tissue signatures; (iii) epigenetic-biomarker cross-omic associations, and (iv) CpG-level variance decomposition mapping stable, individual-specific, tissue-restricted, and intervention-responsive methylation patterns. We further show that ageing-linked features are selectively malleable: highly compliant intermittent fasting participants exhibited attenuated or even age-opposing molecular trajectories within six months. The atlas enables unprecedented within-cohort comparisons across omic layers and tissues, supporting discovery of context-dependent biomarkers, cross-system coordination, and intervention responsiveness. Data are available via an interactive portal, with sensitive data under controlled access (https://eutops.github.io/lifestyle-atlas/). This resource provides a foundation for exploring biomarker association and multi-tissue epigenetics, enabling hypothesis generation and benchmarking for systems biology and human healthspan research.
Longevity Relevance Analysis
(5)
The paper claims that highly compliant intermittent fasting participants exhibit age-opposing molecular trajectories within six months. This research is relevant as it explores lifestyle interventions that may directly influence the biological mechanisms of aging, contributing to the understanding of healthspan extension.
Thalida Em Arpawong, Belinda Hernandez, Claire Potter ...
· GeroScience
· Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA. [email protected].
· pubmed
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces-termed epigenetic clocks-that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological hea...
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces-termed epigenetic clocks-that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological health Age (PhysAge) score, comprised of eight DNA methylation surrogates to represent multi-system physiology and developed from commonly measured clinical biomarkers: CRP, peak flow, pulse pressure, HDL-cholesterol, Hba1c, waist-to-height ratio (WHR), cystatin C, and dehydroepianrosterone sulphate (DHEAS). We use data from the population-representative US Health and Retirement Study (HRS), split into a training (n = 1589) and test sample (n = 1588) and corroborate findings in two independent cohorts: The Irish Longitudinal Study of Aging (TILDA; n = 488) and the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA; n = 1830). PhysAge and the predominant second-generation epigenetic clocks, PhenoAge, GrimAge2, and DunedinPACE, were tested for their prediction of mortality and multiple age-related clinical measures (i.e., grip strength, gait speed, cognitive function, disability, frailty). PhysAge was comparable to extant clocks in predicting health measures and was indistinguishable from GrimAge2 in predicting mortality, despite not being trained on mortality. Moreover, the eight individual surrogates comprising PhysAge predicted health outcomes better than the measured values in many instances. The established clinical relevance of the biomarkers from which surrogates were derived opens up new opportunities for cross-study and cross-country comparisons of population health. Findings suggest that the DNA methylation PhysAge can be leveraged as a single biomarker to represent multiple physiological systems and offers utility in the context of clinical monitoring.
Longevity Relevance Analysis
(5)
The paper claims that the DNA methylation-based Physiological health Age (PhysAge) score can predict health outcomes and mortality in older adults. This research is relevant as it addresses biological aging through a novel multi-system approach, potentially offering insights into the root causes of aging and improving health monitoring in older populations.
Lu, Y. R., Cameron, J. C., Hu, Y. ...
· genetics
· Whitehead Institute for Biomedical Research
· biorxiv
Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration ...
Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.
Longevity Relevance Analysis
(5)
The paper claims that OSK factors activate a non-canonical oxidative resilience pathway that rejuvenates retinal pigmented epithelium and restores vision in aged mice. This research addresses mechanisms of rejuvenation and oxidative stress resilience, which are central to understanding and potentially mitigating age-related degeneration.
Maria Grazia Perino, Miguel Calvo-Rubio Barrera, Daniel R Riordon ...
· GeroScience
· Laboratory of Cardiovascular Science, Intramural Research Program, National Institute On Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD, 21224, USA. [email protected].
· pubmed
Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VII...
Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VIII (TG
Longevity Relevance Analysis
(4)
The paper claims that the failure of cardiac proteostatic adaptations to chronic cAMP-stress accelerates heart aging. This research addresses the mechanisms of aging at the cellular level, specifically focusing on proteostasis in the context of heart aging, which is directly relevant to understanding and potentially mitigating age-related decline.
Hiebert, L. S., Soesbe, A., Cui, Q. ...
· evolutionary biology
· University of California Santa Barbara
· biorxiv
While most knowledge of animal DNA methylation comes from vertebrates, this epigenetic mark remains poorly understood in invertebrates, which comprise the majority of animal diversity. For instance, how promoter and gene body methylation contribute to gene regulation, and how met...
While most knowledge of animal DNA methylation comes from vertebrates, this epigenetic mark remains poorly understood in invertebrates, which comprise the majority of animal diversity. For instance, how promoter and gene body methylation contribute to gene regulation, and how methylation relates to aging, are still relatively unknown in most invertebrates. Focusing on the California mussel (Mytilus californianus), we paired whole-genome resequencing and whole-genome bisulfite sequencing from the same individuals and evaluated relationships among promoter methylation, gene body methylation, gene expression, and age. Using seven individuals spanning a range of body sizes from the Santa Barbara Channel, California, we found standing genetic variation levels similar to related species and a relatively small effective population size. CpG methylation was enriched in gene bodies, and gene body methylation was positively associated with expression. Promoter methylation was less frequent but showed a strong negative association with expression and remained the best predictor of repression after accounting for gene body methylation, aligning with patterns widely documented in vertebrates and adding to the limited evidence in invertebrates that promoter methylation can be regulatory. We identified thousands of age-associated differentially methylated loci with directional changes across age classes, providing candidate sites for epigenetic clocks that could enable assessment of biological age, health, and stress resilience in wild and cultured populations.
Longevity Relevance Analysis
(4)
The paper claims that promoter methylation is a key regulatory mechanism in gene expression and is associated with aging in the California mussel. This research contributes to understanding the epigenetic factors influencing aging, which is relevant to the root causes of longevity and biological age assessment.
Calvo-Asensio, I., Tarcevski, A., Dhalla, F. ...
· immunology
· Institute of Medical Sciences, University of Aberdeen
· biorxiv
The thymus is a primary lymphoid organ which provides essential structural and functional support for the development of naive T cells. Thymic epithelial cells (TECs), key components of the thymic stroma, are classified into cortical (cTEC) and medullary (mTEC) lineages based on ...
The thymus is a primary lymphoid organ which provides essential structural and functional support for the development of naive T cells. Thymic epithelial cells (TECs), key components of the thymic stroma, are classified into cortical (cTEC) and medullary (mTEC) lineages based on their distinct molecular, structural, transcriptional, and functional characteristics. Advances in single-cell RNA sequencing (scRNA-seq) have revealed significant TEC heterogeneity, including the identification of intertypical TECs that share properties of both cTEC and mTEC and have been postulated to play a role in the development and maintenance of thymic function. To date, the identity and maintenance of postnatal TEPCs remain unclear, with debates on whether bipotent TEPCs persist after birth or if lineage-restricted progenitors independently maintain TEC compartments. Using an inducible lineage-tracing system based on {beta}5t expression, we explored the early dynamics of the relationships between TEPC and mTEC progenitors and their progeny. Our results identified two potential lineage-biassed TEPC subpopulations, distinguished by Ly6d expression. Additionally, we observed that ageing disproportionately affects Ly6d- compared to Ly6d+ TEPCs, with implications for the rejuvenation of the ageing thymic epithelium. This study provides insights into the developmental pathways of TEC lineages and their maintenance, contributing to strategies for enhancing thymic function in ageing and disease.
Longevity Relevance Analysis
(4)
The study identifies two subpopulations of thymic epithelial progenitor cells (TEPCs) and their differential response to aging, suggesting potential strategies for rejuvenating thymic function. This research is relevant as it explores the mechanisms underlying thymic aging, which is a critical aspect of immune system decline associated with aging.
Rebecca C S Ong, Alexander D Tang
· Aging cell
· Experimental and Regenerative Neurosciences, The University of Western Australia, Perth, Australia.
· pubmed
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain,...
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain, and where these changes occur in the brain are unknown. Furthermore, it is not known why different rTMS protocols induce different changes in the aged brain, or why rTMS is less effective in older adults compared to younger adults. Using spatial transcriptomics, we uncovered that rTMS primarily acts on genes related to synaptic plasticity in both cortical and subcortical circuits in aged mice, but the specific changes were dependent on the brain region and even down to individual cortical layers in the motor and somatosensory cortices. Comparing our results from aged mice to young adult mice revealed that rTMS acts on a larger variety of neural plasticity mechanisms in the young adult brain, and that rTMS was less effective at altering gene expression related to neural plasticity in the aged brain, but this varied between brain regions and the protocol of rTMS applied. These findings provide a comprehensive map of the mechanisms altered by rTMS across the aged brain and highlight the need to consider the effect of ageing when optimising rTMS protocols for older populations.
Longevity Relevance Analysis
(4)
The paper claims that repetitive transcranial magnetic stimulation (rTMS) induces different neural plasticity mechanisms in the aged brain compared to younger brains. This research is relevant as it explores the underlying mechanisms of neural plasticity in the context of aging, which could inform strategies for promoting healthy brain aging and addressing age-related neurological conditions.
Dimitris-Foivos Thanos, Orestis A Ntintas, Emmanouil I Athanasiadis ...
· Cellular Senescence
· Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
· pubmed
Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin acc...
Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin accessibility and functional interactions that govern gene regulation across multiple biological processes, including aging and one of its hallmarks, cellular senescence. Cellular senescence constitutes a defensive stress response to various intrinsic and extrinsic stimuli, preserving cellular and organismal homeostasis through a generally irreversible cell cycle arrest. In this review article we discuss epigenetic alterations occurring to DNA and chromatin that drive and fuel the onset of this complex phenomenon. As such, we describe major large-scale chromatin events, including the formation of higher-order chromatin structures and the 3D spatial alterations of the genome that occur during senescence. We also discuss global heterochromatin loss, deficiencies in nuclear lamins, the depletion of core histones and their modifications, as well as the epigenetic regulation of the senescence-associated secretory phenotype (SASP), all of which serve key roles in the epigenome of senescent cells. To clearly demonstrate the significance of epigenetic modifications, data from a computational meta-analysis are presented, aiming to further underpin key epigenetic mechanisms occurring in senescent cells. Last, we highlight promising epigenetic modulators implemented in therapeutic strategies for senescent cell detection and elimination, possibly leading to significant clinical advances against various age-related diseases as well as the delay and prevention of the aging onset.
Longevity Relevance Analysis
(4)
The paper discusses the epigenetic alterations in cellular senescence and their implications for aging and age-related diseases. This research is relevant as it addresses the underlying mechanisms of cellular senescence, which is a key contributor to the aging process and potential therapeutic strategies for longevity.
Thi Quynh Trang Nguyen, Kyung A Cho
· Experimental & molecular medicine
· Department of Biochemistry, Chonnam National University Medical School, Hwasun-gun, Republic of Korea.
· pubmed
Here we examine the crucial role of the immune system in aging, with a particular focus on two interconnected processes: immunosenescence and inflammaging, which contribute to age-related decline. Our goal is to provide a thorough overview of the various factors that lead to immu...
Here we examine the crucial role of the immune system in aging, with a particular focus on two interconnected processes: immunosenescence and inflammaging, which contribute to age-related decline. Our goal is to provide a thorough overview of the various factors that lead to immune aging while introducing therapeutic approaches that can partially restore immune function. Additionally, we discuss recent strategies that go beyond localized immune improvement to actively modulate immune balance, influencing systemic aging and extending healthspan. Through this exploration, we propose that regulating the immune system is essential for managing immune aging and may serve as a key mechanism for controlling the overall aging process and promoting healthy longevity.
Longevity Relevance Analysis
(4)
Regulating the immune system can manage immune aging and promote healthy longevity. The paper addresses the root causes of aging by focusing on immunosenescence and inflammaging, which are critical processes in the aging mechanism.
Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field im...
Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field imaging, which is non-quantitative and tedious to perform. We have developed an effective and reproducible multiplex high-content analysis system for high-throughput screen and evaluation of senescence modulators. The IC
Longevity Relevance Analysis
(4)
The paper claims to have developed a multiplex high-content analysis system for high-throughput screening of senescence modulators. This research is relevant as it addresses cellular senescence, a key factor in aging and age-related diseases, and proposes a novel method for evaluating potential anti-senescence therapies.
Jiayu Huang, Lu Sun, Yuehan Yin ...
· Cell reports
· Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
· pubmed
Aging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissue function. However, the relationship between aging and the...
Aging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissue function. However, the relationship between aging and the stem Leydig cell (SLC) pool homeostasis remains unclear. Here, we demonstrate that extracellular matrix (ECM) stiffness increases in aging testes, and SLC pool homeostasis is imbalanced. Mechanistically, high ECM stiffness increases calcium influx mediated by Piezo1, leading to mitochondrial dysfunction and excessive reactive oxygen species (ROS). Excessive ROS promotes Gli1 degradation via the ubiquitin-proteasome pathway, ultimately inhibiting the proliferation and differentiation ability of SLCs. Together, these findings reveal the role of ECM stiffness, a biomechanical property in testes, in regulating SLC pool homeostasis and suggest that pretreatment of SLCs with low ECM stiffness in vitro may be an effective strategy for their expansion and for restoring testosterone levels in aging males.
Longevity Relevance Analysis
(4)
High matrix stiffness in aging testes disrupts stem Leydig cell pool homeostasis, leading to decreased testosterone production. This paper addresses a potential root cause of aging-related decline in male reproductive function, making it relevant to longevity research.
Haiyue Tang, Wenjie Ma, Guoyou Zhang ...
· Molecular diversity
· Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
· pubmed
SIRT6, a pivotal member of the NAD
SIRT6, a pivotal member of the NAD
Longevity Relevance Analysis
(4)
The paper claims to elucidate the mechanistic basis of allostery in SIRT6, which is implicated in metabolic regulation and DNA repair. Understanding SIRT6's role could provide insights into mechanisms of aging and longevity, making it relevant to the field.
Bopp, V., LeeBae, J., Oeckl, P. ...
· neuroscience
· German Center for Neurodegenerative Diseases (DZNE)
· biorxiv
Aging as well as the presence of a-synuclein (a-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biologi...
Aging as well as the presence of a-synuclein (a-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with a-syn oligomers for the onset of PD symptoms remains unclear. Using an inducible a-syn oligomer mouse model of PD, we demonstrate that the induction of PD associated a-syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that a-syn oligomer formation precedes motor decline in these aged mice, and age together with a-syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of a-syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the a-syn model of PD.
Longevity Relevance Analysis
(4)
The paper claims that biological processes of aging are a major causative driver for the onset of Parkinson's Disease in an a-synuclein model. This research is relevant as it explores the intersection of aging mechanisms and neurodegenerative disease, potentially addressing root causes rather than just symptoms.
Tripathi, U., Suda, M., Kulshreshtha, V. ...
· cell biology
· Center for Advanced Gerotherapeutics, Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA
· biorxiv
The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that ar...
The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become senolytic-resistant. Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated {beta}-galactosidase (SA{beta}gal), {gamma}H2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as senosensitizers), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.
Longevity Relevance Analysis
(4)
The paper claims that senolytic-resistant senescent cells have a distinct SASP profile that could inform the development of senosensitizers. This research is relevant as it addresses the mechanisms of senescence and potential interventions that could mitigate age-related dysfunction, contributing to the understanding of aging and longevity.
Chandramouli Muralidharan, Enikő Zakar-Polyák, Anita Adami ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, 221 84, Sweden.
· pubmed
Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, human cell-type-specific transcriptomic aging clocks are developed using high-quality single-nucleus RNA sequencing data fr...
Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, human cell-type-specific transcriptomic aging clocks are developed using high-quality single-nucleus RNA sequencing data from post mortem human prefrontal cortex tissue of 31 donors aged 18-94 years, encompassing 73,941 high-quality nuclei. Distinct transcriptomic changes are observed across major cell types, including upregulation of inflammatory response genes in microglia from older samples. Aging clocks trained on each major cell type accurately predict chronological age, capture biologically relevant pathways, and remain robust in independent single-nucleus RNA-sequencing datasets, underscoring their broad applicability. Notably, cell-type-specific age acceleration is identified in individuals with Alzheimer's disease and schizophrenia, suggesting altered aging trajectories in these conditions. These findings demonstrate the feasibility of cell-type-specific transcriptomic clocks to measure biological aging in the human brain and highlight potential mechanisms of selective vulnerability in neurodegenerative diseases.
Longevity Relevance Analysis
(5)
The paper develops human cell-type-specific transcriptomic aging clocks that can measure biological aging in the brain. This research is relevant as it addresses the biological mechanisms of aging and their implications for neurodegenerative diseases, contributing to the understanding of aging processes rather than merely treating symptoms.
Masato Horino, Kenji Ikeda, Rei Okazaki ...
· Reactive Oxygen Species
· Department of Molecular Endocrinology and Metabolism, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan.
· pubmed
The induction of beige adipocytes is significantly reduced in aged mice due to the senescence of adipocyte progenitor cells (APCs). Recent studies have revealed the existence of beige adipocyte subtypes, suggesting that APCs comprise a heterogeneous population. Therefore, in this...
The induction of beige adipocytes is significantly reduced in aged mice due to the senescence of adipocyte progenitor cells (APCs). Recent studies have revealed the existence of beige adipocyte subtypes, suggesting that APCs comprise a heterogeneous population. Therefore, in this study, we aimed to elucidate the mechanism through which long-term cold exposure induces the production of beige adipocytes even in aged mice. Single-cell RNA sequencing identified carbonic anhydrase 4 (Car4)-positive APCs. The number of Car4-positive APCs increased with age and cold exposure. Car4 knockdown (KD) mitigated intracellular pH reduction and significantly suppressed beige adipocyte differentiation. Furthermore, Car4 KD cells demonstrated reduced expression of genes in the glutathione pathway and increased susceptibility to reactive oxygen species (ROS), which was alleviated by glutathione supplementation. Our findings suggest that ROS resistance is an adaptation to the cellular aging environment. Our study provides insights into the age-related decline in beige adipocyte induction and identifies Car4 as a potential therapeutic target for enhancing energy expenditure in elderly individuals. This may pave the way for the development of new strategies to combat age-related metabolic diseases and offer hope for improved health and longevity in an aging population.
Longevity Relevance Analysis
(4)
The study claims that Car4-positive adipocyte progenitor cells adapt to aging by enhancing resistance to reactive oxygen species through glutathione metabolism. This research is relevant as it explores mechanisms that could potentially mitigate age-related metabolic decline and improve health in the elderly, addressing root causes of aging rather than merely treating symptoms.
Manmeet Bhalla, Shaunna R Simmons, Alexsandra Lenhard ...
· mSphere
· Department of Microbiology and Immunology, University at Buffalo School of Medicine, , Buffalo, New York, USA.
· pubmed
In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four...
In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four G-protein receptors: A1, A2A, A2B, and A3, which can have opposing downstream effects on immune responses. In this minireview, we follow up on our mSphere of Influence commentary that focused on the A2B receptor (2019) to give a broader view of the role of the extracellular adenosine signaling pathway in host defense against infections. Studies demonstrate that extracellular adenosine serves as a key signaling molecule regulating the balance between effective pathogen clearance and immunopathology during infection. Extracellular adenosine displays dose- and time-dependent roles during infection, with individual adenosine receptors playing specific roles in controlling immune responses. Age-driven changes in this pathway contribute to the increased susceptibility of older hosts to certain infections, although there are several key unanswered questions about the role of the extracellular adenosine pathway in immunosenescence. Clinical and translational findings reveal a role for extracellular adenosine production and signaling in infections in humans, and there have been recent advances, but several ongoing challenges remain in pharmacologically targeting this pathway to reshape host immune responses.
Longevity Relevance Analysis
(4)
The paper discusses the role of extracellular adenosine signaling in regulating immune responses during infections, particularly in the context of aging. This research is relevant as it explores how age-related changes in immune signaling pathways may contribute to increased susceptibility to infections in older individuals, addressing a key aspect of immunosenescence.