bims-caglex 2024-10-27 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–10–27
33 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

The Anti-Aging Effects of Collagen Type VII (COL7A1) as Longevity Mediator in Caenorhabditis elegans Healthspan Extension and Skin Collagen Synthesis.
Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
Cellular senescence contributes to spontaneous repair of the rat meniscus.
Kaempferol enhances intestinal repair and inhibits the hyperproliferation of aging intestinal stem cells in Drosophila.
The role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression.
HMGB1, an evolving pleiotropic protein critical for cellular and tissue homeostasis: role in aging and age-related diseases.
The dietary exposome: a brief history of diet, longevity, and age-related health in rodents.
Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
Skin Rejuvenation by Modulation of DNA Methylation.
Genetic and Epigenetic Alterations in Aging and Rejuvenation of Human.
Aging 'clocks' battle for science glory and cash.
Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.
Inhibiting IL11: a novel approach to turning back the clock.
Phosphoproteomic analysis reveals the mechanisms of human umbilical cord mesenchymal stem cell-derived exosomes attenuate renal aging.
Antiaging in a Bottle: Bioactive Competency of Plasma-Generated Nitric Oxide Water for Modulation of Aging-Related Signature in Human Dermal Cells.
The complex effects of dietary restriction on longevity and health.
A nuclear morphology-based machine learning algorithm for senescence detection.
Intestinal tuft cells act as reserve stem cells after injury.
G-quadruplex DNA and RNA in cellular senescence.
The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells.
Late-onset caloric restriction improves cognitive performance and restores circadian patterns of neurotrophic, clock and epigenetic factors in the hippocampus of male old rats.
Senescence landscape in the liver following sepsis and senolytics as potential therapeutics.
Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells.
AI-designed DNA sequences regulate cell-type-specific gene expression.
Downregulation of carnitine acetyltransferase by promoter hypermethylation regulates ultraviolet-induced matrix metalloproteinase-1 expression in human dermal fibroblasts.
Contrasting Effects of an Atherogenic Diet and High-Protein/Unsaturated Fatty Acids Diet on the Accelerated Aging Mouse Model SAMP8 Phenotype.
SRSF2 safeguards efficient transcription of DNA damage and repair genes.
The double-edged sword of eliminating senescent cells.
METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.
Disease background influences fate of transplanted stem cells.
Asparagine614 Determines the Transport and Function of the Murine Anti-Aging Protein Klotho.
Thermostable bFGF Improves Cell Lifespan by Enhancing Cell Activity in the Long-Term Culture of Human Orbicularis Oculi Stem Cells.
The dynamic crosslinking between gut microbiota and inflammation during aging: reviewing the nutritional and hormetic approaches against dysbiosis and inflammaging.

Biomol Ther (Seoul). 2024 Oct 21.

The Anti-Aging Effects of Collagen Type VII (COL7A1) as Longevity Mediator in Caenorhabditis elegans Healthspan Extension and Skin Collagen Synthesis.

Juewon Kim, Hyeryung Kim, Woo-Young Seo, Eunji Lee, Donghyun Cho.

  Longevity genes and senescence-related signaling proteins are crucial targets in aging research, which aims to enhance the healthy period and quality of life. Identifying these target proteins remains challenging because of the need for precise categorization and validation methods. Our multifaceted approach combined bioinformatics with transcriptomic data to identify collagen as a key element associated with the lifespan of the model organism, Caenorhabditis elegans. By analyzing transcriptomic data from long-lived mutants that involved mechanisms such as antioxidation, dietary restriction, and genetic background, we identified collagen as a common longevity-associated gene. We validated these findings by confirming that collagen peptides positively affect lifespan, thereby strengthening the validity of the target. Further verification through healthspan factors in C. elegans and functional assays in skin fibroblasts provided additional evidence of the role of collagen in organismal aging. Specifically, our study revealed that collagen type VII is a significant target protein for mitigating age-related decline. By validating these findings across different aging models and cell-based studies, we present compelling evidence for the anti-aging effects of collagen type VII, highlighting its potential as a target for promoting healthy aging. This study proposes that collagen not only serves as an indicative marker of organismal longevity across various senescence-related signaling pathways, but also offers a mechanistic understanding of skin degeneration. Consequently, collagen is an effective target for interventions aimed at mitigating skin aging. This study underscores the potential of collagen type VII (bonding collagen T7) as a therapeutic target for enhancing skin health and overall longevity.

Keywords:  Bonding collagen; C. elegans; Collagen VII; Healthspan; Skin aging

DOI:  https://doi.org/10.4062/biomolther.2024.127
Nat Commun. 2024 Oct 24. 15(1): 9181

Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.

Leighton H Daigh, Debarya Saha, David L Rosenthal, Katherine R Ferrick, Tobias Meyer.

DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.

DOI: https://doi.org/10.1038/s41467-024-52820-6
Aging Cell. 2024 Oct 22. e14385

Cellular senescence contributes to spontaneous repair of the rat meniscus.

Yusuke Aimono, Kentaro Endo, Ichiro Sekiya.

  Cellular senescence, traditionally associated with aging and chronic diseases, has recently been identified as a potential facilitator of tissue regeneration via a senescence-associated secretory phenotype (SASP). In rodents, the meniscus is known to regenerate spontaneously from the surrounding synovium, but the mechanism, and especially its relationship to cellular senescence, remains unclear. This study investigated the contribution of cellular senescence to spontaneous repair of the rat meniscus. We created a rat partial medial meniscectomy (pMx) model to evaluate time-course changes in regenerative tissue. Immunohistochemistry revealed marked increases in p16 expression and senescence-associated beta-galactosidase (SA-β-gal) activity in the regenerating tissue at the early phase after pMx surgery. RNA sequencing of regenerating tissues identified the upregulation of genes related to aging, extracellular matrix organization, and cell proliferation. Fluorescence staining identified high expression of SOX9, a master regulator of cartilage/meniscus development, adjacent to p16-positive cells. In vitro investigations of the effect of SASP factors on synovial fibroblasts (SFs) demonstrated that conditioned medium from senescent SFs stimulated the proliferation and chondrogenic differentiation of normal SFs. In vivo histological evaluation to determine whether selective elimination of senescent cells with a senolytic drug (ABT-263) retarded spontaneous repair of meniscus in vivo confirmed that ABT-263 decreased the meniscus score and expression of SOX9, aggrecan, and type 1 collagen. Our findings indicate that transient senescent cell accumulation and SASP in regenerating tissues beneficially contribute to spontaneous repair of the rat meniscus. Further research into the molecular mechanism will provide a novel strategy for meniscus regeneration based on cellular senescence.

Keywords:  ABT‐263; cellular senescence; meniscus; senescent cell; synovial fibroblast

DOI:  https://doi.org/10.1111/acel.14385
Front Cell Dev Biol. 2024 ;12 1491740

Kaempferol enhances intestinal repair and inhibits the hyperproliferation of aging intestinal stem cells in Drosophila.

Liusha Zhao, Ting Luo, Hong Zhang, Xinxin Fan, Qiaoqiao Zhang, Haiyang Chen.

   Introduction: Intestinal stem cells (ISCs) are crucial for tissue repair and homeostasis because of their ability to self-renew and differentiate. However, their functionality declines significantly with age, resulting in reduced tissue regeneration and a higher risk of age-related diseases. Addressing this decline in ISC performance during aging presents a substantial challenge. The specific impact of nutrients or dietary elements on ISC adaptive resizing is urgent to explore.
Methods: Drosophila ISCs are an ideal model for studying development and aging because of their genetic richness, ease of manipulation, and similarity to mammalian tissues. As the primary mitotically active cells in the Drosophila gut, ISCs are flexible in response to dietary and stress signals. Manipulating signaling pathways or dietary restrictions has shown promise in regulating ISC functions and extending lifespan in flies, these approaches face broader applications for aging research.
Results: Kaempferol is well-regarded for its antioxidant, anti-inflammatory, and potential anticancer effects. However, its impacts on ISCs and the associated mechanisms remain inadequately understood. Our findings indicate that Kaempferol accelerates gut recovery after damage and improves the organism's stress tolerance. Moreover, Kaempferol suppresses the hyperproliferation of aging ISCs in Drosophila. Further investigation revealed that the regulatory effects of Kaempferol on ISCs are mediated through the reduction of endoplasmic reticulum (ER) stress in aging flies and the modulation of excessive reactive oxygen species (ROS) levels via ER-stress pathways. Furthermore, Kaempferol exerts regulatory effects on the insulin signaling pathway, thereby contributing to the attenuation of ISC senescence.
Discussion: This study reveals that Kaempferol promotes intestinal homeostasis and longevity in aging flies by targeting ER stress and insulin signaling pathways, though the exact molecular mechanisms require further exploration. Future research will aim to dissect the downstream signaling events involved in these pathways to better understand how Kaempferol exerts its protective effects at the molecular level.

Keywords:  Drosophila; Kaempferol; ROS; aging; intestinal stem cell

DOI:  https://doi.org/10.3389/fcell.2024.1491740
NPJ Aging. 2024 Oct 24. 10(1): 48

The role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression.

Nirmalya Dasgupta, Rouven Arnold, Anais Equey, Armin Gandhi, Peter D Adams.

Senescence and epigenetic alterations stand out as two well-characterized hallmarks of aging. When cells become senescent, they cease proliferation and release inflammatory molecules collectively termed the Senescence-Associated Secretory Phenotype (SASP). Senescence and SASP are implicated in numerous age-related diseases. Senescent cell nuclei undergo epigenetic reprogramming, which intricately regulates SASP expression. This review outlines the current understanding of how senescent cells undergo epigenetic changes and how these alterations govern SASP expression.

DOI: https://doi.org/10.1038/s41514-024-00172-2
Ageing Res Rev. 2024 Oct 18. pii: S1568-1637(24)00368-4. [Epub ahead of print] 102550

HMGB1, an evolving pleiotropic protein critical for cellular and tissue homeostasis: role in aging and age-related diseases.

Elena Ruggieri, Erika Di Domenico, Andrea Giacomo Locatelli, Flavio Isopo, Sarah Damanti, Rebecca De Lorenzo, Enrico Milan, Giovanna Musco, Patrizia Rovere-Querini, Simone Cenci, Emilie Vénéreau.

  Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity.

Keywords:  DAMP (damage-associated molecular pattern); DNA; HMGB1 (high mobility group protein B1); aging; autophagy; biomarker; homeostasis; inflammation; redox; regeneration

DOI:  https://doi.org/10.1016/j.arr.2024.102550
Clin Sci (Lond). 2024 Nov 06. 138(21): 1343-1356

The dietary exposome: a brief history of diet, longevity, and age-related health in rodents.

Colin Selman.

  It has been recognized for over a century that feeding animals less food than they would normally eat increases lifespan and leads to broad-spectrum improvements in age-related health. A significant number of studies have subsequently shown that restricting total protein, branched chain amino acids or individual amino acids in the diet, as well as ketogenic diets, can elicit similar effects. In addition, it is becoming clear that fasting protocols, such as time-restricted-feeding or every-other-day feeding, without changes in overall energy intake can also profoundly affect rodent longevity and late-life health. In this review, I will provide a historical perspective on various dietary interventions that modulate ageing in rodents and discuss how this understanding of the dietary exposome may help identify future strategies to maintain late-life health and wellbeing in humans.

Keywords:  Ageing; Aging; Caloric restriction; Dietary restriction; Fasting; Lifespan

DOI:  https://doi.org/10.1042/CS20241248
Nat Commun. 2024 Oct 21. 15(1): 9063

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.

Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.

DOI: https://doi.org/10.1038/s41467-024-53127-2
Exp Dermatol. 2024 Oct;33(10): e70005

Skin Rejuvenation by Modulation of DNA Methylation.

Elke Grönniger, Heiner Max, Frank Lyko.

  Skin aging is driven by a complex set of cellular pathways. Among these, epigenetic mechanisms have garnered particular attention, because of their sensitivity to environmental and lifestyle factors. DNA methylation represents the longest known and best understood epigenetic mechanism. We explain how DNA methylation might function as an interface between the environment and the genome of human skin. Exposures to different environmental factors and lifestyles are known to modulate age-related methylation patterns, as illustrated by their effect on DNA methylation clocks. Human skin provides a particularly well-suited tissue for understanding age-related methylation changes and it has been shown recently that modulation of DNA methylation can induce skin rejuvenation. We explain how the use of mildly demethylating agents can be safeguarded to ensure the specific removal of age-related DNA methylation changes. We also identify important areas of future research, leading to a deeper understanding of the mechanisms that drive epigenetic aging and to the development of further refined intervention strategies.

Keywords:  DNA methylation; DNA methylation clock; aging; dihydromyricetin; rejuvenation; skin

DOI:  https://doi.org/10.1111/exd.70005
Mol Cells. 2024 Oct 19. pii: S1016-8478(24)00162-6. [Epub ahead of print] 100137

Genetic and Epigenetic Alterations in Aging and Rejuvenation of Human.

Kyunghyuk Park, Min Chul Jeon, Dakyung Lee, Jong-Il Kim, Sun-Wha Im.

  All the information essential for life is encoded within our genome and epigenome, which orchestrates diverse cellular states spatially and temporally. In particular, the epigenome interacts with internal and external stimuli, encoding and preserving cellular experiences, and it serves as the regulatory base of the transcriptome across diverse cell types. The emergence of single-cell transcriptomic and epigenomic data collection has revealed unique omics signatures in diverse tissues, highlighting cellular heterogeneity. Recent research has documented age-related epigenetic changes at the single-cell level, alongside the validation of cellular rejuvenation through partial reprogramming, which involves simultaneous epigenetic modifications. These dynamic shifts, primarily fueled by stem cell plasticity, have catalyzed significant interest and cross-disciplinary research endeavors. This review explores the genomic and epigenomic alterations with aging, elucidating their reciprocal interactions. Additionally, it seeks to discuss the evolving landscape of rejuvenation research, with a particular emphasis on dissecting stem cell behavior through the lens of single-cell analysis. Moreover, it proposes potential research methodologies for future studies.

Keywords:  Aging; Cell differentiation; Cellular reprogramming; Cellular senescence; DNA damage; DNA repair; Double strand breaks; Epigenetics; Epigenomic instability; Genomic instability; Rejuvenation; Stem cell

DOI:  https://doi.org/10.1016/j.mocell.2024.100137
Science. 2024 Oct 25. 386(6720): 364-365

Aging 'clocks' battle for science glory and cash.

Mitch Leslie.

Contest aims to improve molecular assays needed to test aging treatments.

DOI: https://doi.org/10.1126/science.adu0711
Z Naturforsch C J Biosci. 2024 Oct 24.

Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.

Sandeep Singh, Avnish Kumar Verma, Geetika Garg, Abhishek Kumar Singh, Syed Ibrahim Rizvi.

  Impaired redox homeostasis is an important hallmark of aging. Among various anti-aging interventions, caloric restriction mimetics (CRMs) are the most effective in promoting health and longevity. The potential role of spermidine (SPD) as a CRM in modulating oxidative stress and redox homeostasis during aging remains unclear. This study aimed to investigate the protective effect of SPD in D-galactose (D-gal) accelerated induced senescence model and naturally aged rats. Young male rats (4 months), D-gal induced (500 mg/kg b. w., subcutaneously) aging model and naturally aged (22 months) rats were supplemented with SPD (10 mg/kg b. w., orally) for 6 weeks. The results showed that SPD supplementation suppresses the age induced increase in reactive oxygen species, lipid peroxidation and protein oxidation. Additionally, it increases the level of antioxidants, plasma membrane redox system in erythrocytes and membrane. These results also indicate that membrane transporter activity is correlated with the susceptibility of the erythrocyte towards oxidative damage. We therefore present evidence that SPD improves redox status and membrane impairments in erythrocytes in experimental and naturally aging rat models, however, more research is required to recommend a potential therapeutic role for SPD as an anti-aging intervention strategy.

Keywords:  aging; erythrocytes; membrane transporters; oxidative stress; spermidine

DOI:  https://doi.org/10.1515/znc-2024-0181
Immun Ageing. 2024 Oct 21. 21(1): 71

Inhibiting IL11: a novel approach to turning back the clock.

Osama Ahmad, Muhammad Haris.

  The World Health Organization recognizes frailty and multimorbidity as major global health issues and underscores the need for effective interventions. Recent advances have identified interleukin-11 (IL-11), a pro-inflammatory cytokine, as a key player in modulating aging pathways (such as ERK, AMPK, mTOR and JAK-STAT3). Studies have shown that IL-11 inhibition can lead to improved health span and lifespan in animal models, with potential applications in humans. By targeting IL-11, researchers aim to mitigate age-related diseases, such as cancer, fibrosis, and multimorbidity, which pose significant healthcare challenges worldwide. IL-11 inhibition offers a promising strategy, with preclinical trials demonstrating its ability to regenerate renal cells, reduce hepatocyte death, and mitigate liver fibrosis. Further research is necessary to fully elucidate the mechanisms of IL-11 inhibition and its therapeutic potential. If successful, this approach could lead to the development of novel pharmacological interventions, promoting healthier aging and increasing human lifespan.

Keywords:  Anti-aging therapies; Cellular senescence; Chronic disease prevention; Geroprotective interventions; IL-11 inhibition

DOI:  https://doi.org/10.1186/s12979-024-00477-6
J Proteomics. 2024 Oct 20. pii: S1874-3919(24)00267-7. [Epub ahead of print]310 105335

Phosphoproteomic analysis reveals the mechanisms of human umbilical cord mesenchymal stem cell-derived exosomes attenuate renal aging.

Wenzhuo Yu, Xu Jia, Han Qiao, Di Liu, Yan Sun, Rong Yan, Chenglong Zhang, Na Yu, Yiping Song, Mingying Ling, Zhen Zhang, Xuehui Li, Chuanli Zhao, Yanqiu Xing.

  Aging is a critical biological process, with particularly notable impacts on the kidneys. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) are capable of transferring various bioactive molecules, which exhibit beneficial therapeutic effects on kidney diseases. This study demonstrates that exosomes derived from hUC-MSCs ameliorate cellular senescence in the kidneys of naturally aging mice. These exosomes reduce the protein expression of senescence markers and senescence-associated secretory phenotypes (SASP) leading to fewer DNA damage foci and increased expression of the proliferation indicator Ki67. During the aging process, many proteins undergo phosphorylation modifications. We utilized data-independent acquisition (DIA) phosphoproteomics to study kidneys of naturally aging mice and those treated with hUC-MSC-derived exosomes. We observed elevated phosphorylation levels of the differentially phosphorylated proteins, Lamin A/C, at Ser390 and Ser392 sites, which were subsequently verified by western blotting. Overall, this study provides a new molecular characterization of hUC-MSC-derived exosomes in mitigating cellular senescence in the kidneys. SIGNIFICANCE: DIA phosphoproteomics was employed to investigate phosphorylated proteins in the kidney tissues of naturally aging mice with hUCMSC-exos treated. The results demonstrated that the DIA technique detected a higher abundance of phosphorylated proteins. We identified 24 significantly differentially phosphorylated proteins, and found that the phosphorylation of specific Lamin A/C sites is crucial for preventing cellular senescence. This study will help to better reveal the related phosphorylated proteins involved in hUCMSC-exos intervention in the kidneys of naturally aging mice, providing a foundation for future research on specific phosphorylation sites of proteins as potential therapeutic targets for renal aging-related diseases.

Keywords:  Aging; Cellular senescence; Exosomes; Kidney; Phosphoproteomics

DOI:  https://doi.org/10.1016/j.jprot.2024.105335
ACS Appl Mater Interfaces. 2024 Oct 22.

Antiaging in a Bottle: Bioactive Competency of Plasma-Generated Nitric Oxide Water for Modulation of Aging-Related Signature in Human Dermal Cells.

Apurva Jaiswal, Neha Kaushik, Tirtha Raj Acharya, Han Sup Uhm, Eun Ha Choi, Nagendra Kumar Kaushik.

  Nitric oxide (NO), a potential therapeutic antiaging molecule, modulates various physiological and cellular processes. However, alterations in endogenous NO levels brought on by aging impact multiple organ systems and heighten susceptibility to age-related skin diseases. This correlation underscores the importance of investigating NO-based antiaging interventions. Nonthermal plasma-generated NO is a promising avenue for cosmetic and regenerative medicine due to its capacity to stimulate cellular growth. Herein, we examine the potential of plasma-generated nitric oxide water (NOW) as a bioactive agent in human dermal fibroblasts, emphasizing gene expression patterns linked to extracellular matrix (ECM) breakdown and cellular senescence. The findings of our study indicate that administering NOW at lower dosages enhances cell migration and proliferation. Moreover, the genetic signatures associated with ECM synthesis, antioxidant defense, and antisenescence pathways have been analyzed in NOW-exposed cells. Notably, the downregulation of ECM-degrading enzyme transcripts─collagenase, elastase, and hyaluronidase─suggests NOW's potential in mitigating the intrinsic skin aging phenomena, emphasizing the promise of NO-based interventions in advancing antiaging strategies within regenerative medicine.

Keywords:  ECM degradation; NOW; antiaging; antioxidants; collagen synthesis; nitric oxide

DOI:  https://doi.org/10.1021/acsami.4c14051
Nat Rev Endocrinol. 2024 Oct 22.

The complex effects of dietary restriction on longevity and health.

Claire Greenhill.

DOI: https://doi.org/10.1038/s41574-024-01051-2
Nat Rev Mol Cell Biol. 2024 Oct 23.

A nuclear morphology-based machine learning algorithm for senescence detection.

Imanol Duran.

DOI: https://doi.org/10.1038/s41580-024-00796-y
Nature. 2024 Oct 23.

Intestinal tuft cells act as reserve stem cells after injury.



Keywords:  Regeneration; Stem cells

DOI:  https://doi.org/10.1038/d41586-024-03383-5
Front Aging. 2024 ;5 1491389

G-quadruplex DNA and RNA in cellular senescence.

Rocio Diaz Escarcega, Paul Marshall, Andrey S Tsvetkov.

  Normal cells divide, are damaged, and are repaired across their lifetime. As cells age, they enter cellular senescence, characterized by a permanent state of cell-cycle arrest triggered by various stressors. The molecular mechanisms that regulate senescent phenotypes have been actively investigated over the last several decades; however, one area that has been neglected is how G-quadruplex (G4) DNA and RNA (G4-DNA and G4-RNA) mediate senescence. These non-canonical four-stranded DNA and RNA structures regulate most normative DNA and RNA-dependent processes, such as transcription, replication, and translation, as well as pathogenic mechanisms, including genomic instability and abnormal stress granule function. This review also highlights the contribution of G4s to sex differences in age-associated diseases and emphasizes potential translational approaches to target senescence and anti-aging mechanisms through G4 manipulation.

Keywords:  DNA and RNA; G-quadruplex; age-associated disease; aging; senescence

DOI:  https://doi.org/10.3389/fragi.2024.1491389
J Orthop Translat. 2024 Nov;49 107-118

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells.

Cuicui Yang, Wanxin Qiao, Qi Xue, David Goltzman, Dengshun Miao, Zhan Dong.

   Background/Objective: Active vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells.
Methods: Bone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/-) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups.
Results: ABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins.
Conclusion: ABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency.
The translational potential of this article: This study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

Keywords:  Cellular senescence; Osteoporosis; SASP; Senolytics; Vitamin D insufficiency

DOI:  https://doi.org/10.1016/j.jot.2024.08.012
J Gerontol A Biol Sci Med Sci. 2024 Oct 24. pii: glae252. [Epub ahead of print]

Late-onset caloric restriction improves cognitive performance and restores circadian patterns of neurotrophic, clock and epigenetic factors in the hippocampus of male old rats.

Fernando Gabriel Altamirano, Ivanna Castro-Pascual, Ivana Tamara Ponce, Cinthia Daiana Coria-Lucero, Ethelina Cargnelutti, Mariana Lucila Ferramola, Marcela Silvia Delgado, Ana Cecilia Anzulovich, María Gabriela Lacoste.

  Aging is a complex multifactorial process that results in a general functional decline, including cognitive impairment. Caloric restriction (CR) can positively influence the aging processes and delay cognitive decline. There is a rhythmic variation in memory and learning processes throughout the day, indicating the involvement of the circadian clock in the regulation of these processes. Despite growing evidence on the efficacy of CR, it has not yet been fully determined whether starting this strategy at an advanced age is beneficial for improving quality of life and eventually, for protection against age-related diseases. Here, we investigated the effect of late-onset CR on the temporal organization of the molecular clock machinery, molecules related to cognitive processes and epigenetic regulation, in the hippocampus of male old rats maintained under constant darkness conditions. Our results evidenced the existence of a highly coordinated temporal organization of Bmal1, Clock, Bdnf, Trkb, Dnmts, Sirt1, and Pgc-1α in the hippocampus of young adult rats. We observed that aging led to cognitive deficits and loss of circadian oscillations of all the above variables. Interestingly, CR restored circadian rhythmicity in all cases and, in addition, improved the cognitive performance of the old animals. This work would highlight the importance of the circadian clock and its synchronization with feeding signals, as the basis of the beneficial effects of CR. Thus, lifestyle modifications, such as CR, might be a powerful intervention to preserve hippocampal circadian organization and cognitive health during aging.

Keywords:  Aging; Brain; Chronobiology; Dietary restriction; Memory and learning

DOI:  https://doi.org/10.1093/gerona/glae252
Aging Cell. 2024 Oct 23. e14354

Senescence landscape in the liver following sepsis and senolytics as potential therapeutics.

Rupa Lavarti, Lun Cai, Tatiana Alvarez Diaz, Thalia Medina Rodriguez, Sergei Bombin, Raghavan Pillai Raju.

  Senescence, caused by cell-cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP-induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA-βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21-expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single-cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis.

Keywords:   Cdkn1a Cip1 ; SASP; aging; dasatinib; quercetin; senescence; senolytics; sepsis

DOI:  https://doi.org/10.1111/acel.14354
Cell Mol Immunol. 2024 Oct 24.

Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells.

Anna Nogalska, Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y Chowdhury, Bowen Wang, Colin G Cess, Stacey D Finley, Rong Lu.

  The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in early aging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In early aging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayed aging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.

Keywords:  aging; clonal tracking; hematopoietic stem cells; lineage bias; myelopoiesis

DOI:  https://doi.org/10.1038/s41423-024-01225-y
Nature. 2024 Oct 23.

AI-designed DNA sequences regulate cell-type-specific gene expression.

Andreas R Pfenning.



Keywords:  Biotechnology; Genomics; Machine learning; Synthetic biology

DOI:  https://doi.org/10.1038/d41586-024-03170-2
J Dermatol Sci. 2024 Sep 27. pii: S0923-1811(24)00198-1. [Epub ahead of print]

Downregulation of carnitine acetyltransferase by promoter hypermethylation regulates ultraviolet-induced matrix metalloproteinase-1 expression in human dermal fibroblasts.

Min Ji Song, Min-Kyoung Kim, Chi-Hyun Park, Haesoo Kim, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung.

   BACKGROUND: Overexposure to ultraviolet (UV) radiation accelerates skin aging, resulting in wrinkle formation, reduced skin elasticity, and hyperpigmentation. UV irradiation induces increased matrix metalloproteinases (MMPs) that degrade collagen in the extracellular matrix. Skin aging is also accompanied by epigenetic alterations such as promoter methylation by DNA methyltransferases, leading to the activation or suppression of gene expression. Although carnitine acetyltransferase (CRAT) is implicated in aging, the effect of UV on the expression of CRAT and regulatory mechanisms of UV-induced MMP-1 expression remain unknown.
OBJECTIVE: We investigated changes in CRAT expression upon UV irradiation and its effect on MMP-1 expression.
METHODS: Primary human dermal fibroblasts were UV irradiated with either control or 5-AZA-dC. CRAT knockdown or overexpression was performed to investigate its effect on MMP-1 expression. The mRNA level was analyzed by quantitative real-time PCR, and protein level by western blotting.
RESULTS: The expression of CRAT was decreased in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. CRAT was downregulated upon UV irradiation by hypermethylation, and treatment with 5-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, reversed UV-induced downregulation of CRAT. CRAT knockdown activated the JNK, ERK, and p38 MAPK signaling pathways, which increased MMP-1 expression. Stable overexpression of CRAT alleviated UV-induced MMP-1 induction.
CONCLUSION: CRAT downregulation caused by promoter hypermethylation may play an important role in UV-induced skin aging via upregulation of MMP-1 expression.

Keywords:  Carnitine acetyltransferase; Extracellular matrix degradation; Matrix metalloproteinase 1; Promoter methylation; Skin aging and photoaging; UV irradiation

DOI:  https://doi.org/10.1016/j.jdermsci.2024.09.005
Neurol Int. 2024 Sep 23. 16(5): 1066-1085

Contrasting Effects of an Atherogenic Diet and High-Protein/Unsaturated Fatty Acids Diet on the Accelerated Aging Mouse Model SAMP8 Phenotype.

Jesús Llanquinao, Claudia Jara, Daniela Cortés-Díaz, Bredford Kerr, Cheril Tapia-Rojas.

  Background/Objectives: Aging has been extensively studied, with a growing interest in memory impairment by a neurobiological approach. Mitochondrial dysfunction is a hallmark of aging, contributing to the aging phenotype; therefore, mitochondrial interventions seem fundamental. The diet is a physiological approximation for modifying mitochondria, which could impact the age-related phenotype. Methods: We studied two diets with low-carbohydrate and high-fat compositions, differing in the amount of protein and the fat type disposable-the atherogenic diet Cocoa (high protein/high saturated fat/high cholesterol) and the South Beach diet (very high-protein/high-unsaturated fat)-on oxidative stress, mitochondrial state, and hippocampus-dependent memory in 3-month-old Senescence-Accelerated Mouse Model (SAMP8) seed over 3 months to determine their pro- or anti-aging effects. Results: Despite its bad reputation, the Cocoa diet reduces the reactive oxygen species (ROS) content without impacting the energy state and hippocampus-dependent spatial acuity. In contrast to the beneficial impact proposed for the South Beach diet, it induced a pro-aging phenotype, increasing oxidative damage and the levels of NR2B subunit of the NMDA, impairing energy and spatial acuity. Surprisingly, despite the negative changes observed with both diets, this led to subtle memory impairment, suggesting the activation of compensatory mechanisms preventing more severe cognitive decline. Conclusions: Our results demonstrated that diets usually considered good could be detrimental to the onset of aging. Also, probably due to the brain plasticity of non-aged animals, they compensate for the damage, preventing a more aggravated phenotype. Nevertheless, these silent changes could predispose or increase the risk of suffering pathologies at advanced age.

Keywords:  SAMP8 mice; cognitive function; diets; hippocampus; mitochondrial function

DOI:  https://doi.org/10.3390/neurolint16050080
Cell Rep. 2024 Oct 23. pii: S2211-1247(24)01220-8. [Epub ahead of print]43(11): 114869

SRSF2 safeguards efficient transcription of DNA damage and repair genes.

Rebecca E Wagner, Leonie Arnetzl, Thiago Britto-Borges, Anke Heit-Mondrzyk, Ali Bakr, Etienne Sollier, Nikoletta A Gkatza, Jasper Panten, Sylvain Delaunay, Daniela Sohn, Peter Schmezer, Duncan T Odom, Karin Müller-Decker, Christoph Plass, Christoph Dieterich, Pavlo Lutsik, Susanne Bornelöv, Michaela Frye.

  The serine-/arginine-rich splicing factor 2 (SRSF2) plays pivotal roles in pre-mRNA processing and gene transcription. Recurrent mutations, particularly a proline-to-histidine substitution at position 95 (P95H), are common in neoplastic diseases. Here, we assess SRSF2's diverse functions in squamous cell carcinoma. We show that SRSF2 deletion or homozygous P95H mutation both cause extensive DNA damage leading to cell-cycle arrest. Mechanistically, SRSF2 regulates efficient bi-directional transcription of DNA replication and repair genes, independent from its function in splicing. Further, SRSF2 haploinsufficiency induces DNA damage without halting the cell cycle. Exposing mouse skin to tumor-promoting carcinogens enhances the clonal expansion of heterozygous Srsf2 P95H epidermal cells but unexpectedly inhibits tumor formation. To survive carcinogen treatment, Srsf2 P95H+/- cells undergo substantial transcriptional rewiring and restore bi-directional gene expression. Thus, our study underscores SRSF2's importance in regulating transcription to orchestrate the cell cycle and the DNA damage response.

Keywords:  CP: Cancer; CP: Molecular biology; DNA damage; DNA repair; DNA replication; Transcription; bi-directional promoters; epithelia; skin

DOI:  https://doi.org/10.1016/j.celrep.2024.114869
Nat Rev Mol Cell Biol. 2024 Oct 24.

The double-edged sword of eliminating senescent cells.

Eric Gilson.

DOI: https://doi.org/10.1038/s41580-024-00798-w
Nat Aging. 2024 Oct 23.

METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

Huiru Jing, Jiayu Song, Jie Sun, Shaojun Su, Jin Hu, Haojian Zhang, Yanmin Bi, Bing Wu.

Given its central role in immune aging, it is important to identify the regulators of thymic involution. While conventional programmed cell death has a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution are unclear. In this study, we found that CD4+CD8+ double-positive (DP) thymocytes acquired the characteristics of senescence in aged mice undergoing thymic involution, while expression of the m6A methyltransferase-like protein 3 (METTL3), which is enriched in DP cells from young mice, decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival and in restraining the features of aging in DP thymocytes by preventing ferroptosis signaling through glutathione peroxidase 4. Mechanistically, glutathione peroxidase 4 was maintained by METTL3 at the translational level, independently of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival and attenuated the features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution and identify strategies to restore thymic function.

DOI: https://doi.org/10.1038/s43587-024-00724-x
Nature. 2024 Oct 23.

Disease background influences fate of transplanted stem cells.

Teng Gao, Vijay G Sankaran.



Keywords:  Medical research; Regeneration; Stem cells

DOI:  https://doi.org/10.1038/d41586-024-03112-y
Cells. 2024 Oct 21. pii: 1743. [Epub ahead of print]13(20):

Asparagine614 Determines the Transport and Function of the Murine Anti-Aging Protein Klotho.

Zahra Fanaei-Kahrani, Christoph Kaether.

  Klotho is an anti-aging protein whose deletion significantly reduces lifespan in mice, while its over-expression increases lifespan. Klotho is a type-I transmembrane protein that is N-glycosylated at eight positions within its ectodomain. Our study demonstrates that N-glycosylation or mutation at position N614, but not at N161, N285, or N346 in mouse Klotho, is critically involved in the transport of Klotho out of the endoplasmic reticulum (ER). Consequently, while wild-type Klotho-EGFP as well as the N-glycosylation mutants N161Q, N285Q, and N346Q were present at the plasma membrane (PM), only small amounts of the N614Q Klotho-EGFP were present at the PM, with most of the protein accumulating in the ER. Protein interactome analysis of Klotho-EGFP N614Q revealed increased interactions with proteasome-related proteins and proteins involved in ER protein processing, like heat shock proteins and protein disulfide isomerases, indicative of impaired protein folding. Co-immunoprecipitation experiments confirmed the interaction of Klotho-EGFP N614Q with ER chaperons. Interestingly, despite the low amounts of Klotho-EGFP N614Q at the PM, it efficiently induced FGF receptor-mediated ERK activation in the presence of FGF23, highlighting its efficacy in triggering downstream signaling, even in limited quantities at the PM.

Keywords:  ER chaperone; ER-Golgi trafficking; Klotho; N-glycosylation; aging

DOI:  https://doi.org/10.3390/cells13201743
Int J Stem Cells. 2024 Oct 23.

Thermostable bFGF Improves Cell Lifespan by Enhancing Cell Activity in the Long-Term Culture of Human Orbicularis Oculi Stem Cells.

Geun-Ho Kang, Yeo Kyung Shin, Kyung Min Lim, Se Jong Kim, Myeongjin Song, Kwonwoo Song, Jung Hyun Kim, Dae Young Kim, Hang-Cheol Shin, Hyun Jin Shin, Ssang-Goo Cho.

  Stem cells derived from human orbicularis oculi muscle (hOOM) are a valuable resource for cell therapy. However, when stem cells are continuously cultured, their abilities tend to deteriorate over time. One method to address this issue is to use basic fibroblast growth factor (bFGF) to maintain the stem cell functionality. The limitation is that bFGF is unstable under mammalian cell culture conditions with a half-life of only 8 hours, which poses a significant challenge to the production and maintenance of high-quality stem cells. In this study, we used thermostable bFGF (TS-bFGF) and demonstrated that hOOM-derived stem cells cultured with TS-bFGF exhibited superior proliferation, stem cell function, reduced reactive oxygen species, and cellular senescence delay effect compared to cells cultured with wild-type bFGF. Considering the pivotal role of stem cells in broad ranges of applications such as regenerative medicine and cultured meat, we anticipate that TS-bFGF, owing to its thermostability and long-lasting properties, will contribute significantly to the acquisition of high-quality stem cells.

Keywords:  Basic fibroblast growth factor; Cellular lifespan; Orbicularis oculi muscle stem cells; Thermostability

DOI:  https://doi.org/10.15283/ijsc24039
Biogerontology. 2024 Oct 23. 26(1): 1

The dynamic crosslinking between gut microbiota and inflammation during aging: reviewing the nutritional and hormetic approaches against dysbiosis and inflammaging.

Sakshi Chaudhary, Pardeep Kaur, Thokchom Arjun Singh, Kaniz Shahar Bano, Ashish Vyas, Alok Kumar Mishra, Prabhakar Singh, Mohammad Murtaza Mehdi.

  The early-life gut microbiota (GM) is increasingly recognized for its contributions to human health and disease over time. Microbiota composition, influenced by factors like race, geography, lifestyle, and individual differences, is subject to change. The GM serves dual roles, defending against pathogens and shaping the host immune system. Disruptions in microbial composition can lead to immune dysregulation, impacting defense mechanisms. Additionally, GM aids digestion, releasing nutrients and influencing physiological systems like the liver, brain, and endocrine system through microbial metabolites. Dysbiosis disrupts intestinal homeostasis, contributing to age-related diseases. Recent studies are elucidating the bacterial species that characterize a healthy microbiota, defining what constitutes a 'healthy' colonic microbiota. The present review article focuses on the importance of microbiome composition for the development of homeostasis and the roles of GM during aging and the age-related diseases caused by the alteration in gut microbial communities. This article might also help the readers to find treatments targeting GM for the prevention of various diseases linked to it effectively.

Keywords:  Aging; Gut microbiota; Homeostasis; Hormesis; Inflammation; Nutrition

DOI:  https://doi.org/10.1007/s10522-024-10146-2