bims-caglex 2024-01-21 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–01–21
nineteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Bioinformatics procedure for investigating senolytic (anti-aging) agents: A digital signal processing technique.
Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells.
Causality-enriched epigenetic age uncouples damage and adaptation.
Calcium transferring from ER to mitochondria via miR-129/ITPR2 axis controls cellular senescence in vitro and in vivo.
Senolytic treatment alleviates doxorubicin-induced chemobrain.
Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.
Coptisine prevents angiotensin II‑induced endothelial cell injury and senescence via the lncRNA SNHG12/miR‑603/NAMPT pathway.
Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases.
Sertraline promotes health and longevity in Caenorhabditis elegans.
NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation.
Dietary Marine Hydrolysate Improves Memory Performance and Social Behavior through Gut Microbiota Remodeling during Aging.
An accurate aging clock developed from large-scale gut microbiome and human gene expression data.
Sustained exposure to high glucose induces differential expression of cellular senescence markers in murine macrophages but impairs immunosurveillance response to senescent cells secretome.
NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
Agathobaculum butyriciproducens improves ageing-associated cognitive impairment in mice.
Senolytic treatment does not mitigate oxidative stress-induced muscle atrophy but improves muscle force generation in CuZn superoxide dismutase knockout mice.
Stem cell therapy for cardiac regeneration: past, present, and future.
Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing.

Aging Med (Milton). 2023 Dec;6(4): 338-346

Bioinformatics procedure for investigating senolytic (anti-aging) agents: A digital signal processing technique.

Norbert Nwankwo, Ignatius Okafor.

   Objective: Cell growth involves cell division. This stops after reaching a certain limit. Some cells become inactive and unable to undergo apoptosis (programmed cell death). These cells accumulate at sites of tissue damage or disease, thus accelerating aging. They are called senescent cells. Therapeutic interventions that can either eliminate senescent cells (senolytics) or suppress their harmful effects (senomorphics) have been developed. Senescence (aging) is caused by the inter- and intramolecular interactions between the domains of forkhead (FHD) and transactivation (TAD), as well as C-terminal region 3 (CR3) and DNA binding (DBD). On the other hand, anti-senescent/senolytic (anti-aging) activities are achieved by disrupting these interactions with CR3- and forkhead box protein O4 (FOXO4)-based peptides, such as ES2 and DRI, respectively. In this study, we use a computerized procedure based on digital signal processing to systematically analyze the inter-molecular interactions between senolytics and their targets.
Methods: Informational spectrum method (ISM) is engaged.
Results: We obtained the sequences of the peptides from the interacting proteins of CR3 and FOXO4 and evaluated their ability to disrupt the inter-molecular interactions between FOXO4 and DRI and CR3 and BDB, which are responsible for senescence (aging). Our results show that the peptides have different degrees of senolytic (anti-aging) activity, depending on their affinity for CR3 and BDB, or FOXO4 and DRI. We found that enhanced senescence 2 (ES2) has a higher affinity for CR3 and BDB than FOXO4 and DRI, and that the interaction between CR3 and BDB is crucial for aging. Therefore, ES2 and other CR3-based peptides are more potent senolytics than FOXO4-based peptides. Our findings are consistent with previous studies and reveal new insights into the mechanisms of senescence and senolytics. ES2 is considered the best senolytic candidate, as it is 3-7 times more effective than DRI. We verified that ES2 has a weaker interaction with FOXO4 than CR3. However, the performance of DRI has been noted to depend on its intramolecular interactions and stability. Hence, intramolecular analyses using the digital signal processing-based technique has become very vital and will follow.
Conclusion: CR3-based peptides are promising candidates for senolytic therapy. Senolytics are linear chains of amino acids that can target and eliminate senescent cells, which are cells that have stopped dividing and contribute to aging and age-related diseases. By using this proposed, novel computerized technique that is based on digital signal processing, senolytics can be easily analyzed and optimized for their effectiveness and safety. This provides a more rational approach to enhancing our longevity and well-being by offering interventions that can delay or reverse aging and insights that can advance the field of gerontology. This procedure also will compliment other approaches such as molecular stimulation, etc.

Keywords:  C‐terminal region 3; DNA binding; D‐retro‐inverso; digital signal processing; enhanced senescence 2; eterone 1; forkhead box protein O4; forkhead domain; senolytics; senomorphics

DOI:  https://doi.org/10.1002/agm2.12274
Adv Exp Med Biol. 2023 ;1442 201-210

Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells.

Zhiyang Chen, Zhenyu Ju, Yan Sun.

  Hematopoietic stem cells (HSCs) undergo an age-related functional decline, which leads to a disruption of the blood system and contributes to the development of aging-associated hematopoietic diseases and malignancies. In this section, we provide a summary of the key hallmarks associated with HSC aging. We also examine the causal factors that contribute to HSC aging and emphasize potential approaches to mitigate HSC aging and age-related hematopoietic disorders.

Keywords:  Aging; HSC; Niche; Therapeutic strategies

DOI:  https://doi.org/10.1007/978-981-99-7471-9_12
Nat Aging. 2024 Jan 19.

Causality-enriched epigenetic age uncouples damage and adaptation.

Kejun Ying, Hanna Liu, Andrei E Tarkhov, Marie C Sadler, Ake T Lu, Mahdi Moqri, Steve Horvath, Zoltán Kutalik, Xia Shen, Vadim N Gladyshev.

Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits. We established a new framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge-clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed landscape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

DOI: https://doi.org/10.1038/s43587-023-00557-0
Mech Ageing Dev. 2024 Jan 11. pii: S0047-6374(24)00002-2. [Epub ahead of print] 111902

Calcium transferring from ER to mitochondria via miR-129/ITPR2 axis controls cellular senescence in vitro and in vivo.

Yue Gao, Lei Xu, Yaru Li, Dandan Qi, Chaofan Wang, Changjiao Luan, Shihui Zheng, Qiu Du, Weili Liu, Guotao Lu, Weijuan Gong, Xingjie Ma.

  Senescent cells are known to be accumulated in aged organisms. Although the two main characteristics, cell cycle arrest (for dividing cells) and secretion of senescence-associated secretory phenotype (SASP) factors, have been well described, the lack of sufficient senescent markers and incomplete understanding of mechanisms have limited the progress of the anti-senescence field. Calcium transferred from the endoplasmic reticulum (ER) via inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to mitochondria has emerged as a key player during cellular senescence and aging. However, the internal regulatory mechanisms, particularly those of endogenous molecules, remain only partially understood. Here we identified miRNA-129 (miR-129) as a direct repressor of ITPR2. Interestingly, miR-129 controlled a cascade of intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), DNA damage, and consequently cellular senescence through ITPR2 and mitochondrial calcium uniporter (MCU). In addition, miR-129 was repressed in different senescence models and delayed bleomycin-induced cellular senescence. Importantly, intraperitoneal injection of miR-129 partly postponed bleomycin-accelerated lung aging and natural aging markers as well as reduced immunosenescence markers in mice. Altogether, these findings demonstrated that miR-129 regulated cellular senescence and aging markers via intracellular calcium signaling by directly targeting ITPR2.

Keywords:  ITPR2; MCU; calcium signaling; cellular senescence; miR-129

DOI:  https://doi.org/10.1016/j.mad.2024.111902
Aging Cell. 2024 Jan 15. e14037

Senolytic treatment alleviates doxorubicin-induced chemobrain.

Vivekananda Budamagunta, Ashok Kumar, Asha Rani, Sahana Manohar Sindhu, Yang Yang, Daohong Zhou, Thomas C Foster.

  Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment.

Keywords:  chemobrain; cognition; inflammation; oxidative stress; senolytic NMDA receptor; transcription

DOI:  https://doi.org/10.1111/acel.14037
Proc Natl Acad Sci U S A. 2024 Jan 23. 121(4): e2311313121

Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.

Enric Ureña, Bowen Xu, Jennifer C Regan, Magda L Atilano, Lucy J Minkley, Danny Filer, Yu-Xuan Lu, Ekin Bolukbasi, Mobina Khericha, Nazif Alic, Linda Partridge.

  Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Keywords:  Drosophila; Pol III; Trametinib; aging; gut pathology

DOI:  https://doi.org/10.1073/pnas.2311313121
Exp Ther Med. 2024 Feb;27(2): 68

Coptisine prevents angiotensin II‑induced endothelial cell injury and senescence via the lncRNA SNHG12/miR‑603/NAMPT pathway.

Jing Meng, Xiaoying Song, Xinyue Xing, Jingyi Chen, Danfei Lou.

  Atherosclerosis (AS) is a major health problem and targeting the associated molecular pathways is critical for developing therapies. The present study investigated the effect of coptisine on human umbilical vein endothelial cells (HUVECs) in response to angiotensin II (Ang II) induction by focusing on cellular senescence, apoptosis and inflammation. HUVECs were treated with different Ang II concentrations and long non-coding RNA small nucleolar RNA host gene 12 (SNHG12), microRNA (miRNA/miR)-603 and nicotinamide phosphoribosyltransferase (NAMPT) expressions were assessed. Cell viability, nicotinamide adenine dinucleotide (NAD+) levels, senescence, apoptosis and inflammation were assessed. The interactions among SNHG12, miR-603 and NAMPT were investigated using dual-luciferase reporter gene assays and RNA pull-down experiments. Coptisine treatment increased SNHG12 expression and attenuated Ang II-induced adverse effects in HUVECs. SNHG12 silencing abrogated coptisine's protective effects, indicating that SNHG12 is a key mediator. SNHG12 targets miR-603, which then directly targets NAMPT, an age-related gene involved in NAD(+) regulation. Coptisine modulated the SNHG12/miR-603/NAMPT pathway and miR-603 inhibition enhanced the protective effects of coptisine. NAMPT overexpression reversed the negative effects of miR-603 and enhanced the protective effect of the miR-603 inhibitor. Finally, the protective mechanism of coptisine is linked to the regulation of NAD(+), sirtuin 3 (SIRT3) and p53. Coptisine treatment counteracted the AngII-induced increase in SIRT3 and p53 protein levels, whereas the miR-603 inhibitor potentiated the effect of coptisine. SNHG12 knockdown partially abolished these effects, which were reversed by NAMPT overexpression. In conclusion, the present study revealed a novel protective mechanism involving the SNHG12/miR-603/NAMPT pathway in HUVECs exposed to Ang II, highlighting the potential therapeutic application of coptisine in treating atherosclerosis. These results suggested that coptisine exerts its protective effects by modulating the SNHG12/miR-603/NAMPT axis, which ultimately affects the regulation of NAD(+), SIRT3 and p53. Future studies should explore the potential of the SNHG12/miR-603/NAMPT pathway as a target for developing novel AS therapies.

Keywords:  atherosclerosis; cellular senescence; coptisine; long non-coding RNA small nucleolar RNA host gene 12; microRNA 603; nicotinamide phosphoribosyltransferase

DOI:  https://doi.org/10.3892/etm.2023.12356
Redox Biol. 2024 Jan 13. pii: S2213-2317(24)00008-9. [Epub ahead of print]70 103032

Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases.

Bowen Yang, Yumeng Lin, Yibo Huang, Ying-Qiang Shen, Qianming Chen.

  Thioredoxin (Trx) is a compact redox-regulatory protein that modulates cellular redox state by reducing oxidized proteins. Trx exhibits dual functionality as an antioxidant and a cofactor for diverse enzymes and transcription factors, thereby exerting influence over their activity and function. Trx has emerged as a pivotal biomarker for various diseases, particularly those associated with oxidative stress, inflammation, and aging. Recent clinical investigations have underscored the significance of Trx in disease diagnosis, treatment, and mechanistic elucidation. Despite its paramount importance, the intricate interplay between Trx and cellular senescence-a condition characterized by irreversible growth arrest induced by multiple aging stimuli-remains inadequately understood. In this review, our objective is to present a comprehensive and up-to-date overview of the structure and function of Trx, its involvement in redox signaling pathways and cellular senescence, its association with aging and age-related diseases, as well as its potential as a therapeutic target. Our review aims to elucidate the novel and extensive role of Trx in senescence while highlighting its implications for aging and age-related diseases.

Keywords:  Age-related diseases; Anti-oxidative; Cellular senescence; ROS; Thioredoxin

DOI:  https://doi.org/10.1016/j.redox.2024.103032
Gerontology. 2024 Jan 16.

Sertraline promotes health and longevity in Caenorhabditis elegans.

Yu Liang, Yiming Zhou, Can Zhou, Xinqi Cai, Li Liu, Fang Wei, Guolin Li.

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in lifespan and healthspan of Caenorhabditis elegans (C. elegans).
METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of the 5-HT signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants.
RESULTS: Sertraline extended lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants.
CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.

DOI: https://doi.org/10.1159/000536227
J Cell Biochem. 2024 Jan 15.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.

Bin Ye, Yingting Pei, Lujing Wang, Dehao Meng, Yu Zhang, Shuang Zou, Henian Li, Jinying Liu, Ziying Xie, Changhong Tian, Yuqi Jiang, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma.

  Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.

Keywords:  SASP; cGAS-STING; mitochondria; nicotinamide mononucleotide; senescence

DOI:  https://doi.org/10.1002/jcb.30522
Angew Chem Int Ed Engl. 2024 Jan 17. e202315425

Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation.

Mengyang Chang, Yue Dong, Hang Xu, Alexis B Cruickshank-Taylor, Jacob S Kozora, Baran Behpour, Wei Wang.

  Although clearance of senescent cells has been proved to slow down aging process and promote anti-cancer chemotherapy, the development of senolytics remains challenging. Herein, we report a senolytic strategy enabled by senescent cell-sensitive bioorthogonal tetrazine ligation. Our design is engineering a galactose (Gal) moiety into dihydrotetrazine, which serves both as recognition moiety for senescence-associated β-galactosidase (SA-β-gal) and a caging group for control of tetrazine activity. We demonstrate that Gal-Tz enables efficient click-release of fluorescent HCA and doxorubicin (Dox) from TCO caged HCA and Dox prodrug to detect and eliminate senescent HeLa and A549 cells over non-senescent counterparts with 16.44 senolytic index. Furthermore, we leverage the strategy for selective activation and delivery of proteolysis-targeting chimeras (PROTACs) as senolytics. PROTAC prodrug TCO-ARV-771 can be selectively activated by Gal-Tz and delivered into senescent HeLa and A549 cells to induce BRD4 degradation. The proof of concept of PROTACs as senolytics may offer an efficient way for intervention of cell senescence due to their unique capacity capable of degrading targeted proteins in a sub-stoichiometric and catalytic fashion. The results of the study establish the bioorthogonal tetrazine ligation approach as a viable strategy for selective removal of senescent cells.

Keywords:  Bioorthogonal chemistry Senolytics Senescence Prodrug Tetrazine click-release

DOI:  https://doi.org/10.1002/anie.202315425
Foods. 2023 Nov 21. pii: 4199. [Epub ahead of print]12(23):

Dietary Marine Hydrolysate Improves Memory Performance and Social Behavior through Gut Microbiota Remodeling during Aging.

Camille Mougin, Mathilde Chataigner, Céline Lucas, Quentin Leyrolle, Véronique Pallet, Sophie Layé, Elodie Bouvret, Anne-Laure Dinel, Corinne Joffre.

  Aging is characterized by a decline in social behavior and cognitive functions leading to a decrease in life quality. In a previous study, we show that a fish hydrolysate supplementation prevents age-related decline in spatial short-term memory and long-term memory and anxiety-like behavior and improves the stress response in aged mice. The aim of this study was to determine the effects of a fish hydrolysate enriched with EPA/DHA or not on the cognitive ability and social interaction during aging and the biological mechanisms involved. We showed for the first time that a fish hydrolysate enriched with EPA/DHA or not improved memory performance and preference for social novelty that were diminished by aging. These changes were associated with the modulation of the gut microbiota, normalization of corticosterone, and modulation of the expression of genes involved in the mitochondrial respiratory chain, circadian clock, neuroprotection, and antioxidant activity. Thus, these changes may contribute to the observed improvements in social behavior and memory and reinforced the innovative character of fish hydrolysate in the prevention of age-related impairments.

Keywords:  aging; cognitive decline; gut microbiota; low-molecular-weight peptides; marine functional food; memory; n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs); social behavior; stress response

DOI:  https://doi.org/10.3390/foods12234199
iScience. 2024 Jan 19. 27(1): 108538

An accurate aging clock developed from large-scale gut microbiome and human gene expression data.

Vishakh Gopu, Francine R Camacho, Ryan Toma, Pedro J Torres, Ying Cai, Subha Krishnan, Sathyapriya Rajagopal, Hal Tily, Momchilo Vuyisich, Guruduth Banavar.

  Accurate measurement of the biological markers of the aging process could provide an "aging clock" measuring predicted longevity and enable the quantification of the effects of specific lifestyle choices on healthy aging. Using machine learning techniques, we demonstrate that chronological age can be predicted accurately from (1) the expression level of human genes in capillary blood and (2) the expression level of microbial genes in stool samples. The latter uses a very large metatranscriptomic dataset, stool samples from 90,303 individuals, which arguably results in a higher quality microbiome-aging model than prior work. Our analysis suggests associations between biological age and lifestyle/health factors, e.g., people on a paleo diet or with IBS tend to have higher model-predicted ages and people on a vegetarian diet tend to have lower model-predicted ages. We delineate the key pathways of systems-level biological decline based on the age-specific features of our model.

Keywords:  Microbiome; Omics

DOI:  https://doi.org/10.1016/j.isci.2023.108538
Biogerontology. 2024 Jan 19.

Sustained exposure to high glucose induces differential expression of cellular senescence markers in murine macrophages but impairs immunosurveillance response to senescent cells secretome.

Bhawna Diwan, Rahul Yadav, Rohit Goyal, Rohit Sharma.

  The influence of chronic diseases on various facets of macrophage cellular senescence is poorly understood. This study evaluated the impact of chronic hyperglycemia on the induction of cellular senescence and subsequent immunosurveillance functions in RAW264.7 macrophages. Macrophages were cultured under normal glucose (NG; 5 mM), high glucose (HG; 20 mM), and very high glucose (VHG; 40 mM) conditions and assessed for markers of cellular senescence. Hyperglycemia induced strong upregulation of SA-β-gal activity, and loss of PCNA and Lamin B1 gene expression while markers of cell cycle arrest generally decreased. Non-significant changes in SASP-related proteins were observed while ROS levels slightly decreased and mitochondrial membrane potential increased. Protein concentration on the exosome membrane surface and their stability appeared to increase under hyperglycemic conditions. However, when macrophages were exposed to the secretory media (SM) of senescent preadipocytes, a dramatic increase in the levels of all inflammatory proteins was recorded especially in the VHG group that was also accompanied by upregulation of NF-κB and NLRP3 gene expression. SM treatment to hyperglycemic macrophages activated the TLR-2/Myd88 pathway but decreased the expression of scavenger receptors RAGE, CD36, and Olr-1 while CD44 and CXCL16 expression increased. On exposure to LPS, a strong upregulation in NO, ROS, and inflammatory cytokines was observed. Together, these results suggest that primary markers of cellular senescence are aberrantly expressed under chronic hyperglycemic conditions in macrophages with no significant SASP activation. Nonetheless, hyperglycemia strongly deregulates macrophage functions leading to impaired immunosurveillance of senescent cells and aggravation of inflamm-aging. This work provides novel insights into how hyperglycemia-induced dysfunctions can impact the potency of macrophages to manage senescent cell burden in aging tissues.

Keywords:  Hyperglycemia; Macrophage; RAGE; SASP; Scavenger receptors; Senescence

DOI:  https://doi.org/10.1007/s10522-024-10092-z
Nat Commun. 2024 Jan 16. 15(1): 546

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.

Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.

Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

DOI: https://doi.org/10.1038/s41467-024-44808-z
Life Sci. 2024 Jan 12. pii: S0024-3205(24)00002-X. [Epub ahead of print]339 122413

Agathobaculum butyriciproducens improves ageing-associated cognitive impairment in mice.

Jun Go, So-Young Maeng, Dong-Ho Chang, Hye-Yeon Park, Kyeong-Seon Min, Ju-Eun Kim, Young-Keun Choi, Jung-Ran Noh, Hyunju Ro, Byoung-Chan Kim, Kyoung-Shim Kim, Chul-Ho Lee.

   AIMS: The gut microbiota is increasingly recognised as a pivotal regulator of immune system homeostasis and brain health. Recent research has implicated the gut microbiota in age-related cognitive impairment and dementia. Agathobaculum butyriciproducens SR79 T (SR79), which was identified in the human gut, has been reported to be beneficial in addressing cognitive deficits and pathophysiologies in a mouse model of Alzheimer's disease. However, it remains unknown whether SR79 affects age-dependent cognitive impairment.
MAIN METHOD: To explore the effects of SR79 on cognitive function during ageing, we administered SR79 to aged mice. Ageing-associated behavioural alterations were examined using the open field test (OFT), tail suspension test (TST), novel object recognition test (NORT), Y-maze alternation test (Y-maze), and Morris water maze test (MWM). We investigated the mechanisms of action in the gut and brain using molecular and histological analyses.
KEY FINDINGS: Administration of SR79 improved age-related cognitive impairment without altering general locomotor activity or depressive behaviour in aged mice. Furthermore, SR79 increased mature dendritic spines in the pyramidal cells of layer III and phosphorylation of CaMKIIα in the cortex of aged mice. Age-related activation of astrocytes in the cortex of layers III-V of the aged brain was reduced following SR79 administration. Additionally, SR79 markedly increased IL-10 production and Foxp3 and Muc2 mRNA expression in the colons of aged mice.
SIGNIFICANCE: These findings suggest that treatment with SR79 may be a beneficial microbial-based approach for enhancing cognitive function during ageing.

Keywords:  Age-related diseases; Butyrate-producing microbe; Cognitive decline; Gut microbiota; Neurodegenerative disorders

DOI:  https://doi.org/10.1016/j.lfs.2024.122413
Geroscience. 2024 Jan 18.

Senolytic treatment does not mitigate oxidative stress-induced muscle atrophy but improves muscle force generation in CuZn superoxide dismutase knockout mice.

Agnieszka K Borowik, Marcus M Lawrence, Frederick F Peelor, Katarzyna M Piekarz, Abby Crosswhite, Arlan Richardson, Benjamin F Miller, Holly Van Remmen, Jacob L Brown.

  Oxidative stress is associated with tissue dysfunctions that can lead to reduced health. Prior work has shown that oxidative stress contributes to both muscle atrophy and cellular senescence, which is a hallmark of aging that may drive in muscle atrophy and muscle contractile dysfunction. The purpose of the study was to test the hypothesis that cellular senescence contributes to muscle atrophy or weakness. To increase potential senescence in skeletal muscle, we used a model of oxidative stress-induced muscle frailty, the CuZn superoxide dismutase knockout (Sod1KO) mouse. We treated 6-month-old wildtype (WT) and Sod1KO mice with either vehicle or a senolytic treatment of combined dasatinib (5 mg/kg) + quercetin (50 mg/kg) (D + Q) for 3 consecutive days every 15 days. We continued treatment for 7 months and sacrificed the mice at 13 months of age. Treatment with D + Q did not preserve muscle mass, reduce NMJ fragmentation, or alter muscle protein synthesis in Sod1KO mice when compared to the vehicle-treated group. However, we observed an improvement in muscle-specific force generation in Sod1KO mice treated with D + Q when compared to Sod1KO-vehicle mice. Overall, these data suggest that reducing cellular senescence via D + Q is not sufficient to mitigate loss of muscle mass in a mouse model of oxidative stress-induced muscle frailty but may mitigate some aspects of oxidative stress-induced muscle dysfunction.

Keywords:  Cellular senescence; Muscle atrophy; Oxidative stress

DOI:  https://doi.org/10.1007/s11357-024-01070-x
Can J Physiol Pharmacol. 2024 Jan 16.

Stem cell therapy for cardiac regeneration: past, present, and future.

Jaideep Kaur Gill, Sargun Kaur Rehsia, Elika Verma, Niketa Sareen, Sanjiv Dhingra.

  Cardiac disorders remain the leading cause of mortality worldwide. Current clinical strategies, including drug therapy, surgical interventions, and organ transplantation offer limited benefits to patients without regenerating the damaged myocardium. Over the past decade, stem cell therapy has generated a keen interest owing to its unique self-renewal and immune privileged characteristics. Furthermore, the ability of stem cells to differentiate into specialized cell types, has made them a popular therapeutic tool against various diseases. This comprehensive review provides an overview of therapeutic potential of different types of stem cells in reference to cardiovascular diseases. Furthermore, it sheds light on the advantages and limitations associated with each cell type. An in-depth analysis of the challenges associated with stem cell research and the hurdles for its clinical translation and their possible solutions have also been elaborated upon. It examines the controversies surrounding embryonic stem cells and the emergence of alternative approaches, such as the use of induced pluripotent stem cells for cardiac therapeutic applications. Overall, this review serves as a valuable resource for researchers, clinicians, and policymakers involved in the field of regenerative medicine, guiding the development of safe and effective stem cell-based therapies to revolutionize patient care.

Keywords:  cardiac regeneration; induced pluripotent stem cells; mesenchymal stem cells; myocardial ischemia

DOI:  https://doi.org/10.1139/cjpp-2023-0202
Nat Metab. 2024 Jan 19.

Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing.

Jengmin Kang, Daniel I Benjamin, Soochi Kim, Jayesh S Salvi, Gurkamal Dhaliwal, Richard Lam, Armon Goshayeshi, Jamie O Brett, Ling Liu, Thomas A Rando.

The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di/tri-methylation and HP1, decrease with age in muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (SAM). We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features, including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation, but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.

DOI: https://doi.org/10.1038/s42255-023-00955-z