bims-caglex 2024-04-14 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–04–14
27 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Chemical Strategies for the Detection and Elimination of Senescent Cells.
Telomeres and aging: on and off the planet!
Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.
Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging.
Aging Gut Microbiome in Healthy and Unhealthy Aging.
Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model.
Temporal Single-Cell Sequencing Analysis Reveals That GPNMB-Expressing Macrophages Potentiate Muscle Regeneration.
Giardia telomeres and telomerase.
Evidence of a pan-tissue decline in stemness during human aging.
Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population.
BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.
FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway.
Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases.
Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan.
ptx3a+ fibroblast/epicardial cells provide a transient macrophage niche to promote heart regeneration.
Research Progress on Bioactive Factors against Skin Aging.
Food is medicine: clinical trials show the health benefits of dietary interventions.
Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice.
Unusual lineage plasticity revealed by YY1 knockout in pro-B cells.
Apoptotic vesicles are required to repair DNA damage and suppress premature cellular senescence.
Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP.
Maintaining ideal cardiovascular health is associated with higher serum anti-aging protein klotho in the middle-aged and older populations.
Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis.
Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
Low-molecular-weight fucoidan increases telomere length and immunostimulatory effects on NK-92 cells following inhaled anesthetic injury.
Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism.
DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.

Acc Chem Res. 2024 Apr 11.

Chemical Strategies for the Detection and Elimination of Senescent Cells.

Jessie García-Fleitas, Alba García-Fernández, Vicente Martí-Centelles, Félix Sancenón, Andrea Bernardos, Ramón Martínez-Máñez.

ConspectusCellular senescence can be defined as an irreversible stopping of cell proliferation that arises in response to various stress signals. Cellular senescence is involved in diverse physiological and pathological processes in different tissues, exerting effects on processes as differentiated as embryogenesis, tissue repair and remodeling, cancer, aging, and tissue fibrosis. In addition, the development of some pathologies, aging, cancer, and other age-related diseases has been related to senescent cell accumulation. Due to the complexity of the senescence phenotype, targeting senescent cells is not trivial, is challenging, and is especially relevant for in vivo detection in age-related diseases and tissue samples. Despite the elimination of senescent cells (senolysis) using specific drugs (senolytics) that have been shown to be effective in numerous preclinical disease models, the clinical translation is still limited due to the off-target effects of current senolytics and associated toxicities. Therefore, the development of new chemical strategies aimed at detecting and eliminating senescent cells for the prevention and selective treatment of senescence-associated diseases is of great interest. Such strategies not only will contribute to a deeper understanding of this rapidly evolving field but also will delineate and inspire new possibilities for future research.In this Account, we report our recent research in the development of new chemical approaches for the detection and elimination of senescent cells based on new probes, nanoparticles, and prodrugs. The designed systems take advantage of the over-representation in senescent cells of certain biomarkers such as β-galactosidase and lipofuscin. One- and two-photon probes, for higher tissue penetration, have been developed. Moreover, we also present a renal clearable fluorogenic probe for the in vivo detection of the β-galactosidase activity, allowing for correlation with the senescent burden in living animals. Moreover, as an alternative to molecular-based probes, we also developed nanoparticles for senescence detection. Besides, we describe advances in new therapeutic agents to selectively eradicate senescent cells using β-galactosidase activity-sensitive gated nanoparticles loaded with cytotoxic or senolytic agents or new prodrugs aiming to increase the selectivity and reduction of off-target toxicities of current drugs. Moreover, new advances therapies have been applied in vitro and in vivo. Studies with the probes, nanoparticles, and prodrugs have been applied in several in vitro and in vivo models of cancer, fibrosis, aging, and drug-induced cardiotoxicity in which senescence plays an important role. We discuss the benefits of these chemical strategies toward the development of more specific and sophisticated probes, nanoparticles, and prodrugs targeting senescent cells.

DOI: https://doi.org/10.1021/acs.accounts.3c00794
Biogerontology. 2024 Apr;25(2): 313-327

Telomeres and aging: on and off the planet!

Christopher E Mason, Maria A Sierra, Henry J Feng, Susan M Bailey.

  Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Keywords:  Aging; Mitochondrial dysregulation; Omics; Oxidative stress; Radiation; Space; Telomeres

DOI:  https://doi.org/10.1007/s10522-024-10098-7
Nutrients. 2024 Mar 26. pii: 952. [Epub ahead of print]16(7):

Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.

Priya Balasubramanian, Tamas Kiss, Rafal Gulej, Adam Nyul Toth, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar.

  High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.

Keywords:  ageing; endothelial cells; high-fat diet; obesity; prediabetes; senescence; stress resistance; unhealthy diet

DOI:  https://doi.org/10.3390/nu16070952
Front Aging. 2024 ;5 1380016

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging.

Andre Pires da Silva, Rhianne Kelleher, Luke Reynoldson.

  The gonad has become a central organ for understanding aging in C. elegans, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.

Keywords:  diapause; evolution of aging; germline; lipids; reproduction

DOI:  https://doi.org/10.3389/fragi.2024.1380016
Aging Dis. 2024 Apr 09.

Aging Gut Microbiome in Healthy and Unhealthy Aging.

Yangyanqiu Wang, Zhanbo Qu, Jian Chu, Shuwen Hun.

The characteristics of human aging manifest in tissue and organ function decline, heightening susceptibility to age-related ailments, thereby presenting novel challenges to fostering and sustaining healthy longevity. In recent years, an abundance of research on human aging has surfaced. Intriguingly, evidence suggests a pervasive correlation among gut microbiota, bodily functions, and chronic diseases. From infancy to later stages of adulthood, healthy individuals witness dynamic shifts in gut microbiota composition. This microbial community is associated with tissue and organ function deterioration (e.g., brain, bones, muscles, immune system, vascular system) and heightened risk of age-related diseases. Thus, we present a narrative review of the aging gut microbiome in both healthy and unhealthy aging contexts. Additionally, we explore the potential for adjustments to physical health based on gut microbiome analysis and how targeting the gut microbiome can potentially slow down the aging process.

DOI: https://doi.org/10.14336/AD.2024.0331
Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101242

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model.

Silja Hansen Haldrup, Bjørn K Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J Corydon.

  Neovascular age-related macular degeneration (nAMD) is a frequent cause of vision loss among the elderly in the Western world. Current disease management with repeated injections of anti-VEGF agents accumulates the risk for adverse events and constitutes a burden for society and the individual patient. Sustained suppression of VEGF using gene therapy is an attractive alternative, which we explored using adeno-associated virus (AAV)-based delivery of novel RNA interference (RNAi) effectors in a porcine model of choroidal neovascularization (CNV). The potency of VEGFA-targeting, Ago2-dependent short hairpin RNAs placed in pri-microRNA scaffolds (miR-agshRNA) was established in vitro and in vivo in mice. Subsequently, AAV serotype 8 (AAV2.8) vectors encoding VEGFA-targeting or irrelevant miR-agshRNAs under the control of a tissue-specific promotor were delivered to the porcine retina via subretinal injection before CNV induction by laser. Notably, VEGFA-targeting miR-agshRNAs resulted in a significant and sizable reduction of CNV compared with the non-targeting control. We also demonstrated that single-stranded and self-complementary AAV2.8 vectors efficiently transduce porcine retinal pigment epithelium cells but differ in their transduction characteristics and retinal safety. Collectively, our data demonstrated a robust anti-angiogenic effect of VEGFA-targeting miR-aghsRNAs in a large translational animal model, thereby suggesting AAV-based delivery of anti-VEGFA RNAi therapeutics as a valuable tool for the management of nAMD.

Keywords:  AAV; AMD; CNV; RNAi therapeutics; anti-VEGF; large animal model; miR-agshRNA; pig; retinal gene therapy

DOI:  https://doi.org/10.1016/j.omtm.2024.101242
Res Sq. 2024 Mar 28. pii: rs.3.rs-4108866. [Epub ahead of print]

Temporal Single-Cell Sequencing Analysis Reveals That GPNMB-Expressing Macrophages Potentiate Muscle Regeneration.

Yu-Fan Chen.

Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. To address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk , and Nr1h3 . Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo . These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Targeting GPNMB signaling in macrophages could have therapeutic potential for restoring skeletal muscle integrity and homeostasis.

DOI: https://doi.org/10.21203/rs.3.rs-4108866/v1
Parasitol Res. 2024 Apr 08. 123(4): 179

Giardia telomeres and telomerase.

Francisco Alejandro Lagunas-Rangel.

  Giardia duodenalis, the protozoan responsible for giardiasis, is a significant contributor to millions of diarrheal diseases worldwide. Despite the availability of treatments for this parasitic infection, therapeutic failures are alarmingly frequent. Thus, there is a clear need to identify new therapeutic targets. Giardia telomeres were previously identified, but our understanding of these structures and the critical role played by Giardia telomerase in maintaining genomic stability and its influence on cellular processes remains limited. In this regard, it is known that all Giardia chromosomes are capped by small telomeres, organized and protected by specific proteins that regulate their functions. To counteract natural telomere shortening and maintain high proliferation, Giardia exhibits constant telomerase activity and employs additional mechanisms, such as the formation of G-quadruplex structures and the involvement of transposable elements linked to telomeric repeats. Thus, this study aims to address the existing knowledge gap by compiling the available information (until 2023) about Giardia telomeres and telomerase, focusing on highlighting the distinctive features within this parasite. Furthermore, the potential feasibility of targeting Giardia telomeres and/or telomerase as an innovative therapeutic strategy is discussed.

Keywords:  Chromosome ends; Intestinal parasite; TERT; Telomerase RNA; Telomere shortening

DOI:  https://doi.org/10.1007/s00436-024-08200-6
Aging (Albany NY). 2024 Apr 04. 16

Evidence of a pan-tissue decline in stemness during human aging.

Gabriel Arantes Dos Santos, Gustavo Daniel Vega Magdaleno, João Pedro de Magalhães.

  Despite their biological importance, the role of stem cells in human aging remains to be elucidated. In this work, we applied a machine learning methodology to GTEx transcriptome data and assigned stemness scores to 17,382 healthy samples from 30 human tissues aged between 20 and 79 years. We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

Keywords:  longevity; senescence; stem cells; transcriptomics

DOI:  https://doi.org/10.18632/aging.205717
Aging Dis. 2024 Mar 25.

Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population.

Mingwei Wang, Xiangzhi Wu, Yuyao Jiao, Wenli Yin, Lili Zhang.

Numerous bodily processes deteriorate with age, chief among them being the loss of muscle mass and function. The condition referred to as aging myasthenia gravis impairs older persons' quality of life and is linked to a higher risk of several chronic illnesses. An increasing number of studies conducted in the last several years has demonstrated that moderate exercise can halt this process. Specifically, by promoting autophagy, aerobic exercise helps to postpone the onset of senile myasthenia gravis. In this work, we will explore how aerobic exercise modulates autophagy to prevent muscle aging and examine the most recent findings in this area of study. We discovered that exercise-induced autophagy can effectively balance protein degradation and relieve skeletal muscle atrophy by looking through pertinent literature. Aerobic exercise has a direct impact on autophagy, but it can also delay the onset of senile myasthenia gravis by enhancing blood flow, lowering inflammation, and boosting muscle oxidative capacity. In order to postpone the onset of senile myasthenia gravis, research on the mechanism of action of aerobic exercise in inducing autophagy will be discussed in detail in this study.

DOI: https://doi.org/10.14336/AD.2024.0318
Mol Cell. 2024 Apr 02. pii: S1097-2765(24)00221-1. [Epub ahead of print]

BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Aravind Krishnan, Youngho Kwon, Patrick Sung, Roger A Greenberg.

  The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.

Keywords:  ATRX; BLM helicase; DNA damage response; alternative lengthening of telomeres; telomere

DOI:  https://doi.org/10.1016/j.molcel.2024.03.011
JCI Insight. 2024 Apr 08. pii: e172678. [Epub ahead of print]9(7):

FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway.

Hyun Jung Hwang, Donghee Kang, Jae-Ryong Kim, Joon Hyuk Choi, Ji-Kan Ryu, Allison B Herman, Young-Gyu Ko, Heon Joo Park, Myriam Gorospe, Jae-Seon Lee.

  The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are not well known. Here, we identify a potentially novel function of FLRT2 in preventing endothelial cell senescence and vascular aging. We found that FLRT2 expression was lower in cultured senescent endothelial cells as well as in aged rat and human vascular tissues. FLRT2 mediated endothelial cell senescence via the mTOR complex 2, AKT, and p53 signaling pathway in human endothelial cells. We uncovered that FLRT2 directly associated with integrin subunit beta 4 (ITGB4) and thereby promoted ITGB4 phosphorylation, while inhibition of ITGB4 substantially mitigated the induction of senescence triggered by FLRT2 depletion. Importantly, FLRT2 silencing in mice promoted vascular aging, and overexpression of FLRT2 rescued a premature vascular aging phenotype. Therefore, we propose that FLRT2 could be targeted therapeutically to prevent senescence-associated vascular aging.

Keywords:  Cell biology; Cellular senescence; Vascular biology

DOI:  https://doi.org/10.1172/jci.insight.172678
Ageing Res Rev. 2024 Apr 05. pii: S1568-1637(24)00112-0. [Epub ahead of print]97 102294

Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases.

Qing Zeng, Yongzhen Gong, Neng Zhu, Yaning Shi, Chanjuan Zhang, Li Qin.

  Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli, which is mainly characterized by stable cell cycle arrest and complex senescence-associated secretory phenotype (SASP). Once senescent cells accumulate in tissues, they may eventually accelerate the progression of age-related diseases, such as atherosclerosis, osteoarthritis, chronic lung diseases, cancers, etc. Recent studies have shown that the disorders of lipid metabolism are not only related to age-related diseases, but also regulate the cellular senescence process. Based on existing research evidences, the changes in lipid metabolism in senescent cells are mainly concentrated in the metabolic processes of phospholipids, fatty acids and cholesterol. Obviously, the changes in lipid-metabolizing enzymes and proteins involved in these pathways play a critical role in senescence. However, the link between cellular senescence, changes in lipid metabolism and age-related disease remains to be elucidated. Herein, we summarize the lipid metabolism changes in senescent cells, especially the senescent cells that promote age-related diseases, as well as focusing on the role of lipid-related enzymes or proteins in senescence. Finally, we explore the prospect of lipids in cellular senescence and their potential as drug targets for preventing and delaying age-related diseases.

Keywords:  Age-related disease; Cellular senescence; Lipid metabolism; Lipids; Therapy strategies

DOI:  https://doi.org/10.1016/j.arr.2024.102294
FEBS Lett. 2024 Apr 11.

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan.

Francesca Matteini, Sara Montserrat-Vazquez, M Carolina Florian.

  Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.

Keywords:  Cdc42; autophagy; calorie restriction; health span; lifespan; parabiosis; partial reprogramming; senolytic; stem cell aging; stem cell rejuvenation

DOI:  https://doi.org/10.1002/1873-3468.14865
Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00420-0. [Epub ahead of print]43(4): 114092

ptx3a+ fibroblast/epicardial cells provide a transient macrophage niche to promote heart regeneration.

Jisheng Sun, Elizabeth A Peterson, Xin Chen, Jinhu Wang.

  Macrophages conduct critical roles in heart repair, but the niche required to nurture and anchor them is poorly studied. Here, we investigated the macrophage niche in the regenerating heart. We analyzed cell-cell interactions through published single-cell RNA sequencing datasets and identified a strong interaction between fibroblast/epicardial (Fb/Epi) cells and macrophages. We further visualized the association of macrophages with Fb/Epi cells and the blockage of macrophage response without Fb/Epi cells in the regenerating zebrafish heart. Moreover, we found that ptx3a+ epicardial cells associate with reparative macrophages, and their depletion resulted in fewer reparative macrophages. Further, we identified csf1a expression in ptx3a+ cells and determined that pharmacological inhibition of the csf1a pathway or csf1a knockout blocked the reparative macrophage response. Moreover, we found that genetic overexpression of csf1a enhanced the reparative macrophage response with or without heart injury. Altogether, our studies illuminate a cardiac Fb/Epi niche, which mediates a beneficial macrophage response after heart injury.

Keywords:  CP: Immunology; CP: Stem cell research; csf1a; epicardium; heart; macrophage; ptx3a; regeneration; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2024.114092
Int J Mol Sci. 2024 Mar 28. pii: 3797. [Epub ahead of print]25(7):

Research Progress on Bioactive Factors against Skin Aging.

Xin He, Xinyu Gao, Yifan Guo, Weidong Xie.

  The relentless pursuit of effective strategies against skin aging has led to significant interest in the role of bioactive factors, particularly secondary metabolites from natural sources. The purpose of this study is to meticulously explore and summarize the recent advancements in understanding and utilization of bioactive factors against skin aging, with a focus on their sources, mechanisms of action, and therapeutic potential. Skin, the largest organ of the body, directly interacts with the external environment, making it susceptible to aging influenced by factors such as UV radiation, pollution, and oxidative stress. Among various interventions, bioactive factors, including peptides, amino acids, and secondary metabolites, have shown promising anti-aging effects by modulating the biological pathways associated with skin integrity and youthfulness. This article provides a comprehensive overview of these bioactive compounds, emphasizing collagen peptides, antioxidants, and herbal extracts, and discusses their effectiveness in promoting collagen synthesis, enhancing skin barrier function, and mitigating the visible signs of aging. By presenting a synthesis of the current research, this study aims to highlight the therapeutic potential of these bioactive factors in developing innovative anti-aging skin care solutions, thereby contributing to the broader field of dermatological research and offering new perspectives for future studies. Our findings underscore the importance of the continued exploration of bioactive compounds for their potential to revolutionize anti-aging skin care and improve skin health and aesthetics.

Keywords:  biological activity factor; collagen; enzyme; oxidative stress; polypeptide; skin aging

DOI:  https://doi.org/10.3390/ijms25073797
Nat Med. 2024 Apr 08.

Food is medicine: clinical trials show the health benefits of dietary interventions.

Priya Venkatesan.

DOI: https://doi.org/10.1038/s41591-024-02891-1
J Nutr Health Aging. 2024 Apr 05. pii: S1279-7707(24)00306-3. [Epub ahead of print]28(6): 100219

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice.

Carlos J Padilla, Hallie Harris, Jeff S Volek, Brian C Clark, W David Arnold.

   OBJECTIVE: Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice.
DESIGN: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention.
SETTING: Preclinical laboratory study.
SAMPLE SIZE: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)].
MEASUREMENTS: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels.
STATISTICAL ANALYSIS: Primary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function.
RESULTS: Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871).
CONCLUSION: KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

Keywords:  Aging; Ketogenic diet; Motor function; Motor units number estimation

DOI:  https://doi.org/10.1016/j.jnha.2024.100219
bioRxiv. 2024 Mar 27. pii: 2024.03.22.586298. [Epub ahead of print]

Unusual lineage plasticity revealed by YY1 knockout in pro-B cells.

Sarmistha Banerjee, Sulagna Sanyal, Suchita Hodawadekar, Sarah Naiyer, Nasreen Bano, Anupam Banerjee, Joshua Rhoades, Dawei Dong, David Allman, Michael L Atchison.

During B cell development, cells progress through multiple developmental stages with the pro-B cell stage defining commitment to the B cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We find here that knockout of YY1 at the pro-B cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9- DL4 feeder system, as well as in vivo after injection into sub-lethally irradiated Rag1 -/- mice. These T lineage-like cells lose their B lineage transcript profile and gain a T cell lineage profile. Single cell-RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages indicating unusual lineage plasticity. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 likely regulates commitment in multiple cell lineages.

DOI: https://doi.org/10.1101/2024.03.22.586298
J Extracell Vesicles. 2024 Apr;13(4): e12428

Apoptotic vesicles are required to repair DNA damage and suppress premature cellular senescence.

Zhiqing Huang, Yuzhi Zhuang, Wenwen Li, Mingchen Ma, Fangcao Lei, Yan Qu, Jiaqi Li, Huigen Luo, Changzheng Li, Lu Lu, Lan Ma, Xiao Zhang, Xiaoxing Kou, Linjia Jiang, Xueli Mao, Songtao Shi.

  It is well known that DNA damage can cause apoptosis. However, whether apoptosis and its metabolites contribute to DNA repair is largely unknown. In this study, we found that apoptosis-deficient Fasmut and Bim- /- mice show significantly elevated DNA damage and premature cellular senescence, along with a significantly reduced number of 16,000 g apoptotic vesicles (apoVs). Intravenous infusion of mesenchymal stromal cell (MSC)-derived 16,000 g apoVs rescued the DNA damage and premature senescence in Fasmut and Bim-/- mice. Moreover, a sublethal dose of radiation exposure caused more severe DNA damage, reduced survival rate, and loss of body weight in Fasmut mice than in wild-type mice, which can be recovered by the infusion of MSC-apoVs. Mechanistically, we showed that apoptosis can assemble multiple nuclear DNA repair enzymes, such as the full-length PARP1, into 16,000 g apoVs. These DNA repair components are directly transferred by 16,000 g apoVs to recipient cells, leading to the rescue of DNA damage and elimination of senescent cells. Finally, we showed that embryonic stem cell-derived 16,000 g apoVs have superior DNA repair capacity due to containing a high level of nuclear DNA repair enzymes to rescue lethal dose-irradiated mice. This study uncovers a previously unknown role of 16,000 g apoVs in safeguarding tissues from DNA damage and demonstrates a strategy for using stem cell-derived apoVs to ameliorate irradiation-induced DNA damage.

Keywords:  DDR‐apoV complexes; DNA damage repair; PARP1; apoptosis; apoptotic vesicles; embryonic stem cells; mesenchymal stromal cells; premature senescence; radiation damage

DOI:  https://doi.org/10.1002/jev2.12428
Chin Med. 2024 Apr 09. 19(1): 61

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP.

Xiaogang Shen, Mengnan Li, Yawen Li, Yuning Jiang, Kunxu Niu, Shixiong Zhang, Xuan Lu, Runtao Zhang, Zhiqin Zhao, Liangxing Zhou, Zhifang Guo, Siwei Wang, Cong Wei, Liping Chang, Yunlong Hou, Yiling Wu.

   BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice.
METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or β-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging.
RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP).
CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Keywords:  Bazi Bushen (BZBS); Energy metabolism; Inflammation; Lipid metabolism; Omics analysis

DOI:  https://doi.org/10.1186/s13020-024-00927-9
J Nutr Health Aging. 2024 Apr 05. pii: S1279-7707(24)00311-7. [Epub ahead of print]28(6): 100224

Maintaining ideal cardiovascular health is associated with higher serum anti-aging protein klotho in the middle-aged and older populations.

Kaisaierjiang Kadier, Pengfei Liu, Diliyaer Dilixiati, Xinliang Peng, Aikeliyaer Ainiwaer, Dinigeer Kadier, Jiande Lu, Xiaozhu Liu, Mierxiati Ainiwan, Qi Wang, Xiang Ma, Yitong Ma.

   OBJECTIVES: Maintaining ideal cardiovascular health (CVH) is believed to have potential anti-aging benefits. The American Heart Association (AHA) recently updated the "Life's Essential 8 (LE8)" metrics to measure ideal CVH, but its connection with the anti-aging protein klotho is still unclear. We aimed to explore the relationship between ideal cardiovascular health and serum anti-aging protein klotho in a nationally representative US middle-aged and older population.
DESIGN: A cross-sectional study.
SETTING: The National Health and Nutrition Examination Survey (2007-2016).
PARTICIPANTS: A total of 9457 middle-aged and older participants.
MEASUREMENTS: Ideal CVH scores and their components were defined according to the guidelines set by the AHA. Serum klotho detected by enzyme-linked immunosorbent assay. Weighted multivariable linear regression and restricted cubic spline were employed to examine the association between CVH score and klotho. Subgroup analyses were conducted, stratified by age (40-59 and 60-79), sex (Male and Female), race (Mexican American, non-Hispanic White, non-Hispanic Black, and Others) and chronic kidney disease (Yes and No) in fully adjusted models.
RESULTS: A total of 9457 middle-aged and older participants were included in this study, with a mean age of 55.27 ± 0.17 years. The mean serum klotho level in the population was 849.33 ± 5.39 pg/mL. After controlling for potential confounders, the LE8 score showed a positive correlation with serum klotho levels (β: 1.32; 95% CI 0.73, 1.91), and a non-linear dose-response relationship was observed. Furthermore, we also discovered a positive relationship between health behaviors score and health factors score and serum klotho levels (β: 0.48; 95% CI 0.07, 0.88 and β: 1.05; 95% CI 0.54, 1.56, respectively), particularly a stronger correlation between health factors and serum klotho. In the subgroup analysis, we observed a significant interaction between LE8 score and sex and race. (P for interaction <0.05).
CONCLUSIONS: LE8 and its subscale scores were positively associated with serum klotho levels in the middle-aged and older populations. Promoting the maintenance of ideal CVH can contribute to delaying the aging process.

Keywords:  Biomarker of aging; Cardiovascular health; Klotho; Life’s Essential 8; NHANES

DOI:  https://doi.org/10.1016/j.jnha.2024.100224
Front Pharmacol. 2024 ;15 1349199

Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis.

Chuncai Li, Yincong Liu, Mingxing Deng, Jun Li, Shengqi Li, Xiaoyu Li, Yuling Zuo, Chongyang Shen, Yichao Wang.

  Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.

Keywords:  Th17/Treg; immunoregulatory activity; macrophage polarization; mesenchymal stem cells; osteoporosis

DOI:  https://doi.org/10.3389/fphar.2024.1349199
Sci Adv. 2024 Apr 12. 10(15): eadl0372

Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.

Yu Zhuang, Shengjie Jiang, Xiaoling Deng, An Lao, Xiaolin Hua, Yun Xie, Lingyong Jiang, Xudong Wang, Kaili Lin.

Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.

DOI: https://doi.org/10.1126/sciadv.adl0372
Mutat Res. 2024 Apr 03. pii: S0027-5107(24)00007-1. [Epub ahead of print]828 111857

Low-molecular-weight fucoidan increases telomere length and immunostimulatory effects on NK-92 cells following inhaled anesthetic injury.

Cheng-Hsi Chang, Pai-An Hwang.

  Inhaled anesthetics, such as isoflurane, may cause side effects, including short-term immunosuppression and DNA damage. In contrast, low molecular weight fucoidan (LMF), derived from brown seaweed, exhibits promising immunomodulatory effects. In this study, we determined the effect of isoflurane on telomeres and examined the potential of LMF to ameliorate the harmful effects of isoflurane. Male Lewis rats, the mouse lymphoma cell line YAC-1, and the human nature killer cell line NK-92 MI were exposed to isoflurane. The relative telomere length (T/S) ratio and mRNA expression were determined by quantitative PCR. The viability assay was used to assess cell viability. In vivo, 2% isoflurane exposure, which is a clinically relevant concentration, reduced telomere length, and correlated with exposure frequency and duration. Isoflurane concentrations above 2% shortened YAC-1 telomeres, with minimal impact on cell viability. LMF pre-treatment enhanced NK-92 MI cell survival resulting from isoflurane exposure and exerted superior telomere protection compared with LMF post-treatment. Furthermore, adding LMF during isoflurane exposure resulted in a significant increase in IFN-γ, TNF-α, and IL-10 mRNA compared with the untreated group. LMF protected against isoflurane-induced telomere shortening, enhanced NK cell viability, and modulated cytokine expression, thus mitigating postoperative immune suppression and risk of tumor metastasis.

Keywords:  Anesthetic; Low molecular weight fucoidan; NK-92 cell; Telomere length

DOI:  https://doi.org/10.1016/j.mrfmmm.2024.111857
Cell Stress Chaperones. 2024 Apr 10. pii: S1355-8145(24)00065-8. [Epub ahead of print]

Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism.

Bideep Shrestha, Anni I Nieminen, Olli Matilainen.

  Histone H3/H4 chaperone ASF1 is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the H3K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNAi enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism (OCM), and that downregulation of the OCM component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.

Keywords:  ASF-1; C. elegans; UNC-85; lifespan; one-carbon metabolism

DOI:  https://doi.org/10.1016/j.cstres.2024.04.003
Res Sq. 2024 Mar 29. pii: rs.3.rs-4049366. [Epub ahead of print]

DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.

Alyssa Johnson, Cristian Ricaurte-Perez, P Wall, Olga Dubuisson, K Bohnert.

Although life expectancy has increased, longer lifespans do not always align with prolonged healthspans and, as a result, the occurrence of age-related degenerative diseases continues to increase. Thus, biomedical research has been shifting focus to strategies that enhance both lifespan and healthspan concurrently. Two major transcription factors that have been heavily studied in the context of aging and longevity are DAF-16/FOXO and HLH-30/TFEB; however, how these two factors coordinate to promote longevity is still not fully understood. In this study, we reveal a new facet of their cooperation that supports healthier aging in C. elegans. Namely, we demonstrate that the combinatorial effect of daf-16 and hlh-30 is required to trigger robust lysosomal tubulation, which contributes to systemic health benefits in late age by enhancing cross-tissue proteostasis mechanisms. Remarkably, this change in lysosomal morphology can be artificially induced via overexpression of SVIP, a previously characterized tubular lysosome stimulator, even when one of the key transcription factors, DAF-16, is absent. This adds to growing evidence that SVIP could be utilized to employ tubular lysosome activity in adverse conditions or disease states. Mechanistically, intestinal overexpression of SVIP leads to nuclear accumulation of HLH-30 in gut and non-gut tissues and triggers global gene expression changes that promotes systemic health benefits. Collectively, our work reveals a new cellular process that is under the control of DAF-16 and HLH-30 and provides further insight into how these two transcription factors may be exerting their pro-health effects.

DOI: https://doi.org/10.21203/rs.3.rs-4049366/v1