bims-caglex 2024-03-17 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–03–17
sixteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come.
The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis.
AMPK-upregulated microRNA-708 plays as a suppressor of cellular senescence and aging via downregulating disabled-2 and mTORC1 activation.
WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8.
Dietary pyrroloquinoline quinone hinders aging progression in male mice and D-galactose-induced cells.
Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.
Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.
Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.
Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy.
Codonopsis pilosula water extract delays D-galactose-induced aging of the brain in mice by activating autophagy and regulating metabolism.
MicroRNA-18a prevents senescence of mesenchymal stem cells by targeting CTDSPL.
miR-873-5p Suppression Reinvigorates Aging Mesenchymal Stem Cells and Improves Cardiac Repair after Myocardial Infarction.
Melasolv™: a potential preventive and depigmenting agent for the senescence of melanocytes.
Paeonol promotes longevity and fitness in Caenorhabditis elegans through activating the DAF-16/FOXO and SKN-1/Nrf2 transcription factors.
Osteopontin Rejuvenates Senescent Adipose-Derived Stem Cells and Restores their Bone Tissue Regenerative Function.
Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene.

Expert Opin Ther Targets. 2024 Mar 13.

Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come.

Caitlin J Lewis, Aubrey D de Grey.

   INTRODUCTION: Longevity research has matured to the point where significantly postponing age-related decline in physical and mental function is now achievable in the laboratory and foreseeable in the clinic. The most promising strategies involve rejuvenation, i.e. reducing biological age, not merely slowing its progression.
AREAS COVERED: We discuss therapeutic strategies for rejuvenation and results achieved thus far, with a focus on in vivo studies. We discuss the implications of interventions which act on mean or maximum lifespan and those showing effects in accelerated disease models. While the focus is on work conducted in mice, we also highlight notable insights in the field from studies in other model organisms.
EXPERT OPINION: Rejuvenation was originally proposed as easier than slowing aging because it targets initially inert changes to tissue structure and composition, rather than trying to disentangle processes that both create aging damage and maintain life. While recent studies support this hypothesis, a true test requires a panel of rejuvenation interventions targeting multiple damage categories simultaneously. Considerations of cost, profitability and academic significance have dampened enthusiasm for such work, but it is vital. Now is the time for the field to take this key step toward the medical control of aging.

Keywords:  Aging; lifespan; longevity; rejuvenation; rodents; senescence; synergy; translation

DOI:  https://doi.org/10.1080/14728222.2024.2330425
Stem Cells Transl Med. 2024 Mar 09. pii: szae015. [Epub ahead of print]

The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis.

Sen Ren, Chengcheng Li, Hewei Xiong, Qian Wu, Xiaohui Wu, Zhongwei Xiong, Lixing Dong, Bing Shu, Wei Wei, Chao Ma, Xiang Li, Jincao Chen.

  Adipose stem cell (ASC)-based therapies provide an encouraging option for tissue repair and regeneration. However, the function of these cells declines with aging, which limits their clinical transformation. Recent studies have outlined the involvement of long non-coding RNAs in stem cell aging. Here, we reanalyzed our published RNA sequencing (RNA-seq) data profiling differences between ASCs from young and old donors and identified a lncRNA named double homeobox A pseudogene 10 (DUXAP10) as significantly accumulated in aged ASCs. Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. In addition, DUXAP10 was located in the cytoplasm and functioned as a decoy for miR-214-3p. miR-214-3p was downregulated in aged ASCs, and its overexpression rejuvenated aged ASCs and reversed the harm caused by DUXAP10. Furthermore, Ras Association Domain Family Member 5 (RASSF5) was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing. Overall, this study offers new insights into the mechanism of age-related ASC dysfunction and names DUXAP10 and miR-214-3p as potential targets for energizing aged stem cells.

Keywords:  DUXAP10; RASSF5; adipose stem cell; aging; miR-214-3p; non-coding RNA

DOI:  https://doi.org/10.1093/stcltm/szae015
MedComm (2020). 2024 Mar;5(3): e475

AMPK-upregulated microRNA-708 plays as a suppressor of cellular senescence and aging via downregulating disabled-2 and mTORC1 activation.

Jian Zhang, Hui Gong, Tingting Zhao, Weitong Xu, Honghan Chen, Tiepeng Li, Yu Yang, Ming Yang, Ning Huang, Chuhui Gong, Fangfang Wang, Cuiying Zhang, Jin Liu, Hengyi Xiao.

  Senescence-associated microRNAs (SA-miRNAs) are important molecules for aging regulation. While many aging-promoting SA-miRNAs have been identified, confirmed aging-suppressive SA-miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR-708 expression is decreased in senescent cells and aged tissues and revealed that miR-708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR-708, we unraveled that miR-708 directly targets the 3'UTR of the disabled 2 (Dab2) gene and inhibits the expression of DAB2. Interestingly, miR-708-caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP-activated protein kinase (AMPK) activation can upregulate miR-708 via the elevation of DICER expression, and miR-708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR-708 as an aging-suppressive SA-miRNA for the first time and uncovered a new signaling cascade, in which miR-708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR-708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1.

Keywords:  AMP‐activated protein kinase (AMPK); Disabled 2 (DAB2); aging; mammalian traget of rapamycin coplex 1 (mTORC1); miR‐708

DOI:  https://doi.org/10.1002/mco2.475
Int J Biol Sci. 2024 ;20(5): 1763-1777

WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8.

Lei Zhou, Yun Zhong, Fan Wang, Yi Guo, Rui Mao, Hongfu Xie, Yiya Zhang, Ji Li.

  N6-methyladenosine (m6A), the most prevalent posttranscriptional RNA modification, involved in various diseases and cellular processes. However, the underlying mechanisms of m6A regulation in skin aging are still not fully understood. In this study, proteomics analysis revealed a significant correlation between Wilms' tumor 1-associating protein (WTAP) expression and cellular senescence. Next, upregulated WTAP was detected in aging skin tissues and senescent human dermal fibroblasts (HDFs). Functionally, overexpressed WTAP induced senescence and knockdown of WTAP rescued senescence of HDFs. Mechanistically, WTAP directly targeted ELF3 and promoted its expression in an m6A-dependent manner. Exogenous-ELF3 overexpression evidently reversed shWTAP-suppressed fibroblast senescence. Furthermore, ELF3 induced IRF8-mediated senescence-associated secretory phenotype (SASP) by binding to the (-817 to -804) site of the IRF8 promoter directly. In vivo, overexpression of WTAP evidently increased senescence cells in skin and induced skin aging. In summary, these findings revealed the critical role of WTAP-mediated m6A modification in skin aging and identified ELF3 as an important target of m6A modification in HDFs senescence, providing a new idea for delaying the aging process.

Keywords:  ELF3; IRF8; WTAP; m6A; senescence

DOI:  https://doi.org/10.7150/ijbs.90459
Front Aging. 2024 ;5 1351860

Dietary pyrroloquinoline quinone hinders aging progression in male mice and D-galactose-induced cells.

Nur Syafiqah Mohamad Ishak, Midori Kikuchi, Kazuto Ikemoto.

  Background: Understanding and promoting healthy aging has become a necessity in the modern world, where life expectancy is rising. The prospective benefits of the antioxidant pyrroloquinoline quinone (PQQ) in healthy aging are promising. However, its role in aging remains unclear. Thus, this study aimed to investigate the effect of PQQ on preventing the progression of aging and to explore its underlying molecular mechanisms. Methods: Naturally aged C57BL/6J male mice were fed a normal diet with or without PQQ (20 mg/kg/day) for 10 weeks. Body composition was measured by bioimpedance at weeks 0 and 8. The integument conditions were evaluated at weeks 0, 4, and 8. Muscle strength and function were examined at week 8. At the ninth week, computed tomography images of the mice were captured, and blood and tissue samples were collected. The levels of inflammatory cytokines in the gastrocnemius muscle were measured, and the muscle fiber cross-sectional area in the soleus muscle was examined. Additionally, a D-galactose (D-gal)-induced cell aging model was used to study the effects of PQQ intervention on cell proliferation, senescence, differentiation, ROS levels, and mitochondrial function in myoblasts (C2C12). Cell proliferation and monolayer permeability of D-gal-induced intestinal epithelial cells (IEC6) were also examined. Results: Aged mice suffered from malnutrition; however, PQQ supplementation ameliorated this effect, possibly by improving metabolic dysfunction and small intestinal performance. PQQ prevented rapid loss of body fat and body fluid accumulation, attenuated muscle atrophy and weakening, reduced chronic inflammation in skeletal muscles, and improved skin and coating conditions in aged mice. Furthermore, PQQ intervention in D-gal-treated C2C12 cells improved mitochondrial function, reduced cellular reactive oxygen species (ROS) levels and senescence, and enhanced cell differentiation, consequently preventing age-related muscle atrophy. In addition, PQQ increased cell proliferation in D-gal-treated IEC6 cells and consequently improved intestinal barrier function. Conclusion: PQQ could hinder the aging process and particularly attenuate muscle atrophy, and muscle weakness by improving mitochondrial function, leading to reduced age-related oxidative stress and inflammation in muscles. PQQ may also ameliorate malnutrition caused by intestinal barrier dysfunction by enhancing IEC proliferation. This study provides evidence for the role of PQQ in aging and suggests that PQQ may be a potential nutritional supplementation that can be included in healthy aging strategies.

Keywords:  PQQ; aging; antioxidant; inflammation; muscle atrophy; sarcopenia

DOI:  https://doi.org/10.3389/fragi.2024.1351860
Aging Cell. 2024 Mar 14. e14143

Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.

Yingying Sun, Le Xu, Yi Li, Shunze Jia, Gang Wang, Xufeng Cen, Yuyan Xu, Zhongkai Cao, Jingjing Wang, Ning Shen, Lidan Hu, Jin Zhang, Jianhua Mao, Hongguang Xia, Zhihong Liu, Xudong Fu.

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.

Keywords:  HGPS; UMI-77; aging; mitophagy

DOI:  https://doi.org/10.1111/acel.14143
Biomed Pharmacother. 2024 Mar 12. pii: S0753-3322(24)00299-3. [Epub ahead of print]173 116415

Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.

Lulin Nie, Kaiwu He, Chaoming Qiu, Qing Li, Bocheng Xiong, Chuanyue Gao, Xiufen Zhang, Mei Jing, Wei Wu, Jianjun Liu, Gaoxiao Zhang, Zaijun Zhang, Xifei Yang, Yewei Sun, Yuqiang Wang.

  Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1β, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.

Keywords:  AMPK signaling; Mitochondrial function; Motor deficits; Muscle aging; Tetramethylpyrazine nitrone (TBN)

DOI:  https://doi.org/10.1016/j.biopha.2024.116415
Acta Pharm Sin B. 2024 Mar;14(3): 1166-1186

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.

Shanshan Rao, Zehui He, Zun Wang, Hao Yin, Xiongke Hu, Yijuan Tan, Tengfei Wan, Hao Zhu, Yi Luo, Xin Wang, Hongming Li, Zhenxing Wang, Xinyue Hu, Chungu Hong, Yiyi Wang, Mingjie Luo, Wei Du, Yuxuan Qian, Siyuan Tang, Hui Xie, Chunyuan Chen.

  Aging increases the risks of various diseases and the vulnerability to death. Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases. This study demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors' ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase (PLAU) and tissue inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

Keywords:  Anti-aging; Cellular senescence; Extracellular vesicles; Natural aging mice; PLAU; Senescence-accelerated mice; TIMP1; Urine-derived stem cells

DOI:  https://doi.org/10.1016/j.apsb.2023.12.009
Cells. 2024 Feb 27. pii: 415. [Epub ahead of print]13(5):

Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy.

Jingchun Bai, Xinyu Wang, Yiqiu Chen, Qiongyu Yuan, Zhaoyu Yang, Yuling Mi, Caiqiao Zhang.

  With the increase in the age of laying chickens, the aging of follicles is accelerated, and the reproductive ability is decreased. Increased oxidative stress and mitochondrial malfunction are indispensable causes of ovarian aging. In this study, the physiological condition of prehierarchical small white follicles (SWFs) was compared between D280 high-producing chickens and D580 aging chickens, and the effect of a plant-derived flavonoid nobiletin (Nob), a natural antioxidant, on senescence of SWFs granulosa cells (SWF-GCs) was investigated. The results showed that Nob treatment activated cell autophagy by activating the AMP-activated protein kinase (AMPK) and Sirtuin-1 (SIRT1) pathways in D-galactose (D-gal)-generated senescent SWF-GCs, restoring the expression of proliferation-related mRNAs and proteins. In addition, the expression of inflammation-related protein NF-κB was significantly enhanced in aging GCs that were induced by D-gal. Nob supplementation significantly increased the antioxidant capacity and decreased the expression of several genes associated with cell apoptosis. Furthermore, Nob promoted activation of PINK1 and Parkin pathways for mitophagy and alleviated mitochondrial edema. Either the AMPK inhibitor dorsomorphin (Compound C) or SIRT1 inhibitor selisistat (EX-527) attenuated the effect of Nob on mitophagy. The protective effect of Nob on natural aging, GC proliferation, and elimination of the beneficial impact on energy regulation of naturally aging ovaries was diminished by inhibition of Nob-mediated autophagy. These data suggest that Nob treatment increases the expression of mitophagy-related proteins (PINK1 and Parkin) via the AMPK/SIRT1 pathways to prevent ovarian aging in the laying chickens.

Keywords:  chicken; mitophagy; nobiletin; ovarian aging; oxidative stress

DOI:  https://doi.org/10.3390/cells13050415
J Ethnopharmacol. 2024 Mar 08. pii: S0378-8741(24)00315-5. [Epub ahead of print] 118016

Codonopsis pilosula water extract delays D-galactose-induced aging of the brain in mice by activating autophagy and regulating metabolism.

Xuewen Wang, Jiachao Kang, Xuechan Li, Pingmin Wu, Yong Huang, Yongqiang Duan, Juan Feng, Jing Wang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Codonopsis pilosula (C. pilosula), also called "Dangshen" in Chinese, is derived from the roots of Codonopsis pilosula (Franch.) Nannf. (C. pilosula), Codonopsis pilosula var. Modesta (Nannf.) L.D.Shen (C. pilosula var. modesta) or Codonopsis pilosula subsp. Tangshen (Oliv.) D.Y.Hong (C. pilosula subsp. tangshen), is a well-known traditional Chinese medicine. It has been regularly used for anti-aging, strengthening the spleen and tonifying the lungs, regulating blood sugar, lowering blood pressure, strengthening the body's immune system, etc. However, the mechanism, by which, C. pilosula exerts its therapeutic effects on brain aging remains unclear.
AIM OF THE STUDY: This study aimed to investigate the underlying mechanisms of the protective effects of C. pilosula water extract (CPWE) on the hippocampal tissue of D-galactose-induced aging mice.
MATERIALS AND METHODS: In this research, plant taxonomy has been confirmed in the "The Plant List" database (www.theplantlist.org). First, an aging mouse model was established through the intraperitoneal injections of D-galactose solution, and low-, medium-, and high-dose CPWE were administered to mice by gavage for 42 days. Then, the learning and memory abilities of the mice were examined using the Morris water maze tests and step-down test. Hematoxylin and eosin staining was performed to visualize histopathological damage in the hippocampus. A transmission electron microscope was used to observe the ultrastructure of hippocampal neurons. Immunohistochemical staining was performed to examine the expression of glial fibrillary acidic protein (GFAP), the marker protein of astrocyte activation, and autophagy-related proteins, including microtubule-associated protein light chain 3 (LC3) and sequestosome 1 (SQSTM1)/p62, in the hippocampal tissues of mice. Moreover, targeted metabolomic analysis was performed to assess the changes in polar metabolites and short-chain fatty acids in the hippocampus.
RESULTS: First, CPWE alleviated cognitive impairment and ameliorated hippocampal tissue damage in aging mice. Furthermore, CPWE markedly alleviated mitochondrial damage, restored the number of autophagosomes, and activated autophagy in the hippocampal tissue of aging mice by increasing the expression of LC3 protein and reducing the expression of p62 protein. Meanwhile, the expression levels of the brain injury marker protein GFAP decreased. Moreover, quantitative targeted metabolomic analysis revealed that CPWE intervention reversed the abnormal levels of L-asparagine, L-glutamic acid, L-glutamine, serotonin hydrochloride, succinic acid, and acetic acid in the hippocampal tissue of aging mice. CPWE also significantly regulated pathways associated with D-glutamine and D-glutamate metabolism, nitrogen metabolism, arginine biosynthesis, alanine, aspartate, and glutamate metabolisms, and aminoacyl-tRNA biosynthesis.
CONCLUSIONS: CPWE could improve cognitive and pathological conditions induced by D-galactose in aging mice by activating autophagy and regulating metabolism, thereby slowing down brain aging.

Keywords:  Aging; Autophagy; Codonopsis pilosula; D-galactose; Hippocampus; Target metabolomics

DOI:  https://doi.org/10.1016/j.jep.2024.118016
Aging (Albany NY). 2024 Mar 07. 16

MicroRNA-18a prevents senescence of mesenchymal stem cells by targeting CTDSPL.

Bo Sun, Xian-Hui Meng, Yu-Min Li, Hao Lin, Zhong-Dang Xiao.

  Stem cell therapy requires massive-scale homogeneous stem cells under strict qualification control. However, Prolonged ex vivo expansion impairs the biological functions and results in senescence of mesenchymal stem cells (MSCs). We investigated the function of CTDSPL in the premature senescence process of MSCs and clarified that miR-18a-5p played a prominent role in preventing senescence of long-term cultured MSCs and promoting the self-renewal ability of MSCs. Over-expression of CTDSPL resulted in an enlarged morphology, up-regulation of p16 and accumulation of SA-β-gal of MSCs. The reduced phosphorylated RB suggested cell cycle arrest of MSCs. All these results implied that CTDSPL induced premature senescence of MSCs. We further demonstrated that miR-18a-5p was a putative regulator of CTDSPL by luciferase reporter assay. Inhibition of miR-18a-5p promoted the expression of CTDSPL and induced premature senescence of MSCs. Continuous overexpression of miR-18a-5p improved self-renewal of MSCs by reducing ROS level, increased expression of Oct4 and Nanog, and promoted growth rate and differentiation capability. We reported for the first time that the dynamic interaction of miR-18a-5p and CTDSPL is crucial for stem cell senescence.

Keywords:  CTDSPL; mesenchymal stem cells; miR-18a-5p; senescence

DOI:  https://doi.org/10.18632/aging.205642
ACS Pharmacol Transl Sci. 2024 Mar 08. 7(3): 743-756

miR-873-5p Suppression Reinvigorates Aging Mesenchymal Stem Cells and Improves Cardiac Repair after Myocardial Infarction.

Wenwu Zhu, Wei Du, Rui Duan, Yan Liu, Bin Zong, Xin Jin, Zishuang Dong, Hui Wang, Siyamak Shahab, Haoran Wang, Yimei Hong, Bing Han.

Aging poses obstacles to the functionality of human mesenchymal stem cells (MSCs), resulting in a notable decline in their valuable contribution to myocardial infarction (MI). MicroRNAs (miRNAs) play a pivotal role in governing MSC aging; nonetheless, the specific mechanisms remain puzzling. This research delved into the value of miR-873-5p in the management of MSC aging and investigated whether the restraint of miR-873-5p could regenerate aged MSCs (AMSCs), thereby enhancing their healing success for MI. In this study, MSCs were isolated from both young donors (referred to as YMSCs) and aged donors (referred to as AMSCs). The senescence status of these MSCs was evaluated through the application of age-related β-galactosidase (SA-β-gal) staining. Following this assessment, the MSCs, including those treated with anti-miR-873-5p-AMSCs, were then transplanted into the hearts of Sprague-Dawley rats experiencing acute myocardial infarction. Increasing miR-873-5p levels in YMSCs resulted in elevated cellular aging, whereas reducing miR-873-5p expression decreased aging in AMSCs. Mechanistically, miR-873-5p inhibited autophagy in MSCs through the AMPK signaling pathway, leading to cellular aging by suppressing the Cab39 expression. Partial alleviation of these effects was achieved by the administration of the autophagy inhibitor 3-methyladenine. Grafting of anti-miR-873-5p-AMSCs, by enhancing angiogenesis and bolstering cell survival, led to an improvement in cardiac function in the rat model, unlike the transplantation of AMSCs. miR-873-5p which serves as a pivotal element in mediating MSC aging through its regulation of the Cab39/AMPK signaling pathway. It represents an innovative target for revitalizing AMSCs and enhancing their heart-protective abilities.

DOI: https://doi.org/10.1021/acsptsci.3c00293
Front Mol Biosci. 2023 ;10 1228640

Melasolv™: a potential preventive and depigmenting agent for the senescence of melanocytes.

Yeonju Cho, Suh-Yeon Choi, Hyunjung Choi, Mira Ham, Kyu-Han Kim.

  Introduction: Senescent melanocytes are major contributors to age-related changes in the skin, highlighting the contribution to skin aging. Moreover, prolonged photodamage, such as that caused by UV exposure, can result in melanin accumulation and accelerated melanocyte senescence, thereby exacerbating aging. Melasolv™ is a substance that induces potent depigmentation effects and exhibits low toxicity. The present study aimed to investigate the potential effect of Melasolv™ on senescent melanocytes. Methods: We profiled the transcriptomics of Melasolv™-treated melanocytes and identified the possible mechanism of action (MOA) and targets using connectivity mapping analysis. We identified differentially expressed genes in response to treatment with Melasolv™ and validated the data using quantitative real-time PCR. Moreover, we performed an in vitro β-gal assay in senescent melanocytes for further validation. Results: Melasolv™ reduced β-gal and melanin levels in senescent melanocytes. Moreover, the identified MOAs are associated with anti-aging and anti-senescence effects. Discussion: Our findings clearly indicate that Melasolv™ not only exhibits anti-senescent properties but can also potentially alleviate melanin accumulation in senescent cells. These findings could have far-reaching implications in the treatment of age-related photodamaged skin conditions, such as senile lentigo and melasma.

Keywords:  MelasolvTM; anti-aging; depigmenting; melanocyte; senescence

DOI:  https://doi.org/10.3389/fmolb.2023.1228640
Biomed Pharmacother. 2024 Mar 11. pii: S0753-3322(24)00252-X. [Epub ahead of print]173 116368

Paeonol promotes longevity and fitness in Caenorhabditis elegans through activating the DAF-16/FOXO and SKN-1/Nrf2 transcription factors.

Rong Li, Qingping Yi, Jinsong Wang, Yuanxin Miao, Qingchan Chen, Yan Xu, Mingfang Tao.

  Paeonol, as one of the most abundant plant-derived polyphenols, has multiple bioactivities including anti-inflammatory, anti-tumor, and anti-cardiovascular diseases. Nevertheless, the anti-aging effects and related mechanisms of paeonol are rarely reported. In this study, we found that paeonol significantly prolonged the mean lifespan of Caenorhabditis elegans (C. elegans) by 28.49% at a dose of 200 μM. Moreover, paeonol promoted the health of C. elegans by increasing the body bending and pharyngeal pumping rates and reducing the lipofuscin accumulation level. Meanwhile, paeonol induced the expression of stress-related genes or proteins by activating the transcription factors DAF-16/FOXO, SKN-1/Nrf2, and HSF-1, which in turn enhanced oxidative and thermal stress tolerance. The mechanism behind the anti-aging effect of paeonol occurred by down-regulating the insulin/IGF-1 signaling (IIS) pathway. Our findings shed new light on the application of paeonol for longevity promotion and human health.

Keywords:  Anti-aging; Caenorhabditis elegans; IIS pathway; Paeonol; Stress resistance

DOI:  https://doi.org/10.1016/j.biopha.2024.116368
Stem Cell Rev Rep. 2024 Mar 12.

Osteopontin Rejuvenates Senescent Adipose-Derived Stem Cells and Restores their Bone Tissue Regenerative Function.

Yiran Zhang, Junni Zhang, Pooria Lesani, Zufu Lu, Hala Zreiqat.

  The regenerative function of stem cells is compromised when the proportion of senescent stem cells increases with ageing advance. Therefore, combating stem cell senescence is of great importance for stem cell-based tissue engineering in the elderly, but remains largely unexplored. Osteopontin (OPN), a glycosylated phosphoprotein, is one of the key extracellular matrix molecules in bone tissue. OPN activates various signalling pathways and modulates cellular activities, including cell senescence. However, the role of OPN in stem cell senescence remains largely unknown. This study aims to investigate if OPN modulates cell senescence and bone regenerative function in human adipose-derived mesenchymal stem cells (ASCs), and to determine the underlying mechanisms. We first developed a senescent ASC model using serial passaging until passage 10 (P10), in which senescent cells were characterised by reduced proliferation and osteogenic differentiation capacity compared to P4 ASCs. The conditioned medium from P10 ASCs exhibited a diminished trophic effect on human osteoblasts (HOBs), compared to that from P4 ASCs. P10 ASCs on OPN-coated surface showed rejuvenated phenotype and enhanced osteogenic differentiation. The conditioned medium from P10 ASCs on OPN-coating improved trophic effects on HOBs. OPN regulated the morphology of senescent ASCs, transforming them from a more rounded and flattened cell shape to an elongated shape with a smaller area. These findings demonstrated the effects of OPN in restoring senescent ASCs functions, possibly through a mechanism that involves the modulation of cell morphology, indicating that OPN might hold a great potential for rejuvenating senescent stem cells and could potentially open a new venue for regenerating bone tissue in age-related diseases.

Keywords:  Ageing; Bone; Cell shape and morphology; Osteopontin; Senescence; Stem cells

DOI:  https://doi.org/10.1007/s12015-024-10707-5
Bone Rep. 2024 Mar;20 101746

Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene.

Qiming Xu, Lijia Cui, Yude Lin, Leigh-Anne Cui, Weibo Xia.

  Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNBG1586R/G1586R and FLNBWT/G1586R mice, compared to FLNBWT/WT mice. Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNBG1586R/G1586R mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period.

Keywords:  CRISPR-Cas9; Filamin B; HOX; In situ hybridization of embryo; Skeletal segmentation

DOI:  https://doi.org/10.1016/j.bonr.2024.101746