bims-caglex 2024-12-08 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–12–08
twenty-one papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Mitigating Glycation and Oxidative Stress in Aesthetic Medicine: Hyaluronic Acid and Trehalose Synergy for Anti-AGEs Action in Skin Aging Treatment.
The senotherapeutic potential of phytochemicals for age-related intestinal disease.
Editorial Commentary: M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats.
Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.
Role of chemokines in aging and age-related diseases.
Exosomes derived stem cells as a modern therapeutic approach for skin rejuvenation and hair regrowth.
Ageing of stem cells reduces their capacity to form tumours.
SIRT7 promotes dental pulp stem cells replicative senescence through desuccinylation of ROCK1.
Cross-talk of inflammation and cellular senescence: a new insight into the occurrence and progression of osteoarthritis.
The Impact of Vitamin E Supplementation on Oxidative Stress, Cognitive Functions, and Aging-Related Gene Expression in Aged Mice.
Epigenetic control of dental stem cells: progress and prospects in multidirectional differentiation.
Discovering geroprotectors through the explainable artificial intelligence-based platform AgeXtend.
Nicotinamide mononucleotide suppresses cellular senescence and increases aquaporin 5 expression in the submandibular gland of aged male mice to ameliorate aging-related dry mouth.
RNA m6A methylation regulatory mechanism of resveratrol in premature senescence cells.
Phenotypic upregulation of hexocylceramides and ether-linked phosphocholines as markers of human extreme longevity.
Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.
Yes-associated protein-mediated melatonin regulates the function of periodontal ligament stem cells under oxidative stress conditions.
Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability.
Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids.
Metabolic signatures of combined exercise and fasting: an expanded perspective on previous telomere length findings.
The effects of advanced age on electrocardiographic parameters, lipid profile and redox balance in male rats: role of long-term cinnamon consumption.

Clin Cosmet Investig Dermatol. 2024 ;17 2701-2712

Mitigating Glycation and Oxidative Stress in Aesthetic Medicine: Hyaluronic Acid and Trehalose Synergy for Anti-AGEs Action in Skin Aging Treatment.

Robert Chmielewski, Aleksandra Lesiak.

  This comprehensive review explores the pivotal roles of glycation and oxidative stress in the aging process of the skin, emphasizing their targeted therapeutic applications in aesthetic and regenerative medicine, as well as anti-aging interventions. Glycation, a biochemical process involving the non-enzymatic attachment of sugars to proteins, lipids, or nucleic acids, culminates in the formation of Advanced Glycation End products (AGEs). These AGEs are significant contributors to aging and various chronic ailments, triggering oxidative stress and inflammatory pathways, thereby manifesting as wrinkles, diminished skin elasticity, and other age-related dermal alterations. A central focus of this review is the synergistic interplay between Hyaluronic Acid (HA) and Trehalose in combating these aging mechanisms. HA, renowned for its anti-inflammatory and antioxidative properties, assumes a pivotal role in modulating Reactive Oxygen Species (ROS) levels and safeguarding against oxidative damage. Concurrently, trehalose targets glycation and oxidative stress, exhibiting promising outcomes in augmenting skin health, providing Ultraviolet B (UVB) photoprotection, and manifesting notable anti-photoaging effects. The combined administration of HA and trehalose not only addresses existing skin damage but also confers preventive and reparative benefits, particularly in stabilizing HA and mitigating glycation-induced stress. Their synergistic action significantly enhances skin quality and mitigates inflammation. The implications of these findings are profound for the future of anti-aging therapeutics in aesthetic medicine, suggesting that the integration of HA and trehalose holds promise for revolutionary advancements in preserving skin vitality and health. Moreover this paper underscores the imperative for continued research into the combined efficacy of these compounds, advocating for innovative therapeutic modalities in aesthetic medicine and enhanced strategies for combating aging, glycation, and oxidative stress.

Keywords:  anti-aging therapies; glycation; hyaluronic acid; oxidative stress; skin aging; trehalose

DOI:  https://doi.org/10.2147/CCID.S476362
Ageing Res Rev. 2024 Dec 03. pii: S1568-1637(24)00437-9. [Epub ahead of print] 102619

The senotherapeutic potential of phytochemicals for age-related intestinal disease.

Célia Maria Costa, Sílvia Santos Pedrosa, James L Kirkland, Flávio Reis, Raquel Madureira.

  During the last few decades, life expectancy has increased worldwide along with the prevalence of several age-related diseases. Among aging pathways, cellular senescence and chronic inflammation (or "inflammaging") appear to be connected to gut homeostasis and dysbiosis of the microbiome. Cellular senescence is a state of essentially irreversible cell cycle arrest that occurs in response to stress. Although senescent cells (SC) remain metabolically active, they do not proliferate and can secrete inflammatory and other factors comprising the senescence-associated secretory phenotype (SASP). Accumulation of SCs has been linked to onset of several age-related diseases, in the brain, bones, the gastrointestinal tract, and other organs and tissues. The gut microbiome undergoes substantial changes with aging and is tightly interconnected with either successful (healthy) aging or disease. Senotherapeutic drugs are compounds that can clear senescent cells or modulate the release of SASP and hence attenuate the impact of the senescence-associated pro-inflammatory state. Phytochemicals, phenolic compounds and terpenes, which have antioxidant and anti-inflammatory activities, could also be senotherapeutic given their ability to act upon senescence-linked cellular pathways. The aim of this review is to dissect links among the gut microbiome, cellular senescence, inflammaging, and disease, as well as to explore phytochemicals as potential senotherapeutics, focusing on their interactions with gut microbiota. Coordinated targeting of these inter-related processes might unveil new strategies for promoting healthy aging.

Keywords:  cellular senescence; gut microbiota; microbiota-derived metabolites; phenolic compounds; phytochemicals; senotherapeutics

DOI:  https://doi.org/10.1016/j.arr.2024.102619
Arthroscopy. 2024 Nov 30. pii: S0749-8063(24)01008-9. [Epub ahead of print]

Editorial Commentary: M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats.

Anne Gingery.

Aging has long been associated with increased pathology in musculoskeletal tissues. Aging results in accumulation of senescent cells, stem cell exhaustion, sterile inflammation and immune cell dysfunction systemically and locally. Improving healing and regeneration during musculoskeletal aging is a significant area of clinical need. Recently the targeting of senescent cells has become an exciting area of research. Pathological accumulation of senescent cells in tissues is associated with tissue dysfunction. Immune system dysfunction has also been a proposed mechanism for the accumulation of senescent cells, where the immune system fails to clear senescent cells from tissue. Therapeutics that target senescent cells are an active area of research. Additionally stem cells in tissues decline with age. Stem cell exhaustion is one proposed mechanism for the declines in regeneration and healing that is found with aging. Declines in stem cells have been noted in patients with musculoskeletal injuries including rotator cuff tears. Shifts in immune cell populations has been shown to occur with aging and disease. The increase in sterile inflammation is associated with this shift in immune cell function. Polarized regenerative macrophages have been suggested to attenuate inflammation and promote healing. Exosomes from mesenchymal stem cells and immune cells, such as macrophages, are actively being pursued as important biologic therapies to improve regeneration and healing. Exosomes are small extracellular vesicles that are released from cells. Exosomes can carry DNA, RNA, lipids, and metabolites and appear to be important for intercellular communication. Assessing the efficacy of exosomes to promote healing and regeneration in musculoskeletal injuries in aged or diseased conditions is an active area of research. It is essential in this work to thoroughly define the cell sources of exosomes and determine their mechanistic response in tissues. Rigorous evidenced-based research is needed to determine the potential efficacy of exosomes to improve tissue healing for patients.

DOI: https://doi.org/10.1016/j.arthro.2024.11.078
Aging (Albany NY). 2024 Dec 03. 16

Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.

Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Joy Ha, Jannat Dhillon, Grace H Shin, Jack Crouch, Adam C Gower, Sami Gritli, Daniel S Roh.

  Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescence markers p16 and p21, accompanied by reductions in SA-β-gal- and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

Keywords:  ABT-263; aging; senescence; senolytic; wound healing

DOI:  https://doi.org/10.18632/aging.206165
Mech Ageing Dev. 2024 Dec 02. pii: S0047-6374(24)00109-X. [Epub ahead of print] 112009

Role of chemokines in aging and age-related diseases.

Jitendra Kumar Chaudhary, Ajay Kumar Danga, Anita Kumari, Akshay Bhardwaj, Pramod C Rath.

  Chemokines (chemotactic cytokines) play essential roles in developmental process, immune cell trafficking, inflammation, immunity, angiogenesis, cellular homeostasis, aging, and tumorigenesis. Chemokines also modulate response to immunotherapy, and consequently influence the therapeutic outcome. The mechanisms underlying these processes are accomplished by interaction of chemokines with their cognate cell surface G protein-coupled receptors (GPCRs) and subsequent cellular signaling pathways. Chemokines play crucial role in influencing aging process and age-related diseases across various tissues and organs, primarialy through inflammatory responses (inflammaging), recruitment of macrophages, and orchestrated trafficking of other immune cells. Chemokines are categorized in four distinct groups based on the position and number of the N-terminal cysteine residues; namely, the CC, CXC, CX3C, and (X)C. They mediate inflammatory responses, and thereby considerably impact aging process across multiple organ-systems. Therefore, understanding the underlying mechanisms mediated by chemokines may be of crucial importance in delaying and/or modulating the aging process and preventing age-related diseases. In this review, we highlight recent progress accomplished in understanding the role of chemokines and their cellular signaling pathways involved in aging and age-relaed diseases of various organs. Moreover, we explore potential therapeutic strategies involving chemokines and chemokine receptor antagonists aimed at reducing aging and mitigating age-related diseases. One of the modern methods in this direction involves use of chemokine receptor antagonists and anti-chemokines, which suppress the pro-inflammatory response, thereby helping in resolution of inflammation. Considering the wide-spectrum of functional involvements of chemokines in aging and associated diseases, several clinical trials are being conducted to develop therapeutic approaches using chemokine receptor antagonists to improve life span and promote healthy aging.

Keywords:  Chemokines and chemokine receptor antagonists; aging; cell trafficking; clinical trials; inflammation

DOI:  https://doi.org/10.1016/j.mad.2024.112009
Regen Ther. 2024 Jun;26 1124-1137

Exosomes derived stem cells as a modern therapeutic approach for skin rejuvenation and hair regrowth.

Fatemeh Norouzi, Sanaz Aghajani, Nasim Vosoughi, Shiva Sharif, Kazem Ghahremanzadeh, Zeinab Mokhtari, Javad Verdi.

   Background: The skin covers the surface of the body and acts as the first defense barrier against environmental damage. Exposure of the skin to environmental physical and chemical factors such as mechanical injuries, UV rays, air pollution, chemicals, etc. Leads to numerous damages to skin cells such as fibroblasts, keratinocytes, melanocytes, etc. The harmful effects of environmental factors on skin cells could lead to various skin diseases, chronic wounds, wrinkles, and skin aging. Hair is an essential part of the body, serving multiple functions such as regulating body temperature and protecting against external factors like dust (through eyelashes and eyebrows). It also reflects an individual's personality. Therefore, the need for new treatment methods for skin diseases and lesions and at the same time preserving the youth, freshness, and beauty of the skin has been highly noticed by experts. Exosomes are nanovesicles derived from cells that contain various biological compounds such as lipids, proteins, nucleic acids, and carbohydrates. They are secreted by a variety of mammalian cells and even different plants. Exosomes are of great interest as a new therapeutic approach due to their stability, ability to be transported throughout the body, paracrine and endocrine effects, as well as the ability to carry various compounds and drugs to target cells.
Aim: In this review, we have discussed the characteristics of exosomes, their cellular sources, and their therapeutic effects on wrinkles, skin aging, and rejuvenation and hair regrowth.

Keywords:  Exosomes; Hair regrowth; Skin aging; Skin rejuvenation; Wrinkles

DOI:  https://doi.org/10.1016/j.reth.2024.10.001
Nature. 2024 Dec 04.

Ageing of stem cells reduces their capacity to form tumours.

Tatiana Cañeque, Raphaël Rodriguez.



Keywords:  Ageing; Cancer; Stem cells

DOI:  https://doi.org/10.1038/d41586-024-03721-7
Tissue Cell. 2024 Nov 22. pii: S0040-8166(24)00337-9. [Epub ahead of print]92 102636

SIRT7 promotes dental pulp stem cells replicative senescence through desuccinylation of ROCK1.

Rui Zhang, Jie Chen, Yuanyuan Chen, Yangyang Li.

  The therapeutic effectiveness of dental pulp stem cells (DPSCs) is limited. Sirtuin 7 (SIRT7) has been reported to be associated with a variety of age-related diseases. We aimed to identify the regulatory role of SIRT7 in DPSC senescence and investigate the underlying mechanism. DPSCs were isolated from healthy adults, the stem markers were verified by flow cytomerty analysis. Replicative senescence was induced in DPSCs by serial passage and cells were analyzed at PD16 and 54. DPSC senescence was evaluated by observing senescence-associated β-galactosidase (SA-β-gal) and telomerase reverse transcriptase (TERT) activity. Meanwhile, the markers of senescence levels were monitored by western blotting assay. SIRT7 protein was pulled-down, and the binding relationship between SIRT7 and ROCK1 was verified by immunoprecipitation and western blotting methods. Replicative senescence was induced in DPSCs at PD54. The number of SA-β-gal stained DPSCs significantly increased in the PD54 group while the level of TERT activity was decreased. The cyclin-dependent kinase inhibitors p53, p21, and p16, which are markers of senescence, were markedly up-regulated at PD54. SIRT7 was also found to be lowly expressed at PD54. Inhibition of SIRT7 significantly accelerated the senescence of DPSCs. Moreover, SIRT7 can bind with ROCK1, and SIRT7 could lead to ROCK1 desuccinylation at K520. Inhibited ROCK1 significantly reversed the effects of SIRT7 knockdown on regulating DPSCs senescence. Our results demonstrate that the SIRT7/ROCK1 axis plays a key role in the regulation of DPSC senescence and provide a candidate target to improve the functional and therapeutic potential of DPSCs.

Keywords:  Dental pulp stem cell; Desuccinylation; ROCK1; SIRT7; Senescence

DOI:  https://doi.org/10.1016/j.tice.2024.102636
Bone Res. 2024 Dec 03. 12(1): 69

Cross-talk of inflammation and cellular senescence: a new insight into the occurrence and progression of osteoarthritis.

Zeyu Han, Ketao Wang, Shenglong Ding, Mingzhu Zhang.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

DOI: https://doi.org/10.1038/s41413-024-00375-z
Food Sci Nutr. 2024 Nov;12(11): 9834-9845

The Impact of Vitamin E Supplementation on Oxidative Stress, Cognitive Functions, and Aging-Related Gene Expression in Aged Mice.

Farnoosh Molavi Vasei, Mohammad Yasin Zamanian, Maryam Golmohammadi, Mehdi Mahmoodi, Morteza Khademalhosseini, Tayyebeh Tavakoli, Ozra Sadat Esmaeili, Sadegh Zarei, Mohammad Reza Mirzaei, Mohammad Reza Hajizadeh.

  This study investigated the effects of different doses of vitamin E on oxidative stress, cognitive function, and gene expression in aged mice. A total of 32 male mice, aged 12 months, were divided into a control group and three treatment groups. These groups received varying daily doses of vitamin E for a period of 28 days. The results showed significant improvements in cognitive function, specifically in working memory and spatial learning, in the groups that received vitamin E (100, 200, or 400 mg/kg) compared to the control group. The markers of oxidative stress and antioxidant enzyme activities also demonstrated improvements, with higher doses of vitamin E showing greater effects. The analysis of gene expression revealed increased expression of SIRT1, Nrf2, and Calstabin2, particularly at higher doses of vitamin E. These findings suggest that vitamin E supplementation may help counteract age-related cellular changes. The study concludes that vitamin E supplementation can reduce oxidative stress, enhance cognitive function, and affect genetic markers of aging in mice, which may have therapeutic benefits in addressing age-related cognitive decline and oxidative damage. Further research is necessary to investigate the clinical implications of these findings in humans.

Keywords:  aging; mice; oxidative stress; vitamin E

DOI:  https://doi.org/10.1002/fsn3.4548
Epigenetics Chromatin. 2024 Dec 03. 17(1): 37

Epigenetic control of dental stem cells: progress and prospects in multidirectional differentiation.

Yan Li, Xinwei Guo, Hua Yao, Zhimin Zhang, Hongyan Zhao.

  Dental stem cells, with their exceptional proliferative capacity and multidirectional differentiation potential, hold significant promise for dental and oral tissue regeneration. Epigenetic inheritance, which involves stable and heritable changes in gene expression and function without alterations to the DNA sequence, plays a critical role in numerous biological processes. Environmental factors are particularly influential in epigenetic inheritance, as variations in exposure can lead to changes in epigenetic modifications that subsequently impact gene expression. Epigenetic mechanisms are widely involved in processes such as bone homeostasis, embryogenesis, stem cell fate determination, and disease development. Recently, the epigenetic regulation of dental stem cells has attracted considerable research attention. This paper reviews studies focused on the epigenetic mechanisms governing the multidirectional differentiation of dental stem cells.

Keywords:  Dental stem cells; Epigenetic regulation; Stem cell differentiation

DOI:  https://doi.org/10.1186/s13072-024-00563-5
Nat Aging. 2024 Dec 03.

Discovering geroprotectors through the explainable artificial intelligence-based platform AgeXtend.

Sakshi Arora, Aayushi Mittal, Subhadeep Duari, Sonam Chauhan, Nilesh Kumar Dixit, Sanjay Kumar Mohanty, Arushi Sharma, Saveena Solanki, Anmol Kumar Sharma, Vishakha Gautam, Pushpendra Singh Gahlot, Shiva Satija, Jeet Nanshi, Nikita Kapoor, Lavanya Cb, Debarka Sengupta, Parul Mehrotra, Tarini Shankar Ghosh, Gaurav Ahuja.

Aging involves metabolic changes that lead to reduced cellular fitness, yet the role of many metabolites in aging is unclear. Understanding the mechanisms of known geroprotective molecules reveals insights into metabolic networks regulating aging and aids in identifying additional geroprotectors. Here we present AgeXtend, an artificial intelligence (AI)-based multimodal geroprotector prediction platform that leverages bioactivity data of known geroprotectors. AgeXtend encompasses modules that predict geroprotective potential, assess toxicity and identify target proteins and potential mechanisms. We found that AgeXtend accurately identified the pro-longevity effects of known geroprotectors excluded from training data, such as metformin and taurine. Using AgeXtend, we screened ~1.1 billion compounds and identified numerous potential geroprotectors, which we validated using yeast and Caenorhabditis elegans lifespan assays, as well as exploring microbiome-derived metabolites. Finally, we evaluated endogenous metabolites predicted as senomodulators using senescence assays in human fibroblasts, highlighting AgeXtend's potential to reveal unidentified geroprotectors and provide insights into aging mechanisms.

DOI: https://doi.org/10.1038/s43587-024-00763-4
Biogerontology. 2024 Dec 04. 26(1): 18

Nicotinamide mononucleotide suppresses cellular senescence and increases aquaporin 5 expression in the submandibular gland of aged male mice to ameliorate aging-related dry mouth.

Jun Wakabayashi, Takahiro Hamaguchi, Masashi Morifuji, Masashi Nagata.

  Dry mouth results from decreased saliva secretion due to aging or drug side effects. Decreased saliva secretion causes dryness in the oral cavity that makes swallowing difficult and increases the risk of aspiration pneumonia. There are few fundamental treatments for dry mouth. Here we investigated whether treatment of old mice with nicotinamide mononucleotide (NMN) improved factors associated with dry mouth. Young (16-week-old) and old (113-week-old) male mice were treated subcutaneously with saline or NMN (300 mg/kg) once every two days for four weeks and saliva secretion was measured. The amount of nicotinamide adenine dinucleotide (NAD+) in salivary gland tissues was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene expression in the intestinal tract and salivary glands was measured by real-time PCR. The population of cells with acetylation in the submandibular gland was quantified by immunohistological staining. SA-β-gal activity in the submandibular gland was measured to assess cell senescence. Statistical analysis was performed by one-way analysis of variance with Tukey post hoc analysis. The submandibular glands from old mice treated with NMN exhibited increased saliva secretion and NAD+ levels, which both decrease with aging. In addition, the submandibular glands from NMN-treated old mice had decreased acetylation, numbers of senescent cells, and levels of senescence-associated secretory phenotype (SASP) factors, which all increase with aging, as well as increased aquaporin5 (AQP5) mRNA expression. NMN administration may improve dry mouth by regulating cellular senescence in the submandibular gland and increasing expression of AQP5, a water channel involved in saliva secretion, to inhibit age-related decreases in saliva secretion. It is necessary to elucidate further mechanism and confirm its effectiveness in humans.

Keywords:  Aquaporin5; Dry mouth; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Saliva secretion; Senescence

DOI:  https://doi.org/10.1007/s10522-024-10162-2
Food Sci Nutr. 2024 Nov;12(11): 9238-9251

RNA m6A methylation regulatory mechanism of resveratrol in premature senescence cells.

Xinyu Zhang, Chenyu Zhu, Luyun Zhang, Luyi Tan, Wenli Cheng, Min Li, Xingtan Zhang, Wenjuan Zhang, Wenji Zhang.

  Resveratrol, a natural compound found in various plants, is known for its anti-inflammatory, antioxidant, and senescence-delaying properties. RNA N6-methyladenosine (m6A) methylation plays a crucial role in oxidative stress and premature cellular senescence processes and is closely associated with age-related disorders. However, the anti-premature senescence via RNA m6A methylation mechanism of resveratrol is still not fully understood. In this study, based on premature senescence model of human embryonic lung fibroblasts (HEFs) induced by hydrogen peroxide (H2O2), a widely accepted model of premature senescence caused by oxidative stress, we explored the anti-aging regulatory effects of resveratrol at the RNA m6A methylation level. Our data suggested that resveratrol significantly delayed premature senescence by increasing cell viability, reducing SA-β-gal blue staining rate, ROS levels, and senescence-associated secretory phenotypes (SASP) expression in HEFs. Meanwhile, resveratrol increased the whole RNA methyltransferases activity and the overall m6A level during senescence. Furthermore, three genes CCND2, E2F1, and GADD45B have been identified as the main ones regulating premature by resveratrol. Specifically, it decreased E2F1, GADD45B RNA m6A methylation level, and increased CCND2 level in premature cells. Our study provided new clues for exploring the mechanism and application of resveratrol in the field of premature aging.

Keywords:  RNA m6A methylation; human embryonic lung fibroblasts; hydrogen peroxide; premature senescence; resveratrol

DOI:  https://doi.org/10.1002/fsn3.4487
Aging Cell. 2024 Dec 05. e14429

Phenotypic upregulation of hexocylceramides and ether-linked phosphocholines as markers of human extreme longevity.

Anna Fernàndez-Bernal, Joaquim Sol, José Daniel Galo-Licona, Natàlia Mota-Martorell, Cristina Mas-Bargues, Ángel Belenguer-Varea, Èlia Obis, José Viña, Consuelo Borrás, Mariona Jové, Reinald Pamplona.

  Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age-related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass-spectrometry-based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether-PC and ether-LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether-linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.

Keywords:  centenarians; cententarians' offspring; ether lipids; extreme longevity; hexocylceramides; lipidomics

DOI:  https://doi.org/10.1111/acel.14429
ACS Biomater Sci Eng. 2024 Dec 04.

Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.

Maciej Wnuk, Susel Del Sol-Fernández, Dominika Błoniarz, Julia Słaby, Tomasz Szmatoła, Michał Żebrowski, Pablo Martínez-Vicente, Grzegorz Litwinienko, María Moros, Anna Lewińska.

  The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Keywords:  CD26; HSP90 inhibitor; drug-induced senescence; iron oxide nanoparticles; senolysis; skin cells

DOI:  https://doi.org/10.1021/acsbiomaterials.4c00771
World J Stem Cells. 2024 Nov 26. 16(11): 926-943

Yes-associated protein-mediated melatonin regulates the function of periodontal ligament stem cells under oxidative stress conditions.

Ke Gu, Xiao-Mei Feng, Shao-Qing Sun, Xing-Yao Hao, Yong Wen.

   BACKGROUND: Human periodontal ligament stem cells (PDLSCs) regenerate oral tissue. In vitro expansion causes replicative senescence in stem cells. This causes intracellular reactive oxygen species (ROS) accumulation, which can impair stem cell function. Tissue engineering efficiency is reduced by exogenous ROS stimulation, which causes premature senescence under oxidative stress. Melatonin (MT), a powerful free radical scavenger, can delay PDLSCs senescence but may not maintain stemness under oxidative stress. This experiment examined the effects of hydrogen peroxide-induced oxidative stress on PDLSCs' apoptosis, senescence, and stemness.
AIM: To determine if MT can reverse the above effects along with the underlying molecular mechanisms involved.
METHODS: PDLSCs were isolated from human premolars and cultured in different conditions. Flow cytometry was used to characterize the cell surface markers of PDLSCs. Hydrogen peroxide was used to induce oxidative stress in PDLSCs. Cell cycle, proliferation, apoptosis, differentiation, ROS, and senescence-associated β-galactosidase activity were assessed by various assays. Reverse transcription-polymerase chain reaction and western blot were used to measure the expression of genes and proteins related to stemness and senescence.
RESULTS: MT increases Yes-associated protein expression and maintains cell stemness in an induced inflammatory microenvironment, which may explain its therapeutic effects. We examined how MT affects PDLSCs aging and stemness and its biological mechanisms.
CONCLUSION: Our study reveals MT's role in regulating oxidative stress in PDLSCs and Yes-associated protein-mediated activity, providing insights into cellular functions and new therapeutic targets for tissue regeneration.

Keywords:  Human periodontal ligament stem cells; Melatonin; Reactive oxygen species; Senescence; Yes-associated protein

DOI:  https://doi.org/10.4252/wjsc.v16.i11.926
Nat Commun. 2024 Dec 03. 15(1): 10532

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability.

Chiara Masnovo, Zohar Paleiov, Daniel Dovrat, Laurel K Baxter, Sofia Movafaghi, Amir Aharoni, Sergei M Mirkin.

Trinucleotide repeats, including Friedreich's ataxia (GAA)n repeats, become pathogenic upon expansions during DNA replication and repair. Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. Supporting this conclusion, live-cell microscopy experiments reveal increased replication fork stalling at the repeat in mcm10-1 cells. Unexpectedly, the viability of strains containing a single (GAA)100 repeat at an essential chromosomal location strongly depends on Mcm10 function and cellular RPA levels. This coincides with Rad9 checkpoint activation, which promotes cell viability, but initiates repeat expansions via DNA synthesis by polymerase δ. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

DOI: https://doi.org/10.1038/s41467-024-54977-6
Mech Ageing Dev. 2024 Nov 30. pii: S0047-6374(24)00107-6. [Epub ahead of print] 112007

Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids.

Mariangela Scalise, Eleonora Cianflone, Claudia Quercia, Loredana Pagano, Antonio Chiefalo, Antonio Stincelli, Annalaura Torella, Barbara Puccio, Gianluca Santamaria, Hiram P Guzzi, Pierangelo Veltri, Antonella De Angelis, Konrad Urbanek, Georgina M Ellison-Hughes, Daniele Torella, Fabiola Marino.

BACKGROUND: Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying cellular and molecular features of aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies but their potential to reverse aging-related human cardiomyopathy remains largely unexplored.
METHODS: We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context. hCardioids were treated with DOXO and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q).
RESULTS: DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16INK4A) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function. Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit.
CONCLUSIONS: Doxorubicin triggers an age-associated phenotype in hCardioids reliably modelling the main cellular and molecular features of aging cardiomyopathy. Senescence is a key mechanism of the aged-hCOs phenotype as senolytics rejuvenated aged-hCardioids restoring their structure and function while reverting the age-associated regenerative deficit.

DOI: https://doi.org/10.1016/j.mad.2024.112007
Front Aging. 2024 ;5 1494095

Metabolic signatures of combined exercise and fasting: an expanded perspective on previous telomere length findings.

Shamma Almuraikhy, Khaled Naja, Najeha Anwardeen, Maha Sellami, Hadaia Saleh Al-Amri, Haya Al-Sulaiti, Sara S Bashraheel, Amina Ali Aden, Mohamed A Elrayess.

   Introduction: Aging is a complex process marked by a gradual decline in physiological function and increased susceptibility to diseases. Telomere length is frequently regarded as one of the primary biomarkers of aging. Metabolic profiles are key features in longevity and have been associated with both age and age-related diseases. We previously reported an increase in the telomere length in healthy female subjects when Ramadan fasting was combined with physical training. This study aims to characterize the metabolic signature differentiating the combined effects of exercise and fasting from exercise alone and explore the correlations with the previously reported telomere length changes.
Methods: Twenty-nine young, non-obese, and healthy female subjects were previously randomized into two groups: one group followed a 4-week exercise program, while the other group followed the same 4-week exercise program but also fasted during Ramadan. Metabolic profiles were assessed pre- and post-intervention using untargeted metabolomics.
Results and Discussion: Our results showed a significant decrease in many lipid metabolites in the exercise-while-fasting group, particularly ceramides. Our study sheds light on the dynamic changes in lipid metabolism and its potential role in inflammation and age-related diseases, and contributes to the broader understanding of how lifestyle factors can influence cellular aging and metabolic health.

Keywords:  aging; exercise; fasting; metabolomics; telomere length

DOI:  https://doi.org/10.3389/fragi.2024.1494095
Iran J Vet Res. 2024 ;25(2): 107-116

The effects of advanced age on electrocardiographic parameters, lipid profile and redox balance in male rats: role of long-term cinnamon consumption.

M Salari, S Nakhaee, Z Ataie, K Farrokhfall.

   Background: Oxidative stress damages biological molecules and plays a role in aging-related cardiovascular diseases. Cinnamomum zeylanicum is a major source of antioxidants that may work against age-related cardiovascular changes.
Aims: This study aimed to assess the changes in electrocardiography and lipid profile as well as indicators of the oxidant-antioxidant system with advanced age in rats. Also, the possible beneficial effect of cinnamon on these parameters has been investigated.
Methods: In this experimental study, thirty male Sprague-Dawley rats were randomly assigned to five groups. The control groups of 12, and 20 months received a normal chow diet, while the investigation group was given a control diet mixed with cinnamon powder (1% of the diet). Also, a control group of 3-month-old rats was considered for assessment of age effects. Systolic blood pressure (SBP), ECG, serum lipid profiles, and heart oxidative stress markers were compared in different groups at the end of the study.
Results: Systolic BP, serum cholesterol, HDL and LDL-cholesterol, the heart level of malondialdehyde (MDA) and nitric oxide metabolites (NOx), the ECG parameters including QRS duration, PR, Tpeak-Tend, and QT interval, as well as QTc increased significantly in older rats (20 months vs 3 months). Cinnamon consumption restored MDA levels, QRS duration, and Tpeak-Tend interval in aging hearts. Whereas, neither aging nor cinnamon consumption could affect SOD activity.
Conclusion: The results demonstrated that aging is associated with ECG alteration, oxidative stress, and an increase in TC, LDL, and HDL cholesterol. Cinnamon improved electrical heart activity in aged rats (20 months) by restoration of QRS duration and Tpeak-Tend interval as well as amelioration of heart oxidative stress. Altogether, cinnamon supplementation has a cardioprotective effects during aging in rats.

Keywords:  Aging; Cinnamomum zeylanicum; Electrocardiography; Heart; Oxidative stress

DOI:  https://doi.org/10.22099/IJVR.2024.47879.6948