bims-senagi 2022-09-18 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–09–18
25 papers selected by
Maria Grazia Vizioli, Mayo Clinic

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.
STING mediates nuclear PD-L1 targeting-induced senescence in cancer cells.
Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna.
Inorganic arsenic exposure-induced premature senescence and senescence-associated secretory phenotype (SASP) in human hepatic stellate cells.
Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection.
Long term high glucose exposure induces premature senescence in retinal endothelial cells.
FBXW7 inactivation induces cellular senescence via accumulation of p53.
Interplay between aging and other factors of the pathogenesis of age-related macular degeneration.
Editorial: Insights in aging and the immune system: 2021.
Can 3D bioprinting solve the mystery of senescence in cancer therapy?
Senolytics in the treatment of diabetic retinopathy.
Aging and cancer epigenetics: Where do the paths fork?
The interaction between cellular senescence and chronic kidney disease as a therapeutic opportunity.
The emergent role of mitochondrial surveillance in cellular health.
A cellular senescence-centric integrated approach to understanding organismal aging.
Drugs, clocks and exercise in aging: hype and hope, facts and fiction.
Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.
Exogenous hydrogen sulfide inhibits the senescence of cardiomyocytes through modulating mitophagy in rats.
Molecular inhibition of RAS signalling to target ageing and age-related health.
Keep calm and transcribe on: chromatin changes with age, but transcription can learn to live with it.
Molecular explanation of Wnt/βcatenin antagonist pyrvinium mediated calcium equilibrium changes in aging cardiovascular disorders.
Myeloid cell-specific mutation of Spi1 selectively reduces M2-biased macrophage numbers in skeletal muscle, reduces age-related muscle fibrosis and prevents sarcopenia.
Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses.
Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging.
2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside improves female ovarian aging.

Nat Cell Biol. 2022 Sep 15.

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.

Alessio Lanna, Bruno Vaz, Clara D'Ambra, Salvatore Valvo, Claudia Vuotto, Valerio Chiurchiù, Oliver Devine, Massimo Sanchez, Giovanna Borsellino, Arne N Akbar, Marco De Bardi, Derek W Gilroy, Michael L Dustin, Brendan Blumer, Michael Karin.

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.

DOI: https://doi.org/10.1038/s41556-022-00991-z
Cell Death Dis. 2022 Sep 15. 13(9): 791

STING mediates nuclear PD-L1 targeting-induced senescence in cancer cells.

Je-Jung Lee, So Young Kim, Songhee H Kim, Seoyeon Choi, Bin Lee, Jeon-Soo Shin.

Immune checkpoint molecule programmed death-ligand 1 (PD-L1) is overexpressed in cancer cells and imparts resistance to cancer therapy. Although membrane PD-L1 has been targeted for cancer immune therapy, nuclear PD-L1 was reported to confer cancer resistance. Therefore, it is important to regulate the nuclear PD-L1. The mechanisms underlying the therapeutic efficacy of PD-L1 targeting have not been well-established. Cellular senescence has been considered a pivotal mechanism to prevent cancer progression, and recently, PD-L1 inhibition was shown to be involved in cancer cell senescence. However, the relevance of PD-L1 targeting-induced senescence and the role of stimulator of interferon genes (STING) has not been reported. Therefore, we aimed to identify the role of PD-L1 in cancer progression and how it regulates cancer prevention. In this study, we found that PD-L1 depletion-induced senescence via strong induction of STING expression in mouse melanoma B16-F10 and colon cancer CT26 cells, and in human melanoma A375 and lung cancer A549 cells. Interestingly, nuclear PD-L1 silencing increased STING promoter activity, implying that PD-L1 negatively regulates STING expression via transcriptional modulation. Furthermore, we showed that PD-L1 binds to the STING promoter region, indicating that PD-L1 directly controls STING expression to promote cancer growth. In addition, when we combined PD-L1 silencing with the senescence-inducing chemotherapeutic agent doxorubicin, the effect of PD-L1-targeting was even more powerful. Overall, our findings can contribute to the understanding of the role of PD-L1 in cancer therapy by elucidating a novel mechanism for PD-L1 targeting in cancer cells.

DOI: https://doi.org/10.1038/s41419-022-05217-6
Sci Adv. 2022 Sep 16. 8(37): eabo5482

Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna.

Anastasia V Shindyapina, Yongmin Cho, Alaattin Kaya, Alexander Tyshkovskiy, José P Castro, Amy Deik, Juozas Gordevicius, Jesse R Poganik, Clary B Clish, Steve Horvath, Leonid Peshkin, Vadim N Gladyshev.

Development is tightly connected to aging, but whether pharmacologically targeting development can extend life remains unknown. Here, we subjected genetically diverse UMHET3 mice to rapamycin for the first 45 days of life. The mice grew slower and remained smaller than controls for their entire lives. Their reproductive age was delayed without affecting offspring numbers. The treatment was sufficient to extend the median life span by 10%, with the strongest effect in males, and helped to preserve health as measured by frailty index scores, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome and epigenome of treated mice were younger at the completion of treatment. Analogous to mice, rapamycin exposure during development robustly extended the life span of Daphnia magna and reduced its body size. Overall, the results demonstrate that short-term rapamycin treatment during development is a novel longevity intervention that acts by slowing down development and aging, suggesting that aging may be targeted already early in life.

DOI: https://doi.org/10.1126/sciadv.abo5482
Toxicol Appl Pharmacol. 2022 Sep 09. pii: S0041-008X(22)00376-3. [Epub ahead of print]454 116231

Inorganic arsenic exposure-induced premature senescence and senescence-associated secretory phenotype (SASP) in human hepatic stellate cells.

Kazuyuki Okamura, Miyuki Sato, Takehiro Suzuki, Keiko Nohara.

  Exposure to inorganic arsenic has been known to induce cancers in various organs, however, the underlying mechanisms remain unclear. Premature senescence refers to the irreversible growth arrest induced by stress stimuli. The senescence-associated secretory phenotype (SASP), particularly in fibroblasts, has been shown to promote cancer development. In this study, we examined whether arsenite exposure causes premature senescence and induction of SASP in liver fibroblasts using the human hepatic stellate cell line, LX-2. Exposure of LX-2 cells to 5 or 7.5 μM of sodium arsenite for 144 h induced the features of senescence in the cells, including morphological changes, growth inhibition, increased senescence-associated β-galactosidase activity, increased P21 gene expression, and decreased LAMINB1 gene expression. The mRNA expressions of SASP factors, such as MMP1, MMP3, IL-8, IL-1β, and CXCL1, were also highly upregulated. The wound healing assay revealed that the conditioned medium from LX-2 cells with arsenite-induced senescence increased the migration activity of cells of the human hepatoma cell line, Huh-7. Gene expression data of liver cancer samples from the Human Protein Atlas showed that high expression levels of the SASP factors that were upregulated in the cells with arsenite-induced senescence were strongly associated with a poor prognosis. In addition, the cellular levels of γ-H2AX, a DNA double-strand break marker, were increased by arsenite exposure, suggesting that DNA damage could contribute to premature senescence induction. These results show that arsenite exposure induces premature senescence in hepatic stellate cells and suggest that the SASP factors from the senescent cells promote hepatic carcinogenesis.

Keywords:  Arsenic; Cancer; Hepatic stellate cell (HSC); Liver; Senescence; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1016/j.taap.2022.116231
Pharmaceut Med. 2022 Sep 13.

Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection.

Kingsley C Mbara, Nikita Devnarain, Peter M O Owira.

Cellular senescence, a hallmark of ageing, contributes to tissue or organ dysfunction and the pathophysiology of diverse age-related diseases (ARD) by various mechanisms. Targeting it by selective elimination of senescent cells (SCs) or blocking senescence-associated secretory phenotypes (SASP) with natural or synthetic compounds has been suggested to improve lifespan. Dietary phytochemicals possess a broad spectrum of biochemical and pharmacological effects that are beneficial to human health. Flavonoids, which are widely consumed in fruits and vegetables worldwide, are emerging as potential therapeutic agents to mitigate senescence. Naringenin, hesperetin, hesperidin, quercetin, fisetin, kaempferol, rutin, apigenin, luteolin, nobiletin, tangeretin, genistein, wogonin, epigallocatechin gallate (EGCG), theaflavin-3-gallate (TF2A), and procyanidin C1 possess potent antisenescence effects. A single biochemical process may not explain their pleiotropic pharmacological impact. Flavonoids directly modulate underlying cellular senescence processes or interact with molecular targets that regulate ageing-related pathways. This review discusses the potential use of flavonoids to mitigate senescence and consequently delay the onset of ageing-related diseases. We also highlight the underlying mechanisms of action of flavonoids as potential senotherapeutics and reflect on future perspectives and possible strategies to optimize and increase the translatability from bench to bedside in senotherapy.

DOI: https://doi.org/10.1007/s40290-022-00444-w
Front Physiol. 2022 ;13 929118

Long term high glucose exposure induces premature senescence in retinal endothelial cells.

Pietro Maria Bertelli, Edoardo Pedrini, David Hughes, Shannon McDonnell, Varun Pathak, Elisa Peixoto, Jasenka Guduric-Fuchs, Alan W Stitt, Reinhold J Medina.

  Purpose: Features of cellular senescence have been described in diabetic retinal vasculature. The aim of this study was to investigate how the high glucose microenvironment impacts on the senescence program of retinal endothelial cells. Methods: Human retinal microvascular endothelial cells were cultured under control and high glucose conditions of 5 mM and 25 mM D-glucose, respectively. Isomeric l-glucose was used as the osmotic control. Cells were counted using CASY technology until they reached their Hayflick limit. Senescence-associated β-Galactosidase was used to identify senescent cells. Endothelial cell functionality was evaluated by the clonogenic, 3D tube formation, and barrier formation assays. Cell metabolism was characterized using the Seahorse Bioanalyzer. Gene expression analysis was performed by bulk RNA sequencing. Retinal tissues from db/db and db/+ mice were evaluated for the presence of senescent cells. Publicly available scRNA-sequencing data for retinas from Akimba and control mice was used for gene set enrichment analysis. Results: Long term exposure to 25 mM D-Glucose accelerated the establishment of cellular senescence in human retinal endothelial cells when compared to 5 mM D-glucose and osmotic controls. This was shown from 4 weeks, by a significant slower growth, higher percentages of cells positive for senescence-associated β-galactosidase, an increase in cell size, and lower expression of pRb and HMGB2. These senescence features were associated with decreased clonogenic capacity, diminished tubulogenicity, and impaired barrier function. Long term high glucose-cultured cells exhibited diminished glycolysis, with lower protein expression of GLUT1, GLUT3, and PFKFB3. Transcriptomic analysis, after 4 weeks of culture, identified downregulation of ALDOC, PFKL, and TPI1, in cells cultured with 25 mM D-glucose when compared to controls. The retina from db/db mice showed a significant increase in acellular capillaries associated with a significant decrease in vascular density in the intermediate and deep retinal plexuses, when compared to db/+ mice. Senescent endothelial cells within the db/db retinal vasculature were identified by senescence-associated β-galactosidase staining. Analysis of single cell transcriptomics data for the Akimba mouse retina highlighted an enrichment of senescence and senescence-associated secretory phenotype gene signatures when compared to control mice. Conclusion: A diabetic-like microenvironment of 25 mM D-glucose was sufficient to accelerate the establishment of cellular senescence in human retinal microvascular endothelial cells.

Keywords:  diabetic retina; diabetic retina complications; endothelial cell; retinal microvasculature; senescence; senescence-associated secretory phenotype; vascular biology

DOI:  https://doi.org/10.3389/fphys.2022.929118
Cell Death Dis. 2022 Sep 14. 13(9): 788

FBXW7 inactivation induces cellular senescence via accumulation of p53.

Longyuan Gong, Danrui Cui, Dian Liu, Xiao Shen, Hui Pan, Xiufang Xiong, Yongchao Zhao.

F-box and WD repeat domain containing 7 (FBXW7) acts as a substrate receptor of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and plays crucial roles in the regulation of several cellular processes, including cell growth, division, and differentiation, by targeting diverse key regulators for degradation. However, its role in regulating cellular senescence remains elusive. Here, we found that FBXW7 inactivation by siRNA-based knockdown or CRISPR/Cas9-based knockout induced significant cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells, along with activation of both the p53/p21 and p16INK4a/Rb pathways. Simultaneous p53 inactivation abrogated senescence and cell growth arrest induced by FBXW7 deficiency as well as the alteration of both the p53/p21 and p16INK4a/Rb pathways. Moreover, Fbxw7 deletion accelerated replicative senescence of primary mouse embryonic fibroblasts in a p53-dependent manner. In addition, FBXW7 deletion induced the senescence-associated secretory phenotype to trigger secondary senescence. Importantly, in a radiation-induced senescence mouse model, simultaneous deletion of p53 rescued accelerated senescence and aging caused by Fbxw7 loss. Thus, our study uncovered a novel role for FBXW7 in the regulation of senescence by eliminating p53.

DOI: https://doi.org/10.1038/s41419-022-05229-2
Ageing Res Rev. 2022 Sep 13. pii: S1568-1637(22)00177-5. [Epub ahead of print] 101735

Interplay between aging and other factors of the pathogenesis of age-related macular degeneration.

Janusz Blasiak, Piotr Sobczuk, Elzbieta Pawlowska, Kai Kaarniranta.

  Age-related macular degeneration is a complex eye disease with the retina as the target tissue and aging as per definition the most serious risk factor. However, the retina contains over 60 kinds of cells that form different structures, including the neuroretina and retinal pigment epithelium (RPE) which can age at different rates. Other established or putative AMD risk factors can differentially affect the neuroretina and RPE and can differently interplay with aging of these structures. The occurrence of β-amyloid plaques and increased levels of cholesterol in AMD retinas suggest that AMD may be a syndrome of accelerated brain aging. Therefore, the question about the real meaning of age in AMD is justified. In this review we present and update information on how aging may interplay with some aspects of AMD pathogenesis, such as oxidative stress, amyloid beta formation, circadian rhythm, metabolic aging and cellular senescence. Also, we show how this interplay can be specific for photoreceptors, microglia cells and REP cells as well as in Bruch's membrane and the choroid. Therefore, the process of aging may differentially affect different retinal structures. As an accurate quantiﬁcation of biological aging is important for risk stratiﬁcation and early intervention for age-related diseases, the determination how photoreceptors, microglial and RPE cells age in AMD may be helpful for a precise diagnosis and treatment of this largely untreatable disease.

Keywords:  Age-related macular degeneration; biological aging; cellular senescence; chronological aging; circadian rhythm; metabolic aging; microglia; neural retina; retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.arr.2022.101735
Front Aging. 2022 ;3 999299

Editorial: Insights in aging and the immune system: 2021.

Laura Haynes, Leena P Bharath.



Keywords:  T cells; aging; autoimmune disease; inflammation; senescence

DOI:  https://doi.org/10.3389/fragi.2022.999299
Ageing Res Rev. 2022 Sep 12. pii: S1568-1637(22)00174-X. [Epub ahead of print]81 101732

Can 3D bioprinting solve the mystery of senescence in cancer therapy?

Sofian Al Shboul, Valerie J DeLuca, Yazan Al Dweiri, Tareq Saleh.

  Tumor dormancy leading to cancer relapse is still a poorly understood mechanism. Several cell states such as quiescence and diapause can explain the persistence of tumor cells in a dormant state, but the potential role of tumor cell senescence has been met with hesitance given the historical understanding of the senescent growth arrest as irreversible. However, recent evidence has suggested that senescence might contribute to dormancy and relapse, although its exact role is not fully developed. This limited understanding is largely due to the paucity of reliable study models. The current 2D cell modeling is overly simplistic and lacks the appropriate representation of the interactions between tumor cells (senescent or non-senescent) and the other cell types within the tumor microenvironment (TME), as well as with the extracellular matrix (ECM). 3D cell culture models, including 3D bioprinting techniques, offer a promising approach to better recapitulate the native cancer microenvironment and would significantly improve our understanding of cancer biology and cellular response to treatment, particularly Therapy-Induced Senescence (TIS), and its contribution to tumor dormancy and cancer recurrence. Fabricating a novel 3D bioprinted model offers excellent opportunities to investigate both the role of TIS in tumor dormancy and the utility of senolytics (drugs that selectively eliminate senescent cells) in targeting dormant cancer cells and mitigating the risk for resurgence. In this review, we discuss literature on the possible contribution of TIS in tumor dormancy, provide examples on the current 3D models of senescence, and propose a novel 3D model to investigate the ultimate role of TIS in mediating overall response to therapy.

Keywords:  3D bioprinting; Dormancy; Recurrence; Senescence; Senolytic; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.arr.2022.101732
Front Pharmacol. 2022 ;13 896907

Senolytics in the treatment of diabetic retinopathy.

Jannah Waled Hassan, Ashay D Bhatwadekar.

  Diabetic retinopathy (DR) is the most common complication of diabetes. DR is characterized by damage to retinal vasculature resulting in vision impairment and, if untreated, could eventually lead to blindness. The pathogenic mechanism of DR is complex; emerging studies suggest that premature senescence of retinal cells and subsequent secretion of inflammatory cytokines exacerbate DR disease state by stimulating paracrine senescence, pathological angiogenesis, and reparative vascular regeneration. Senolytics are a new class of drugs that can selectively clear out senescent cells from the retina, thus holding a significant promise in DR treatment and prevention. In this review, we discuss the critical role of cellular senescence in DR's pathogenesis; A literature review was conducted in September of 2021 to explore the therapeutic potential of senolytics in the treatment of DR. Studies that were relevant to the research topic were selected through multiple keyword searches in the search engine, PubMed and thoroughly reviewed using abstracts and full-text articles. We present evidence from animal models for studying cellular senescence in DR and discuss multiple pathogenic mechanisms in cellular senescence and its involvement in DR. We also discuss the current state of pharmaceutical development at preclinical and clinical stages focusing on the senolytic drugs navitoclax, 17-DMAG, piperlongumine, UBX-1325, dasatinib quercetin, and fisetin. In particular, UBX-1325 holds a promising prospect for DR treatment based on the positive outcome of early clinical studies in individuals with diabetic macular edema (DME) and wet age-related macular degeneration.

Keywords:  diabetes; diabetic retinopathy; inflammation; pharmacological agents; senolytics

DOI:  https://doi.org/10.3389/fphar.2022.896907
Aging Cell. 2022 Sep 14. e13709

Aging and cancer epigenetics: Where do the paths fork?

Raúl Fernández Pérez, Juan Ramón Tejedor, Agustín Fernández Fernández, Mario Fernández Fraga.

  Aging and cancer are clearly associated processes, at both the epidemiological and molecular level. Epigenetic mechanisms are good candidates to explain the molecular links between the two phenomena, but recent reports have also revealed considerable differences, particularly regarding the loss of DNA methylation in the two processes. The large-scale generation and availability of genome-wide epigenetic data now permits systematic studies to be undertaken which may help clarify the similarities and differences between aging and cancer epigenetic alterations. In addition, the development of epigenetic clocks provides a new dimension in which to investigate diseases at the molecular level. Here, we examine current and future questions about the roles of DNA methylation mechanisms as causal factors in the processes of aging and cancer so that we may better understand if and how aging-associated epigenetic alterations lead to tumorigenesis. It seems certain that comprehending the molecular mechanisms underlying epigenetic clocks, especially with regard to somatic stem cell aging, combined with applying single-cell epigenetic-age profiling technologies to aging and cancer cohorts, and the integration of existing and upcoming epigenetic evidence within the genetic damage models of aging will prove to be crucial to improving understanding of these two interrelated phenomena.

Keywords:  DNA methylation; aging; cancer; epigenetic clock; stem cells

DOI:  https://doi.org/10.1111/acel.13709
Front Pharmacol. 2022 ;13 974361

The interaction between cellular senescence and chronic kidney disease as a therapeutic opportunity.

Jing-Li Zhao, Xiao-Hui Qiao, Jian-Hua Mao, Fei Liu, Hai-Dong Fu.

  Chronic kidney disease (CKD) is an increasingly serious public health problem in the world, but the effective therapeutic approach is quite limited at present. Cellular senescence is characterized by the irreversible cell cycle arrest, senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Renal senescence shares many similarities with CKD, including etiology, mechanism, pathological change, phenotype and outcome, however, it is difficult to judge whether renal senescence is a trigger or a consequence of CKD, since there is a complex correlation between them. A variety of cellular signaling mechanisms are involved in their interactive association, which provides new potential targets for the intervention of CKD, and then extends the researches on senotherapy. Our review summarizes the common features of renal senescence and CKD, the interaction between them, the strategies of senotherapy, and the open questions for future research.

Keywords:  cellular senescence; chronic kidney disease; interaction; mechanism; therapy

DOI:  https://doi.org/10.3389/fphar.2022.974361
Aging Cell. 2022 Sep 11. e13710

The emergent role of mitochondrial surveillance in cellular health.

Elissa Tjahjono, Daniel R Kirienko, Natalia V Kirienko.

  Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.

Keywords:  aging; mitochondria; mitochondrial membrane transport proteins; mitophagy; physiological stress; reactive oxygen species; surveillance

DOI:  https://doi.org/10.1111/acel.13710
Curr Aging Sci. 2022 Sep 14.

A cellular senescence-centric integrated approach to understanding organismal aging.

Rohit Sharma, Bhawna Diwan.

  Aging remains the fundamental cause of the increased rate of morbidity and mortality in the elderly. Despite continuing research, an integrative and holistic understanding of the molecular mechanisms and effects of aging is still elusive. This presents a major challenge in biogerontology, and therefore novel strategies aimed at integrating the multifaceted nature of aging for the identification and development of successful therapeutic targets are highly desirable. At present, cellular senescence, immunosenescence, and gut microbiota dysbiosis are key known modulators of aging. However, a cellular senescence-centric integrative view that relates to the seemingly distinct processes of immunosenescence and gut microbiota dysbiosis can be envisaged which implies a more inclusive and targetable understanding of aging. The present manuscript discusses the emerging evidence and significance of cellular senescence vis-à-vis immunosenescence and gut microbiota dysbiosis in the development of potential anti-aging therapies. Underlying interconnections and mechanisms amongst these individual modulators have been deliberated to present a more coherent and tangible understanding of biological aging. It is emphasized that aging be studied within the integrative purview of these processes that may ultimately help devise a new inclusive and consolidated theory of aging with well-defined therapeutic targets.

Keywords:  Aging; Cellular senescence; Gut microbiota dysbiosis; Immunity; Immunosenescence; Longevity; Microbiome; Nutrition

DOI:  https://doi.org/10.2174/1874609815666220914104548
J Physiol. 2022 Sep 16.

Drugs, clocks and exercise in aging: hype and hope, facts and fiction.

Regula Furrer, Christoph Handschin.

  Aging is a biological process that is linked to a functional decline, ultimately resulting in death. Large interindividual differences exist in terms of life- and healthspan, representing life expectancy and the number of years spent in the absence of major diseases, respectively. The genetic and molecular mechanisms that are involved in the regulation of the aging process, and those that render age the main risk factor for many diseases are still poorly understood. Nevertheless, a growing number of compounds have been put forward to affect this process. However, for scientists and laypeople alike, it is difficult to separate facts from fiction, and hype from hope. In this review, we discuss the currently pursued pharmacological anti-aging approaches. These are compared to non-pharmacological interventions, some of which confer powerful effects on health and well-being, in particular an active lifestyle and exercise. Moreover, functional parameters and biological clocks as well as other molecular marks are compared in terms of predictive power of morbidity and mortality. Then, conceptual aspects and roadblocks in the development of anti-aging drugs are outlined. Finally, an overview on current and future strategies to mitigate age-related pathologies and the extension of life- and healthspan is provided. Abstract figure legend Modulation of the human aging process. Aging leads to a functional decline with increased frailty and morbidity, ultimately resulting in death. This process is affected by the genetic setup, epigenetic predisposition, and random events, leading to large interindividual differences in regard to health, well-being and life expectancy. Exercise, diet and other lifestyle-based interventions as well as societal measures can help to maximize the chance for healthy aging. Proposed drugs, cellular, epigenetic, and other non-pharmacological approaches such as caloric restriction await validation for safe and efficacious application in human geroprotection. This article is protected by copyright. All rights reserved.

Keywords:  aging; exercise; healthspan; lifespan; longevity; rapamycin; rejuvenation; reprogramming; senolytics

DOI:  https://doi.org/10.1113/JP282887
Aging Cell. 2022 Sep 11. e13708

Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.

Luis R Cassinotti, Lingchao Ji, Beatriz C Borges, Nathan D Cass, Aditi S Desai, David C Kohrman, M Charles Liberman, Gabriel Corfas.

  Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age-related IHC synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials compared with age-matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with larger sound-evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age-matched controls. Our results also provide evidence that an age-related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age-related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.

Keywords:  age-related hearing loss; auditory nerve; hidden hearing loss; neurotrophins; synapse regeneration

DOI:  https://doi.org/10.1111/acel.13708
Cell Signal. 2022 Sep 07. pii: S0898-6568(22)00227-3. [Epub ahead of print]100 110465

Exogenous hydrogen sulfide inhibits the senescence of cardiomyocytes through modulating mitophagy in rats.

Jinghui Hao, Yuxin Xi, Lijie Jiao, Xin Wen, Ren Wu, Guiquan Chang, Fengqi Sun, Can Wei, Hongzhu Li.

  Hydrogen sulfide (H2S), a gaseous molecule, has been shown to be involved in the regulation of body pathophysiological processes. Aging is related to structural and functional alterations within the heart. There is evidence that diminished mitophagy accelerates the aging process. Studies in recent years have revealed that plasma levels of H2S in humans and old rats decrease with age, and H2S acts as a cytoprotective mediator in the aging process. However, it is unclear whether H2S can delay the senescence of cardiomyocytes by regulating mitophagy. Our present results showed that exogenous H2S inhibited mitochondrial damage, oxidative stress and cell apoptosis, and enhanced mitophagy through upregulating the SIRT1-PINK1-parkin pathway in myocardial tissues of aged rats and cultured aged cardiomyocytes. Furthermore, the effect of exogenous H2S on the above indicators was the same as that of SRT1720 (a SIRT1 agonist) and kinetin (a PINK1 activator). Our findings suggest that exogenous H2S inhibits the senescence of cardiomyocytes by increasing mitophagy via upregulation of the SIRT1-PINK1-parkin pathway in rats.

Keywords:  Cardiomyocytes; Hydrogen sulfide; Mitophagy; Rats; Senescence

DOI:  https://doi.org/10.1016/j.cellsig.2022.110465
Dis Model Mech. 2022 Oct 01. pii: dmm049627. [Epub ahead of print]15(10):

Molecular inhibition of RAS signalling to target ageing and age-related health.

Mihails Laskovs, Linda Partridge, Cathy Slack.

  The RAS/MAPK pathway is a highly conserved signalling pathway with a well-established role in cancer. Mutations that hyperactivate this pathway are associated with unregulated cell proliferation. Evidence from a range of model organisms also links RAS/MAPK signalling to ageing. Genetic approaches that reduce RAS/MAPK signalling activity extend lifespan and also improve healthspan, delaying the onset and/or progression of age-related functional decline. Given its role in cancer, therapeutic interventions that target and inhibit this pathway's key components are under intense investigation. The consequent availability of small molecule inhibitors raises the possibility of repurposing these compounds to ameliorate the deleterious effects of ageing. Here, we review evidence that RAS/MAPK signalling inhibitors already in clinical use, such as trametinib, acarbose, statins, metformin and dihydromyricetin, lead to lifespan extension and to improved healthspan in a range of model systems. These findings suggest that the repurposing of small molecule inhibitors of RAS/MAPK signalling might offer opportunities to improve health during ageing, and to delay or prevent the development of age-related disease. However, challenges to this approach, including poor tolerance to treatment in older adults or development of drug resistance, first need to be resolved before successful clinical implementation.

Keywords:  Ageing; MEK inhibitor; RAS pathway

DOI:  https://doi.org/10.1242/dmm.049627
Mol Syst Biol. 2022 Sep;18(9): e11276

Keep calm and transcribe on: chromatin changes with age, but transcription can learn to live with it.

Cian J Lynch, Manuel Serrano.

Assessing age-related tissue dysfunction represents an emerging field and involves analyses that are far from trivial, often requiring the integration of several large-scale ("omic") techniques. In their recent work, Tessarz and colleagues (Bozukova et al, 2022) characterize changes in the transcriptional machinery during aging in mice and report some surprising findings.

DOI: https://doi.org/10.15252/msb.202211276
Mol Biol Rep. 2022 Sep 15.

Molecular explanation of Wnt/βcatenin antagonist pyrvinium mediated calcium equilibrium changes in aging cardiovascular disorders.

Khalid Saad Alharbi, Yogendra Singh, Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Imran Kazmi, Fahad A Al-Abbasi, Sami I Alzarea, Dinesh Kumar Chellappan, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta.

  The symptoms of ageing are somewhat different and can lead to the altered role of the cardiovascular system at the levels of genetic, biochemical, tissue, organ, and systems. Ageing is an autonomous cardiovascular risk factor. In the ageing rat heart, oxidative and inflammatory stress, immune cell infiltration, increasing myeloperoxidase function, elevated caspase-3 activity, and protein fibronectins were detected and associated with ageing and cardiovascular disease. The intracellular Ca2 + homeostasis disturbed in an older heart dramatically increases cardiomyopathy, atherosclerosis, stroke, ischemia, myocardial infarction, hypertrophy, remodelling, and hypertension. Evidence shows that suppression of Wnt/β signals prevents cardiovascular dysfunction, such as remodelling, high blood pressure, and excessive overload stress. However, one study has shown that the pharmacological disruption of Wnt-β-catenin by decreasing expression of α-smooth muscle actin, fibronectin and collagen I proteins attenuates angiotensin II mediated hypertension cardiac fibrosis. Thus, this review examined the impacts of calcium overload and age-related diseases, including cardiovascular. Energy dysregulation, calcium overloading, and mitochondrial dysfunction are the main activities causing cardiovascular disease linked with age. Therefore, the current study explores that age-associated cardiovascular disease has triggered the WNT/β-catenin pathway, and pharmacological inhibition can delay pathological changes by attenuating calcium dyshomeostasis.

Keywords:  Aging; Calcium; Cardiovascular disease; WNT/β-catenin

DOI:  https://doi.org/10.1007/s11033-022-07863-7
Aging Cell. 2022 Sep 13. e13690

Myeloid cell-specific mutation of Spi1 selectively reduces M2-biased macrophage numbers in skeletal muscle, reduces age-related muscle fibrosis and prevents sarcopenia.

Ying Wang, Steven S Welc, Michelle Wehling-Henricks, Ying Kong, Connor Thomas, Enca Montecino-Rodriguez, Kenneth Dorshkind, James G Tidball.

  Intramuscular macrophages play key regulatory roles in determining the response of skeletal muscle to injury and disease. Recent investigations showed that the numbers and phenotype of intramuscular macrophages change during aging, suggesting that those changes could influence the aging process. We tested that hypothesis by generating a mouse model that harbors a myeloid cell-specific mutation of Spi1, which is a transcription factor that is essential for myeloid cell development. The mutation reduced the numbers of macrophages biased to the CD163+/CD206+ M2 phenotype in muscles of aging mice without affecting the numbers of CD68-expressing macrophages and reduced the expression of transcripts associated with the M2-biased phenotype. The mutation did not affect the colony-forming ability or the frequency of specific subpopulations of bone marrow hematopoietic cells and did not affect myeloid/lymphoid cell ratios in peripheral blood leukocyte populations. Cellularity of most myeloid lineage cells was not influenced by the mutation. The Spi1 mutation in bone marrow-derived macrophages in vitro also did not affect expression of transcripts that indicate the M2-biased phenotype. Thus, myeloid cell-targeted mutation of Spi1 influences macrophage phenotype in muscle but did not affect earlier stages of differentiation of cells in the macrophage lineage. The mutation reduced age-related muscle fibrosis, which is consistent with the reduction of M2-biased macrophages, and reduced expression of the pro-fibrotic enzyme arginase. Most importantly, the mutation prevented sarcopenia. Together, our observations indicate that intramuscular, M2-biased macrophages play significant roles in promoting detrimental, age-related changes in muscle.

Keywords:  Sarcopenia; aging; macrophage; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13690
Aging Cell. 2022 Sep 15. e13665

Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses.

Edmund Charles Jenkins, Mrittika Chattopadhyay, Maria Gomez, Denis Torre, Avi Ma'ayan, Miguel Torres-Martin, Daniela Sia, Doris Germain.

  A major limitation in the use of mouse models in breast cancer research is that most mice develop estrogen receptor-alpha (ERα)-negative mammary tumors, while in humans, the majority of breast cancers are ERα-positive. Therefore, developing mouse models that best mimic the disease in humans is of fundamental need. Here, using an inducible MMTV-rtTA/TetO-NeuNT mouse model, we show that despite being driven by the same oncogene, mammary tumors in young mice are ERα-negative, while they are ERα-positive in aged mice. To further elucidate the mechanisms for this observation, we performed RNAseq analysis and identified genes that are uniquely expressed in aged female-derived mammary tumors. We found these genes to be involved in the activation of the ERα axis of the mitochondrial UPR and the ERα-mediated regulation of XBP-1s, a gene involved in the endoplasmic reticulum UPR. Collectively, our results indicate that aging alters the oncogenic trajectory towards the ERα-positive subtype of breast cancers, and that mammary tumors in aged mice are characterized by the upregulation of multiple UPR stress responses regulated by the ERα.

Keywords:  ER stress; XBP-1; aged mammary gland; aging; endoplasmic reticulum; estrogen receptor-alpha; mitochondrial UPR; unfolded protein response

DOI:  https://doi.org/10.1111/acel.13665
Life Sci Alliance. 2022 Dec;pii: e202201501. [Epub ahead of print]5(12):

Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging.

Jean Philippe Trani, Raphaël Chevalier, Leslie Caron, Claire El Yazidi, Natacha Broucqsault, Léa Toury, Morgane Thomas, Karima Annab, Bernard Binetruy, Annachiara De Sandre-Giovannoli, Nicolas Levy, Frédérique Magdinier, Jérôme D Robin.

Progeroid syndromes are rare genetic diseases with most of autosomal dominant transmission, the prevalence of which is less than 1/10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type lamins belong to a group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated aging of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. To identify pathways altered in progeroid patients' MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford progeria syndrome (HGPS, c.1824C>T-p.G608G), HGPS-like syndrome (HGPS-L; c.1868C>G-p.T623S) associated with farnesylated prelamin A accumulation, or atypical progeroid syndromes (APS; homozygous c.1583C> T-p.T528M; heterozygous c.1762T>C-p.C588R; compound heterozygous c.1583C>T and c.1619T>C-p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient's MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern; an increased response to double-strand DNA damage; and telomere erosion in HGPS, HGPS-L, and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared with APS cells.

DOI: https://doi.org/10.26508/lsa.202201501
Front Cell Dev Biol. 2022 ;10 862045

2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside improves female ovarian aging.

Hung-Yun Lin, Yung-Ning Yang, Yi-Fong Chen, Tung-Yung Huang, Dana R Crawford, Hui-Yu Chuang, Yu-Tang Chin, Hung-Ru Chu, Zi-Lin Li, Ya-Jung Shih, Yi-Ru Chen, Yu-Chen S H Yang, Yih Ho, Paul J Davis, Jacqueline Whang-Peng, Kuan Wang.

  Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-β expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-β expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.

Keywords:  Polygoni multiflori extract; THSG; aging; aging-induced infertility; fertility

DOI:  https://doi.org/10.3389/fcell.2022.862045