bims-senagi 2022-09-25 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022‒09‒25
28 papers selected by
Maria Grazia Vizioli
Mayo Clinic

Targeting cellular senescence in metabolic disease.
P16INK4A-More Than a Senescence Marker.
From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs.
Alteration of E2F2 Expression in Governing Endothelial Cell Senescence.
Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice.
Cellular senescence is a key mediator of lung aging and susceptibility to infection.
Circular RNAs Involved in the Regulation of the Age-Related Pathways.
Senescent Phenotype of Astrocytes Leads to Activation of BV2 Microglia and N2a Neuronal Cells Death.
Extracellular vesicle-associated microRNA-30b-5p activates macrophages through the SIRT1/ NF-κB pathway in cell senescence.
Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.
RNAa-mediated epigenetic attenuation of the cell senescence via locus specific induction of endogenous SIRT1.
Does senescence play a role in age-related macular degeneration?
Senotherapies: A novel strategy for synergistic anti-tumor therapy.
Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites.
Exaggerated hypoxic vascular breakdown in aged brain due to reduced microglial vasculo-protection.
2-month ketogenic diet preferentially alters skeletal muscle and augments cognitive function in middle aged female mice.
Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis.
The role of aging in cancer.
Telomeres to go.
Vascular senescence in progeria: role of endothelial dysfunction.
Senescent Fibroblasts Generate a CAF Phenotype through the Stat3 Pathway.
Alternate day fasting and time-restricted feeding may confer similar neuroprotective effects during aging in male rats.
Hexosamine pathway activation improves memory but does not extend lifespan in mice.
Novel pathophysiological roles of α-synuclein in age-related vascular endothelial dysfunction.
Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence.
Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors.
The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease.
Age-related metabolic and neurodegenerative changes in SAMP8 mice.

Mol Metab. 2022 Sep 16. pii: S2212-8778(22)00170-3. [Epub ahead of print] 101601

Targeting cellular senescence in metabolic disease.

Allyson K Palmer, Tamar Tchkonia, James L Kirkland.

  Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states.

Keywords:  Adipose; Aging; Cellular senescence; Obesity; Senolytics

DOI:  https://doi.org/10.1016/j.molmet.2022.101601
Life (Basel). 2022 Aug 28. pii: 1332. [Epub ahead of print]12(9):

P16INK4A-More Than a Senescence Marker.

Hasan Safwan-Zaiter, Nicole Wagner, Kay-Dietrich Wagner.

  Aging is a biological feature that is characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation of environmental factors and stresses with time. Several factors have been attributed to aging such as oxidative stress and augmented production or exposure to reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, the deposit of senescent cells. These are irreversibly mitotically inactive, yet metabolically active cells. The reason underlying their senescence lies within the extrinsic and the intrinsic arms. The extrinsic arm is mainly characterized by the expression and the secretory profile known as the senescence-associated secretory phenotype (SASP). The intrinsic arm results from the impact of several genes meant to regulate the cell cycle, such as tumor suppressor genes. P16INK4A is a tumor suppressor and cell cycle regulator that has been linked to aging and senescence. Extensive research has revealed that p16 expression is significantly increased in senescent cells, as well as during natural aging or age-related pathologies. Based on this fact, p16 is considered as a specific biomarker for detecting senescent cells and aging. Other studies have found that p16 is not only a senescence marker, but also a protein with many functions outside of senescence and aging. In this paper, we discuss and shed light on several studies that show the different functions of p16 and provide insights in its role in several biological processes besides senescence and aging.

Keywords:  aging; cancer; development; p16; pathologies; senescence

DOI:  https://doi.org/10.3390/life12091332
Open Biol. 2022 Sep;12(9): 220171

From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs.

Valentin L'Hôte, Carl Mann, Jean-Yves Thuret.

  Senescence is a cellular stress response that involves prolonged cell survival, a quasi-irreversible proliferative arrest and a modification of the transcriptome that sometimes includes inflammatory gene expression. Senescent cells are resistant to apoptosis, and if not eliminated by the immune system they may accumulate and lead to chronic inflammation and tissue dysfunction. Senolytics are drugs that selectively induce cell death in senescent cells, but not in proliferative or quiescent cells, and they have proved a viable therapeutic approach in multiple mouse models of pathologies in which senescence is implicated. As the catalogue of senolytic compounds is expanding, novel survival strategies of senescent cells are uncovered, and variations in sensitivity to senolysis between different types of senescent cells emerge. We propose herein a mechanistic classification of senolytic drugs, based on the level at which they target senescent cells: directly disrupting BH3 protein networks that are reorganized upon senescence induction; downregulating survival-associated pathways essential to senescent cells; or modulating homeostatic processes whose regulation is challenged in senescence. With this approach, we highlight the important diversity of senescent cells in terms of physiology and pathways of apoptosis suppression, and we describe possible avenues for the development of more selective senolytics.

Keywords:  ageing; cell survival; cellular senescence; drug discovery; mechanisms of action; senolytics

DOI:  https://doi.org/10.1098/rsob.220171
Genes (Basel). 2022 Aug 24. pii: 1522. [Epub ahead of print]13(9):

Alteration of E2F2 Expression in Governing Endothelial Cell Senescence.

Hongfei Liu, Liping Chen, Wanli Xiao, Jiankun Liu, Changkun Long, Wenxing Zhan, Cui Cui, Lin Yang, Shenghan Chen.

  Endothelial cell senescence has a vital implication for vascular dysfunction, leading to age-related cardiovascular disease, especially hypertension and atherosclerosis. E2F transcription factor 2 (E2F2) plays a critical role in cell proliferation, differentiation, and DNA damage response. Up to date, no study has ever connected E2F2 to vascular endothelial cell senescence. Here, we demonstrate that E2F2 is involved in endothelial cellular senescence. We found that E2F2 expression is decreased during the replicative senescence of human umbilical vein endothelial cells (HUVECs) and the aortas of aged mice. The knockdown of E2F2 in young HUVECs induces premature senescence characterized by an increase in senescence-associated β-galactosidase (SA-β-gal) activity, a reduction in phosphorylated endothelial nitric oxide synthase (p-eNOS) and sirtuin 1 (SIRT1), and the upregulation of senescence-associated secretory phenotype (SASP) IL-6 and IL-8. The lack of E2F2 promoted cell cycle arrest, DNA damage, and cell proliferation inhibition. Conversely, E2F2 overexpression reversed the senescence phenotype and enhanced the cellular function in the senescent cells. Furthermore, E2F2 deficiency downregulated downstream target genes including CNNA2, CDK1, and FOXM1, and overexpression restored the expression of these genes. Our findings demonstrate that E2F2 plays an indispensable role in endothelial cell senescence.

Keywords:  E2F2; cell cycle; endothelial cell; proliferation; senescence

DOI:  https://doi.org/10.3390/genes13091522
Mech Ageing Dev. 2022 Sep 20. pii: S0047-6374(22)00122-1. [Epub ahead of print] 111740

Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice.

Nadia Salerno, Fabiola Marino, Mariangela Scalise, Luca Salerno, Claudia Molinaro, Andrea Filardo, Antonio Chiefalo, Giuseppe Panuccio, Antonella De Angelis, Konrad Urbanek, Daniele Torella, Eleonora Cianflone.

  Cardiovascular diseases (CVD) are predominantly an aging disease. Important sex-specific differences exist and the mechanism(s) by which this sex-by-age interaction influences CVD development and progression remains elusive. Accordingly, it is still unknown whether cell senescence, a main feature of cardiac male aging, is a significant feature also of the female aged mouse heart and whether senolytics, senescence-clearing compounds, promote myocardial repair and regeneration after myocardial infarction (MI) in aged female mice. To this aim, the combination of two senolytics, dasatinib and quercetin (D+Q) or just their vehicle was administered to 22-24 months old C57BL/6 female mice after MI. D+Q improved global left ventricle function and myocardial performance after MI whereby female cardiac aging is characterized by accumulation of cardiac senescent cells that are further increased by MI. Despite their terminal differentiation nature, also cardiomyocytes acquire a senescent phenotype with age in females. D+Q removed senescent cardiac non-myocyte and myocyte cells ameliorating cardiac remodeling and regeneration. Senolytics removed aged dysfunctional cardiac stem/progenitor cells (CSCs), relieving healthy CSCs with normal proliferative and cardiomyogenic differentiation potential. In conclusions, cardiac senescent cells accumulate in the aged female hearts. Removing senescent cells is a key therapeutic target for efficient repair of the aged female heart.

Keywords:  Cardiac Aging; Cardiac Progenitor cells; Cardiac Regeneration; Cell Senescence; Senolytics

DOI:  https://doi.org/10.1016/j.mad.2022.111740
Front Immunol. 2022 ;13 1006710

Cellular senescence is a key mediator of lung aging and susceptibility to infection.

Blake L Torrance, Laura Haynes.

  Aging results in systemic changes that leave older adults at much higher risk for adverse outcomes following respiratory infections. Much work has been done over the years to characterize and describe the varied changes that occur with aging from the molecular/cellular up to the organismal level. In recent years, the systemic accumulation of senescent cells has emerged as a key mediator of many age-related declines and diseases of aging. Many of these age-related changes can impair the normal function of the respiratory system and its capability to respond appropriately to potential pathogens that are encountered daily. In this review, we aim to establish the effects of cellular senescence on the disruption of normal lung function with aging and describe how these effects compound to leave an aged respiratory system at great risk when exposed to a pathogen. We will also discuss the role cellular senescence may play in the inability of most vaccines to confer protection against respiratory infections when administered to older adults. We posit that cellular senescence may be the point of convergence of many age-related immunological declines. Enhanced investigation into this area could provide much needed insight to understand the aging immune system and how to effectively ameliorate responses to pathogens that continue to disproportionately harm this vulnerable population.

Keywords:  aging; immunity; influenza; lung; senescence

DOI:  https://doi.org/10.3389/fimmu.2022.1006710
Int J Mol Sci. 2022 Sep 09. pii: 10443. [Epub ahead of print]23(18):

Circular RNAs Involved in the Regulation of the Age-Related Pathways.

Siqi Wang, Feng Xiao, Jiamei Li, Xiaolan Fan, Zhi He, Taiming Yan, Mingyao Yang, Deying Yang.

  Circular RNAs (circRNAs) are a class of covalently circular noncoding RNAs that have been extensively studied in recent years. Aging is a process related to functional decline that is regulated by signal transduction. An increasing number of studies suggest that circRNAs can regulate aging and multiple age-related diseases through their involvement in age-related signaling pathways. CircRNAs perform several biological functions, such as acting as miRNA sponges, directly interacting with proteins, and regulating transcription and translation to proteins or peptides. Herein, we summarize research progress on the biological functions of circRNAs in seven main age-related signaling pathways, namely, the insulin-insulin-like, PI3K-AKT, mTOR, AMPK, FOXO, p53, and NF-κB signaling pathways. In these pathways, circRNAs mainly function as miRNA sponges. In this review, we suggest that circRNAs are widely involved in the regulation of the main age-related pathways and are potential biomarkers for aging and age-related diseases.

Keywords:  age-related pathway; aging; circRNAs; regulatory roles

DOI:  https://doi.org/10.3390/ijms231810443
Molecules. 2022 Sep 12. pii: 5925. [Epub ahead of print]27(18):

Senescent Phenotype of Astrocytes Leads to Activation of BV2 Microglia and N2a Neuronal Cells Death.

Wenyou Zhang, Xuehan Yang, Jingyue Liu, Yichen Pan, Ming Zhang, Li Chen.

  (1) Background: Astrocytes, the most abundant cell type in the central nervous system, are essential to tune individual-to-network neuronal activity. Senescence in astrocytes has been discovered as a crucial contributor to several age-related neurological diseases. Here, we aim to observe if astrocytes demonstrate senescence in the process of brain aging, and whether they bring adverse factors, especially harm to neuronal cells. (2) Methods: In vivo, mice were housed for four, 18, and 26 months. An in vitro cell model of aged astrocytes was constructed by serial passaging until passage 20-25, and those within 1-5 were invoked as young astrocytes. Meanwhile, an oxidative induced astrocyte senescence model was constructed by H2O2 induction. (3) Results: In vitro aged astrocytes all showed manifest changes in several established markers of cellular senescence, e.g., P53, P21, and the release of inflammatory cytokine IL-6 and SA-β-gal positive cells. Results also showed mitochondrial dysfunction in the oxidative stress-induced astrocyte senescence model and treatment of berberine could ameliorate these alterations. Two types of senescent astrocytes' conditioned medium could impact on neuron apoptosis in direct or indirect ways. (4) Conclusions: Senescent astrocyte might affect neurons directly or indirectly acting on the regulation of normal and pathological brain aging.

Keywords:  aging; cell-to-cell interaction; microglia activation; neurons; senescent phenotype of astrocytes

DOI:  https://doi.org/10.3390/molecules27185925
Front Immunol. 2022 ;13 955175

Extracellular vesicle-associated microRNA-30b-5p activates macrophages through the SIRT1/ NF-κB pathway in cell senescence.

Yu Xiao, Jiaqi Liang, Kenneth W Witwer, Ying Zhang, Qian Wang, Hang Yin.

  Chronic inflammation is widely observed in aging, but it is unclear whether extracellular vesicles (EVs) play a role in chronic disease-associated senescence. In our study, LC/MS profiling revealed that senescent cell derived EVs (SEN EVs) activate the immune response pathways of macrophages. Significantly more EVs were found in the supernatant of SEN than of control (CON) cell cultures, and SEN EVs were enriched in miR-30b-5p, which directly target sirtuin1 (SIRT1). In vitro, we found that SEN EV treatment resulted in increased cellular levels of interleukin-1β (IL-1β) and IL-6 and decreased levels of SIRT1. Increased cytokine levels could be reversed by SIRT1 activation and miR-30b-5p inhibition. Furthermore, miR-30b-5p significantly increased with age in both mouse liver tissue and EVs harvested from the tissue, with differences in EVs observed both earlier and in the later magnitude of aging. Western blot and qPCR proved that miR-30b-5p downregulated the level of SIRT1 in mouse macrophages. Collectively, we propose that EVs carrying miR-30b-5p from SEN cells can induce chronic inflammation through macrophage activation. This occurs through the downregulation of SIRT1 and the corresponding activation of NF-κB pathways that enhance pro-inflammatory cytokine production. Collectively, these results demonstrate that EVs carrying pro-inflammatory signals are released by SEN cells and then activate immune cells in the SEN microenvironment, changing the inflammatory balance. Our results also explain why inflammation increases with age even though SEN cells can be immediately eliminated under rigorous immune surveillance.

Keywords:  NF-κB; SIRT1; cell senescence; extracellular vesicles; miRNA

DOI:  https://doi.org/10.3389/fimmu.2022.955175
Aging Cell. 2022 Sep 18. e13713

Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.

Gregory J Krause, Antonio Diaz, Maryam Jafari, Rabia R Khawaja, Esperanza Agullo-Pascual, Olaya Santiago-Fernández, Alicia L Richards, Kuei-Ho Chen, Phillip Dmitriev, Yan Sun, Stephanie K See, Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Nevan J Krogan, Myriam Gorospe, Danielle L Swaney, Simone Sidoli, Jose Javier Bravo-Cordero, Martin Kampmann, Ana Maria Cuervo.

  Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub-proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age-related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.

Keywords:  aging; autophagy; chaperones; endosomal microautophagy; exocyst complex; late endosomes; protein secretion; proteostasis

DOI:  https://doi.org/10.1111/acel.13713
Sci Rep. 2022 Sep 22. 12(1): 15826

RNAa-mediated epigenetic attenuation of the cell senescence via locus specific induction of endogenous SIRT1.

Neda Mokhberian, Kazem Sharifi, Ehsan Soleimaninejadian, Mohamad Eftekhary, Seyed Mahmoud Hashemi, Shohreh Farhadi, Satomi Miwa, Hossein Ghanbarian.

SIRT1, a known regulator of cellular senescence, is a therapeutic target for age related disorders and its upregulation is a strategy to improve the cell therapeutic potentials of human mesenchymal stem cell (MSCs). Knockdown of natural antisense transcripts via small activating RNAs (RNAa) is an emerging approach for safe and locus specific gene regulation. We have recently identified a natural antisense transcript at human SIRT1 locus (SIRT1-NAT), the expression of which shows a negative correlation with that of SIRT1. To test the hypothetic upregulation of SIRT1 via knockdown of SIRT1-NAT, in this study we designed a single stranded oligonucleotide (SIRT1-antagoNAT) against the antisense transcript, transfection of which efficiently knocked down the SIRT1-NAT and induced SIRT1 transcription in human MSCs. In addition, activation of SIRT1 transfection via knockdown of SIRT1-NAT in human MSCs enhanced their proliferation and differentiation potentials, reduced senescence associated β-galactosidase activity and reversed the senescence associated molecular alterations. Our findings introduce an RNAa mediated approach for epigenetic induction of endogenous SIRT1 and the consequent attenuation of senescence. Further studies should evaluate the therapeutic potentials of this approach against various age related disorders.

DOI: https://doi.org/10.1038/s41598-022-17972-9
Exp Eye Res. 2022 Sep 20. pii: S0014-4835(22)00334-7. [Epub ahead of print] 109254

Does senescence play a role in age-related macular degeneration?

Goldis Malek, Judith Campisi, Koji Kitazawa, Corey Webster, Aparna Lakkaraju, Dorota Skowronska-Krawczyk.

  Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathological molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells' ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss the current thoughts on the potential role of senescence in AMD development and progression, considering the model systems used and their relevance to human disease.

Keywords:  Age-related macular degeneration; Aging; Retinal pigment epithelium; Senescence

DOI:  https://doi.org/10.1016/j.exer.2022.109254
Drug Discov Today. 2022 Sep 14. pii: S1359-6446(22)00358-0. [Epub ahead of print] 103365

Senotherapies: A novel strategy for synergistic anti-tumor therapy.

Xuxin Qi, Li Jiang, Ji Cao.

  Cellular senescence was initially considered an effective antitumor mechanism, and senescence-induced therapy has previously been regarded as an efficient treatment. However, increasing studies have discovered that persistent senescent cells (SNCs) might have unanticipated negative repercussions for antitumor treatment. The long-term build-up of SNCs exacerbates toxic side effects, treatment resistance, and poor prognosis, and tumor cells that undergo senescence escape can acquire stemness to repopulate the tumor, leading to cancer recurrence. Thus, senotherapies that eliminate SNCs could be used as a new strategy for synergistic antitumor therapy. In this review, we summarize the adverse effects of SNCs in tumor development and the mechanisms by which senescent tumor cells escape senescence, discuss the relationship between senescence and polyploidy, and highlight the potential of senotherapies as an emerging adjuvant antitumor treatment strategy. Such a strategy is expected to provide new approaches for antitumor drug development from the perspective of cellular senescence.

Keywords:  Antitumor therapy; Cellular senescence; Polyploid; Senescence escape; Senotherapy

DOI:  https://doi.org/10.1016/j.drudis.2022.103365
Crit Rev Food Sci Nutr. 2022 Sep 21. 1-17

Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites.

Bulei Wang, Xin Tang, Bingyong Mao, Qiuxiang Zhang, Fengwei Tian, Jianxin Zhao, Shumao Cui, Wei Chen.

  Aging, a natural and inevitable physiological process, is the primary risk factor for all age-related diseases; it severely threatens the health of individuals and places a heavy burden on the public health-care system. Thus, strategies to extend the lifespan and prevent and treat age-related diseases have been gaining increasing scientific interest. Anthocyanins (ACNs) are a subclass of flavonoids widely distributed in fruits and vegetables. Growing evidence suggests that ACNs delay aging and relieve age-related diseases. However, owing to the low bioavailability of ACNs, their gut metabolites have been proposed to play a critical role in mediating health benefits. In this review, we introduce the biological fate of ACNs after consumption and highlight ACNs metabolites (phenolic acids) from intestinal microorganisms. Additionally, ACNs and gut metabolites exhibit outstanding anti-aging ability in Caenorhabditis elegans, Drosophila melanogaster, and mouse models, probably associated with increasing antioxidation, anti-inflammation, protein homeostasis, antiglycation, mitochondrial function, and inhibition of insulin/IGF-1 signaling (IIS). ACNs and gut metabolites have great application prospects as functional foods and drugs to delay aging and manage age-related diseases. Further investigation should focus on the interaction between ACNs and gut microbiota, including clarifying the complex metabolic pathway and maximizing the health effects of ACNs.

Keywords:  Anthocyanins; age-related diseases; anti-aging ability; gut metabolites

DOI:  https://doi.org/10.1080/10408398.2022.2123444
Aging Cell. 2022 Sep 21. e13720

Exaggerated hypoxic vascular breakdown in aged brain due to reduced microglial vasculo-protection.

Sebok K Halder, Richard Milner.

  In a recent study of young mice, we showed that chronic mild hypoxia (CMH, 8% O2 ) triggers transient blood-brain barrier (BBB) disruption, and that microglia play an important vasculo-protective function in maintaining BBB integrity. As hypoxia is a common component of many age-related diseases, here we extended these studies to aged mice and found that hypoxia-induced vascular leak was greatly amplified (5-fold to 10-fold) in aged mice, being particularly high in the olfactory bulb and midbrain. While aged mice showed no obvious difference in the early stages of hypoxic angiogenic remodeling, the compensatory increase in vascularity and vessel maturation was significantly delayed. Compared with young brain, microglia in the normoxic aged brain were markedly activated, and this was further increased under hypoxic conditions, but paradoxically, this correlated with reduced vasculo-protection. Microglial depletion studies showed that microglial still play an important vasculo-protective role in aged brain, but interestingly, partial attenuation of microglial activation with minocycline resulted in fewer vascular leaks and reduced loss of endothelial tight junction proteins. Taken together, these findings suggest that increased BBB disruption in hypoxic aged mice can be explained both by a delayed vascular remodeling response and reduced microglial vasculo-protection. Importantly, they show that overly activated microglia in the aged brain are less effective at maintaining vascular integrity, though this can be improved by reducing microglial activation with minocycline, suggesting therapeutic potential for enhancing BBB integrity in the hypoxia-predisposed elderly population.

Keywords:  aging; angiogenesis; blood vessels; blood-brain barrier integrity; brain; chronic mild hypoxia; endothelial proliferation; fibrinogen; microglia

DOI:  https://doi.org/10.1111/acel.13720
Aging Cell. 2022 Sep 23. e13706

2-month ketogenic diet preferentially alters skeletal muscle and augments cognitive function in middle aged female mice.

Suraj J Pathak, Zeyu Zhou, Danielle Steffen, Tommy Tran, Yael Ad, Jon J Ramsey, Jennifer M Rutkowsky, Keith Baar.

  The effect of a ketogenic diet (KD) on middle aged female mice is poorly understood as most of this work have been conducted in young female mice or diseased models. We have previously shown that an isocaloric KD started at middle age in male mice results in enhanced mitochondrial mass and function after 2 months on diet and improved cognitive behavior after being on diet for 14 months when compared with their control diet (CD) fed counterparts. Here, we aimed to investigate the effect of an isocaloric 2-month KD or CD on healthy 14-month-old female mice. At 16 months of age cognitive behavior tests were performed and then serum, skeletal muscle, cortex, and hippocampal tissues were collected for biochemical analysis. Two months on a KD resulted in enhanced cognitive behavior associated with anxiety, memory, and willingness to explore. The improved neurocognitive function was associated with increased PGC1α protein in the gastrocnemius (GTN) muscle and nuclear fraction. The KD resulted in a tissue specific increase in mitochondrial mass and kynurenine aminotransferase (KAT) levels in the GTN and soleus muscles, with a corresponding decrease in kynurenine and increase in kynurenic acid levels in serum. With KAT proteins being responsible for converting kynurenine into kynurenic acid, which is unable to cross the blood brain barrier and be turned into quinolinic acid-a potent neurotoxin, this study provides a potential mechanism of crosstalk between muscle and brain in mice on a KD that may contribute to improved cognitive function in middle-aged female mice.

Keywords:  Alzheimer's disease; acetylation; cognitive behavior; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13706
Cells. 2022 Sep 13. pii: 2848. [Epub ahead of print]11(18):

Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis.

Juan Urista, Mariel Maldonado, Fernanda Toscano-Marquez, Remedios Ramírez, Yalbi Itzel Balderas-Martínez, Carina Becerril, Yair Romero, Moisés Selman, Annie Pardo.

  Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFβ-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated β Galactosidase activity, p53, p21, and the histone variant γH2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence.

Keywords:  TGFβ-1; cellular senescence; pulmonary fibrosis; zinc finger protein ZNF365

DOI:  https://doi.org/10.3390/cells11182848
Mol Oncol. 2022 Sep;16(18): 3213-3219

The role of aging in cancer.

Aaron Havas, Shanshan Yin, P D Adams.

Many cancers show an increase in incidence with age, and age is the biggest single risk factor for many cancers. However, the molecular basis of this relationship is poorly understood. Through a collection of review articles, our thematic issue discusses the link between aging and cancer in aspects including somatic mutations, proteostasis, mitochondria, metabolism, senescence, epigenetic regulation, immune regulation, DNA damage, and telomere function.

DOI: https://doi.org/10.1002/1878-0261.13302
Sci Signal. 2022 Sep 20. 15(752): eade9136

Telomeres to go.

John F Foley.

By acquiring telomeres from antigen-presenting cells, some T cells are protected from senescence.

DOI: https://doi.org/10.1126/scisignal.ade9136
Eur Heart J Open. 2022 Jul;2(4): oeac047

Vascular senescence in progeria: role of endothelial dysfunction.

Qiu Xu, Anahita Mojiri, Luay Boulahouache, Elisa Morales, Brandon K Walther, John P Cooke.

  Aims: Hutchinson-Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cell (VSMC) loss is the primary vascular manifestation, which is different from the arterial occlusive disease seen in older patients.Methods and results: To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenic endothelial cells (ECs) and VSMCs from HGPS-induced pluripotent stem cells (iPSCs) and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, up-regulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin, and altered shelterin protein complex (SPC) expression. However, at similar days after differentiation, even with lower levels of progerin, HGPS-ECs manifested more severe signs of senescence, as indicated in part by a higher percentage of β-galactosidase positive cells, shorter telomere length, and more DNA damage signals. We observed increased γH2A.X binding to RAP1 and reduced TRF2 binding to lamin A in HGPS-ECs but not in HGPS-VSMCs. The expression of γH2A.X was greater in HGPS-ECs than in HGPS-VSMCs and is associated with greater telomere shortening, impaired SPC interactions, and loss of heterochromatin.
Conclusion: Although progerin expression has a deleterious effect on both ECs and VSMCs, the dysfunction is greater in HGPS-ECs compared with HGPS-VSMCs. This study suggests that an endothelial-targeted therapy may be useful for HGPS patients.

Keywords:  Endothelial cells; Progeria; Senescence; Telomere; Vascular smooth muscle cells; iPSCs

DOI:  https://doi.org/10.1093/ehjopen/oeac047
Genes (Basel). 2022 Sep 02. pii: 1579. [Epub ahead of print]13(9):

Senescent Fibroblasts Generate a CAF Phenotype through the Stat3 Pathway.

Hao Li, Lei Qiu, Qing Liu, Zelong Ma, Xiaoli Xie, Ying Luo, Xiaoming Wu.

  Aging has been recently reported to promote lung cancer initiation and progression. Senescent fibroblasts gain a cancer-associated fibroblast (CAF) phenotype, and exert a powerful influence on cancer behavior, such as tumor cell growth and metastasis. However, mechanisms linking fibroblast senescence with CAF activation remain poorly understood. Our study shows that senescent fibroblasts displayed CAF properties, including the highly expressed CAF markers, α-SMA and Vimentin, and CAF-specific factors, CXCL12, FGF10, IL6 and COL1A1, which significantly increased collagen contractile activity and promoted the migration and invasion of lung cancer cells, H1299 and A549. We were further able to show that CAF characteristics in senescent fibroblasts could be regulated by the Stat3 pathway. Intracellular ROS accumulation activates the Stat3 pathway during senescence. Thus, our findings indicate that senescent fibroblasts mediate a CAF function with the Stat3 pathway. We further propose a novel Stat3 dependent targetable mechanism, which is instrumental in mediating the migration and invasion of lung cancer cells.

Keywords:  Stat3 pathway; cancer-associated fibroblasts; fibroblast senescence

DOI:  https://doi.org/10.3390/genes13091579
Biogerontology. 2022 Sep 22.

Alternate day fasting and time-restricted feeding may confer similar neuroprotective effects during aging in male rats.

Sukanya Bhoumik, Rashmi Kesherwani, Raushan Kumar, Syed Ibrahim Rizvi.

  Age associated neurodegenerative changes are acknowledged to play a causative role in a majority of neurological diseases that accompany aging in organisms. To alleviate the deteriorative effects of aging in the brain, we investigated the effects oftwo types of intermittent fasting (IF) methods: alternate day fasting (ADF) and time- restricted feeding (TRF) in young (3 months) and old (24 months) in male Wistar rats comparing the results with age matched controls. The evaluation of biomarkers of oxidative stress showed significant decline in the old (ADF and TRF) groups in addition to up regulation in antioxidant levels. It was observed that ADF and TRF methods helped reduce ROS accumulation in the mitochondria and increased the activity of the electron transport chain complexes especially C-I and III. Gene expression analysis of autophagy genes like beclin and LC3B showed upregulated expression in ADF and TRF group. Sirtuin1 expression too significantly increased during fasting in both young and old groups showing fasting induced protection from aging. Histological analysis of sections of cerebral cortex and CA1 area provide evidence that fasting protected neurons against degeneration with age. Our results prompt us to conclude that the efficacy of these fasting methods ADF and TRF are reliable anti- aging strategies with respect to dietary restriction interventions. Moreover, both these methods compete closely in conferring protection from oxidative stress and inducing neuroprotective changes in brain of aged rats when compared to their young counterparts.

Keywords:  Aging; Alternate day fasting; Brain; Dietary restriction intervention; Neuroprotection; Time- restricted feeding

DOI:  https://doi.org/10.1007/s10522-022-09991-w
Aging Cell. 2022 Sep 19. e13711

Hexosamine pathway activation improves memory but does not extend lifespan in mice.

Kira Allmeroth, Matías D Hartman, Martin Purrio, Andrea Mesaros, Martin S Denzel.

  Glucosamine feeding and genetic activation of the hexosamine biosynthetic pathway (HBP) have been linked to improved protein quality control and lifespan extension. However, as an energy sensor, the HBP has been implicated in tumor progression and diabetes. Given these opposing outcomes, it is imperative to explore the long-term effects of chronic HBP activation in mammals. Thus, we asked if HBP activation affects metabolism, coordination, memory, and survival in mice. N-acetyl-D-glucosamine (GlcNAc) supplementation in the drinking water had no adverse effect on weight in males but increased weight in young females. Glucose or insulin tolerance was not affected up to 20 months of age. Of note, we observed improved memory in young male mice supplemented with GlcNAc. Survival was not changed by GlcNAc treatment. To assess the effects of genetic HBP activation, we overexpressed the pathway's key enzyme GFAT1 and a constitutively activated mutant form in all mouse tissues. We detected elevated levels of the HBP product UDP-GlcNAc in mouse brains, but did not find any effects on behavior, memory, or survival. Together, while dietary GlcNAc supplementation did not extend survival in mice, it positively affected memory and is generally well tolerated.

Keywords:  GFAT1; hexosamine biosynthetic pathway; memory; metabolism; mouse survival

DOI:  https://doi.org/10.1111/acel.13711
FASEB J. 2022 Oct;36(10): e22555

Novel pathophysiological roles of α-synuclein in age-related vascular endothelial dysfunction.

Yoichi Takami, Cheng Wang, Hironori Nakagami, Koichi Yamamoto, Yoichi Nozato, Yuki Imaizumi, Motonori Nagasawa, Hikari Takeshita, Tsuneo Nakajima, Shuko Takeda, Yasushi Takeya, Yasufumi Kaneda, Hiromi Rakugi.

  Although α-synuclein (SNCA) is a well-known pathological molecule involved in synucleinopathy in neurons, its physiological roles remain largely unknown. We reported that serum SNCA levels have a close inverse correlation with blood pressure and age, which indicates the involvement of SNCA in age-related endothelial dysfunction. Therefore, this study aimed to elucidate the molecular functions of SNCA in the endothelium. We confirmed that SNCA was expressed in and secreted from endothelial cells (ECs). Exogenous treatment with recombinant SNCA (rSNCA) activated the Akt-eNOS axis and increased nitric oxide production in ECs. Treatment with rSNCA also suppressed TNF-α- and palmitic acid-induced NF-κB activation, leading to the suppression of VCAM-1 upregulation and restoration of eNOS downregulation in ECs. As for endogenous SNCA expression, replicative senescence resulted in the attenuation of SNCA expression in cultured ECs, similar to the effects of physiological aging on mice aortas. The siRNA-mediated silencing of SNCA consistently resulted in senescent phenotypes, such as eNOS downregulation, increased β-gal activity, decreased Sirt1 expression, and increased p53 expression, in ECs. Ex vivo assessment of endothelial functions using aortic rings revealed impaired endothelium-dependent acetylcholine-induced relaxation in SNCA knockout (KO) mice. Furthermore, SNCA KO mice, especially those on a high-fat diet, displayed elevated blood pressure compared with wild-type mice; this could be eNOS dysfunction-dependent because of the lower difference caused by L-NAME administration. These results indicate that exogenous and endogenous SNCA in ECs might physiologically maintain vascular integrity, and age-related endothelial dysfunction might be partially ascribed to loss-of-function of SNCA in ECs.

Keywords:  aging; eNOS; endothelial function; α-synuclein

DOI:  https://doi.org/10.1096/fj.202101621R
Geroscience. 2022 Sep 22.

Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence.

Alistaire D Ruggiero, Matthew A Davis, Ashley T Davis, Darla DeStephanis, Abigail G Williams, Ravichandra Vemuri, Katherine M Fanning, Chrissy Sherrill, J Mark Cline, David L Caudell, Kylie Kavanagh.

  The pathogenesis of many age-related diseases is linked to cellular senescence, a state of inflammation-inducing, irreversible cell cycle arrest. The consequences and mechanisms of age-associated cellular senescence are often studied using in vivo models of radiation exposure. However, it is unknown whether radiation induces persistent senescence, like that observed in ageing. We performed analogous studies in mice and monkeys, where young mice and rhesus macaques received sub-lethal doses of ionizing radiation and were observed for ~ 15% of their expected lifespan. Assessments of 8-hydroxy-2' -deoxyguanosine (8-OHdG), senescence-associated beta-galactosidase (SAβ-gal), and p16Ink4a and p21 were performed on mitotic and post-mitotic tissues - liver and adipose tissue - 6 months and 3 years post-exposure for the mice and monkeys, respectively. No elevations in 8-OHdG, SA-βgal staining, or p16 Ink4a or p21 gene or protein expression were found in mouse and monkey liver or adipose tissue compared to control animals. Despite no evidence of senescence, progenitor cell dysfunction persisted after radiation exposure, as indicated by lower in situ CD34+ adipose cells (p = 0.03), and deficient adipose stromal vascular cell proliferation (p < 0.05) and differentiation (p = 0.04) ex vivo. Our investigation cautions that employing radiation to study senescence-related processes should be limited to the acute post-exposure period and that stem cell damage likely underpins the dysfunction associated with delayed effects of radiation.

Keywords:  Adipose; Adipose progenitors; Liver; Radiation; Senescence

DOI:  https://doi.org/10.1007/s11357-022-00660-x
Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01233-5. [Epub ahead of print]40(12): 111396

Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors.

Letizia Granieri, Federica Marocchi, Marine Melixetian, Neda Mohammadi, Paola Nicoli, Alessandro Cuomo, Tiziana Bonaldi, Stefano Confalonieri, Federica Pisati, Giuseppina Giardina, Giovanni Bertalot, Daniela Bossi, Luisa Lanfrancone.

  Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.

Keywords:  CP: Cancer; DUBs; PDX; cellular senescence; combination therapy; metastatic melanoma

DOI:  https://doi.org/10.1016/j.celrep.2022.111396
Aging Cell. 2022 Sep 22. e13717

The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease.

Lucia Privitera, Ellen L Hogg, Marcia Lopes, Luana B Domingos, Matthias Gaestel, Jürgen Müller, Mark J Wall, Sonia A L Corrêa.

  A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling.

Keywords:  APP/PS1 mouse; Arc/Arg3.1; hippocampus; mGluR5 signalling; p38 MAPK signalling; synaptic plasticity

DOI:  https://doi.org/10.1111/acel.13717
Aging (Albany NY). 2022 Sep 16. 14(undefined):

Age-related metabolic and neurodegenerative changes in SAMP8 mice.

Andrea Pačesová, Martina Holubová, Lucie Hrubá, Veronika Strnadová, Barbora Neprašová, Helena Pelantová, Marek Kuzma, Blanka Železná, Jaroslav Kuneš, Lenka Maletínská.

  The most important risk factor for the development of sporadic Alzheimer's disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6th month. With ageing, increasing plasma concentrations of proinflammatory cytokines in SAMP8 mice were detected as well as significantly increased astrocytosis in the cortex and microgliosis in the brainstem. Moreover, from the 3rd month, SAMP8 mice displayed a decreased number of neurons and neurogenesis in the hippocampus. From the 6th month, increased pathological phosphorylation of tau protein at Thr231 and Ser214 was observed in the hippocampi of SAMP8 mice. In conclusion, changes specific for neurodegenerative processes were observed between the 3rd and 6th month of age in SAMP8 mice; thus, potential neuroprotective interventions could be applied between these ages.

Keywords:  Alzheimer’s disease; insulin resistance; neuroinflammation; senescence accelerated mouse prone 8; tau pathology

DOI:  https://doi.org/10.18632/aging.204284