Senescent Phenotype Research Articles

Deletion of Stimulator of Interferons Genes Aggravated Cardiac Dysfunction in Physiological Aged Mice

BackgroundStimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear. MethodsGene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice. ResultsBioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice. ConclusionAlthough reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.

A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1

A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1

Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as “mito-NAD(P)H age clocks.” Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.

Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A

Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome.

Prostaglandin E2 regulates senescence and post-senescence neoplastic escape in primary human keratinocytes.

Aging of the epidermis partially occurs as a consequence of epidermal cell senescence, a non-proliferative state in which cells remain metabolically active and acquire changes in their secretome. We previously reported that senescent normal human epidermal keratinocytes (NHEKs) have two opposite outcomes: either cell death by excess of autophagic activity or escape from senescence to give rise to post-senescence neoplastic emerging (PSNE) cells. In this study, we investigated the role of PTGS2, the inducible enzyme of the prostaglandin biosynthesis pathway, in the onset of NHEK senescence and in the switch from senescence to pre-transformation. We provide evidence that the PTGS2/PGE2/EP4 pathway plays a critical role in NHEK senescence as well as in senescence escape. We show that treating proliferating NHEKs with prostaglandin E2 (PGE2) or with an agonist of one of its receptors, EP4, induced the establishment of the senescent phenotype, according to several markers including the senescence-associated β-galactosidase activity. Conversely, treating already senescent NHEKs with an antagonist of EP4, or knocking-down PTGS2 by siRNA resulted in the decrease of the percentage of senescence-associated β-galactosidase-positive cells. We also demonstrate that the PSNE frequency was significantly decreased upon PTGS2 silencing by siRNA, pharmacological PTGS2 inhibition, or treatment by an EP4 antagonist, while on the contrary treatments with PGE2 or EP4 agonist increased the PSNE frequency. These results indicate that the PTGS2/PGE2/EP4 pathway is required to induce and maintain the senescent phenotype of NHEKs, and that PGE2 level is a potential determinant of the initial steps of the age-related oncogenic process.

Cellular senescence: mechanisms and relevance to cancer and aging

Summary Cellular senescence is an irreversible cell cycle arrest induced by stresses such as telomere shortening and oncogene activation. It acts as a tumor suppressor mechanism that prevents the proliferation of potentially tumorigenic cells. Paradoxically, senescent stromal cells that arise in the tumor microenvironment have been shown to promote tumor progression. In addition, senescent cells that accumulate in vivo over time are thought to contribute to aging and age-related diseases. These deleterious effects of senescent cells involve the secretion of bioactive molecules such as inflammatory cytokines and chemokines, a phenomenon known as the senescence-associated secretory phenotype (SASP). While the role of cellular senescence in vivo is becoming increasingly clear, the intracellular signaling pathways that induce the expression of senescent phenotypes are not fully understood. In this review, we outline senescence-associated signaling pathways and their relevance to cancer and aging.

Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility.

Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.

P63 affects distinct metabolic pathways during keratinocyte senescence, evaluated by metabolomic profile and gene expression analysis

Unraveling the molecular nature of skin aging and keratinocyte senescence represents a challenging research project in epithelial biology. In this regard, depletion of p63, a p53 family transcription factor prominently expressed in human and mouse epidermis, accelerates both aging and the onset of senescence markers in vivo animal models as well as in ex vivo keratinocytes. Nonetheless, the biochemical link between p63 action and senescence phenotype remains largely unexplored. In the present study, through ultrahigh performance liquid chromatography–tandem mass spectroscopy (UPLC–MS/MS) and gas chromatography/mass spectrometry (GC/MS) metabolomic analysis, we uncover interesting pathways linking replicative senescence to metabolic alterations during p63 silencing in human keratinocytes. Integration of our metabolomic profiling data with targeted transcriptomic investigation empowered us to demonstrate that absence of p63 and senescence share similar modulation profiles of oxidative stress markers, pentose phosphate pathway metabolites and lyso-glycerophospholipids, the latter due to enhanced phospholipases gene expression profile often under p63 direct/indirect gene control. Additional biochemical features identified in deranged keratinocytes include a relevant increase in lipids production, glucose and pyruvate levels as confirmed by upregulation of gene expression of key lipid synthesis and glycolytic enzymes, which, together with improved vitamins uptake, characterize senescence phenotype. Silencing of p63 in keratinocytes instead, translates into a blunted flux of metabolites through both glycolysis and the Krebs cycle, likely due to a p63-dependent reduction of hexokinase 2 and citrate synthase gene expression. Our findings highlight the potential role of p63 in counteracting keratinocyte senescence also through fine regulation of metabolite levels and relevant biochemical pathways. We believe that our research might contribute significantly to the discovery of new implications of p63 in keratinocyte senescence and related diseases.

Abstract A018: Alternative Polyadenylation Regulates Pancreatic Cancer Fibroblast Metabolism

Abstract Dense, fibrotic stroma is a defining feature of pancreatic ductal adenocarcinoma (PDAC), comprising up to 90% of tumor volume. Multiple studies have shown that this stroma strongly influences cancer progression and response to treatment. Cancer Associated Fibroblasts (CAFs) make up the majority of the Tumor Microenvironment (TME) and directly alter the tumor landscape and response to therapeutics. CAFs are a heterogenous population comprising of a mixture of inflammatory, myofibroblastic, and antigen-presenting CAFs, with both pro- and anti- tumorigenic functions. While we have been able to define CAFs phenotypically, we lack a deeper understanding of the mechanisms underlying their transcriptional heterogeneity and ultimately their contribution to driving PDAC progression. Our lab has previously shown 3’UTR-Alternative Polyadenylation (APA) to be an important driver of genetic dysregulation in PDAC. APA is an important process regulating mRNA stability, protein localization, and expression, ultimately determining cellular processes such as proliferation, metastasis, and migration. We have also shown that increased 3’ UTR shortening is associated with the pro- tumorigenic inflammatory CAF subtype. However, how APA regulates CAF function is unknown. We are now trying to understand the possible mechanisms of these changes in vitro using human-derived CAF cell lines and treating them with a known pharmacological modulator of APA. We performed PAC-Seq analyses on these samples and show that important drivers of CAF metabolism are hindered by APA, ultimately affecting the ability of CAFs to support cancer cell growth. We find that inhibition of APA drives CAF migration and senescence phenotype and alters gene expression of critical genes required for CAF function, and metabolism. We identified a novel mechanism by which a key metabolic gene SLC7A11 is regulated by APA. To our knowledge, our work is one of the first studies to study how APA is an important regulator of CAF function. Citation Format: Aditi H Chaubey, Michael E Feigin, Eric J Wagner. Alternative Polyadenylation Regulates Pancreatic Cancer Fibroblast Metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A018.

Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism

The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.Graphical abstracts

Combined Effect of Ambient Temperature and Relative Humidity on Skin Aging Phenotypes in the Era of Climate Change: Results From an Indian Cohort Study.

Background: There is no doubt that global warming, with its extreme heat events, is having an increasing impact on human health. Heat is not independent of ambient temperature but acts synergistically with relative humidity (RH) to increase the risk of several diseases, such as cardiovascular and pulmonary diseases. Although the skin is the organ in direct contact with the environment, it is currently unknown whether skin health is similarly affected. Objective: While mechanistic studies have demonstrated the mechanism of thermal aging, this is the first epidemiological study to investigate the effect of long-term exposure to heat index (HI) as a combined function of elevated ambient temperature and RH on skin aging phenotypes in Indian women. Methods: The skin aging phenotypes of 1510 Indian women were assessed using the Score of Intrinsic and Extrinsic Skin Aging (SCINEXA™) scoring tool. We used data on ambient temperature and RH, combined into an HI with solar ultraviolet radiation (UVR), and air pollution (particulate matter <2.5 µm [PM2.5]; nitrogen dioxide [NO2]) from secondary data sources with a 5-year mean residential exposure window. An adjusted ordinal multivariate logistic regression model was used to assess the effects of HI on skin aging phenotypes. Results: HI increased pigmentation such as hyperpigmented macula on the forehead (odds ratios [OR]: 1.31, 95% confidence interval [CI]: 1.12, 1.54) and coarse wrinkles such as crow's feet (OR: 1.17, 95% CI: 1.05, 1.30) and under-eye wrinkles (OR: 1.3, 95% CI: 1.15, 1.47). These associations were robust to the confounding effects of solar UVR and age. Prolonged exposure to extreme heat, as indicated by high HI, contributes to skin aging phenotypes. Conclusion: Thus, ambient temperature and RH are important factors in assessing the skin aging exposome.

Adolescents and young adults with sickle cell disease exhibit accelerated aging with elevated T-cell p16INK4a expression.

People living with sickle cell disease (SCD) experience complications indicative of an accelerated aging phenotype typified by early decline in physical function and increased risk for age-related conditions. Cellular senescence, measured by expression of p16INK4a in peripheral T-lymphocytes, is recognized as one of the underlying contributors to organismal aging. To examine if cellular senescence is increased in SCD patients, we cross-sectionally measured and compared expression of p16 mRNA in peripheral blood T lymphocytes in 18 adolescents and young adults with SCD to 27 similarly aged individuals without SCD. Expression of p16 was dramatically higher in individuals with SCD vs. without SCD (10.1 vs. 8.7 log2 p16 units, respectively, p < 0.001) - a gap of 43 years in biological age - consistent with accelerated aging in the SCD population. Race was not associated with the increased p16 expression in the SCD group. These initial results suggest that individuals with SCD have a significantly higher cellular senescence burden which may contribute to premature aging, physiological decline, and excess morbidities. Additional longitudinal assessment and consideration for trials of senolytic therapies among individuals living with SCD and high p16 expression are warranted to improve their health span.

Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old: The ARIC Study.

Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. However, the genetic underpinnings of differences in arterial aging remain unclear. We sought to determine the independent association of 2 polygenic scores for coronary heart disease (CHD) with CAC in adults ≥75 years of age. There were 1865 ARIC (Atherosclerosis Risk in Communities) participants who underwent genetic testing at visit 1 (1987-1989) and CAC scans at visit 7 (2018-2019). In the primary analysis, an externally derived multi-ancestry polygenic CHD risk score was calculated for both White and Black participants. Results were confirmed using a separate ARIC-derived polygenic CHD risk score, including ≥6 million variants computed for White participants. We used multivariable logistic regression models to assess the association of polygenic CHD risk with CAC, after adjusting for baseline, time-averaged lifestyle, traditional risk factors, and local ancestry principal components. In the primary analysis, the average age was 80.6 years old, 61.6% were women, and the median CAC score was 246 (189 participants with CAC=0, 364 participants with CAC≥1000). Compared with persons below the 20th percentile of polygenic CHD risk, persons with polygenic-CHD risk above the 80th percentile had 82% lower odds of having CAC=0 (odds ratio, 0.18 [95% CI, 0.09-0.37]) and had >4-fold higher odds of CAC≥1000 (odds ratio, 4.77 [95% CI, 2.88-7.88]). On a continuous scale, each SD increment increase in the polygenic risk score was associated with a 78% higher CAC score. Results were nearly identical using a second confirmatory polygenic CHD risk score in White participants. Polygenic CHD risk is robustly associated with a lower prevalence of CAC=0 and a higher prevalence of CAC≥1000 in adults ≥75 years of age, beyond lifestyle and traditional risk factors. These results suggest a heritable contribution to distinct healthy and unhealthy arterial aging phenotypes that persist throughout the life course.

Abstract 4147601: Associations between Accelerated Aging Phenotypes with Cancer-Specific and Cardiovascular-Specific Mortality in Long-Term Cancer Survivorship

Background: The consequences of cancer and anti-cancer treatments are often described as representing an “accelerated aging” phenotype. However, little is known about how the “accelerated aging” phenotype affects mortality risks in long-term cancer survivors. Purpose: To investigate the association between accelerated aging phenotype and cause-specific mortality in a sample of long-term cancer survivors Methods: Data for cancer survivors (CS) were extracted from the National Health and Nutrition Examination Survey between the years 1999-2010. Participants missing vital data and those diagnosed with multiple cancers, childhood cancers, cancer within the previous 5 years, or skin cancer were excluded. Mortality outcomes were collected from the National Death Index through December 2019. The Phenotype Age score was derived from blood biochemistry measures such as albumin, creatinine, and c-reactive protein. Accelerated Aging (AA) was defined as a Phenotype Age greater than the participants’ chronological age. CS were grouped by time since diagnosis: 5-10, 10-15, 15-20, and ≥20 years. Within each group, hazard ratios (HR) were derived from competing-risk hazard regression for the AA phenotype association with cancer-specific and cardiovascular-specific mortality. Regressions were modeled with participant age as the time-scale to account for the predictive nature of chronological age. Results: A total of 875 CS (65.6±12.9 years, 62% female, 31% non-white, 15.6±9.4 years from cancer diagnosis) were included. The most common cancer types were prostate (16%) and breast (21%) cancer. There were 107 cancer and 113 cardiovascular deaths over a 10.8±4.6 year follow-up. The AA phenotype was significantly associated with cardiovascular-specific mortality in each survivor group (all p&lt;0.05). Conversely, the AA phenotype was only significantly associated with cancer-specific mortality in the 5-10 years of survivorship group (p=0.01). Results are displayed in Figure 1, along with cubic splines fit to the HR of each survivorship group. Conclusions: Present results suggest that the AA phenotype may demonstrate time-dependent associations with cancer-specific and cardiovascular-specific risks, two leading causes of death in CS.

TRX h2-PP2AC2 module serves as a convergence node for aluminum stress and leaf senescence signals, regulating cell death via ABA-mediated ROS pathway.

ROS/redox signaling plays an important role in the regulation of signal transduction and acclimation pathways activated by multiple abiotic stresses and leaf senescence. However, the regulatory events that produce ROS under different stimuli are far from clear. Here, we report the elucidation of the molecular mechanism of an h type thioredoxin, AhTRX h2, positively regulates Al sensitivity and leaf senescence by promoting ROS. AhTRX h2 transcript levels increased greatly during both natural senescence and Al stress condition in peanut. Ectopic expression of AhTRX h2 in Arabidopsis conferred Al sensitivity as well as premature leaf senescence, manifested by multiple indices, including inhibiting root elongation, severe cell death, and accelerated expression of MC1 and CEX17. AhTRX h2 exhibited similar functions to AtTRX h2, as AhTRX h2 was able to restore the phenotypes of the AtTRX h2 defective mutant (trxh2-4) which showed Al tolerant and late senescence phenotypes. The knock down of AhTRX h2 markedly suppressed Al- and senescence-induced cell death in peanut. AhTRX h2 could recruit catalytic subunit of protein phosphatase 2A (PP2AC2) to form a stable complex. The interaction between AhTRX h2 and AtPP2AC2, as well as AhPP2AC2 and AtTRX h2 was also proved. Overexpression of AhPP2AC2 significantly enhanced Al sensitivity and leaf senescence in Arabidopsis. Protein stability assay revealed that AhTRX h2 was more stable during aging or aluminum stress. Moreover, PP2AC2 could greatly enhance the stability of AhTRX h2 in vivo. Consistent with these observations, overexpression of AhPP2AC2 effectively enhanced AhTRX h2-induced Al sensitivity and precocious leaf senescence. AhTRX h2 and AhPP2AC2 required ABA and ROS in response to cell death under Al stress and senescence, and it was evidence to suggest that ABA acted upstream of ROS in this process. Together, AhTRX h2 and AhPP2AC2 constitute a stable complex that promotes the accumulation of ABA and ROS, effectively regulate cell death. These findings suggest that TRX h2-PP2AC2-mediated pathway may be a widespread mechanism in regulating Al stress and leaf senescence.

S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis.

As the aging process progresses, age-related intervertebral disc degeneration (IVDD) is becoming an emerging public health issue. Site-1 protease (S1P) has recently been found to be associated with abnormal spinal development in patients with mutations and has multiple biological functions. Here, we discovered a reduction of S1P in degenerated and aging intervertebral discs, primarily regulated by DNA methylation. Furthermore, through drug treatment and siRNA-mediated S1P knockdown, nucleus pulposus cells were more prone to exhibit degenerative and aging phenotypes. Conditional KO of S1P in mice resulted in spinal developmental abnormalities and premature aging. Mechanistically, S1P deficiency impeded COP II-mediated transport vesicle formation, which leads to protein retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow and resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.

Robust assembly of electron transfer chain in the brain of Naked Mole-Rat during aging

Naked mole-rats (NMR, Heterocephalus glaber) are the longest-lived rodent species, with a maximum life span of more than 30 years. These long-lived mammals exhibit delayed aging phenotypes and resistance to age-related pathologies including neurodegeneration. Multiple regulatory pathways have been proposed for the anti-aging mechanisms in NMR including enhanced mitochondrial function and suppressed oxidative stress. In this study, we investigated the assembly of the electron transfer chain (ETC) which constitutes the structural base for the regulation of both oxidative phosphorylation and the production of reactive oxygen species (ROS), in brains from young and old NMR and C57BL/6 mice. While ETC assembly declined with aging in C57BL/6 mice, we found that NMR display a robust respiratory chain assembly at older ages in both males and females. Among them, individual complex IV and supercomplexes containing complex I and III or complex III and IV showed the most pronounced differences between two species. Our results indicate that a preserved robust assembly of ETC during aging contributes to enhanced mitochondrial oxidative phosphorylation and suppressed oxidative stress, which may contribute to the longevity and resistance to age-related pathologies in NMR.

Integration of single-cell and spatial transcriptome sequencing identifies CDKN2A as a senescent biomarker in endothelial cells implicating hepatocellular carcinoma malignancy.

Highly complex tumor microenvironment makes hepatocellular carcinoma (HCC) as one of the most malignant tumors worldwide. The role of cellular senescence in HCC has been gradually recognized. The present study aimed to comprehensively elucidate the senescence-related features of HCC in single-cell and spatial dimension. Single-cell RNA sequencing (scRNA-Seq) data was used to clarify the heterogeneity of senescence-related genes (SRGs) among multiple cell types within HCC. Spatial transcriptome RNA sequencing (stRNA-Seq) data was used for depicting SRGs features in spatial dimension. A prognostic model based on SRGs was constructed by using of bulk sequencing (bulk-Seq) data of HCC. The cell-cell interaction of senescent endothelial cells (ECs) in tumor microenvironment was analyzed. Then, the role of senescent ECs was verified through in vitro and in vivo experiments. The level of senescence demonstrated substantial heterogeneity among different cell types within tumor microenvironment of HCC, where ECs exhibited the most prominent senescent phenotype. Senescent ECs activated specific regulatory pathways through communicating with other cell types, with a potential impact on tumor progression. Spatial analysis revealed senescent ECs mainly located in the core region of HCC. The interaction of senescent ECs and immune cells implicated their role in tumor progression and immunotherapeutic response. In addition, CDKN2A was identified as an independent risk factor for HCC prognosis by constructing a prognostic model. Patients with high risk displayed an even worse outcome. The experimental verification indicated senescence of ECs determined by CDKN2A exhibited a secretory phenotype. Furthermore, senescent ECs with CDKN2A overexpression promote the proliferation and migration of HCC. The present study recognizes the critical effect of senescent ECs defined by CDKN2A in the promotion of tumor progression, which sheds new light on the investigation of ECs senescence in HCC.

Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes.

Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes. We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists. Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing. A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes.

ASK-1 activation exacerbates kidney dysfunction via increment of glomerular permeability and accelerates cellular aging in diabetic kidney disease model mice

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD.