Senescence Markers Research Articles

Stress resistance, antiaging, and neuroprotective activities of baicalein 5,6-dimethyl ether and Alnus rugosa extract in Caenorhabditis elegans model.

The leaf extract of Alnus rugosa (AR) together with the isolated compound baicalein 5,6-dimethyl ether (BME) were investigated for their antioxidant, radical scavenging, antiaging, and neuroprotective properties using the Caenorhabditis elegans model. The stress resistance and antiaging potential of AR and BME were assessed in wild-type N2 and transgenic C. elegans strains CF1553, TJ356, and BA17. Transgenic CL4176 expressing the human amyloid-beta peptide (Aβ) was used as a model for Aβ toxicity, whereas transgenic AM141 expressing polyQ aggregates was employed as a model for Huntington's disease. An in silico molecular docking study using Discovery Studio 4.5 was performed to elucidate the putative binding mode of BME to the active sites of Daf-2 protein, involved in longevity and oxidative stress resistance in C. elegans. BME and AR significantly delayed the appearance of oxidative stress markers in wild-type N2 and transgenic strains TJ356 and CF1553, affecting the DAF-16/FOXO transcription factor subcellular distribution and inducing expression of the sod-3 antioxidative gene. Pretreatment with AR significantly reduced the aging marker lipofuscin accumulation in BA17 worms, its effect was greater than that of epigallocatechin gallate, suggesting a potential antiaging effect. Neuroprotective effects of AR and BME were confirmed in AM141 transgenic worms, inducing a significant reduction in the score of polyQ40::GFP aggregates. Moreover, BME (25 µg/mL) resulted in a significant delay in Aβ-induced paralysis in CL4176 worms. In silico molecular modeling revealed that BME exhibited good fitting scores within the active sites of the Daf-2 protein. AR and BME exert beneficial effects in the modulation of age-related markers and attenuation of neurotoxicity in neurodegenerative disorders. Hence, AR and BME could be recognized as promising antioxidant and neuroprotective natural drug candidates that could be included in neuro-nutraceuticals.

β-asarone protects against age-related motor decline via activation of SKN-1/Nrf2 and subsequent induction of GST-4

Decelerating motor decline is important for promoting healthy aging in the elderly population. Acorus tatarinowii Schott is a traditional Chinese medicine that contains β-asarone as a pharmacologically active constituent. We found that β-asarone can decelerate motor decline in various age groups of Caenorhabditis elegans, while concurrently prolonging their lifespan and modulating synaptic transmission. To understand the mechanisms of its efficacy in motor improvement, we investigated and discovered that mitochondrial fragmentation, a marker for aging, is delayed after β-asarone treatment. Moreover, their efficacy is blocked by dysfunctional mitochondria. Corresponding to their role in regulating mitochondrial homeostasis, we found that SKN-1/Nrf2 and GST-4 are critical in the β-asarone treatment, and they appear to be activated via the insulin/IGF-1 signaling pathway. Well-developed intestinal microvilli are required for this process. Our study demonstrates the efficacy and mechanism of β-asarone treatment in age-related motor decline, contributing to the discovery of drugs for achieving healthy aging.

Brain Iron in signature regions relating to cognitive aging in older adults: the Taizhou Imaging Study

BackgroundRecent magnetic resonance imaging (MRI) studies have established that brain iron accumulation might accelerate cognitive decline in Alzheimer’s disease (AD) patients. Both normal aging and AD are associated with cerebral atrophy in specific regions. However, no studies have investigated aging- and AD-selective iron deposition-related cognitive changes during normal aging. Here, we applied quantitative susceptibility mapping (QSM) to detect iron levels in cortical signature regions and assessed the relationships among iron, atrophy, and cognitive changes in older adults.MethodsIn this Taizhou Imaging Study, 770 older adults (mean age 62.0 ± 4.93 years, 57.5% women) underwent brain MRI to measure brain iron and atrophy, of whom 219 underwent neuropsychological tests nearly every 12 months for up to a mean follow-up of 2.68 years. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Domain-specific cognitive scores were obtained from MoCA subscore components. Regional analyses were performed for cortical regions and 2 signature regions where atrophy affected by aging and AD only: Aging (AG) -specific and AD signature meta-ROIs. The QSM and cortical morphometry means of the above ROIs were also computed.ResultsSignificant associations were found between QSM levels and cognitive scores. In particular, after adjusting for cortical thickness of regions of interest (ROIs), participants in the upper tertile of the cortical and AG-specific signature QSM exhibited worse ZMMSE than did those in the lower tertile [β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\\beta\\:$$\\end{document} = -0.104, p = 0.026; β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\\beta\\:$$\\end{document} = -0.118, p = 0.021, respectively]. Longitudinal analysis suggested that QSM values in all ROIs might predict decline in ZMoCA and key domains such as attention and visuospatial function (all p < 0.05). Furthermore, iron levels were negatively correlated with classic MRI markers of cortical atrophy (cortical thickness, gray matter volume, and local gyrification index) in total, AG-specific signature and AD signature regions (all p < 0.05).ConclusionAG- and AD-selective iron deposition was associated with atrophy and cognitive decline in elderly people, highlighting its potential as a neuroimaging marker for cognitive aging.

Shuttle Time for Seniors: The Impact of 8-Week Structured Badminton Training on Markers of Healthy Aging and Evaluation of Lived Experiences-A Quasi-Experimental Study.

Engagement in sport offers the potential for improved physical and psychological well-being and has been shown to be beneficial for promoting healthy aging. Opportunities for older adults to (re)engage with sport are limited by a paucity of age-appropriate introductory sports intervention programs. As such, the study evaluated the efficacy of a newly designed 8-week badminton training program (Shuttle Time for Seniors) on markers of healthy aging and the lived experiences of participation. Forty-three older adults assigned to a control (N = 20) or intervention group (N = 23) completed pre-post assessment of physical and cognitive function, self-efficacy for exercise, and well-being. Focus groups were conducted for program evaluation and to understand barriers and enablers to sustained participation. Those in the intervention group increased upper body strength, aerobic fitness, coincidence anticipation time, and self-efficacy for exercise. Objectively improved physical and cognitive functions were corroborated by perceived benefits indicated in thematic analysis. Shuttle Time for Seniors was perceived as appropriate for the population, where the age-appropriate opportunity to participate with likeminded people of similar ability was a primary motivator to engagement. Despite willingness to continue playing, lack of badminton infrastructure was a primary barrier to continued engagement. Shuttle Time for Seniors offered an important opportunity for older adults to (re)engage with badminton, where the physical and psychosocial benefits of group-based badminton improved facets important to healthy aging. Significance/Implications: Age-appropriate introductory intervention programs provide opportunity for older adults to (re)engage with sport. However, important barriers to long-term engagement need to be addressed from a whole systems perspective.

Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis

Background & AimExpression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. MethodsCDKN1A expression levels were evaluated in different patients‘ cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH binges, or a DuAL diet. Primary hepatocytes were isolated and functional assays performed. ResultsA significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAS and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in – fatty acid oxidation (FAO) and reduction in free fatty acid (FFA) uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. ConclusionsCdkn1a deletion protected against preclinical SLD by promoting FAO and preventing FFA uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAS and fibrosis in SLD patients. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in SLD patients, with and without alcohol consumption.

Lens capsule advanced glycation end products induce senescence in epithelial cells: Implications for secondary cataracts.

Posterior capsule opacification (PCO) is a common complication after cataract surgery. Residual lens epithelial cells (LECs) on the anterior lens capsule, after cataract surgery, migrate to the posterior lens capsule and undergo transdifferentiation into myofibroblast-like cells. Those cells synthesize excessive amounts of extracellular matrix and contribute to fibrosis during PCO. Cellular senescence, a phenomenon that increases with aging, has been implicated in several fibrotic diseases. Here, we have investigated the prevalence of senescent LECs within the lens posterior capsule and the ability of advanced glycation end products (AGEs) in lens capsules to induce senescence, contributing to PCO. Aged lens capsules from pseudophakic human cadaver eyes showed the presence of senescent LECs. In human capsular bags, LECs showed an age-dependent increase in senescence after 28 days of culture. Human LECs cultured on aged lens capsules for 3 days underwent senescence; this effect was not seen in LECs cultured on young lens capsules. Human LECs cultured on an AGE-modified extracellular matrix (ECM-AGEs) showed an AGE-concentration-dependent increase in the expression of senescence markers and reactive oxygen species (ROS) levels. Treatment with a RAGE antagonist and ROS inhibitor reduced the expression of senescence and fibrotic markers. Additionally, conditioned media from ECM-AGEs-treated cells induced the expression of fibrotic markers in naïve LECs. Together, these suggest that AGEs in the capsule induce senescence of LECs, which triggers the mesenchymal transition of neighboring non-senescent LECs and contributes to PCO.

Sex-differential markers of psychiatric risk and treatment response based on premature aging of functional brain network dynamics and peripheral physiology

BackgroundAging is a multilevel process of gradual decline that predicts morbidity and mortality. Independent investigations have implicated senescence of brain and peripheral physiology in psychiatric risk, but it is unclear whether these effects stem from unique or shared mechanisms. MethodsTo address this question, we analyzed clinical, blood chemistry and resting state functional neuroimaging data in a healthy aging cohort (N= 427; age 36-100 years) and two disorder-specific samples encompassing patients with early psychosis (100 patients, 16-35 years) and major depressive disorder (MDD) (104 patients, 20-76 years). ResultsWe identified sex-dependent coupling between blood chemistry markers of metabolic senescence (i.e., homeostatic dysregulation), functional brain network aging, and psychiatric risk. In females, premature aging of frontoparietal and somatomotor networks was linked to greater homeostatic dysregulation. It also predicted the severity and treatment resistance of mood symptoms (depression/anxiety [all three samples], anhedonia [MDD]) and social withdrawal/behavioral inhibition (avoidant personality disorder [healthy aging]; negative symptoms [early psychosis]). In males, premature aging of the default mode, cingulo-opercular, and visual networks was linked to reduced homeostatic dysregulation and predicted severity and treatment resistance of symptoms relevant to hostility/aggression (antisocial personality disorder [healthy aging]; mania/positive symptoms [early psychosis]), impaired thought processes (early psychosis, MDD) and somatic problems (healthy aging, MDD). ConclusionsOur findings identify sexually dimorphic relationships between brain dynamics, peripheral physiology, and risk for psychiatric illness, suggesting that the specificity of putative risk biomarkers and precision therapeutics may be improved by considering sex and other relevant personal characteristics.

Transcription Factor Analysis to Investigate Immunosenescence in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is linked to various signs of advanced aging, such as premature immunosenescence which occurs due to decline in regenerative ability of T cells. RA T cells develop a unique aggressive inflammatory senescent phenotype with an imbalance of Th17/T regulatory (Treg) cell homeostasis and presence of CD28- T cells. The phenotypic analysis and characterization of T cell subsets become necessary to ascertain if any functional deficiencies exist within with the help of transcription factor (TF) analysis. These subset-specific TFs dictate the functional characteristics of T-cell populations, leading to the production of distinct effector cytokines and functions. Examining the expression, activity, regulation, and genetic sequence of TFs not only aids researchers in determining their importance in disease processes but also aids in immunological monitoring of patients enrolled in clinical trials, particularly in evaluating various T-cell subsets [Th17 (CD3+CD4+IL17+RORγt+) cells and T regulatory (Treg) (CD3+CD4+CD25+CD127-FOXP3+) cells], markers of T-cell aging [aged Th17 cells (CD3+CD4+IL17+RORγt+CD28-), and aged Treg cells (CD3+CD4+CD25+CD127-FOXP3+CD28-)]. In this context, we propose and outline the protocols for assessing the expression of TFs in aged Th17 and Treg cells, highlighting the crucial aspects of this cytometric approach.

Methylation of Selected CpG-Sites of the Gene CSF1 as a Factor in Regulation of Its Expression and a Marker of Human Biological Aging

—Age-associated transformation of methylation patterns is considered to be an important predictor of human biological age. Changes in the level of CpG-dinucleotide methylation contribute to a shift in the function of a number of genes, including those associated with the functioning of the immune system. One such gene is CSF1. The protein product of this gene is associated with inflammatory aging, making it an important biomarker of age-related diseases. We studied the methylation profile of the promoter-associated CpG island of the CSF1 gene by MALDI-TOF mass spectrometry. Dependences between the character of CpG-site methylation within the investigated regions and the relative level of the gene mRNA and its protein product in people of different age groups were sought. For two CpG sites, a high level of correlation with the studied parameters is shown. A search for the landing sites of transcription factor binding sites associated with gene transcription showed that these CpG dinucleotides are part of motifs for the NFI family transcription factors and the EGR1 factor. We hypothesize that these CpG sites play an important role in the regulation of CSF1 gene expression.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

Differentiating primary from metastatic ovarian tumors of gastrointestinal origin by CT

PurposeTo determine differentiating CT imaging features of primary ovarian cancers from ovarian metastases of gastrointestinal origin. MethodsRetrospective study of 50 patients with new ovarian lesions on CT, half were primary ovarian cancers and half gastrointestinal metastases. Two blinded independent readers described tumor characteristics on CT (size, laterality, margin, etc.) and ancillary features (ascites, peritoneal seeding, lymphadenopathy, etc.). Patient age, sex, cancer history, and tumor marker levels for CA-125 and CEA were collected. Wilcoxon test and Pearson's chi-squared test were used for statistical analysis. Results50 patients with mean age of 62.1 years were included. Ovarian metastases were more likely to be cystic/mainly cystic (p=0.013), have smooth margins (p=0.011), and have no/mild enhancement (p<0.001). Primary ovarian lesions were associated with moderate to large volume of ascites (p=0.047) and more commonly seen with lymphadenopathy (p=0.008). Laterality was not significantly different between the two groups. CA-125 level was more commonly elevated in primary ovarian lesions (87% vs 50%, p=0.018), and with much higher values (1076.5 vs 155.1, p=0.013). CEA level was more commonly elevated in metastatic ovarian lesions (83.3% vs 15.4%, p<0.001), and with higher values (72.4 vs 2.1, p<0.001). ConclusionOvarian metastases were more frequently smooth-margined and cystic with little enhancement. Primary ovarian lesions were more commonly associated with lymphadenopathy and larger volume of ascites. Tumor markers CEA and CA-125 were more frequently elevated in metastatic and primary lesions, respectively. Cancer history was the only variable that increased the odds of metastasis and therefore it is important to always correlate with history of cancer.

Deep learning assessment of senescence-associated nuclear morphologies in mammary tissue from healthy female donors to predict future risk of breast cancer: a retrospective cohort study

Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumour-promoting microenvironmental mechanism that secretes proinflammatory paracrine factors. With most work done in non-human models and the heterogeneous nature of senescence, the precise role of senescent cells in the development of cancer in humans is not well understood. Furthermore, more than 1 million non-malignant breast biopsies are taken every year that could be a major resource for risk stratification. We aimed to explore the clinical relevance for breast cancer development of markers of senescence in mammary tissue from healthy female donors. In this retrospective cohort study, we applied single-cell deep learning senescence predictors, based on nuclear morphology, to histological images of haematoxylin and eosin-stained breast biopsy samples from healthy female donors at the Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (Indianapolis, IN, USA). All KTB participants (aged ≥18 years) who underwent core biopsies for research purposes between 2009 and 2019 were eligible for the study. Senescence was predicted in the epithelial (terminal duct lobular units [TDLUs] and non-TDLU epithelium), stromal, and adipose tissue compartments using validated models, previously trained on cells induced to senescence by ionising radiation (IR), replicative exhaustion (or replicative senescence; RS), or antimycin A, atazanavir-ritonavir, and doxorubicin (AAD) exposures. To benchmark our senescence-based cancer prediction results, we generated 5-year Gail scores-the current clinical gold standard for breast cancer risk prediction-for participants aged 35 years and older on the basis of characteristics at the time of tissue donation. The primary outcome was estimated odds of breast cancer via logistic modelling for each tissue compartment based on predicted senescence scores in cases (participants who had been diagnosed with breast cancer as of data cutoff, July 31, 2022) and controls (those who had not been diagnosed with breast cancer). 4382 female donors (median age at donation 45 years [IQR 34-57]) were eligible for the study. As of data cutoff (median follow-up of 10 years [7-11]), 86 (2·0%) had developed breast cancer a mean of 4·8 years (SD 2·84) after date of donation and 4296 (98·0%) had not received a breast cancer diagnosis. Among the 86 cases, we found significant differences in adipose-specific IR and AAD senescence prediction scores compared with controls. Risk analysis showed that individuals in the upper half (above the median) of scores for the adipose tissue IR model had higher odds of developing breast cancer (odds ratio [OR] 1·71 [95% CI 1·10-2·68]; p=0·019), whereas the adipose AAD model revealed a reduced odds of developing breast cancer (OR 0·57 [0·36-0·88]; p=0·013). For the other tissue compartments and the RS model, no significant associations were found (except for stromal tissue via the IR model, had higher odds of developing breast cancer [OR 1·59, 1·03-2·49]). Individuals with both of the adipose risk factors had an OR of 3·32 (1·68-7·03; p=0·0009). Participants with 5-year Gail scores above the median had an OR for development of cancer of 2·33 (1·46-3·82; p=0·0012) compared with those with scores below the median. When combining Gail scores with our adipose AAD risk model, we found that individuals with both of these predictors had an OR of 4·70 (2·29-10·90; p<0·0001). When combining the Gail score with our adipose IR model, we found that individuals with both predictors had an OR of 3·45 (1·77-7·24; p=0·0002). Assessment of senescence-associated nuclear morphologies with deep learning allows prediction of future cancer risk from normal breast biopsy samples. The combination of multiple models improved prediction of future breast cancer compared with the current clinical benchmark, the Gail model. Our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. Novo Nordisk Foundation, Danish Cancer Society, and the US National Institutes of Health.

The Comparative Effects Between Long-Term and Short-Term Treatment of Finasteride on Anxiety-Like and Depression-Like Behaviors in Early Senescent Male Rats.

This study aims to compare the efficacy of 5-alpha-reductase inhibitors (5ARIs) on anxiety and depression between long-term and short-term treatment followed by withdrawal in d-galactose (Dgal)-induced senescent male rats. Thirty-two, 8-week-old, male Wistar rats were divided into two groups: control rats and Dgal-treated rats (150 mg/kg/day; subcutaneously) for 18 weeks. At week 13, Dgal-treated rats were subdivided into three subgroups: (1) vehicle (DgV), (2) long-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 6 weeks (DgF), (3) short-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 2 weeks followed by a 4-week withdrawal period (DgW). Anxiety and depression were assessed using the elevated-plus maze (EPM) and splash test (ST). Blood was collected for biochemical analysis. After euthanasia, the brains were removed to examine brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and brain senescent markers. We found that DgV rats exhibited metabolic disturbance with a reduced preference index of the EPM, and grooming duration in ST. Increased brain neurotoxic metabolites, along with increased brain inflammation/oxidative stress, and reduced microglia complexity were observed in the DgV rats. Both therapeutic approaches improved metabolic parameters and preference index in the open arm of EPM in Dgal-treated rats, while grooming duration and microglia complexity were increased only in DgF rats. Our results indicate that Fin reduces depression-like and anxiety-like behaviors by reducing brain inflammation, oxidative stress, and brain senescent. In conclusion, long-term treatment with 5ARIs is more effective in alleviating depression than short-term treatment followed by withdrawal in Dgal-induced early senescent male rats.

The impact of alternate-day fasting on the salivary gland stem cell compartments in non-obese diabetic mice with newly established Sjögren's syndrome.

Intermittent fasting exerts a profound beneficial influence on a spectrum of diseases through various mechanisms including regulation of immune responses, elimination of senescent- and pathogenic cells and improvement of stem cell-based tissue regeneration in a disease- and tissue-dependent manner. Our previous study demonstrated that alternate-day fasting (ADF) led to alleviation of xerostomia and sialadenitis in non-obese diabetic (NOD) mice, a well-defined model of Sjögren's syndrome (SS). This present study delved into the previously unexplored impacts of ADF in this disease setting and revealed that ADF increases the proportion of salivary gland stem cells (SGSCs), defined as the EpCAMhi cell population among the lineage marker negative submandibular gland (SMG) cells. Furthermore, ADF downregulated the expression of p16INK4a, a cellular senescence marker, which was concomitant with increased apoptosis and decreased expression and activity of NLRP3 inflammasomes in the SMGs, particularly in the SGSC-residing ductal compartments. RNA-sequencing analysis of purified SGSCs from NOD mice revealed that the significantly downregulated genes by ADF were mainly associated with sugar metabolism, amino acid biosynthetic process and MAPK signaling pathway, whereas the significantly upregulated genes related to fatty acid metabolic processes, among others. Collectively, these findings indicate that ADF increases the SGSC proportion, accompanied by a modulation of the SGSC property and a switch from sugar- to fatty acid-based metabolism. These findings lay the foundation for further investigation into the functionality of SGSCs influenced by ADF and shed light on the cellular and molecular mechanisms by which ADF exerts beneficial actions on salivary gland restoration in SS.

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence-associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS.

Lifetime chronic stress Exposures, stress Hormones, and biological Aging: Results from the midlife in the United States (MIDUS) study

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26–78 years (Mage = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life.

Universal Markers of Cellular and Replicative Senescence

The investigation into cellular and replicative aging is crucial for both biology and medicine, particularly in light of the increasing percentage of the older population. Gaining a deeper understanding of the mechanisms of these forms of aging can help develop strategies aimed at prolonging active longevity. By comparing the processes of cellular and replicative aging, researchers can reveal both common and distinct molecular mechanisms, thus opening innovative approaches for diagnosing and treating age-related diseases. The identified aging markers can contribute to personalized medicine, improving the diagnosis and treatment of aging cells. Thus, these studies enhance developing methods for combating age-related diseases.AIM. The study aims to analyze cellular and replicative aging in order to identify common mechanisms underlying the aging process. The goal is to understand the relationship between these processes and their influence on age-related changes. Specific objectives include identifying aspects of aging and identifying molecular markers that can be used for the diagnosis and monitoring of age-related disorders. The findings from this study will contribute to the prevention and management of age-related conditions, thereby improving overall population health.MATERIALS AND METHODS. The public datasets E-MTAB-4879 (cellular senescence) and GSE130727 (replicative senescence) were analysed. Quality control was carried out using the FastQC program. Adapter removal was performed by sequencing using the cutadapt 2.3 and Trimmomatic-0.38 programs. Mapping was done using the bowtie2-2.4.0 program. Re-verification of the mapping results was performed using the kallisto-v0.45.0 pseudo-alignment algorithm. Quantification was done using featureCounts. RPKM (Read Per Kilobase per Million) normalization was applied (to the average total reads, coverage depth, and gene length). The mirnet.ca online service was used to search for regulatory miRNAs.RESULTS. For groups of genes that showed decreased (7,275) and increased (5,059) expression levels in the E-MTAB-4879 and GSE130727 datasets after filtering, we identified the biological processes they are involved in. For lists of the top 15 genes, we provided information on their role in the aging process. Additionally, for a group of commonly expressed genes, functional groups were determined using GO. The study compared two aging-related gene datasets and identified a total of 7,275 genes with decreased expression. Of these, 1,342 showed significant decreases in expression, with processes related to G-protein signaling, cholesterol metabolism, and cytokine signaling standing out. Some genes affect aging through inflammatory responses, membrane potential control, neurodegeneration, and cell differentiation. Further analyses identified 143 non-coding RNAs associated with aging and cancer. In a separate group, 1,673 genes exhibited increased expression, involving processes such as glycerolipid biosynthesis and actin filament regulation, as well as wound healing. Among these, 194 non-coding RNAs were linked to oncogenesis and osteogenesis.CONCLUSION. In conclusion, our study has identified key differences and similarities between cellular and replicative aging. This has allowed us to gain a deeper understanding of these aging processes and their roles in age-related changes. The analysis revealed that common molecular mechanisms such as decreased gene expression related to G-protein signaling and cholesterol metabolism significantly influence both forms of aging. Additionally, unique features have been identified, including differences in gene and non-coding RNA expression, which opens up possibilities for the development of personalized diagnostic and treatment strategies. These identified markers and mechanisms have the potential to contribute not only to diagnosis but also to monitoring of age-related changes and improving approaches to age-associated disease treatment. Therefore, our research significantly contributes to the development of techniques to combat age-associated illnesses by emphasizing the significance of investigating both the common and distinctive features of cellular and replicative aging processes.

Nongenetic and Genetic Factors Associated with White Matter Brain Aging: Exposome-Wide and Genome-Wide Association Study.

Human brain aging is a complex process that affects various aspects of brain function and structure, increasing susceptibility to neurological and psychiatric disorders. A number of nongenetic (e.g., environmental and lifestyle) and genetic risk factors are found to contribute to the varying rates at which the brain ages among individuals. In this paper, we conducted both an exposome-wide association study (XWAS) and a genome-wide association study (GWAS) on white matter brain aging in the UK Biobank, revealing the multifactorial nature of brain aging. We applied a machine learning algorithm and leveraged fractional anisotropy tract measurements from diffusion tensor imaging data to predict the white matter brain age gap (BAG) and treated it as the marker of brain aging. For XWAS, we included 107 variables encompassing five major categories of modifiable exposures that potentially impact brain aging and performed both univariate and multivariate analysis to select the final set of nongenetic risk factors. We found current tobacco smoking, dietary habits including oily fish, beef, lamb, cereal, and coffee intake, length of mobile phone use, use of UV protection, and frequency of solarium/sunlamp use were associated with the BAG. In genetic analysis, we identified several SNPs on chromosome 3 mapped to genes IP6K1, GMNC, OSTN, and SLC25A20 significantly associated with the BAG, showing the high heritability and polygenic architecture of human brain aging. The critical nongenetic and genetic risk factors identified in our study provide insights into the causal relationship between white matter brain aging and neurodegenerative diseases.

Measures of spatial memory, peripheral inflammation and negative emotional state predict social-cognitive skills in healthy aging cats

Aging is a complex, multidimensional process. Normative aging is typically accompanied by declines in several cognitive domains, including memory and social cognition. As aging progresses, the often-overlooked early manifestations of cognitive decline can advance, leading to an inability to adapt to new situations and environments. Potential mechanisms influencing cognitive decline remain elusive, but, among other mechanisms, inflammaging, an age-related increase in the chronic production of pro-inflammatory mediators, and emotional stress are implicated. Cognitive function in cats is under-researched, with no studies on the link between potential risk factors and cognitive signs in aging subjects. Understanding this link is essential as it may facilitate the early identification of cognitive decline and encourage preventative, individualized interventions. We carried out a citizen science study to investigate, for the first time, the relationship between cognitive functions, stress, and the inflammatory markers interleukin (IL)-1β and IL-10 in 44 healthy, privately owned pet cats (7–14 years of age), who underwent standardized testing in their home environment. A task was employed to test spatial memory, requiring the cat to recall the location of a food-baited container. An unsolvable task was used to assess cats' social cognition and cognitive flexibility by measuring how they used referential communication (i.e., gaze alternation between the apparatus and the caregivers) compared to their persistence in trying to obtain food which was out of reach. Generalized linear regression analysis, conducted while adjusting for demographic factors and stress behaviors, revealed: 1) a predictive positive relationship connecting spatial memory and the use of social referencing with the caregiver (more gaze alternation) in the unsolvable task, highlighting the importance of the interplay between cognitive domains in sustaining complex behaviors, and 2) a reduced engagement in social referencing toward caregivers (less gaze alternation) in the presence of higher serum levels of IL-1β in the unsolvable task, especially as cats get older. A cat’s social cognitive performance was also negatively predicted by stress-related behaviors, which is not surprising given that cats are sentient creatures whose everyday behavior is also influenced by emotional states. These findings provide new insights into the crosstalk between different cognitive domains during aging and the potential contributions of emotions and inflammation to cognitive changes in healthy aging cats. Further research using this multidimensional approach will help explore these mechanisms of cognitive aging and potential markers for early detection of cognitive changes in older cats, which is critical for timely interventions.

Application of a deep-learning marker for morbidity and mortality prediction derived from retinal photographs: a cohort development and validation study

Biological ageing markers are useful to risk stratify morbidity and mortality more precisely than chronological age. In this study, we aimed to develop a novel deep-learning-based biological ageing marker (referred to as RetiPhenoAge hereafter) using retinal images and PhenoAge, a composite biomarker of phenotypic age. We used retinal photographs from the UK Biobank dataset to train a deep-learning algorithm to predict the composite score of PhenoAge. We used a deep convolutional neural network architecture with multiple layers to develop our deep-learning-based biological ageing marker, as RetiPhenoAge, with the aim of identifying patterns and features in the retina associated with variations of blood biomarkers related to renal, immune, liver functions, inflammation, and energy metabolism, and chronological age. We determined the performance of this biological ageing marker for the prediction of morbidity (cardiovascular disease and cancer events) and mortality (all-cause, cardiovascular disease, and cancer) in three independent cohorts (UK Biobank, the Singapore Epidemiology of Eye Diseases [SEED], and the Age-Related Eye Disease Study [AREDS] from the USA). We also compared the performance of RetiPhenoAge with two other known ageing biomarkers (hand grip strength and adjusted leukocyte telomere length) and one lifestyle factor (physical activity) for risk stratification of mortality and morbidity. We explored the underlying biology of RetiPhenoAge by assessing its associations with different systemic characteristics (eg, diabetes or hypertension) and blood metabolite levels. We also did a genome-wide association study to identify genetic variants associated with RetiPhenoAge, followed by expression quantitative trait loci mapping, a gene-based analysis, and a gene-set analysis. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and corresponding 95% CIs for the associations between RetiPhenoAge and the different morbidity and mortality outcomes. Retinal photographs for 34 061UK Biobank participants were used to train the model, and data for 9429participants from the SEED cohort and for 3986participants from the AREDS cohort were included in the study. RetiPhenoAge was associated with all-cause mortality (HR 1·92 [95% CI 1·42-2·61]), cardiovascular disease mortality (1·97 [1·02-3·82]), cancer mortality (2·07 [1·29-3·33]), and cardiovascular disease events (1·70[1·17-2·47]), independent of PhenoAge and other possible confounders. Similar findings were found in the two independent cohorts (HR 1·67 [1·21-2·31] for cardiovascular disease mortality in SEED and 2·07 [1·10-3·92] in AREDS). RetiPhenoAge had stronger associations with mortality and morbidity than did hand grip strength, telomere length, and physical activity. We identified two genetic variants that were significantly associated with RetiPhenoAge (single nucleotide polymorphisms rs3791224 and rs8001273), and were linked to expression quantitative trait locis in various tissues, including the heart, kidneys, and the brain. Our new deep-learning-derived biological ageing marker is a robust predictor of mortality and morbidity outcomes and could be used as a novel non-invasive method to measure ageing. Singapore National Medical Research Council and Agency for Science, Technology and Research, Singapore.