Longevity Papers

Polycomb repressive complex 1 (PRC1) is a multisubunit, evolutionarily conserved epigenetic regulator critical to numerous biological processes. Being a core component of the canonical PRC1 subunit within the Polycomb group protein complex, Chromobox4 (CBX4), a SUMO E3 ligase, can bind to H3K27me3 and recruit PRC1. This ligase regulates the SUMOylation of various proteins and permits their post-translational modification under different physiological conditions. CBX4 has been reported to regulate the development of senescence and various diseases in vivo. This review delves into the physiological functions and action mechanisms of CBX4 across different tissues and cells, particularly focusing on its primarily roles in migration, cellular senescence, metabolic dysregulation, inflammation development, and tumor proliferation. Targeting CBX4 offers a therapeutic potential for delaying cell senescence and suppressing tumor growth.

T cell senescence and exhaustion represent critical aspects of adaptive immune system dysfunction, with profound implications for health and the development of disease prevention and therapeutic strategies. These processes, though distinct, are interconnected at the molecular level, leading to impaired effector functions and reduced proliferative capacity of T cells. Such impairments increase susceptibility to diseases and diminish the efficacy of vaccines and treatments. Importantly, T cell senescence and exhaustion can dynamically influence each other, particularly in the context of chronic diseases. A deeper understanding of the molecular mechanisms underlying T cell senescence and exhaustion, as well as their interplay, is essential for elucidating the pathogenesis of related diseases and restoring dysfunctional immune responses. This knowledge will pave the way for the development of targeted therapeutic interventions and strategies to enhance immune competence. This review aims to summarize the characteristics, mechanisms, and disease associations of T cell senescence and exhaustion, while also delineating the distinctions and intersections between these two states to enhance our comprehension.

Vascular Endothelial Growth Factor (VEGF) is a critical element in vascular dementia (VD) pathogenesis and therapeutic development while remaining strongly influenced by aging processes and cellular aging mechanisms. VEGF's multiple effects comprise neuroprotective functions, its role in vascular development, and its ability to regulate brain blood flow systems, all leading to cognitive preservation. The prefrontal cortex exhibits elevated VEGF gene levels, which directly matches the advancement of cognitive deficits in patients with Alzheimer's disease and VD. These patients exhibit higher VEGF levels in their CSF fluid, demonstrating that disease pathology includes multiple inseparable factors. Aging dramatically worsens VEGF regulation because endothelial dysfunction combines with chronic inflammation and oxidative stress to generate adverse vascular symptoms that include atherosclerosis and stroke. Cellular senescence convolutes these processes by causing damaging inflammatory reactions alongside impaired vascular healing abilities. The secretion of pro-inflammatory cytokines from senescent cells (SCs) disrupts VEGF signaling and produces harmful consequences for both vascular health and cognitive well-being. The neuroprotective properties of VEGF-A165a and VEGF-A165b variants demonstrate their ability to lessen β-amyloid and tau protein toxicity. The protective mechanisms of VEGF depend heavily on VEGF expression levels and receptor functionality, both of which decrease with aging. The combination of approaches that modulate VEGF signaling and SC accumulation shows potential for designing treatments against VD. People can sustain BBB functionality over a longer period through Mediterranean diet consumption together with aerobic exercise along with developing therapies, including senolytics and senomorphics, which delay neurodegenerative progression. Future investigative efforts must improve VEGF delivery methods while studying cellular senescence mechanisms and developing advanced methods to detect SC cells. A three-dimensional healthcare approach combining VEGF-targeted treatments with anti-ageing interventions and detailed diagnostic techniques shows the potential for effective VD management to achieve better patient results.

Adipogenesis is intricately linked to the onset and progression of muscle aging; however, the relevant biomarkers remain unclear. This study sought to identify key genes associated with adipogenesis in the context of muscle aging. Firstly, gene expression profiles from biopsies of the vastus lateralis muscle in both young and elderly population were retrieved from the GEO database. After intersecting with the results of differential gene analysis, weighted gene co-expression network analysis, and sets of adipogenesis-related genes, 29 adipogenesis-related differential expressed genes (ARDEGs) were selected. Connectivity Map (cMAP) analysis identified tamsulosin, fraxidin, and alaproclate as key target compounds. In further, using three machine learning algorithms and the friends analysis, four hub ARDEGs, ESRRA, RXRG, GADD45A, and CEBPB were identified and verified in vivo aged mice muscles. Immune infiltration analysis showed a strong link between several immune cells and hub ARDEGs. In all, these findings suggested that ESRRA, RXRG, GADD45A, and CEBPB could serve as adipogenesis related biomarkers in muscle aging.

As the population ages, problems pertaining to health and life expectancy due to the aging heart have become increasingly prominent. The gut microbiota has become a potential therapeutic target in several diseases, including cardiovascular diseases. Current studies on the roles of the gut microbiota in the cardiovascular system have focused mainly on cardiovascular diseases; therefore, the effects of the gut microbiota on the natural aging of myocardial tissue remain unclear. The present study aimed to explore the roles and mechanisms of the gut microbiota and related metabolites in the natural aging of the heart. Animal models of fecal microbiota transplantation (FMT) were established in elderly and young rats. 16S rRNA sequencing revealed that the gut microbiota of the recipients shifted toward the profile of the donors, with concomitant cardiac structure and diastolic function changes detected via ultrasound and positron emission tomography-computed tomography (PET-CT). A group of significantly enriched myocardial metabolites detected by LC/MS were involved in the fatty acid β-oxidation process. Together with altered glucose uptake, as revealed by PET-CT, changes in ATP content and mitochondrial structure further verified a metabolic difference related to energy among rats transplanted with the gut microbiota from donors of different ages. This study demonstrated that gut microbes may participate in the physiological aging process of the rat heart by regulating oxidative stress and autophagy. The gut microbiota has been shown to be involved in the natural aging of the heart at multiple levels, from the organ level to the metabolically plastic myocardiocytes and associated molecules.

Aging is associated with a decline in the browning capacity of white adipose tissue (WAT), contributing to metabolic dysfunction. Beige adipocytes, which dissipate excess energy as heat, are a key feature of this process. In this study, we investigate the role of adipose stem and progenitor cells (ASPCs), specifically the Aregs (CD142+) subpopulation, in regulating beige adipocyte formation in aged mice under cold stimulation. Our findings reveal that Aregs significantly increase in the subcutaneous WAT (sWAT) of aged mice following cold exposure. We further demonstrate that Aregs secrete insulin-like growth factor binding protein 3 (IGFBP3), which appears to play a pivotal role in the cross-talk between adipogenesis-regulatory cells (Aregs) and smooth muscle cell-like (SMC-like) cells, thereby leading to the inhibition of beige adipocytes formation. Functional enrichment analysis highlighted the activation of TGFβ, MAPK and p53 signaling pathways in SMC-like cells, all of which are known to induce cell apoptosis and fibrosis. Moreover, IGFBP3 was found to interact with receptors and signaling molecules, including Egfr, Irf1 and Cdkn1a, in SMC-like cells, enhancing their apoptosis. Co-culture experiments confirmed that IGFBP3 significantly suppressed the formation of beige adipocytes, further corroborating its role in impairing browning. Overall, our study provides novel insights into the molecular mechanisms by which Aregs and IGFBP3 contribute to the age-related decline in WAT browning. These findings suggest potential therapeutic targets for reversing impaired WAT browning in aging and related metabolic disorders.

The quest to decipher the determinants of human longevity has intensified with the rise in global life expectancy. Long-lived individuals (LLIs), who exceed the average life expectancy while delaying age-related diseases, serve as a unique model for studying human healthy aging and longevity. Longevity is a complex phenotype influenced by both genetic and non-genetic factors. This review paper delves into the genetic, epigenetic, metabolic, immune, and environmental factors underpinning the phenomenon of human longevity, with a particular focus on LLIs, such as centenarians. By integrating findings from human longevity studies, this review highlights a diverse array of factors influencing longevity, ranging from genetic polymorphisms and epigenetic modifications to the impacts of diet and physical activity. As life expectancy grows, understanding these factors is crucial for developing strategies that promote a healthier and longer life.

Delicate external mechanosensing, efficient intracellular mechanotransduction and effective alveolar bone remodeling lay the foundation of orthodontic tooth movement (OTM). Periodontal ligament stem cells (PDLSCs) are thought to be the primary cells that withstand mechanical stimuli and respond to biomechanical signals during orthodontic treatment. Nevertheless, the cellular and molecular mechanisms of orthodontic force-induced mechanosignaling and osteogenesis in PDLSCs still remain unclear. In the present study, we hypothesize that the ageing suppressor, Klotho, is correlated with orthodontic force-triggered mechanical signaling cascades, further contributing to alveolar bone remodeling. This study reveals that Klotho expression is notably upregulated via cytoskeletal-nuclei-mediated epigenetic modifications, consistent with osteogenic differentiation on the tension side during OTM. Additionally, Klotho deficiency undermines tensile force-induced new bone formation in NFκB- and PI3K/Akt-dependent manners. Notably, RNA sequencing (RNA-seq) results and targeted force application experiments unveil that Klotho not only functions as a downstream effector of external stress but also acts as an upstream regulator in mechanical signaling for the first time. In summary, we identify the indispensable role of Klotho in mechanotransduction and alveolar bone formation, which provide a latent target of linking cell senescence to mechanical force in future studies and offer novel insights into orthodontic force-induced tooth movement and bone remodeling.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and associated disability worldwide. The cartilage endplate (CEP) is a critical structure in maintaining the homeostasis of the intervertebral disc, by exosomes (Exos)-mediated intracellular communication between cartilage endplate stem cells (CESCs) and nucleus pulposus cells (NPCs). However, whether the senescence of CESCs influences the functionality of CESCs-derived Exos (CESCs-Exos) and participates in the progress of IVDD remains unclear. In this study, we explored the role and mechanism of the Exos-based intracellular communication between senescent CESCs and NPCs in IVDD. CESCs isolated from aged individuals (S-CESCs) exhibited high levels of senescence compared with CESCs isolated from young individuals (Y-CESCs). Exos from Y-CESCs (Y-Exos) and from S-CESCs (S-Exos) were extracted and identified. Surprisingly, we found that S-Exos lost the therapeutic effects as the Y-Exos exhibited in mitigating IVDD, and even aggravated IVDD by inducing oxidative stress injury in NPCs. MicroRNA-sequencing revealed significant upregulation of miR-29b-3p expression in S-Exos. Through microRNA target prediction, dual luciferase assays, RNA-sequencing, lentivirus-mediated overexpression and suppression, we demonstrated that miR-29b-3p regulates the expression of FOXO3 and downstream antioxidant enzymes to induce oxidative stress injury in NPCs. In vivo experiments further verified that countering miR-29b-3p by antagomir reversed the detrimental effects of S-Exos in exacerbating IVDD. This work elucidates the role and mechanism of senescent CESCs in disrupting redox homeostasis in the nucleus pulposus and exacerbating IVDD by Exos-mediated intracellular communication and offers an experimental foundation for the selection of proper CESCs-Exos to obtain better therapeutic effects in IVDD.

Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to deliver novel therapeutic targets. Here we used spatial transcriptomic data from human MASLD liver biopsies to identify the major cell types and their potential interconnected activities within specific tissue regions across the spectrum of MASLD. Gene expression data were generated using 10X Genomics Visium technology from 33 formalin-fixed paraffin-embedded (FFPE) liver biopsy samples and overlaid with annotated anatomical regions. Differential gene expression (DEG) and pathway analyses, cellular deconvolution and ligand-receptor interactions were conducted separately for each annotated anatomical category, with specific protein expression validated using CODEX spatial proteomics (CO-Detection by Indexing) and immunohistochemistry staining. Unsupervised gene expression data grouped the annotated spots into 2 main clusters enriched for early/intermediate vs late fibrosis and transcriptome-based cellular deconvolution was well aligned with annotated histopathological features. In addition to extracellular matrix/receptor interactions and immune cell recruitment and trafficking, several genes encoding immunoglobulins (IGKC, IGHG, IGHA, IGLC) were highly upregulated in late-stage fibrosis and were spatially associated with a senescence signature. Upregulated DEGs for early/intermediate-stage fibrosis were significantly enriched for metabolic pathways, oxidative phosphorylation and fatty acid metabolism. In contrast glycolysis genes were strongly co-expressed with late stage fibrosis. MASLD progression is accompanied by a decline in normal liver metabolic function and significant reprogramming of metabolic fuel utilisation. The spatial association of a senescence signature with expression of genes encoding immunoglobulins and complement has been linked to aging and is associated with progressive fibrosis. This work provides a valuable discovery dataset spanning different stages of human liver fibrosis and identifies ligand-receptor interactions, as well as metabolic reprogramming and senescence-related genes, associated with fibrosis progression.

Decreased nicotinamide adenine dinucleotide (oxidized form) (NAD

Background: While studies have examined associations between changes in BMI and biological aging, the use of biological age estimates derived from omics other than DNA methylation data as well as nonlinearity and interactions in these associations are underexplored. Objective: We aimed to investigate how BMI at ages 18 and ~60, as well as changes in BMI from age 18 to ~60, relate to downstream epigenetic and proteomic aging. We also examined nonlinearity and interactions in these associations. Methods: We analyzed data from 401 Finnish participants with up to 9 self-reported or measured BMI values collected over 40 years. Olink proteomics and Illumina DNA methylation data were generated from blood samples taken at the last BMI measurement. We calculated 4 and 5 estimates of biological age from proteomic and epigenetic clocks, respectively. Changes in BMI over time were estimated using mixed-effects models. We applied generalized additive models to explore 1) nonlinearity in associations between BMI trajectories and biological aging while adjusting for chronological age and 2) smooth interactions between baseline BMI with changes in BMI and BMI at ~60 years old. Results: BMI at 18 and ~60 years old and changes in BMI were associated with increased biological aging for most aging estimates. We found statistical evidence of nonlinearity for about one-third of the significant associations, mostly observed for proteomic clocks. We identified suggestive evidence for interactions between BMI at 18 years and BMI at ~60 years in explaining variability in two proteomic clocks (p=0.07;p=0.09). Conclusion: Our study illustrates the potential of proteomic clocks in obesity research and highlights that assuming linearity in associations between BMI trajectories and biological aging is a critical oversight. Associations between BMI and biological aging are likely modulated by past BMI, which warrants validation by other studies.

Vascular cognitive impairment (VCI) is a leading cause of age-related cognitive decline, driven by cerebrovascular dysfunction and cerebral small vessel disease (CSVD). Emerging evidence suggests that cerebromicrovascular endothelial senescence plays an important role in the pathogenesis of VCI by promoting cerebral blood flow dysregulation, neurovascular uncoupling, blood-brain barrier (BBB) disruption, and the development of cerebral microhemorrhages (CMHs). This review explores the concept of cerebromicrovascular senescence as a continuum of vascular aging, linking macrovascular atherosclerosis with microvascular dysfunction. It examines the mechanisms by which endothelial senescence drives neurovascular pathology and highlights the impact of cardiovascular risk factors in accelerating these processes. We examine preclinical and clinical studies that provide compelling evidence that atherosclerosis-induced microvascular senescence exacerbates cognitive impairment. In particular, findings suggest that targeting senescent endothelial cells through senolytic therapy can restore cerebrovascular function and improve cognitive outcomes in experimental models of atherosclerosis. Given the growing recognition of microvascular senescence as a therapeutic target, further research is warranted to explore novel interventions such as senolytics, anti-inflammatory agents, and metabolic modulators. The development of circulating biomarkers of vascular senescence (e.g., senescence-associated secretory phenotype [SASP] components and endothelial-derived extracellular vesicles) could enable early detection and risk stratification in individuals at high risk for VCI. Additionally, lifestyle modifications, including the Mediterranean diet, hold promise for delaying endothelial senescence and mitigating cognitive decline. In conclusion, cerebromicrovascular senescence is a key mechanistic link between atherosclerosis and cognitive impairment. Addressing microvascular aging as a modifiable risk factor through targeted interventions offers a promising strategy for reducing the burden of VCI and preserving cognitive function in aging populations.

White matter (WM) microstructural health declines with increasing age, with evidence suggesting that improved cardiorespiratory fitness (CRF) may mitigate this decline. Specifically, higher fit older adults tend to show preserved WM microstructural integrity compared to their lower fit counterparts. However, the extent to which fitness and aging independently impact WM integrity across the adult lifespan is still an open question, as is the extent to which cerebrovascular health mediates these relationships. In a large sample (N = 125, aged 25-72), we assessed the impact of age and estimated cardiorespiratory fitness on fractional anisotropy (FA, derived using diffusion weighted imaging, dwMRI) and probed the mediating role of cerebrovascular health (derived using diffuse optical tomography of the cerebral arterial pulse, pulse-DOT) in these relationships. After orthogonalizing age and estimated fitness and computing a PCA on whole brain WM regions, we found several WM regions impacted by age that were independent from the regions impacted by estimated fitness (hindbrain areas, including brainstem and cerebellar tracts), whereas other areas showed interactive effects of age and estimated fitness (midline areas, including fornix and corpus callosum). Critically, cerebrovascular health mediated both relationships suggesting that vascular health plays a linking role between age, fitness, and brain health. Secondarily, we assessed potential sex differences in these relationships and found that, although females and males generally showed the same age-related FA declines, males exhibited somewhat steeper declines than females. Together, these results suggest that age and fitness impact specific WM regions and highlight the mediating role of cerebrovascular health in maintaining WM health across adulthood.

Aging is associated with increased variability and dysregulation of the immune system. We performed a system-level analysis of serum cytokines in a longitudinal cohort of 133 healthy individuals over 9 y. We found that cancer incidence is a major contributor to increased cytokine abundance variability. Circulating cytokines increase up to 4 y before a cancer diagnosis in subjects with age over 80 y. We also analyzed cytokine expression in 10 types of early-stage cancers from The Cancer Genome Atlas. We found that a similar set of cytokines is upregulated in tumor tissues, specifically after the age of 80 y. Similarly, cellular senescence activity and CDKN1A/p21 expression increase with age in cancer tissues. Finally, we demonstrated that the cytokine levels in serum can be used to predict cancers among subjects age at 80+ y. Our results suggest that latent senescent cancers contribute to age-related chronic inflammation.

Curcumin (Cur) and epigallocatechin gallate (EGCG), the primary active compounds in turmeric and green tea, respectively, have been investigated for their anti-aging potential. The Cur and EGCG combination was encapsulated in sustained-release nanostructured lipid carriers (NLCs) to enhance their bioactivities and pharmaceutical properties. A significant enhancement in the antioxidant activities of the Cur and EGCG combination was observed at an optimal ratio, as demonstrated by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay (118.83 ± 3.78 %), ferric ion reducing antioxidant power assay (217.25 ± 13.45 %), and lipid peroxidation inhibition assay (106.08 ± 12.93 %), compared to Cur alone without compromising the antioxidant activities and total phenolic content of EGCG. This is due to the enhancement of total phenolic content of the combination of 218.83 ± 10.57 %. For anti-aging activities, the combination exhibited stimulation of SIRT1 protein and inhibition of collagenase and elastase of 27.53 ± 0.73 %, 43.70 ± 1.05 % and 51.76 ± 6.52 % compared with that achieved with Cur alone, respectively. The incorporation of the Cur and EGCG combination into NLCs resulted in high entrapment efficiencies of 98.60 ± 0.05 % for Cur and 98.40 ± 0.08 % for EGCG, with corresponding loading capacities of 0.789 ± 0.001 % and 3.935 ± 0.003 %, respectively. When formulated NLCs into an emulgel base, the system demonstrated sustained release profiles over 48 h, with 12.82 ± 0.99 % release of Cur and 63.77 ± 5.76 % release of EGCG. Significant skin retention was also observed after 24 h, with 23.88 ± 1.71 % Cur and 22.79 ± 4.65 % EGCG retained in the skin. Therefore, Cur: EGCG-loaded NLCs in emulgel can deliver the active compounds into the dermis, enhancing skin penetration, sustained delivery, and anti-aging activity superior to each conventional single active compound in topical formulations.

Nicotinamide adenine dinucleotide (NAD) is a crucial coenzyme involved in cellular energy homeostasis whose levels decline notably with aging, which has prompted interest in NAD+ boosting to combat age-related diseases and dysfunction. Numerous clinical trials have demonstrated safety and efficacy for B3 vitamins like nicotinamide riboside (NR) to increase NAD+ levels and augment the NAD+ metabolome. Limited impact on clinically relevant outcomes or quality of life have been demonstrated, however. This randomized, double-blind, placebo-controlled study examined the effects of Qualia NAD+(R) on whole blood NAD+ levels and quality of life measures. Twenty-five healthy adults aged 40 - 65 (56% female) consumed Qualia NAD+ (n = 9) or placebo (n = 16) for 28 consecutive days. NAD+ levels were measured using a novel self-administered, non-invasive blood spot assay test conducted at baseline and at study end, while quality of life measures were reported bi-weekly. Overall, Qualia NAD+ significantly increased NAD+ levels an average of 74% compared to a 4% increase observed in the placebo group (p < 0.001). Within-groups comparisons for Qualia NAD+, and changes in NAD+ levels comparing Qualia NAD+ and placebo were also significant (p < 0.001). Improvements in the overall and sexual categories (p = 0.02 and p = 0.04) were observed for males only comparing baseline to day 28, while no other quality of life changes were noted. Qualia NAD+, a novel nutraceutical formulated with multiple vitamins, nutrients, and botanical compounds, effectively increased whole blood NAD+ levels and improved some symptoms of aging in males. Clinicaltrials.gov identifier: NCT06812416.

Sleep is an essential homeostatic process that undergoes dynamic changes throughout the lifespan, with distinct life stages predisposed to specific sleep pathologies. Similarly, the gut microbiome also varies with age, with different signatures associated with health and disease in the latest decades of life. Emerging research has shown significant cross-talk between the gut microbiota and the brain through several pathways, suggesting the microbiota may influence sleep, though the specific mechanisms remain to be elucidated. Here, we critically examine the existing literature on the potential impacts of the gut microbiome on sleep and how this relationship varies across adulthood. We suggest that age-related shifts in gut microbiome composition and immune function may, in part, drive age-related changes in sleep. We conclude with an outlook on the therapeutic potential of microbiome-targeted interventions aimed at improving sleep across adulthood, particularly for individuals experiencing high stress or with sleep complaints.

Age-Related Hearing Loss (ARHL), or presbycusis, affects two-thirds of U.S. adults over 70 and is linked to cognitive decline and an increased risk of dementia. This study examines associations between white matter integrity and hearing and cognitive function in healthy aging using diffusion tensor imaging (DTI). We recruited 126 participants (92 female) aged 20-79 years (Mean=51.34,SD=20.54) from the Aging Brain Cohort Study at the University of South Carolina (ABC@UofSC). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), and hearing was evaluated through pure-tone thresholds (PTT) and words-in-noise (WIN) thresholds. White matter integrity was measured with fractional anisotropy (FA) and mean diffusivity (MD), and analyses examined relationships between these DTI metrics and hearing and cognitive scores using the region-of-interest regression analysis. Results showed significant associations between lower FA and higher MD values and poorer hearing and cognitive performance, particularly in the anterior and superior corona radiata, corpus callosum, and superior longitudinal fasciculus. Additionally, ANOVA comparisons between older adults with and without hearing impairments revealed significant MD differences in several regions, indicating specific microstructural changes linked to auditory impairment. This study contributes to the understanding of the neural bases of hearing and cognitive impairments, underscoring the potential of DTI as a complementary tool to gray matter-based studies in exploring reliable imaging evidence of hearing and cognitive impairments in healthy aging across adulthood.

The pathology of cardiovascular aging is complex, involving mitochondrial dysfunction, oxidative and nitrative stress, oxidative DNA injury, impaired lipid metabolism, cell death, senescence, and chronic inflammation. These processes lead to remodeling and structural changes in the cardiovascular system, resulting in a progressive decline in cardiovascular reserve capacity and health, and an increased risk of diseases and mortality. Excessive alcohol consumption exacerbates these risks by promoting hypertension, stroke, arrhythmias, coronary artery disease, cardiomyopathy, and sudden cardiac death, yet the effects of chronic alcohol consumption on cardiovascular aging remain unclear. Herein, we explored the impact of a 6-month 5% Lieber-DeCarli alcohol diet in young (3 months old) and aging (24-26 months old) Fisher F344BNF1 rats. We assessed detailed hemodynamics, mitochondrial function, oxidative/nitrative stress, lipid metabolism, inflammation, cell death, senescence, and myocardial fibrosis using the pressure-volume system, isolated vascular rings, and various histological, biochemical, and molecular biology methods. Alcohol consumption in both young and aging rats impaired mitochondrial function, disrupted cholesterol and triglyceride metabolism, and increased oxidative/nitrative stress, inflammation, cell death, and senescence, leading to a decline in systolic contractile function. In aging rats, alcohol further exacerbated diastolic dysfunction and myocardial fibrosis. Alcohol also increased oxidative/nitrative stress, apoptosis, and senescence in the vasculature, contributing to endothelial dysfunction and increased total peripheral resistance. Additionally, alcohol exacerbated the aging-related ventriculo-arterial uncoupling and diminished cardiac efficiency, further reducing cardiovascular reserve capacity. In conclusion, chronic alcohol consumption promotes cardiovascular aging and further diminishes the already impaired cardiac and vascular reserve capacity associated with aging.

Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis. We sought to determine if novel approaches using APOE allele status, age, and other demographic variables as a proxy for neuropathology could still effectively quantify resilience and uncover novel genetic drivers associated with better-than-expected cognitive performance while vastly expanding sample size and statistical power. Leveraging 20,513 participants from eight well-characterized cohort studies of aging, we determined the effects of genetic variants on resilience metrics using mixed-effects regressions. The outcome of interest was residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language) and built within two frameworks: "silver" models, which obviate the requirement for neuropathological data (n=17,241), and "gold" models, which include post-mortem neuropathological assessments (n=3,272). We then performed cross-ancestry genome wide association studies (European ancestry n=18,269, African ancestry n=2,244), gene and pathway-based tests, and genetic correlation analyses. All analyses were conducted across all participants and repeated when restricted to those with unimpaired cognition at baseline. Despite different modeling approaches, the silver and gold phenotypes were highly correlated (R=0.77-0.88) and displayed comparable performance in quantifying better-than or worse-than-expected cognition, enabling silver-gold meta-analyses. Genetic correlation analyses highlighted associations of resilience with multiple neuropsychiatric and cardiovascular traits (PFDR values < 5.0x10-2). In pathway-level tests, we observed three significant associations with resilience: metabolism of amino acids and derivatives (PFDR=4.1x10-2), negative regulation of transforming growth factor beta production (PFDR=1.9x10-2), and severe acute respiratory syndrome (PFDR=3.9x10-4). Finally, in single-variant analyses, we identified a locus on chromosome 17 approaching genome-wide significance among cognitively unimpaired participants (index single nucleotide polymorphism: rs757022, minor allele frequency = 0.18, β=0.08, P=1.1x10-7). The top variant at this locus (rs757022) was significantly associated with expression of numerous ATP-binding cassette genes in brain. Overall, through validating a novel modeling approach, we demonstrate the utility of silver models of resilience to increase statistical power and participant diversity.

The surgical treatment of geriatric patients represents a major challenge in traumatology. It is well known that aging affects fracture healing. However, the exact pathophysiology of age-related changes in angiogenesis, inflammation and bone remodeling remains still elusive. Therefore, we herein studied the differences of femoral fracture healing in young adult (3-4 months) and aged (16-18 months) CD-1 mice by using a stable closed femoral fracture model with intramedullary screw fixation. The callus tissue was analyzed by means of X-ray, micro-computed tomography (µCT), histology and immunohistochemistry. We found a deteriorated trabecular architecture and a reduced bone formation within the callus tissue of aged mice. Moreover, aged animals showed an increased number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts at an early healing time point, whereas the fraction of mature α-smooth muscle actin (SMA)-positive microvessels was significantly reduced. Furthermore, the numbers of macrophages and granulocytes were higher in the callus tissue of aged animals at the end of the healing process. Taken together, these results demonstrate a delayed femoral fracture healing in aged CD-1 mice. This is most likely caused by an early overshooting osteoclast response, a decelerated maturation of the callus microvasculature and a late increased recruitment of pro-inflammatory cells. Targeting these alterations may contribute to the development of novel treatment approaches for the stimulation of bone regeneration in geriatric patients.

Clonal hematopoiesis of indeterminate potential (CHIP) is a non-malignant state characterized by hematopoietic stem cells exhibiting clonality driven by acquired mutations during aging. Using next generation sequencing (NGS), it has been reported that the prevalence of CHIP increases exponentially with age. Thus far, epigenetic mutations including DNMT3A, TET2, and ASXL1 are the most common mutations identified in driving CHIP. CHIP is considered a pre-malignant state, however with reports of its associations with non-malignant disease states, the clinical impact of CHIP has been of great interest, in particular its effect on the renal and cardiac systems. CHIP has been associated with a higher rate of estimated glomerular filtration rate (eGFR) decline and increased risk of acute kidney injury (AKI). CHIP and its driver mutations, have also been shown to increase cardiovascular disease and atherosclerosis through various inflammatory pathways. In this review, we discuss the pathophysiology of CHIP through aging, its impact on kidney disease, and implications on cardiovascular health. We also compare CHIP to another pre-malignant clonal disorder, monoclonal gammopathy of undetermined significance (MGUS).

Successful aging (SA) refers to the ability to maintain high levels of physical, cognitive, psychological, and social engagement in old age, with high cognitive function being the key to achieving SA.

Perivascular spaces (PVS) are cerebrospinal fluid-filled tunnels around brain blood vessels, crucial for the functions of the glymphatic system. Changes in PVS have been linked to vascular diseases and aging, necessitating accurate segmentation for further study. PVS segmentation poses challenges due to their small size, varying MRI appearances, and the scarcity of annotated data. We present a finely segmented PVS dataset from T2-weighted MRI scans, sourced from the Human Connectome Project Aging (HCP-Aging), encompassing 200 subjects aged 30 to 100. Our approach utilizes a combination of unsupervised and deep learning techniques with manual corrections to ensure high accuracy. This dataset aims to facilitate research on PVS dynamics across different ages and to explore their link to cognitive decline. It also supports the development of advanced image segmentation algorithms, contributing to improved medical imaging automation and the early detection of neurodegenerative diseases.

Cellular senescence is a pivotal hallmark of aging, which limits lifespan and contributes to the development of age-related diseases. Efforts to identify senolytics - drugs that selectively eliminate senescent cells, have so far yielded candidates with limited translational potential. Here, we characterize the senescent cell surface proteomic landscape and identify proteins that are abnormally present on the plasma membrane of senescent cells. Many of these proteins are lysosomal enzymes, pointing to lysosomal exocytosis as a likely mechanism that leads to their persistent display on the cell surface. Blocking lysosomal exocytosis via PIKfyve kinase inhibition with a small molecule drug apilimod results in selective killing of senescent cells in vitro, while this treatment does not affect quiescent and proliferating cells. Furthermore, apilimod can be safely administered in vivo and effectively removes senescent cells and reduces tissue remodeling in a bleomycin mouse model of pulmonary fibrosis. We conclude that apilimod is an effective and well-tolerated senolytic that may be useful for the treatment of senescence-associated diseases of aging.

Understanding the trajectory of in vivo locus coeruleus (LC) signal intensity across the adult lifespan and among various demographic groups, particularly during middle age, may be crucial for early detection of neurodegenerative diseases, which begin in the LC decades before symptom onset. Even though pathological changes in the LC are thought to begin in middle age, its characteristics across the adult lifespan, and its consistency and variation across demographic groups, remain not well understood. Using T1-weighted turbo spin echo magnetic resonance (MRI) scans to characterize the LC, we measured LC signal intensity in 134 participants aged 19-86 years, with an effort to recruit a more racially diverse sample (41 % non-White). LC signal intensity was lowest in early adulthood, peaked around age 60, and then decreased again in the oldest adults, particularly in the caudal portion of the LC, which exhibited the greatest overall signal intensity; education, income, and history of early trauma did not alter this general pattern. Rostral LC signal intensity was further heightened in women and Black participants. In higher-performing older adults, increased rostral LC signal intensity was positively associated with higher fluid cognition. The potential accumulation of LC signal intensity across the adult lifespan and its possible dissipation in later life as well as its modification by demographic factors, may be associated with differential susceptibility to neurocognitive aging.

Cellular senescence is an irreversible form of cell-cycle arrest caused by excessive stress or damage. While various biomarkers of cellular senescence have been proposed, there are currently no universal, stand-alone indicators of this condition. The field largely relies on the combined detection of multiple biomarkers to differentiate senescent cells from non-senescent cells. Here we introduce a new approach: unbiased cell culture selections to identify senescent cell-specific folded DNA aptamers from vast libraries of trillions of random DNAs. Senescent mouse adult fibroblasts and their non-senescent counterparts were employed for selection. We demonstrate aptamer specificity for senescent mouse cells in culture, identify a form of fibronectin as the molecular target of two selected aptamers, show increased aptamer staining in naturally aged mouse tissues, and demonstrate decreased aptamer staining when p16 expressing cells are removed in a transgenic INK-ATTAC mouse model. This work demonstrates the value of unbiased cell-based selections to identify new senescence-specific DNA reagents.

The allostatic load (AL) concept measures physiological dysregulation in response to internal and external stressors that accumulate across the life course. AL has been consistently linked to chronic disease risk across studies. However, there is considerable variation in its operationalization. In the present study, DNA methylation (DNAm) data (using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) cohort, a Swiss-based family cohort study, were used in a discovery epigenome-wide association study (EWAS) to identify CpG sites associated with phenotypic measures of AL. Elastic net linear regression models were used to estimate an epigenetic signature of AL (methAL), including an Illumina HumanMethylation450K (HM450K) assay-compatible signature (methALT). The methALT signature was validated in the 1936 Lothian Birth Cohort (LBC1936), population-based prospective cohort study. We found that the methAL signature was positively associated with the clinical phenotype of AL in both the SKIPOGH (R2= 0.59) and LBC1936 (R2=0.16) cohorts. In the validation cohort, a one SD increase in methALT signature was associated with 25% higher odds of reported history of CVD (OR=1.25, 95% CI=1.05-1.50), and a nearly two-fold increase in all-cause mortality rate at the beginning of follow-up (HR= 1.68, 95% CI= 1.33-2.13) when adjusting for all potential confounders. In conclusion, the epigenetic signature for AL not only correlated well with phenotype-based AL scores, but also exhibited a stronger association with history of CVD and all-cause mortality compared to AL scores. The methAL signature could help assuage issues of comparison across studies.

Regeneration of hair cells is a primary target of gene therapy aimed at restoring vestibular and cochlear functions. Indeed, vestibular dysfunction constitutes a major medical concern, as one of its manifestation, dizziness, affects 15-35% of the general population, with a prevalence rate of 85% for those over 80 of age. Age-related alterations of both vestibular function and the integrity of vestibular hair cells has been reported in humans. However, direct comparisons between structural pathology and vestibular dysfunctions quantifications are lacking in humans and rather limited in animal models, representing a significant gap in current knowledge. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded varied and partial results, and the functional identity and quantity of hair cells sufficient to restore minimal or normal vestibular function remain undefined. Here, we further develop an innovative methodology to bridge the gap between hair cells integrity and functional vestibular loss in individuals. Gradual vestibular deficits were induced through a dose-dependent ototoxic compound, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individuals with the loss of type I and type II hair cells in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of hair cells necessary to retain minimal vestibular function, and threshold exceeding 80% to preserve normal function, thus shedding light on population-coding mechanisms for vestibular response. Our data further support the decisive role of type I, rather than type II, HC in the tested VOR functions.

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. The cardiac expression of succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme in ketolysis, decreases with aging in female mice. SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cKO mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.

Skin photoaging, one of the most critical types of exogenous skin aging, occurs when the skin is exposed to excessive ultraviolet radiation, leading to a series of skin-aging problems. The objective of this study was to utilize keratinocytes (HaCaT) treated with medium wave ultraviolet (UVB) as a photoaging model to investigate the anti-photoaging activity of chlorogenic acid (CGA) and preliminarily elucidate its underlying mechanism. The crystal violet assay shows that both 100 and 150 µM of CGA can significantly suppress the cell damage induced by 21.6 mJ/cm² UVB. Furthermore, the results of comet electrophoresis and Western Blot (WB) experiments demonstrate that CGA and OSS-128,167 (SIRT6 inhibitor) can effectively inhibit DNA damage caused by UVB, thereby alleviating cell apoptosis. The co-immunoprecipitation (CO-IP) and WB results suggest that CGA and OSS-128,167 can effectively suppress the activity and expression of the deacetylase of SIRT6, thus enhancing the expression of DDB2 and activating the nucleotide excision repair (NER) of cells to achieve the anti-photoaging effect. The aforementioned results imply that CGA activates NER repair and protects cells from UVB-induced damage by inhibiting the deacetylation activity of SIRT6 and subsequently decreasing the deacetylation modification of DDB2. The study elucidates the molecular mechanisms underlying the beneficial effects of CGA on skin photoaging and establishes a theoretical basis for the development of CGA based sunscreen formulations.

The aging central nervous system (CNS) is often marked by myelin degeneration, yet the underlying mechanisms remain elusive. This study delves into the previously unexplored role of autophagy in maintaining CNS myelin during aging. We generated the transgenic mouse line plpCre

Studies have shown that microRNAs (miRNAs) in red blood cells (RBCs) contribute most of the miRNAs in whole blood, and miRNAs in RBCs are closely related to storage lesions in vitro. However, the role of miRNAs in the process of RBC senescence in vivo remains unclear. We conducted a comprehensive miRNA expression analysis of RBCs collected from enriched mature RBCs in five density layers. The results showed that the type and number of RBC miRNAs changed with the aging of RBCs, the expression levels of 10 RBC miRNAs decreased markedly at the early stage of RBC aging and the levels of 5 RBC miRNAs increased significantly at the terminal stage of RBC senescence. The analysis identified 32 miRNAs whose changes in expression levels were correlated with the two selected aging indexes-pyruvate kinase (PK) activity and RBC indices. The differential expression amounts of the two selected miRNAs (miR-22-3p and miR-144-3p) were confirmed by real-time polymerase chain reaction (PCR) analysis. A bioinformatics analysis identified the potential targets and biological functions of these miRNAs. The experiment of miR-22-3p in the human erythroblast cell line K562 confirmed its negative effects on PK levels. Overall, our research demonstrates, for the first time, that changes in the expression levels of miRNAs during the RBC aging process, and RBC miRNAs thus have the potential to serve as markers of RBC aging in vivo. In addition, the expression of miR-22-3p may regulate RBC senescence by inhibiting PK levels.

Insulin-like growth factor 1 (IGF1) plays a critical role in metabolism and aging, but its role in the brain remains unclear. This study examined whether hypothalamic neurons respond to IGF1 and how its actions are modulated. RT-qPCR and single-cell RNA sequencing indicated that Igf1r mRNA is expressed in NPY/AgRP neurons but has higher expression in POMC neurons. IGF1 binding proteins Igfbp3 and Igfbp5 were significantly expressed, whereby Igfbp5 levels were modulated by fasting, nutrient availability, and circadian rhythms, implying that IGF1 signaling can be controlled by multiple mechanisms. In mouse and human models, IGF1 regulated Agrp, Npy, Pomc, Cartpt, Spx, Gal, and Fam237b expression, producing an overall anorexigenic profile. Hyperinsulinemia induced IGF1 resistance, accompanied by reduced IGF1R protein, as well as Igf1r and Irs2 mRNA expression via over-activation of PI3K-FOXO1 signaling. Thus, hypothalamic neurons respond to IGF1 under physiological conditions, and hyperinsulinemia is novel mechanism that drives cellular IGF1 resistance.

Exercise-induced mechanical load stimulates bone cells, including osteocytes, to promote bone formation. The bone response to loading is less effective with aging, but the cellular and molecular mechanisms responsible for the impaired mechanoresponsiveness remain unclear. Excessive mitochondrial reactive oxygen species (mtROS) and deficient autophagy are common aging mechanisms implicated in decreased bone formation in old mice. Here, we confirmed that the osteogenic effects of tibia compressive loading are lower in old versus young female mice. We also examined whether an increase in mtROS or decreased autophagy in osteoblast-lineage cells of adult female mice could mimic the deleterious effects of aging. To this end, we loaded mice lacking the antioxidant enzyme superoxide dismutase 2 (

Aging is a process of progressive functional decline associated with increasing age. The process and mechanism of aging have long been widely concerned, but long-term in vivo evaluations of the visual nervous system have not been previously reported. In this study, naturally aging mouse models were used for long-term serial evaluation, and the changes in structure and blood flow of the retina and cerebral cortex were systematically analyzed. Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA) were performed on mice at 3, 6, 9, and 12 months of age, respectively. Structural and vascular changes with age were quantitatively evaluated. Results show that the reduction of structural thickness and vascular density of the retinal and cerebral cortex is observed. A significant correlation is also found between structural and vascular changes in the retina and cerebral cortex, indicating a consistent impact of aging on the visual nervous system.

Neuronal mitochondrial function is critical for orchestrating inter-tissue communication essential for overall fitness. Despite its significance, the molecular mechanism underlying the impact of prolonged mitochondrial stresses on neuronal activity and how they orchestrate metabolism and aging remains elusive. Here, we identified the evolutionarily conserved transmembrane protein XBX-6/TMBIM-2 as a key mediator in the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt). Our investigations reveal that intrinsic neuronal mitochondrial stress triggers spatiotemporal Ca2+ oscillations in a TMBIM-2-dependent manner through the Ca2+ efflux pump MCA-3. Notably, persistent Ca2+ oscillations at synapses of ADF neurons are critical for facilitating serotonin release and the subsequent activation of the neuronal-to-intestinal UPRmt. TMBIM2 expression diminishes with age; however, its overexpression counteracts the age-related decline in aversive learning behavior and extends the lifespan of Caenorhabditis elegans. These findings underscore the intricate integration of chronic neuronal mitochondrial stress into neurotransmission processes via TMBIM-2-dependent Ca2+ equilibrium, driving metabolic adaptation and behavioral changes for the regulation of aging.

Cardiovascular-kidney-metabolic (CKM) syndrome, characterized by pathophysiological interactions among metabolic risk factors, chronic kidney disease and the cardiovascular system, is a significant global health concern, particularly in populations with adverse social determinants of health (SDOH). However, the influence of CKM syndrome and the joint effects of SDOH on the risk of developing incident dementia has not been fully elucidated. Here, we examined these associations among 382569 individuals from the UK Biobank. We found that unfavorable SDOH and advanced CKM syndrome (stage 3-4) are independently associated with increased risks of incident all-cause dementia, Alzheimer's disease and vascular dementia. Additionally, joint associations of CKM syndrome stages and SODH with incident dementia were observed. Individuals with [≥]3 unfavorable SDOH and in CKM syndrome stage 4 exhibited the highest dementia risk, even after adjusting for APOE {varepsilon}4 status. Our findings highlighted the importance of maintaining optimal CKM health and addressing unfavorable SODH in cognitive aging.

Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.

Age-related deficits in episodic memory and mnemonic discrimination are associated with an increased risk of neurodegenerative diseases, such as Alzheimer\'s disease (AD) (Stark et al., 2013). While much research has focused on hippocampal contributions to these age-related changes (Stark et al., 2019), less is known about the role of posterior cingulate cortex (PCC) especially reduced inhibition in episodic memory deficit. PCC has connections to the medial temporal lobe and is linked to memory declines (Greicius et al., 2004). It is also one of the most vulnerable regions to amyloid deposition in AD (Yokoi et al., 2018). This study hypothesized and found that age-related declines in GABAergic function (brain\'s major inhibitory neurotransmitter) within the PCC contributes to individual differences in memory performance in healthy older adults. Using Magnetic Resonance Spectroscopy, we measured GABA levels in the PCC in 22 healthy younger and 30 older adults. We assessed episodic memory using Rey Delayed Auditory Verbal Learning Test (RAVLT) and Mnemonic Similarity Task (MST). We found that both raw GABA levels and episodic memory performance are lower in older adults compared to young. This reduction in GABA levels is subserved by age-related changes in tissue-composition as evidenced by no age-group differences in corrected GABA levels. More importantly, lower GABA levels (independent of tissue-correction) were associated with poorer episodic performance including delayed recall and mnemonic discrimination. This research suggests that therapeutically targeting posterior cingulate GABA levels might help slow or alleviate memory decline.

Organismal aging is accompanied by the accumulation of senescent cells in the body, which drives tissue dysfunction. Senescent cells have a distinctive profile, including proliferation arrest, resistance to apoptosis, altered gene expression, and high inflammation. Despite global signaling and metabolic dysregulation during senescence, the underlying reasons for changes in signaling remain unclear. GPCRs are pivotal in cellular signaling, dynamically mediating the complex interplay between cells and their surrounding environment to maintain cellular homeostasis. The chemokine receptor CXCR4 plays a crucial role in modulating immune responses and inflammation. It has been shown that the expression of CXCR4 increases in cells undergoing senescence, which enhances inflammation postactivation. Here, we examine CXCR4 signaling in deeply senescent cells (aged cells), where cholesterol and its oxidized derivatives, oxysterols, affect receptor function. We report elevated oxysterol levels in senescent cells, which altered classical CXCL12-mediated CXCR4 signaling. Tail-oxidized sterols disrupted signaling more than ring-oxidized counterparts. Molecular dynamics simulations revealed that 27-hydroxycholesterol displaces cholesterol and binds strongly to alter the conformation of critical signaling residues, modifying the sterol-CXCR4 interaction landscape. Our study provides a molecular view of the observed mitigated GPCR signaling in the presence of oxysterols, which switched G-protein signaling from Gα

Accumulation of senescent hepatocytes is universal in chronic liver disease (CLD). This study investigates an association between hepatocyte senescence and hepatocellular carcinoma (HCC) and explores the therapeutic role of sirolimus. Background liver biopsies from 15 patients with cirrhosis and HCC and 45 patients with cirrhosis were stained for p16, a marker of cell senescence. STAM™ mice were randomized into 3 groups of 5 at 4 weeks of age and administered vehicle ± sirolimus intraperitoneally, thrice weekly, from 4 to 18 weeks of age. Placebo group was an administered vehicle, early sirolimus group was an administered vehicle with sirolimus, late sirolimus group was an administered vehicle from 4 to 12 weeks then vehicle with sirolimus from 12 to 18 weeks. The primary outcome was HCC nodule development. Senescent hepatocyte burden and senescence-associated secretory phenotype (SASP) factors were assessed in mice livers. In the human study, age (OR 1.282, 95% CI 1.086-1.513, p = 0.003) and p16 (OR 1.429, 95% CI 1.112-1.838, p = 0.005) were independently associated with HCC. In the animal study, all three groups exhibited similar MASLD activity scores (p = 0.39) and fibrosis area (p = 0.92). The number and the maximum diameter of HCC nodules were significantly lower in the early sirolimus group compared to placebo and late sirolimus group. The gene expression of SASP factors was similar in all groups. Protein levels of some SASP factors (TNFα, IL1β, IL-2, CXCL15) were significantly lower in sirolimus administered groups compared to placebo group. The study demonstrates an independent association between senescent hepatocyte burden and HCC. It indicates a potential chemoprophylactic role for sirolimus through SASP factor inhibition. These early results could inform a future human clinical trial.

Oxidative stress induces a rerouting of metabolic flux from glycolysis to the pentose phosphate pathway. One proposed mechanism involves negative feedback via tonic inhibition of glucose-6-phosphate dehydrogenase by NADPH. However, recent evidence shows that NADPH levels do not decrease five seconds after hydrogen peroxide (H2O2) treatment. This finding is inconsistent with the canonical model wherein feedback inhibition loop is modulated by NADPH-depletion. This inconsistency prompts us to test the involvement of feedback inhibition at high temporal resolution. We employed genetically encoded fluorescent indicators for H2O2 (HyPerRed) and NADPH (iNap1) expressed in epithelial HEK293 cells. These tools enable simultaneous real-time, single-cell monitoring of NADPH and H2O2. Glucose sustains NADPH levels under acute oxidative stress in the first seconds following H2O2 exposure. This result contradicts the reported feedback inhibition, which is considered one of the fundamental mechanisms to explain the acute rerouting of glycolysis to PPP. Furthermore, pharmacological inhibition of G6PDH suggests that the PPP is the primary source of cytosolic NADPH under oxidative stress. Monitoring NADPH levels following G6PDH inhibition allows for the assessment of the NADPH consumption flux. This parameter is low under baseline conditions, but rises dramatically under oxidative stress. Our results support an anticipatory phenomenon that maintains NADPH levels under acute H2O2 exposure, thereby discarding the proposed feedback inhibition loop. This work offers a new perspective on the regulatory nuances of a metabolic pathway implicated in aging, cancer and a plethora of pathological conditions associated with the deleterious consequences of oxidative stress.

The detrimental effects of lockdowns have already been proven by numerous studies, mainly using psychometric measurements. Since telomere shortening is a driver of aging and aging-associated disorders, including cognitive decline, the telomere length in the older population has been investigated in the current study. Measurements were taken over a 6-month period just before and during the 6 months that included the first lockdown. The cohort of 55 persons aged 64 to 70 years was investigated in the context of a study focusing on neuroplasticity. Participants were recruited in Germany and Switzerland and characterized by psychometric measurements concerning neurocognition and neuroplasticity. Telomere lengths were measured by real-time PCR-based LTL measurement. We found an impressive and significant decline in telomere lengths in the period that included the lockdown (2.33 (± 0.1) at T1 vs. 1.35 (± 0.1) at T2), whereas it was stable in the phase before the lockdown in the same individuals (T0 was 2.25 (± 0.1 S.E.M.) vs. T1, 2.33 (± 0.1)). Correlation of the sudden decrease revealed no linkage to health issues or general physical activity but was in trend related to a decline in the WHOQOL-BREF Social Score referring to the social interaction of the study participants. Our data support, at a biological level, the results of clinical and psychosocial studies showing the detrimental effects of lockdowns.

Healthy aging is crucial in Asia given its rapidly aging society. Social capital, which refers to the resources derived from social networks, norms, and trust that facilitate cooperation and collective action within a community or society, has demonstrated health benefits for older adults. However, its impact varies by country. Most research focuses on high-income countries, with little attention on low- and middle-income countries.

Menopause is a natural phase, related to the aging reproductive female, characterized by decreased production of hormones steroids, mainly estrogen, involved in multiple physiological process, including cardiovascular function. This estrogen decline can lead to the development of hypertension, as well as other cardiovascular diseases. Strategies therapeutics complementary he comes winning emphasis as option for management women's insurance at menopause, such as photobiomodulation. Photobiomodulation (PBM) is the application of no invasive low light sources level, normally in the forms of low level lasers therapy (LLLT) or light emitting diodes (LEDs) that present potentials benefits therapeutics in the treatment of inflammation and stress oxidative, favoring angiogenesis, improving function cardiac and remodeling tissue. The objective of this work was to evaluate the in vivo effects of photobiomodularion on cardiovascular parameters in ovariectomy-induced menopause in female rats. Twenty-six 70-day-old female Wistar rats were randomly assigned to three experimental groups: sham (SH), ovariectomized (OVX), and ovariectomized treated with photobiomodulation (OVX + PBM). The ovaries of all animals in the OVX groups were surgically removed at 12 weeks of age. The OVX + PBM group received photobiomodulation treatment with 5.6 Joules per point at six points on the abdominal region, using a power of 100mW at a wavelength of 660 nm, applied twice a week for two weeks. Blood pressure was measured using tail plethysmography, and endothelial function was assessed through vascular reactivity tests. At the end of the treatment period, the mean blood pressure in the OVX + PBM group was significantly lower than in the untreated OVX group. PBM treatment also improved endothelium-dependent vasodilation in aortic rings of OVX rats compared to the untreated OVX group, with no significant difference between the OVX + PBM and Sham groups. In addition, PBM increased serum nitric oxide (NO) levels compared to the OVX group. These results suggest that PBM treatment effectively reduced blood pressure, increased serum NO levels, and reversed endothelial dysfunction in ovariectomized rats.

As people live longer with disabilities acquired early in life, the additive effects of aging create unique challenges at the intersection of aging and disability. Technology interventions can minimize barriers and create facilitators to support performance of activities integral to health and quality of life. The absence of a theoretical framework to guide such interventions, in either gerontology or rehabilitation, created gaps in the knowledge base required to meet the needs of these individuals. We proposed the TechSAge Technology Intervention Model (TechSAge-TIM) to support activity engagement of older adults aging with long-term disabilities through technology design that bridges the gap between intrinsic capabilities and functional abilities (Mitzner et al., 2018). We have since utilized the model to advance understanding of technology-based supports for persons aging with long-term mobility, hearing, and vision disabilities. We describe herein applications involving people with mobility disabilities. We identified unmet needs by exploring lived experiences and used the TechSAge-TIM to guide research and development of a seated tele tai chi program for exercise/social engagement, smart bathroom technologies, and an automatic fall detection system for wheelchair users. These applications advanced the field of aging and disability and provided a roadmap for future research and development efforts.

Circular RNAs (circRNAs), constituting a novel class of endogenous non-coding RNAs generated through the reverse splicing of mRNA precursors, possess the capacity to regulate gene transcription and translation. Recently, the pivotal role of circRNAs in controlling vascular aging, as well as the pathogenesis and progression of aging-related vascular diseases, has garnered substantial attention. Vascular aging plays a crucial role in the increased morbidity and mortality of the elderly. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are crucial components of the intima and media layers of the vascular wall, respectively, and are closely involved in the mechanisms underlying vascular aging and aging-related vascular diseases. The review aims to provide a comprehensive exploration of the connection between circRNAs and vascular aging, as well as aging-related vascular diseases. Besides, circRNAs, as potential diagnostic markers or therapeutic targets for vascular aging and aging-related vascular diseases, will be discussed thoroughly, along with the challenges and limitations of their clinical application. Investigating the role and molecular mechanisms of circRNAs in vascular aging and aging-related vascular diseases will provide a novel insight into early diagnosis and therapy, and even effective prognosis assessment of these conditions.

UV exposure leads to skin damage, thus inducing skin aging. The aims of this study were to explore the differences in tRNA-derived small RNAs (tsRNAs) expression in the Human dermal fibroblasts (HDF cells) photoaging cell model and to explore the biological functions of tsRNA in skin photoaging. In this study, we found that in both photoaging cell models and the skin of photoaging mice, the 5'-tiRNA-His-GTG expression levels were significantly elevated. In HDF cells, overexpression of 5'-tiRNA-His-GTG induces cellular senescence. Inhibition of 5'-tiRNA-His-GTG attenuates UVB-induced cellular senescence in the photoaging cell model. Intradermal injection of Adeno-associated virus 9-5'-tiRNA-His-GTG -Inhibition ameliorates UVB-induced skin photoaging in nude mice. We confirmed that 5'-tiRNA-His-GTG targeted nuclear pore proteins 98, which further activated the JNK signaling pathway and induced cell senescence. Targeting 5'-tiRNA-His-GTG may provide a novel therapeutic option for ameliorating skin photoaging.

Healthy "environment-sleep-emotion-exercise-diet" intervention [E(e)SEEDi] lifestyle can improve the quality of life, prolong aging and promote longevity due to improvement of human immunity and prevention of cardiovascular diseases (CVD). Here, the author reviewed the associations between these core elements with CVD and cardiovascular aging, and developed a new scoring system based on the healthy E(e)SEEDi lifestyle for prediction and evaluation of life expectancy. These core factors are assigned 20 points each (120 points in total), and a higher score predicts healthier aging and longevity. The E(e)SEEDi represents "a tree of life" bearing the fruits of longevity as well as "a rocket of anti-ageing" carrying people around the world on a journey of longevity. In conclusion, the E(e)SEEDi can delay aging and increase the life expectancy due to the role of a series of cellular and molecular "mechanisms-hallmarks-biomarkers". It's believed that the novel scoring system has a huge potential and beautiful prospects.

Ovarian aging is the main cause of reduced reproductive life span, yet its metabolic profiles remain poorly understood. This study aimed to reveal the metabolic homogeneity and heterogeneity between physiological and pathological ovarian aging.

Epigenetics, the study of heritable changes in gene expression that do not involve alterations to the deoxyribonucleic acid (DNA) sequence, plays a pivotal role in cellular function, development, and aging. This review explores key epigenetic mechanisms, including DNA methylation (DNAm), histone modifications, chromatin remodeling, RNA-based regulation, and long-distance chromosomal interactions. These modifications contribute to cellular differentiation and function, mediating the dynamic interplay between the genome and environmental factors. Epigenetic clocks, biomarkers based on DNAm patterns, have emerged as powerful tools to measure biological age and predict health span. This article highlights the evolution of epigenetic clocks, from first-generation models such as Horvath's multi-tissue clock to advanced second- and third-generation clocks such as DNAGrimAge and DunedinPACE, which incorporate biological parameters and clinical biomarkers for precise age estimation. Moreover, the role of epigenetics in aging and age-related diseases is discussed, emphasizing its impact on genomic stability, transcriptional regulation, and cellular senescence. Epigenetic dysregulation is implicated in cancer, genetic disorders, and neurodegenerative diseases, making it a promising target for therapeutic interventions. The reversibility of epigenetic modifications offers hope for mitigating age acceleration and enhancing health span through lifestyle changes and pharmacological approaches.

Epigenetic clocks have emerged as novel measures of biological aging and potential predictors of mortality. We examined all-cause, cardiovascular, and cancer mortality prediction by epigenetic age acceleration (EAA) estimated using different epigenetic clocks. Among 2105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥ 50 years old and followed for mortality through 2019, we calculated EAAs from the residuals of nine epigenetic clocks regressed on chronological age. We assessed the association of EAAs and pace of aging with mortality adjusting for covariates. During 17.5 years of median follow-up, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA (P < 0.0001) followed by Hannum (P = 0.005), Pheno (P = 0.004), Horvath (P = 0.03), and Vidal-Bralo (P = 0.04) EAAs. Grim EAA predicted cardiovascular mortality (P < 0.0001), whereas Hannum (P = 0.006), Horvath (P = 0.009), and Grim (P = 0.01) EAAs predicted cancer mortality. Overall mortality prediction differed by race/ethnicity between non-Hispanic White and White participants for Horvath (P

The traditional view of aging as a gradual, progressive process is increasingly being challenged. A growing body of evidence suggests the existence of abrupt transitions in the aging process, marked by sudden molecular shifts. Interestingly, the data indicates that such transitions occur not only in late life but also throughout the entire lifespan. Further research on the nature of such events could enhance our understanding of aging and pave the way for novel therapeutic strategies, including personalized medicine. We propose that these abrupt molecular shifts could serve as biomarkers, dividing the lifespan into distinct stages and providing the foundation for a much-needed staging system for aging. Furthermore, we argue that the sudden changes may be the hallmarks of aging tipping points, that is, points in time where aging processes are quickly amplified after surpassing critical biological thresholds.

There is an increased need to establish the protein requirements for body weight maintenance and optimal health in humans. Different methods were developed in the past to assess protein requirements in which known amounts of protein/amino acids were provided. The purpose of this paper is to propose a new concept of establishing protein requirements in healthy and diseased conditions using a novel stable isotope approach. In the past years, we consistently found that when using a novel stable isotope pulse approach the intracellular production of amino acids (i.e., phenylalanine and tyrosine) is more than double the plasma rate of appearance, as measured by the commonly used primed constant infusion approach, leading to a net protein breakdown that is more than twice than estimated in the past. Net protein breakdown in the fasted state may provide a good estimation of the actual net protein loss that would take place during the day and thus can be used to estimate daily protein requirements. Our recent study found that a net protein breakdown ∼1 g protein/kg body weight/day was equal to the habitual protein intake, suggesting that there is a relation between habitual protein intake and protein requirements. As net protein breakdown is lower with advanced aging and in patient populations with comorbidities, a lower protein requirement for body weight maintenance is suggested. We propose a new concept to establish actual protein requirements of healthy and disease conditions, using a pulse tracer administration and to consider individual habitual protein intake and health conditions.

Alongside recognizing the importance of extending lifespan, an emerging focus has appeared on improving health in longevity, defined as healthspan. Aging is a process for all animal species; however, due to the time limitation in aging studies, Caenorhabditis elegans is an established model used for studying aging. In the current study, we evaluated various markers of muscle functions and determined that bending or pharyngeal pumping rate can represent worms' healthiness. A new concept named 'dynamic-scaled value' was developed, rescaling health markers to the corresponding markers in the control group at the same survival rate. Using these dynamic-scaled values of bending or pumping rates, we determined the health status of various treatments, including whether health improvement over aging depended on lifespan extension. Co-treatment of cranberry juice with Lactobacillus plantarum significantly improved health status during the mid-late life stage, while cranberry juice alone did not improve compared to the control. The dynamic-scaled value can be used as a complementary indicator to the quality-adjusted values to determine the health status. In addition, the dynamic-scaled values would allow us to compare results from others based on adjustments using their respective controls and relatively simple measurements to obtain the results.

Nocturia, defined as waking one or more times per night to urinate, is a prevalent and burdensome condition with few effective treatments. While the primary risk factor for nocturia is advanced age, few preclinical studies have addressed the pathophysiological mechanisms of nocturia in older subjects. Here, we develop a translational model of nocturia using aging mice and a behavioral paradigm that enables circadian assessment of voluntary urination in group-housed animals. We discovered dampened diurnal regulation of urinary behavior in aged mice compared to adult controls. Molecular analyses revealed disrupted diurnal expression of canonical circadian genes in aged mouse kidney and bladder tissues. Notably, we identified age-related loss of diurnal regulation of the bladder mechanosensory ion channel, Piezo1, suggesting a potential mechanism linking circadian disruption to altered bladder sensitivity. Our results reveal a role for circadian dysfunction in age-related nocturia and identify Piezo1 as a promising therapeutic target for chronobiological intervention.

Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular immune response data remain limited.

Clustering effects, such as those introduced by housing animals in shared cages, are often overlooked in preclinical lifespan studies, despite their potential to distort variance estimates and inflate Type I error rates, leading to misleading conclusions. This methodological oversight reduces statistical rigor and may undermine the reliability of findings. To address this gap, the current study examines the impact of accounting for clustering and nesting effects on lifespan analyses by comparing the results of statistical models which both account for and ignore these effects. Using 2019 data from the Interventions Testing Program (ITP), a large-scale initiative evaluating the effects of compounds on lifespan in UM-HET3 mice as a case study, we illustrate how different modeling approaches influence statistical estimates and conclusions. Clustering and nesting effects were addressed using linear mixed effects, and Cox frailty models, both of which explicitly account for cage-level dependencies and different levels of data nesting. Comparisons were made between unadjusted lifespan analyses and those incorporating clustering and nesting adjustments. The results of this case study indicate that properly adjusting for clustering and nesting effects can change the conclusions drawn from statistical significance tests as compared to unadjusted model approaches, and so it remains best practice to properly account for clustering and nesting to reduce the potential for inflated Type I error rates. These findings highlight the importance of accounting for clustering and nesting in preclinical research to ensure valid and robust statistical inference. By demonstrating the practical application of clustering adjustments, this work underscores the broader implications for improving reproducibility and rigor in lifespan studies and other experimental designs.

Rambutan peel is rich in polyphenols such as ellagic acid, corilagin, geraniin, quercetin, and rutin, which contribute to its diverse health benefits, including antioxidant, antimicrobial, antiviral, anti-inflammatory, hypoglycemic, and potential anticancer properties. The polyphenols present in the rambutan peel demonstrate potential for delaying cellular aging by mitigating oxidative stress within cells. Moreover, no study has systematically explored the anti-aging effects and the underlying mechanisms of polyphenols derived from rambutan peel.

Tetrabromobisphenol A (TBBPA) is an extensively employed Brominated flame retardant (BFR), but studies have shown that it has a range of toxicities, and it has been banned from use at present. Tetrabromobisphenol S (TBBPS) is increasingly used in industrial production as a substitute for TBBPA. However, up to now, the toxicity and molecular mechanism of TBBPS in the reproductive system have not been fully revealed. Therefore, we investigated the effects of TBBPS on testicular. In vitro, GC-1 cells and TM4 cells were used as models to perform an array of biochemical tests, and the toxicological impacts of TBBPS on testicular cells were evaluated. It was found that TBBPS could induce testicular cells senescence. Additionally, p16, p21, and p53 expression were also increased after TBBPS treatment. TBBPS also induced oxidative stress and inflammation response. Mechanistic studies have revealed that TBBPS causes mitochondrial damage, which leads to mitochondrial ds-DNA leakage into the cytoplasm, the NLRP3 inflammasome was then activated, in turn leading to inflammatory and senescence responses in testicular cells. In vivo, we found that TBBPS caused testicular tissue aging and inflammatory responses by detecting a series of molecular markers. In summary, the current study demonstrates that TBBPS can induce aging damage and inflammatory responses in testis, and this study lays a foundation for further exploring the reproductive toxicity of TBBPS.