Mechanisms of Ageing and Development最新文献

During aging, general cellular processes, including autophagic clearance and immunological responses become compromised; therefore, identifying compounds that target these cellular processes is an important approach to improve our health span. The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, and tumor immunosurveillance. These key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and cytosolic DNA clearance in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and this warrants further investigation in relevant transgenic animal models.

Background

The kynurenine pathway (KP) is gaining more attention as a common pathway involved in age-related conditions. However, which changes in the KP occur due to normal ageing is still largely unclear. The aim of this systematic review was to summarize the available evidence for associations of KP metabolites with age.

Methods

We used an broad search strategy and included studies up to October 2023.

Results

Out of 8795 hits, 55 studies were eligible for the systematic review. These studies suggest that blood levels of tryptophan decrease with age, while blood and cerebrospinal fluid levels of kynurenine and its ratio with tryptophan increase. Studies investigating associations between cerebrospinal fluid and blood levels of kynurenic acid and quinolinic acid with age reported either positive or non-significant findings. However, there is a large heterogeneity across studies. Additionally, most studies were cross-sectional, and only few studies investigated associations with other downstream kynurenines.

Conclusions

This systematic review suggests that levels of kynurenines are positively associated with age. Larger and prospective studies are needed that also investigate a more comprehensive panel of KP metabolites and changes during the life-course.

Senescence is a cellular state characterized by its near-permanent halted cell cycle and distinct secretory phenotype. Although senescent cells have a variety of beneficial physiological functions, progressive accumulation of these cells due to aging or other conditions has been widely shown to provoke deleterious effects on the normal functioning of the same or higher-level biological organizations. Recently, erasing senescent cells in vivo, using senolytics, could ameliorate diseases identified with an elevated number of senescent cells. Since then, researchers have struggled to develop new senolytics each with different selectivity and potency. In this review, we have gathered and classified the proposed senolytics and discussed their mechanisms of action. Moreover, we highlight the heterogeneity of senolytics regarding their effect sizes, and cell type specificity as well as comment on the exploited strategies to improve these features. Finally, we suggest some prospective routes for the novel methods for ablation of senescent cells.

Brain aging is associated with reduced cognitive function that increases the risk for dementia. Apigenin is a bioactive plant compound that inhibits cellular aging processes and could protect against age-related cognitive dysfunction, but its mechanisms of action in the brain have not been comprehensively studied. We characterized brain transcriptome changes in young and old mice treated with apigenin in drinking water. We observed improved learning/memory in old treated mice, and our transcriptome analyses indicated that differentially expressed genes with aging and apigenin were primarily related to immune responses, inflammation, and cytokine regulation. Moreover, we found that genes/transcripts that were increased in old vs. young mice but downregulated with apigenin treatment in old animals were associated with immune activation/inflammation, whereas transcripts that were reduced with aging but increased with apigenin were related neuronal function and signaling. We also found that these transcriptome differences with aging and apigenin treatment were driven in part by glial cells. To follow up on these in vivo transcriptome findings, we studied aged astrocytes in vitro, and we found that apigenin reduced markers of inflammation and cellular senescence in these cells. Collectively, our data suggest that apigenin may protect against age-related cognitive dysfunction by suppressing neuro-inflammatory processes.

The naked mole-rat (NMR) Heterocephalus glaber (from the Greek/latin words ἕτερος, heteros = divergent, κεφαλή, kephalē = head and glabra = hairless) was first described by Rüppell (Fig. 1) and belongs to the Hystricognath (from the Greek words ὕστριξ, hystrix = porcupine and γνάθος, gnathos = jaw) as a suborder of rodents. NMR are characterized by the highest longevity among rodents and reveal a profound cancer resistance. Details of its skin-specific protective and resistance mechanisms against aging and carcinogenesis have so far not been adequately characterized. Recently, our knowledge of NMR skin biology was complemented and expanded by published data using state-of-the art histological and molecular techniques.

Here we review and integrate novel published data regarding skin morphology and histology of the aging NMR and the underlying mechanisms at the cellular and molecular level. We relate this data to the longevity of the NMR and its resistance to neoplastic transformation and discuss further open questions to understand its extraordinary longevity. In addition, we will address the exposome, defined as “the total of all non-genetic, endogenous and exogenous environmental influences” on the skin, respiratory tract, stomach, and intestine. Finally, we will discuss in perspective further intriguing possibilities arising from the interaction of skin with other organs.

Osteoarthritis (OA) is a prevalent disease among elderly people and is often characterized by chronic joint pain and dysfunction. Recently, growing evidence of chondrocyte senescence in the pathogenesis of OA has been found, and targeting senescence has started to be recognized as a therapeutic approach for OA. Piezo1, a mechanosensitive Ca²⁺ channel, has been reported to be harmful in sensing abnormal mechanical overloading and leading to chondrocyte apoptosis. However, whether Piezo1 can transform mechanical signals into senescence signals has rarely been reported. In this study, we found that severe OA cartilage expressed more Piezo1 and the senescence markers p16 and p21. 24 h of periodic mechanical stress induced chondrocyte senescence in vitro. In addition, we demonstrated the pivotal role of Piezo1 in OA chondrocyte senescence induced by mechanical stress. Piezo1 sensed mechanical stress and promoted chondrocyte senescence via its Ca²⁺ channel ability. Moreover, Piezo1 promoted SASP factors production under mechanical stress, particularly in IL-6 and IL-1β. p38MAPK and NF-κB activation were two key pathways that responded to Piezo1 activation and promoted IL-6 and IL-1β production, respectively. Collectively, our study revealed a connection between abnormal mechanical stress and chondrocyte senescence, which was mediated by Piezo1.

Deteriorated age-related bone loss is the hallmarks of skeletal aging. However, how the aging of bone marrow mesenchymal stem cells (BMSCs) and osteoclasts are linked to the bone microstructure degeneration is not yet very clear. In this study, the characteristics of age-related bone loss, distribution patterns of osteoclasts, functional and transcriptomic alterations of BMSCs, hub genes responsible for BMSCs senescence, were analyzed. Our study revealed an age-related declined trends in trabecular and cortical bones of femur, tibia and lumbar vertebra in mice, which was accompanied by a shift from the trabecular to cortical bones in osteoclasts. Additionally, middle-aged or aged mice exhibited remarkably reduced dynamic bone formation capacities, along with reversed osteogenic-adipogenic differentiation potentials in BMSCs. Finally, transcriptomic analysis indicated that aging-related signaling pathways were significantly activated in BMSCs from aged mice (e.g., cellular senescence, p53 signaling pathway, etc.). Also, weighted correlation network analysis (WGCNA) and venn diagram analysis based on our RNA-Seq data and GSE35956 dataset revealed the critical role of PTPN1 in BMSCs senescence. Targeted inhibition of PTP1B with AAV-Ptpn1-RNAi dramatically postponed age-related bone loss in middle-aged mice. Collectively, our study has uncovered the age-dependent cellular characteristics in BMSCs and osteoclasts underlying progressive bone loss with advancing age.

Oxidative stress plays an important role in the skin aging process; however, the mechanisms are not fully elucidated. Especially the changes in various types of skin cells with aging and the key oxidative stress-related genes that play a regulatory role are not clear. In this study, single-cell RNA sequencing data and microarray transcriptome data were used to explore the changes in oxidative stress response and oxidant detoxification capacity of skin cells during aging and oxidative stress-related genes potentially involved in regulating skin aging were searched. The oxidative stress response and oxidant detoxification ability were weakened in the elderly compared with those of the young. Among the different types of skin cells, keratinocytes, melanocytes, vascular endothelial cells, fibroblasts, and lymphatic endothelial cells exhibited a stronger oxidative stress response and oxidant detoxification ability, while immune cells exhibited a weaker oxidative stress response and detoxification capacity. During aging, the oxidative stress response and oxidant detoxification capacity of keratinocytes, fibroblasts, macrophages, and vascular endothelial cells were significantly weakened. Annexin A1 (ANXA1) and Apolipoprotein E (APOE) may be key oxidative stress-related genes affecting skin aging.

Hutchinson-Gilford progeria syndrome (HGPS), also known as hereditary progeria syndrome, is caused by mutations in the LMNA gene and the expression of progerin, which causes accelerated aging and premature death, with most patients dying of heart failure or other cardiovascular complications in their teens. HGPS patients are able to exhibit cardiovascular phenotypes similar to physiological aging, such as extensive atherosclerosis, smooth muscle cell loss, vascular lesions, and electrical and functional abnormalities of the heart. It also excludes the traditional risk causative factors of cardiovascular disease, making HGPS a new model for studying aging-related cardiovascular disease. Here, we analyzed the pathogenesis and pathophysiological characteristics of HGPS and the relationship between HGPS and cardiovascular disease, provided insight into the molecular mechanisms of cardiovascular disease pathogenesis in HGPS patients and treatment strategies for this disease. Moreover, we summarize the disease models used in HGPS studies to improve our understanding of the pathological mechanisms of cardiovascular aging in HGPS patients.

Elevation of cardiac damage biomarkers is associated with adverse clinical outcomes and increased mortality in COVID-19 patients. This study assessed the association of admission serum levels of sST2 and H-FABP with in-hospital mortality in 191 geriatric patients (median age 86 yrs., IQR 82–91 yrs.) with COVID-19 and available measures of hs-cTnT and NT-proBNP at admission. Cox proportional hazards models were utilized to predict in-hospital mortality, considering clinical/biochemical confounders as covariates. A composite cardiac score was calculated to improve predictive accuracy. Patients deceased during their hospital stay (26%) exhibited higher levels of all biomarkers, which demonstrated good discrimination for in-hospital mortality. Addition of sST2 and H-FABP significantly improved the discriminatory power of hs-cTnT and NT-proBNP. The composite cardiac score (AUC=0.866) further enhanced the predictive accuracy. Crude and adjusted Cox regressions models revealed that both sST2 and H-FABP were independently associated with in-hospital mortality (HR for sST2 ≥129 ng/mL, 4.32 [1.48–12.59]; HR for H-FABP ≥18 ng/mL, 7.70 [2.12–28.01]). The composite cardiac score also independently correlated with in-hospital mortality (HR for 1-unit increase, 1.47 [1.14–1.90]). In older patients with COVID-19, sST2 and H-FABP demonstrated prognostic value, improving the predictive accuracy of the routinely assessed biomarkers hs-cTnT and NT-proBNP.