Aging Cell最新文献

Regulatory T cells (Tregs) are important in maintaining tolerance and are key players in immunity. In aging, increased Treg function along with low-grade inflammation has been reported. This dichotomy of enhanced Treg function along with inflammation highlights the importance of understanding Treg biology and communication patterns in the very old. In this proof-of-concept study, we demonstrate that aged Tregs (85 years) do not significantly communicate with CD4⁺ and CD8⁺ T effectors when compared with healthy < 66-year-olds. Of note was the enhanced communication of aged Tregs with CD3⁺CD8⁺CD56⁺CD161^- NK-like T-cell populations, which are important in antitumor and chronic viral diseases in older individuals. We found that in turn this population of killer-like T cells showed diminished cytotoxic characteristics, and killer receptor expression. Taken together, our proof-of-concept study delineates the biology of Tregs and identifies previously undefined communication patterns in the very old.

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.

The accumulation of senescent cells contributes to aging and related diseases; therefore, discovering safe senolytic agents-compounds that selectively eliminate senescent cells-is a critical priority. Heat shock protein 90 (HSP90) inhibitors (HSP90i), traditionally investigated for cancer treatment, have shown potential as senolytic agents. However, inhibitors face formulation, toxicity, and cost challenges. To overcome these limitations, we employed a virtual screening approach combining structure-based prefiltering with a ligand-based pharmacophore model to identify novel, potentially safe HSP90 alpha isoform inhibitors exhibiting senolytic properties. This strategy identified 14 candidate molecules evaluated for senolytic activity in primary human fetal pulmonary fibroblasts. Four compounds exhibited significant HSP90i and senolytic activity, including two novel compounds, namely K4 and K5. The latter, 1-benzyl-3-(2-methylphenyl)-3,7-dihydro-1H-purine-2,6-dione, structurally related to the xanthinic family, emerged as a promising, well-tolerated senolytic agent. K5 demonstrated senolytic activity across various cellular senescence models, including human fibroblasts, mesenchymal stem cells, and breast cancer cells. It was also effective in vivo, extending lifespan in Drosophila and reducing senescence markers in geriatric mice. Additionally, the xanthinic nature of K5 implicates a multimodal action, now including the inhibition of HSP90α, that might enhance its efficacy and selectivity towards senescent cells, Senolytic index SI > 1320 for IMR90 cells, and SI > 770 for WI38 cells, underscoring its therapeutic potential. These findings advance senolytic therapy research, opening new avenues for safer interventions to combat age-related inflammaging and diseases, including cancer, and possibly extend a healthy lifespan.

Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin (ɑ-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids into an aged skin model and subjecting the tissue to compressive forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration.

The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high-resolution home-cage-based cognitive testing paradigm to delineate mechanisms that contribute to age-related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence-associated secretory phenotype (SASP) in impaired animals, including p16^INK4a, SASP factors (e.g., Il-6, Il-1b, Mmp3), and SA-β-gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment-associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex-specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.

The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism.

Among epigenetic modifiers, telomeres represent attractive modulators of the genome in part through position effects. Telomere Position Effect-Over Long Distances (TPE-OLD) modulates gene expression by changes in telomere-dependent long-distance loops. To gain insights into the molecular mechanisms of TPE-OLD, we performed a genome-wide transcriptome and methylome analysis in proliferative fibroblasts and myoblasts or differentiated myotubes with controlled telomere lengths. By integrating omics data, we identified a common TPE-OLD dependent cis-acting motif that behaves as an insulator or enhancer. Next, we uncovered trans partners that regulate these activities and observed the consistent depletion of one candidate factor, RBPJ, at TPE-OLD associated loci upon telomere shortening. Importantly, we confirmed our findings by unbiased comparisons to recent Human transcriptomic studies, including those from the Genotype-Tissue Expression (GTEx) project. We concluded that TPE-OLD acts at the genome-wide level and can be relayed by RBPJ bridging Alu-like elements to telomeres. In response to physiological (i.e., aging) or pathological cues, TPE-OLD might coordinate the genome-wide impact of telomeres through recently evolved Alu elements acting as enhancers in association with RBPJ.

Physical activity (PA) may delay the onset of age-related diseases by decelerating biological aging. We investigated the association between leisure-time physical activity (LTPA) and metabolomics-based aging markers (MetaboAge and MetaboHealth) in late midlife and during 16 years of follow-up. At the 16-year follow-up, we also investigated the association between device-based PA and MetaboAge and MetaboHealth. We included 1816 individuals (mean age 61.6 years) from the Helsinki Birth Cohort Study at baseline and followed them up for 5 (n = 982) and 16 years (n = 744), respectively. LTPA was assessed via questionnaire at baseline and 16 years later and device-based PA with ActiGraph accelerometer at the 16-year follow-up. Fasting blood samples were applied to calculate MetaboAge acceleration (ΔmetaboAge) and MetaboHealth at baseline and at both follow-ups. Covariate-adjusted multiple regression analyses and linear mixed models were applied to study the associations. A higher volume of LTPA at baseline was associated with a lower MetaboHealth score at the 5-year follow-up (p < 0.0001 for time × LTPA interaction). No associations were detected at the 16-year follow-up. An increase in LTPA over 16 years was associated with a decrease in MetaboHealth score (p < 0.001) and a decrease in LTPA with an increase in MetaboHealth score. Higher device-based PA was associated with a lower MetaboHealth score, but not with ΔmetaboAge. In conclusion, higher LTPA in late midlife and device-based PA in old age were associated with improved MetaboHealth. Increasing LTPA with age may protect against MetaboHealth-based aging. The results support the importance of PA for biological aging in later life.