Aging-Us最新文献

Fibroblast activation is essential for tissue repair following injury; however, prolonged activation drives pathological fibrosis. Idiopathic pulmonary fibrosis (IPF), a progressive and age-associated lung disease, is characterized by aberrant fibroblast activation, with increasing evidence implicating senescent and near-senescent fibroblasts in its pathogenesis. However, the underlying mechanisms remain poorly defined. In this study, we investigated whether histone modification is involved in TGF-β1 treated lung fibroblasts and contributes to the fibrotic phenotype. Human IMR90 lung fibroblasts at low and high population doubling levels (LPDL and HPDL), as well as primary IPF fibroblasts, were used in this study. In response to TGF-β1, both LPDL and HPDL fibroblasts upregulated profibrotic genes, including α-smooth muscle actin (α-SMA) and Collagen type III alpha 1 (Col3A1). Compared with LPDL fibroblasts, HPDL fibroblasts exhibited a delayed and sustained p38 MAPK response. Pharmacological inhibition of p38 MAPK significantly reduced α-SMA and Col3A1 expression in both TGF-β1-stimulated fibroblasts and primary IPF cells. Mechanistically, TGF-β1-induced expression of α-SMA and Col3A1 was mediated by histone H4K16 acetylation (H4K16ac), which was enriched at gene promoter regions and attenuated by p38 MAPK inhibition. These findings suggest that a p38 MAPK-dependent epigenetic mechanism is involved in fibroblast activation, supporting the therapeutic potential of p38 MAPK inhibition for treating age-related fibrotic diseases such as IPF.

Sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine, reduces obesity but also lowers bone mineral density (BMD) and increases marrow adipose tissue. Because the SAAR diet lacks cysteine, it exerts cysteine restriction (CysR), in addition to methionine restriction (MetR). We previously reported that the anti-obesity effect of the SAAR diet was exclusively due to CysR. Follow-up studies revealed that CysR decreases obesity by lowering glutathione (GSH), and that D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, recapitulates the SAAR-induced lean phenotype on a methionine-replete diet. Here, we investigated whether the detrimental effects of the SAAR diet on bone are mediated solely by CysR and whether BSO, similar to the SAAR diet, exerts deleterious effects. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (control diet, CD), 0.12% methionine (SAAR diet), SAAR diet supplemented with a GSH precursor, N-acetylcysteine (NAC) in water, and CD supplemented with BSO in water. Femurs and tibiae of SAAR mice had lower trabecular and cortical BMD, fewer osteoblasts, reduced biomechanical strength, and more marrow adipocytes than in CD mice. NAC reversed all these effects, suggesting that CysR mediates the detrimental effects of the SAAR diet on bone. Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones. Future studies should investigate mechanisms, age-at-onset, tissue-specific, and gender-specific effects of BSO on bone health. Long-term studies to establish the therapeutic efficacy and off-target effects of BSO are critical for developing it as an anti-obesity drug in humans.

Glycolytic ATP production declines with age, contributing to common aging phenotypes such as reduced cell division and impaired DNA & mitochondria repair. Notably, immortal cells exhibit a metabolic profile characterized by sustained, highly active glycolytic ATP production. A key unresolved question is the underlying mechanism driving the gradual decline in glycolytic ATP production during natural aging. We have found that this can be explained by the concept that a decline in glycolytic ATP production was crucial for survival of species, and only those species with an optimal rate of reduction in glycolytic ATP production over time were selected and persisted through generational changes. Sexual reproduction generates new combination of gene pairs with abundant DNA mutations during meiosis, which provides significant advantages in adapting to environmental changes and competence over other species. However, the population of species is limited because of finite food supply in the natural world. The shift from glycolysis to aerobic metabolism increases energy efficiency and the increased energy efficiency in parent generation benefits the species by enhancing survival of parent generation at starvation conditions and limited food allocation to the offspring generation. This conceptual framework can explain the finite lifespans of organisms, significant variations in lifespan across species, cellular immortality of cancer cells, and the exceptionally long life of the naked mole rat (Heterocephalus glaber). Although questions remain, this concept offers new insights into the biology of aging and potential strategies for rejuvenation therapies for humans.

Biological age reflects the current state of the body, considering the aspects of lifestyle, environment, and hereditary component. Currently there is no universal formula for determining it, but there are markers that can be used to calculate it. This study aims to develop and compare two models for calculating biological age based on laboratory blood tests and composition of gut microbiota. The biochemical model of biological age uses 7 indicators and is gender-specific (general - cystatin-C, IGF-1, DHEAS, only for females - homocysteine, urea, glucose, zonulin, only for males - HbA1c, NT-proBNP, free testosterone, hs-CRP). The microbial model requires the input of percentages of 45 bacterial species as indicators of the gut microbiota. Both methods demonstrate high predictive accuracy (MAE ~ 6 years, R2 > 0.8) and the degree of agreement of assessments both with each other and with PhenoAge (correlation > 0.89). For enhanced interpretability of the models, we applied the SHAP explanation algorithm, which made which allowed us to evaluate the contribution of each predictor to the final assessment of the biological age.

During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to mitochondrial chromosome, chrM, in young and old cohorts. The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblast. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction. Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle.

Biomarkers of aging offer insights into how diseases and interventions affect biological systems. However, most current biomarkers are based on bulk cell measurements, making it difficult to distinguish between changes driven by shifts in cell type composition (systemic effects) versus intrinsic changes within individual cells. To address this, we used single-cell RNA sequencing to analyze aging-related changes at both the cellular and bulk levels. We developed Tictock (T immune cell transcriptomic clock), a single-cell transcriptomic clock capable of predicting age and cell type across six human T cell subsets. Applying Tictock, we found that acute COVID-19 is associated with increased proportions of CD8+ cytotoxic T cells, whereas T cell composition remains stable in people with HIV on antiretroviral therapy (HIV+ART). Both COVID-19 and HIV+ART are linked to an increase in transcriptomic age, specifically within naïve CD8+ T cells. Gene Ontology enrichment of 209 genes shared across six clock models identified common pathways including the cytosolic small ribosomal subunit, TNF receptor binding, and cytosolic ribosome components. A correlation was also observed between aging and mean transcript length. These findings underscore the promise of single-cell transcriptomic biomarkers to disentangle the systemic and cell-intrinsic components of immune aging and to measure immune aging.

Background: Interleukin-6 (IL6) signaling plays a key role in inflammation and cardiovascular disease, but its causal effect on long-term mortality remains unclear. We aimed to assess whether genetically proxied levels of IL6, soluble IL6 receptor (IL6R), C-reactive protein (CRP), and growth differentiation factor-15 (GDF15) exert causal effects on long-term all-cause mortality, and to examine potential opposing effects of IL6 and IL6R.

Methods: We conducted Mendelian randomization (MR) using genome-wide association study instruments from >750,000 individuals. The primary outcome was all-cause mortality over a median follow-up of 11.7 years. Secondary outcomes included cardiovascular events and selected non-cardiovascular conditions. Multiple sensitivity analyses were applied to evaluate robustness and directionality.

Results: Genetically higher IL6R levels were associated with reduced mortality (odds ratio (OR) per 1-SD increase: 0.95; 95% CI: 0.91-0.98, p = 0.007) and lower risk of atrial fibrillation, coronary artery disease, stroke, and lung cancer. Conversely, higher IL6 levels were linked to increased mortality (OR: 1.05; 95% CI: 1.02-1.08, p = 0.002). No significant causal effects were observed for CRP or GDF-15. All findings were consistent across sensitivity analyses.

Conclusions: IL6 and IL6R appear to be biologically opposing causal regulators of human survival: IL6 increases, while IL6R reduces mortality through cardiovascular mechanisms. CRP and GDF15 likely reflect disease risk rather than drive it. These results support IL6R antagonism as a potential strategy for cardiovascular disease prevention.