Aging Cell

Lão hóa tái sinh hạn chế sự sinh sản của các tế bào soma được nuôi cấy và có thể phản ánh sự lão hóa tế bào in vivo. Chỉ số sinh học được sử dụng phổ biến nhất để xác định tế bào lão hóa và lão hóa là β‐galactosidase liên quan đến lão hóa (SA‐β‐gal), được định nghĩa là hoạt động β‐galactosidase có thể phát hiện được ở pH 6.0 trong các tế bào lão hóa, nhưng nguồn gốc của SA‐β‐gal và vai trò của nó trong lão hóa còn chưa được biết đến. Chúng tôi chứng minh rằng hoạt động SA‐β‐gal được biểu hiện từ GLB1, gen mã hóa β‐D‐galactosidase lysosome, hoạt động của nó thường được đo ở pH axit 4.5. Các nguyên bào sợi từ bệnh nhân mắc bệnh G_M1-gangliosidosis tự di truyền, những người có β‐galactosidase lysosome khiếm khuyết, không biểu hiện SA‐β‐gal ở các lần nuôi cấy muộn mặc dù họ đã trải qua lão hóa tái sản. Thêm vào đó, các nguyên bào sợi bình thường ở giai đoạn nuôi cấy muộn bộc lộ RNA can thiệp nhỏ gây suy giảm GLB1 mRNA đã trải qua lão hóa nhưng không thành công trong việc biểu hiện SA‐β‐gal. Việc suy giảm GLB1 mRNA cũng đã ngăn chặn biểu hiện hoạt động SA‐β‐gal ở các tế bào ung thư cổ tử cung HeLa được kích thích vào trạng thái lão hóa bằng cách ức chế oncogene E7 của virus papilloma người nội sinh. Việc kích thích SA‐β‐gal trong quá trình lão hóa ít nhất một phần là do tăng cường biểu hiện protein β‐galactosidase lysosome. Những kết quả này cũng chỉ ra rằng SA‐β‐gal không cần thiết cho quá trình lão hóa.

Naked mole‐rats (Heterocephalus glaber), the longest‐lived rodents, live 7–10 times longer than similarly sized mice and exhibit normal activities for approximately 75% of their lives. Little is known about the mechanisms that allow them to delay the aging process and live so long. Neuregulin‐1 (NRG‐1) signaling is critical for normal brain function during both development and adulthood. We hypothesized that long‐lived species will maintain higher levels of NRG‐1 and that this contributes to their sustained brain function and concomitant maintenance of normal activity. We monitored the levels of NRG‐1 and its receptor ErbB4 in H. glaber at different ages ranging from 1 day to 26 years and found that levels of NRG‐1 and ErbB4 were sustained throughout development and adulthood. In addition, we compared seven rodent species with widely divergent (4–32 year) maximum lifespan potential (MLSP) and found that at a physiologically equivalent age, the longer‐lived rodents had higher levels of NRG‐1 and ErbB4. Moreover, phylogenetic independent contrast analyses revealed that this significant strong correlation between MLSP and NRG‐1 levels was independent of phylogeny. These results suggest that NRG‐1 is an important factor contributing to divergent species MLSP through its role in maintaining neuronal integrity.

Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin–angiotensin system (RAS) heptapeptide angiotensin (Ang)‐(1‐7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence‐associated galactosidase (SA‐β‐gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein‐coupled receptor Mas, Ang‐(1‐7) inhibited the pro‐senescence action of Ang II, but also of a non‐RAS stressor such as the cytokine IL‐1β. Moreover, Ang‐(1‐7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti‐senescence action of the heptapeptide. Indeed, both Ang‐(1‐7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase‐1 (HO‐1) pathway. The HO‐1 inhibitor tin protoporphyrin IX prevented the anti‐senescence action evoked by Ang‐(1‐7) or recombinant klotho. Overall, the present study identifies Ang‐(1‐7) as an anti‐senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO‐1. Ang‐(1‐7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.

This study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT‐1 and reduced glutamate uptake occur in the aged (24–27 months) Sprague–Dawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3–5 months) and aged rats are depressed by DL‐TBOA, an inhibitor of glutamate transporter activity, in an N‐Methyl‐d‐Aspartate (NMDA)‐receptor‐dependent manner. In aged but not in young rats, part of the depressing effect of DL‐TBOA also involves metabotropic glutamate receptor (mGluRs) activation as it is significantly reduced by the specific mGluR antagonist d‐methyl‐4‐carboxy‐phenylglycine (MCPG). The paired‐pulse facilitation ratio, a functional index of glutamate release, is reduced by MCPG in aged slices to a level comparable to that in young rats both under control conditions and after being enhanced by DL‐TBOA. These results suggest that the age‐associated glutamate uptake deficiency favors presynaptic mGluR activation that lowers glutamate release. In parallel, 2 Hz‐induced long‐term depression is significantly decreased in aged animals and is fully restored by MCPG. All these data indicate a facilitated activation of extrasynaptic NMDAR and mGluRs in aged rats, possibly because of an altered distribution of glutamate in the extrasynaptic space. This in turn affects synaptic transmission and plasticity within the aged hippocampal CA1 network.

The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network‐based approach for combining multiple large‐scale expression studies in blood (2539 individuals) with protein–protein Interaction (PPI) data for the detection of consistently coexpressed PPI modules that may reflect key processes that change throughout the course of normative aging. Module detection followed by a meta‐analysis on chronological age identified fifteen consistently coexpressed PPI modules associated with chronological age, including a highly significant module (P = 3.5 × 10⁻³⁸) enriched for ‘T‐cell activation’ marking age‐associated shifts in lymphocyte blood cell counts (R² = 0.603; P = 1.9 × 10⁻¹⁰). Adjusting the analysis in the compendium for the ‘T‐cell activation’ module showed five consistently coexpressed PPI modules that robustly associated with chronological age and included modules enriched for ‘Translational elongation’, ‘Cytolysis’ and ‘DNA metabolic process’. In an independent study of 3535 individuals, four of five modules consistently associated with chronological age, underpinning the robustness of the approach. We found three of five modules to be significantly enriched with aging‐related genes, as defined by the GenAge database, and association with prospective survival at high ages for one of the modules including ASF1A. The hereby‐detected age‐associated and consistently coexpressed PPI modules therefore may provide a molecular basis for future research into mechanisms underlying human aging.

Many conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance extend lifespan. We have carried out a systematic lifespan analysis of conditions that inhibit protein synthesis. We find that reducing the levels of ribosomal proteins, ribosomal‐protein S6 kinase or translation‐initiation factors increases the lifespan of Caenorhabditis elegans. These perturbations, as well as inhibition of the nutrient sensor target of rapamycin (TOR), which is known to increase lifespan, all increase thermal‐stress resistance. Thus inhibiting translation may extend lifespan by shifting cells to physiological states that favor maintenance and repair. Interestingly, different types of translation inhibition lead to one of two mutually exclusive outputs, one that increases lifespan and stress resistance through the transcription factor DAF‐16/FOXO, and one that increases lifespan and stress resistance independently of DAF‐16. Our findings link TOR, but not sir‐2.1, to the longevity response induced by dietary restriction (DR) in C. elegans, and they suggest that neither TOR inhibition nor DR extends lifespan simply by reducing protein synthesis.

We have previously described a statistical model capable of distinguishing young (age <65 years) from old (age ≥75 years) individuals. Here we studied the performance of a modified model in three populations and determined whether individuals predicted to be biologically younger than their chronological age had biochemical and functional measures consistent with a younger biological age. Those with ‘younger’ gene expression patterns demonstrated higher muscle strength and serum albumin, and lower interleukin‐6 and blood urea concentrations relative to ‘biologically older’ individuals (odds ratios 2.09, 1.64, 0.74, 0.74; P = 2.4 × 10⁻², 3.5 × 10⁻⁴, 1.8 × 10⁻², 1.5 × 10⁻², respectively). We conclude that our expression signature of age is robust across three populations and may have utility for estimation of biological age.

Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer and aging include significant epigenetic components, but the chromatin changes that take place during cellular senescence are not known. We used formaldehyde assisted isolation of regulatory elements (FAIRE) to map genome‐wide chromatin conformations. In contrast to growing cells, whose genomes are rich with features of both open and closed chromatin, FAIRE profiles of senescent cells are significantly smoothened. This is due to FAIRE signal loss in promoters and enhancers of active genes, and FAIRE signal gain in heterochromatic gene‐poor regions. Chromatin of major retrotransposon classes, Alu, SVA and L1, becomes relatively more open in senescent cells, affecting most strongly the evolutionarily recent elements, and leads to an increase in their transcription and ultimately transposition. Constitutive heterochromatin in centromeric and peri‐centromeric regions also becomes relatively more open, and the transcription of satellite sequences increases. The peripheral heterochromatic compartment (PHC) becomes less prominent, and centromere structure becomes notably enlarged. These epigenetic changes progress slowly after the onset of senescence, with some, such as mobilization of retrotransposable elements becoming prominent only at late times. Many of these changes have also been noted in cancer cells.

Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single‐cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell‐to‐cell variability resulted in a loss of correlation among the expression of several senescence‐associated genes. Many genes encoding senescence‐associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo.