CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.

Data from molecular dynamics simulations in support of the role of human CES1 in the hydrolysis of Amplex Red.

This data article contains the results of molecular dynamics (MD) simulations performed to assess the stability of the previously computed complex between the hCES1 structure and the Amplex Red (AR) substrate (Miwa et al., 2015) [1] and to compare the dynamic behavior of this complex with that of the corresponding hCES1-deacetylAR product. The study involves both standard molecular dynamics (MD) and steered (SMD) simulations to offer a quantitative comparison of the stability for the two complexes. With regard the standard MD runs, the data article graphically reports the r.m.s.d. profile of the ligand׳s atoms as well as the dynamic behavior of key contacts involving the catalytic Ser221 residue. The SMD simulations provide a comparison of the pull forces required to undock the two ligands and reveal that Van der Waals and hydrophobic interactions play a key role in complex stabilization.

Mitochondrial dysfunction and cell senescence--skin deep into mammalian aging.

Thus, we are again left with a chicken-and egg situation: Is disrupted Ca2+ signalling, reduced mTOR activity and increased autophagy found in SOD2-/- cells because there are more senescent cells in the examined population? Or is any of these factors the culprit that triggers senescence in the first place? While the answer to these questions still eludes us, the study from Campisi and colleagues highlights the importance of mitochondrial dysfunction and cellular senescence in vivo and its impact on the aging process.

Quantitative assessment of markers for cell senescence.

Cellular senescence, the irreversible loss of replicative capacity, might be a tumour suppressor and a contributor to age-related loss of tissue function. The absence of quantitative tests for reliability of candidate markers for senescent cells is a major drawback in cell population studies. Fibroblasts in culture constitute mixed populations of proliferation-competent and senescent cells, with transition between these with increasing population doublings (PD). We estimated senescent fraction in human and mouse fibroblasts with high precision from easily observed growth curves using a dynamic simulation model. We also determined senescent fractions, at various PD (over a wide range of senescent cell frequencies) using candidate senescence markers: Ki67, p21 (CDKN1A), γH2AX, SAHF and Sen-ß-Gal either alone or in combination, and compared with those derived from growth curves. This comparison allowed ranking of candidate markers. High rankings were obtained for Sen-ß-Gal, SAHFs and the combination of Ki67 negativity with high (>5 per nucleus) γH2A.X foci density in MRC5 fibroblasts. We demonstrate that this latter marker combination, which can easily be performed in paraffin-embedded tissue, gives quantitative senescent cell frequency estimates in mouse embryonic fibroblast cultures and in mouse intestinal sections. The technique presented is a framework for quantitative assessment of markers for senescence.

ssDNA fragments induce cell senescence by telomere uncapping.

Telomere uncapping is known to induce senescence by activating a DNA damage response (DDR). However, it is still unclear what structural features of uncapped telomeres activate DDR. One hypothesis is that the exposure of the telomeric single-stranded G-rich 3' overhang triggers a DNA damage response and is, thus, equivalent to telomere uncapping. To mimic this, we compared the effects of two short single-stranded oligonucleotides, (TTAGGG)(2) and (CCCTAA)(2). G-rich oligonucleotides induced DNA damage foci containing gammaH2AX and senescence-like arrest, whilst C-rich oligonucleotides had no effect. Oligonucleotides did not co-localize with gammaEta2AlphaX foci, instead the induced DNA damage foci were preferentially localized at telomeres. BrdU incorporation assays showed that the effect of G oligonucleotides on gammaH2AX foci formation was cell cycle-dependent; entry of cells into S phase was necessary for subsequent DNA damage foci formation. Together, our results show that short G-rich single-stranded oligonucleotides induce telomere uncapping in a cell cycle-dependent manner, probably by titrating essential factors like Pot1 away from telomeres.