Association of immunity markers with the risk of incident frailty: the Rugao longitudinal aging study

Background The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are readily available circulatory immunity markers that are associated with components of frailty. However, few studies have investigated the relationship between these immunity markers and frailty, and it remains unknown whether they are predictive of incident frailty in older adults in general. Hence, we aimed to examine the association of these immunity markers with the risk of incident frailty. Results Overall, 1822 older adults (mean age was 78.03 ± 4.46 years) were included in the Rugao Longitudinal Aging Study. NLR, PLR and SII were calculated from blood cell counts. The frailty definition was based on the Fried phenotype. At baseline, 200 (10.98%) individuals were defined as frailty, and no significant associations of NLR, PLR and SII with frailty were found. During the 2-year follow-up, 180 (15.67%) individuals were new-onset frailty. After adjustment, an increased logNLR (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.20–7.18), logPLR (OR 2.54, 95% CI: 1.01–6.53) and logSII (OR 2.34, 95% CI: 1.16–4.78) were significantly associated with a higher risk of incident frailty in all individuals. Additionally, the associations of logNLR (OR 4.21, 95% CI 1.54–11.62 logPLR (OR 3.38, 95% CI: 1.17–9.91) and logSII (OR 2.56, 95% CI: 1.15–5.72) with incident frailty were remained after excluding individuals with comorbidities. In further analyzed, individuals with higher levels of NLR and SII had higher risk of incident frailty when we stratified individuals by quartiles of these immunity markers. Conclusion NLR and SII are easily obtained immunity markers that could be used to predict incident frailty in clinical practice.

Knockdown of lncRNA BDNF-AS inhibited the progression of multiple myeloma by targeting the miR-125a/b-5p-BCL2 axis

Purpose This study aimed to explore the role of long non-coding RNA (lncRNA) BDNF-AS in the progression of multiple myeloma (MM). Methods The expression of BDNF-AS, miR-125a-5p, and miR-125b-5p in MM serum and cell lines were detected by quantitative reverse transcriptase PCR (qRT-PCR). The binding relationships between miR-125a/b-5p and BDNF-AS or Bcl-2 were predicted by Starbase and verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2′-deoxyuridine (EdU) staining assay. Cell migration was evaluated by wound healing assay. The expression levels of apoptosis-related proteins were evaluated by Western blot analysis. The role of BDNF-AS was also investigated in a xenograft tumor model in vivo. Results BDNF-AS was significantly upregulated, while miR-125a-5p and miR-125b-5p were downregulated in MM serum and corresponding cancer cell lines. Knockdown of BDNF-AS effectively inhibited the proliferation and migration of MM.1S and U266 cells, and co-transfection of miR-125a-5p or miR-125b-5p inhibitor and sh-BDNF-AS enhanced cell proliferation and migration compared with that in sh-BDNF-AS group. Knockdown of miR-125a-5p or miR-125b-5p significantly enhanced the proliferation and migration of MM.1S and U266 cells, and co-transfection of sh-Bcl-2 and miR-125a/b-5p inhibitor inhibited cell proliferation compared with that in miR-125a/b-5p inhibitor group. Moreover, knockdown of BDNF-AS increased the expression levels of apoptosis-related proteins (cleaved caspase 3 and cleaved PARP), while knockdown of miR-125a-5p or miR-125b-5p reduced the expression levels of these apoptosis-related proteins compared with knockdown of BDNF-AS. Furthermore, knockdown of BDNF-AS effectively suppressed MM tumor growth in vivo. Conclusion Our findings revealed that knockdown of BDNF-AS inhibited the progression of MM by targeting the miR-125a/b-5p-Bcl-2 axis, indicating that BDNF-AS might serve as a novel drug target for MM.

The immunosenescence-related factor DOCK11 is involved in secondary immune responses of B cells

Background Memory B cells are an antigen-experienced B-cell population with the ability to rapidly differentiate into antibody-producing cells by recall responses. We recently found that dedicator of cytokinesis 11 (DOCK11) contributes to the expansion of antigen-specific populations among germinal center B cells upon immunization. In comparison, limited information is available on the contribution of DOCK11 to secondary humoral immune responses. Results In this study, effects of the DOCK11 deficiency in B cells were examined on secondary immune responses to protein antigen. The lack of DOCK11 in B cells resulted in the impaired induction of antibody-producing cells upon secondary immunization with protein antigen. DOCK11 was dispensable for the recall responses of antigen-experienced B cells, as demonstrated by the comparable induction of antibody-producing cells in mice given transfer of antigen-experienced B cells with no DOCK11 expression. Instead, the lack of DOCK11 in B cells resulted in the impaired secondary immune responses in a B cell-extrinsic manner, which was recovered by the adoptive transfer of cognate T cells. Conclusions We addressed that intrinsic and extrinsic effects of DOCK11 expression in B cells may contribute to secondary humoral immune responses in manner of the induction of cognate T-cell help.

The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.

MicroRNA-425-5p modulates osteoporosis by targeting annexin A2

Background Studies have shown that the decrease of osteogenic differentiation of bone marrow mesenchymal stem cells (MSC) is an important mechanism of osteoporosis. The object of this study was to explore the role and mechanism of microRNA miR-425-5p in the differentiation of MSC. Methods The expression of miR-425-5p in MSC was detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell proliferation, cell cycle and apoptosis were detected by CCK-8 colorimetry and flow cytometry. The expression of TNF were detected by ELISA. Results Our data show that MiR-425-5p could modulate TNF-induced cell apoptosis, proliferation, and differentiation. ANXA2 is also the target of miR-425-5p and ANXA2 was involved in TNF-induced MSC cell apoptosis, proliferation, and differentiation. In addition, MiR-425-5p enhanced osteoporosis in mice. Conclusion MiR-425-5p might serve as a potential therapeutic target for the treatment of osteoporosis.

Quantification of dendritic cell subsets in human thymus tissues of various ages

Background Dendritic cells (DCs) in the thymus are involved in central tolerance formation, but they also have other functions in the thymus, such as pathogen recognition. The density changes of human thymic DCs have been hardly investigated. In this study, human thymus samples of various ages were collected for tissue sectioning and staining. The thymic cortex and medulla area as well as the densities of various subsets of thymic DCs were calculated. Results All common DC subsets were found in the human thymus of various ages. Most DCs had accumulated in the human thymic epithelial space, especially the medulla. We also found that the human thymic cortex had atrophied relatively faster than the medulla, which led to a gradual increase of the area ratio of the medulla to cortex with the increase of age. The densities of DC subsets in the human thymus showed various changes with increasing age, which contributed to the composition changes of DC subsets. The density of plasmacytoid DCs (pDCs) in the human thymus had increased gradually with aging, which suggested that pDCs plays another essential role in the thymus in addition to central tolerance. Conclusions Inconsistent with the shrinking of the epithelial space in the thymus, the densities of DC subsets in the epithelial space of the thymus are maintained at a constant level with aging to preserve highly efficient autoreactive thymocyte screening. An increasing density of the thymic pDCs with aging implies an extra function of DCs in the thymus beyond central tolerance.

Changes in T and B cell subsets in end stage renal disease patients before and after kidney transplantation

Background The incidence of kidney transplantation performed in elderly patients has increased steadily recently. Higher risk of infection and mortality, but lower rate of rejection, are reported in older kidney transplant patients. This study aims to analyze the effect of transplantation on aging of T and B cells in kidney transplant patients, with the emphasis on age and Cytomegalovirus (CMV) latency. Results We included 36 patients before and after (median 2.7 years) kidney transplantation and 27 age- and sex-matched healthy controls (HC). T and B cell subsets were measured by flow cytometry, with a focus on aged T cells (CD28-), and age associated B cells (ABCs, CD19 + CD21-CD11c+). Three years after transplantation a significant increase of total T cells among the lymphocytes was found compared to pre-transplantation and HC. Among the T cells CD4+ cells were decreased, especially naïve CD4+ cells and regulatory T cells. Total CD8+ cell proportions were increased, and proportions of naïve CD8+ cells were significantly decreased after transplantation, while CD8+ effector memory T cells re-expressing CD45RA were increased. CD28− T cells were significantly higher compared to HC after transplantation, especially in CMV seropositive patients. B cells were significantly decreased, while among B cells memory B cells and especially ABCs were increased after transplantation. Conclusions After transplantation T and B cell subsets change towards more terminally differentiated memory cells compared to age-matched HC. Proportions of aged T cells and ABCs were associated with CMV serostatus.

Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice

Background Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated. Methods The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4−/− mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines. Results TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. Conclusion In summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.

SARS-CoV-2 and EBV; the cost of a second mitochondrial “whammy”?

We, and others, have suggested that as the SARS-CoV-2 virus may modulate mitochondrial function, good mitochondrial reserve and health could be key in determining disease severity when exposed to this virus, as the immune system itself is dependent on this organelle’s function. With the recent publication of a paper showing that long COVID could be associated with the reactivation of the Epstein Barr Virus, which is well known to manipulate mitochondria, we suggest that this could represent a second mitochondrial “whammy” that might support the mitochondrial hypothesis underlying COVID-19 severity and potentially, the occurrence of longer-term symptoms. As mitochondrial function declines with age, this could be an important factor in why older populations are more susceptible. Key factors which ensure optimal mitochondrial health are generally those that ensure healthy ageing, such as a good lifestyle with plenty of physical activity. The ability of viruses to manipulate mitochondrial function is well described, and it is now also thought that for evolutionary reasons, they also manipulate the ageing process. Given that slowing the ageing process could well be linked to better economic outcomes, the link between mitochondrial health, economics, COVID-19 and other viruses, as well as lifestyle, needs to be considered.