How good is the evidence that cellular senescence causes skin ageing?

Skin is the largest organ of the body with important protective functions, which become compromised with time due to both intrinsic and extrinsic ageing processes. Cellular senescence is the primary ageing process at cell level, associated with loss of proliferative capacity, mitochondrial dysfunction and significantly altered patterns of expression and secretion of bioactive molecules. Intervention experiments have proven cell senescence as a relevant cause of ageing in many organs. In case of skin, accumulation of senescence in all major compartments with ageing is well documented and might be responsible for most, if not all, the molecular changes observed during ageing. Incorporation of senescent cells into in-vitro skin models (specifically 3D full thickness models) recapitulates changes typically associated with skin ageing. However, crucial evidence is still missing. A beneficial effect of senescent cell ablation on skin ageing has so far only been shown following rather unspecific interventions or in transgenic mouse models. We conclude that evidence for cellular senescence as a relevant cause of intrinsic skin ageing is highly suggestive but not yet completely conclusive.     

Adaptive response of resistant cancer cells to chemotherapy

Despite advances in cancer therapeutics and the integration of personalized medicine, the development of chemoresistance in many patients remains a significant contributing factor to cancer mortality. Upon treatment with chemotherapeutics, the disruption of homeostasis in cancer cells triggers the adaptive response which has emerged as a key resistance mechanism. In this review, we summarize the mechanistic studies investigating the three major components of the adaptive response, autophagy, endoplasmic reticulum (ER) stress signaling, and senescence, in response to cancer chemotherapy. We will discuss the development of potential cancer therapeutic strategies in the context of these adaptive resistance mechanisms, with the goal of stimulating research that may facilitate the development of effective cancer therapy.     

Maladie rénale chronique et immunosénescence prématurée : données et perspectives

Immune senescence is associated with age-related diseases (i.e. infectious disease, cardiovascular diseases and cancers). Chronic kidney disease patients die prematurely when compared with general population, because of a higher occurrence of infections, cardiovascular events and cancer. These diseases are commonly observed in the elderly population and frequently associated with immune senescence. Indeed, chronic kidney disease causes a premature aging of the T lymphocyte compartment, widely related to a decrease in thymic function, a phenomenon that plays a key role in the onset of age-related diseases in chronic kidney disease patients. The degree of immune senescence also influences patients’ outcome after renal transplantation, particularly the risk of acute rejection and infections. Partial reversion of pre-transplant immune senescence is observed for some renal transplant patients. In conclusion, to reduce the increasing incidence of morbidity and mortality of chronic kidney disease patients, a better knowledge of uremia-induced immune senescence would help to pave the way to build clinical studies and promote innovative therapeutic approaches. We believe that therapeutic reversion and immune senescence prevention approaches will be part of the management of chronic kidney disease patients in the future.     

补益营卫方对衰老表皮结构蛋白K17的影响

目的:观察补益营卫方对衰老表皮结构蛋白K17的基因和蛋白水平的影响。方法:将3个月龄小鼠(年轻组)与14个月龄小鼠(老年组)表皮细胞消化分离出来,然后进行传代培养,其中14个月龄小鼠(老年组)的表皮细胞分为2组,一组用常规方法培养细胞,另一组用含2.5%的补益营卫方培养基进行培养,采用荧光定量RT-PCR法和Western Blotting法分别检测细胞K17mRNA表达和细胞K17蛋白表达。结果:与年轻组比较,老年组的K17mRNA和蛋白表达水平均升高(P<0.05);经药物干预后小鼠表皮细胞中K17mRNA和蛋白水平较老年组明显降低(P<0.05)。结论:补益营卫方可通过抑制衰老表皮结构蛋白K17的表达,起到延缓皮肤衰老作用。     

Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age‐related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi‐mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro‐inflammatory cytokines and extracellular matrix–degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi‐related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non‐senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.     

Doxorubicin‐induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2

Clinical dose of doxorubicin (100 nM) induced cellular senescence and various secretory phenotypes in breast cancer and normal epithelial cells. Herein, we reported the detailed mechanism underlying ginsenoside Rh2‐mediated NF‐κB inhibition, and mitophagy promotion were evaluated by antibody array assay, western blotting analysis, and immunocytostaining. Ginsenoside Rh2 suppressed the protein levels of TRAF6, p62, phosphorylated IKK, and IκB, which consequently inactivated NF‐κB activity. Rh2‐mediated secretory phenotype was delineated by the suppressed IL‐8 secretion. Senescent epithelial cells showed increased level of reactive oxygen species (ROS), which was significantly abrogated by Rh2, with upregulation on SIRT 3 and SIRT 5 and subsequent increase in SOD1 and SOD2. Rh2 remarkably favored mitophagy by the increased expressions of PINK1 and Parkin and decreased level of PGC‐1α. A decreased secretion of IL‐8 challenged by mitophagy inhibitor Mdivi‐1 with an NF‐κB luciferase system was confirmed. Importantly, secretory senescent epithelial cells promoted the breast cancer (MCF‐7) proliferation while decreased the survival of normal epithelial cells demonstrated by co‐culture system, which was remarkably alleviated by ginsenoside Rh2 treatment. These data included ginsenoside Rh2 regulated ROS and mitochondrial autophagy, which were in large part attributed to secretory phenotype of senescent breast epithelial cells induced by doxorubicin. These findings also suggested that ginsenoside Rh2 is a potential treatment candidate for the attenuation of aging related disease.     

A small-molecule inhibitor suppresses the tumor-associated mitochondrial NAD(P)+-dependent malic enzyme (ME2) and induces cellular senescence

Here, we found a natural compound, embonic acid (EA), that can specifically inhibit the enzymatic activity of mitochondrial NAD(P)⁺-dependent malic enzyme (m-NAD(P)-ME, ME2) either in vitro or in vivo. The in vitro IC₅₀ value of EA for m-NAD(P)-ME was 1.4 ± 0.4 μM. Mutagenesis and binding studies revealed that the putative binding site of EA on m-NAD(P)-ME is located at the fumarate binding site or at the dimer interface near the site. Inhibition studies reveal that EA displayed a non-competitive inhibition pattern, which demonstrated that the binding site of EA was distinct from the active site of the enzyme. Therefore, EA is thought to be an allosteric inhibitor of m-NAD(P)-ME. Both EA treatment and knockdown of m-NAD(P)-ME by shRNA inhibited the growth of H1299 cancer cells. The protein expression and mRNA synthesis of m-NAD(P)-ME in H1299 cells were not influenced by EA, suggesting that the EA-inhibited H1299 cell growth occurs through the suppression of in vivo m-NAD(P)-ME activity EA treatment further induced the cellular senescence of H1299 cells. However, down-regulation of the enzyme-induced cellular senescence was not through p53. Therefore, the EA-evoked senescence of H1299 cells may occur directly through the inhibition of ME2 or a p53-independent pathway.