Strategies for senolytic drug discovery

Estepa-Fernández A., García-Fernández A., Lérida-Viso A., Morellá-Aucejo Á., Esteve-Moreno J.J., Blandez J.F., Alfonso M., Candela-Noguera V., Vivo-Llorca G., Sancenon-Galarza F., Orzáez M., Martínez-Máñez R.

The engineering of nanoparticle communication has gained growing attention in the last years, however, efforts to communicate nanoparticles with living systems is still a barely studied emerging topic. Here, we explore a nanoparticle cooperation strategy that involves nanoparticle-cell-nanoparticle communication in vivo through stigmergy (a strategy in which nanodevices communicate by modifying the environment). First, mesoporous silica nanoparticles loaded with the senescence inductor palbociclib and coated with a heterobifunctional poly(ethylene glycol) that binds covalently to a MUC1-binding aptamer (NP(palbo)PEG-MUC1), is designed to specifically deliver the pro-senescent drug palbociclib in MDA-MB-231 breast cancer cells. Once the first nanoparticle modifies the environment due to the induction of senescence, a second community of nanoparticles, loaded with the senolytic navitoclax and coated with a hexa-oligo-saccharide (NP(nav)-Gal), releases its cargo to eliminate tumor senescent cells selectively. The targeted therapy through stigmergy communication is tested in vitro, and in vivo, where delays tumor growth and reduces metastases in a mouse model of human triple-negative breast cancer while minimizing undesired drugs side effects.

Deryabin P.I., Shatrova A.N., Borodkina A.V.

Within the present study we proposed a novel approach for senolysis based on the simultaneous disturbance of the several homeostasis-maintaining systems in senescent cells including intracellular ionic balance, energy production and intracellular utilization of damaged products. Of note, we could not induce senolysis by applying ouabain, amiloride, valinomycin or NH4Cl—compounds that modify each of these systems solely. However, we found that ionophore nigericin can disturb plasma membrane potential, intracellular pH, mitochondrial membrane potential and autophagy at once. By affecting all of the tested homeostasis-maintaining systems, nigericin induced senolytic action towards stromal and epithelial senescent cells of different origins. Moreover, the senolytic effect of nigericin was independent of the senescence-inducing stimuli. We uncovered that K+ efflux caused by nigericin initiated pyroptosis in senescent cells. According to our data, the higher sensitivity of senescent cells compared to the control ones towards nigericin-induced death was partially mediated by the lower intracellular K+ content in senescent cells and by their predisposition towards pyroptosis. Finally, we proposed an interval dosing strategy to minimize the negative effects of nigericin on the control cells and to achieve maximal senolytic effect. Hence, our data suggest ionophore nigericin as a new senotherapeutic compound for testing against age-related diseases.

Kim E., Woo J., Shin S., Choi H., Kim Y., Kim J., Kang C.

Lérida-Viso A., Estepa- Fernández A., Morellá-Aucejo Á., Lozano-Torres B., Alfonso M., Blandez J.F., Bisbal V., Sepúlveda P., García-Fernández A., Orzáez M., Martínez-Máñez R.

Many anticancer agents used in clinics induce premature senescence in healthy tissues generating accelerated aging processes and adverse side-effects in patients. Cardiotoxicity is a well-known limiting factor of anticancer treatment with doxorubicin (DOX), a very effective anthracycline widely used as antitumoral therapy in clinical practice, that leads to long-term morbidity and mortality. DOX exposure severely affects the population of cardiac cells in both mice and human hearts by inducing premature senescence, which may represent the molecular basis of DOX-induced cardiomyopathy. Here, we demonstrate that senescence induction in the heart contributes to impaired cardiac function in mice upon DOX treatment. Concomitant elimination of senescent cells with the senolytic Navitoclax in different formulations produces a significant decrease in senescence and cardiotoxicity markers together with the restoration of the cardiac function in mice followed by echocardiography. These results evidence the potential clinical use of senolytic therapies to alleviate cardiotoxicities induced in chemotherapy-treated patients.

Behfar Q., Ramirez Zuniga A., Martino-Adami P.V.

Murakami T., Inagaki N., Kondoh H.

Increased insulin resistance and impaired insulin secretion are significant characteristics manifested by patients with type 2 diabetes mellitus (T2DM). The degree and extent of these two features in T2DM vary among races and individuals. Insulin resistance is accelerated by obesity and is accompanied by accumulation of dysfunctional adipose tissues. In addition, dysfunction of pancreatic β-cells impairs insulin secretion. T2DM is significantly affected by aging, as the β-cell mass diminishes with age. Moreover, both obesity and hyperglycemia-related metabolic changes in developing diabetes are associated with accumulation of senescent cells in multiple organs, that is, organismal aging. Cellular senescence is defined as a state of irreversible cell cycle arrest with concomitant functional decline. It is caused by telomere shortening or senescence-inducing stress. Senescent cells secrete proinflammatory cytokines and chemokines, which is designated as the senescence-associated secretory phenotype (SASP), and this has a negative impact on adipose tissues and pancreatic β-cells. Recent advances in aging research have suggested that senolysis, the removal of senescent cells, can be a promising therapeutic approach to prevent or improve aging-related diseases, including diabetes. The attenuation of a SASP may be beneficial, although the pathophysiological involvement of cellular senescence in diabetes is not fully understood. In the clinical application of senotherapy, tissue-context-dependent senescent cells are increasingly being recognized as an issue to be solved. Recent studies have observed highly heterogenic and complex senescent cell populations that serve distinct roles among tissues, various stages of disease, and different ages. For example, in high-fat-diet induced diabetes with obesity, mouse adipose tissues display accumulation of p21Cip1-highly-expressing (p21high) cells in the early stage, followed by increases in both p21high and p16INK4a-highly-expressing (p16high) cells in the late stage. Interestingly, elimination of p21high cells in visceral adipose tissue can prevent or improve insulin resistance in mice with obesity, while p16high cell clearance is less effective in alleviating insulin resistance. Importantly, in immune-deficient mice transplanted with fat from obese patients, dasatinib plus quercetin, a senolytic cocktail that reduces the number of both p21high and p16high cells, improves both glucose tolerance and insulin resistance. On the other hand, in pancreatic β cells, p16high cells become increasingly predominant with age and development of diabetes. Consistently, elimination of p16high cells in mice improves both glucose tolerance and glucose-induced insulin secretion. Moreover, a senolytic compound, the anti-Bcl-2 inhibitor ABT263 reduces p16INK4a expression in islets and restores glucose tolerance in mice when combined with insulin receptor antagonist S961 treatment. In addition, efficacy of senotherapy in targeting mouse pancreatic β cells has been validated not only in T2DM, but also in type 1 diabetes mellitus. Indeed, in non-obese diabetic mice, treatment with anti-Bcl-2 inhibitors, such as ABT199, eliminates senescent pancreatic β cells, resulting in prevention of diabetes mellitus. These findings clearly indicate that features of diabetes are partly determined by which or where senescent cells reside in vivo, as adipose tissues and pancreatic β cells are responsible for insulin resistance and insulin secretion, respectively. In this review, we summarize recent advances in understanding cellular senescence in adipose tissues and pancreatic β cells in diabetes. We review the different potential molecular targets and distinctive senotherapeutic strategies in adipose tissues and pancreatic β cells. We propose the novel concept of a dual-target tailored approach in senotherapy against diabetes.

Moaddel R., Rossi M., Rodriguez S., Munk R., Khadeer M., Abdelmohsen K., Gorospe M., Ferrucci L.

Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation.

Limbad C., Doi R., McGirr J., Ciotlos S., Perez K., Clayton Z.S., Daya R., Seals D.R., Campisi J., Melov S.

SummaryCellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

Zhang L., Pitcher L.E., Prahalad V., Niedernhofer L.J., Robbins P.D.

The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene-induced stress. Many senescent cells (SnCs) develop a senescent-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up-regulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre-clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.

Xie J., Wang Y., Lu L., Liu L., Yu X., Pei F.

• Current evidence for the role of cellular senescence of different cell types in the onset and progression of osteoarthritis were reviewed. • The underlying mechanisms of senescence in chondrocytes, especially Forkhead family of transcription factors were reviewed. • Potential therapeutic value and implications of targeting senescent cells using senolytic agents or immune therapies, targeting the senescence-associated secretory phenotype of these cells using senomorphic agents, and renewing the plasticity of stem cells and chondrocytes were reviewed. • The review highlights current gaps in understanding of the mechanism of senescence that may, when addressed, provided new options for modifying and treating disease in osteoarthritis. Cellular senescence is the inability of cells to proliferate, which has both beneficial and detrimental effects on tissue development and homeostasis. Chronic accumulation of senescent cells is associated with age-related disease, including osteoarthritis, a common joint disease responsible for joint pain and disability in older adults. The pathology of this disease includes loss of cartilage, synovium inflammation, and subchondral bone remodeling. Senescent cells are present in the cartilage of people with advanced osteoarthritis, but the link between cellular senescence and this disease is unclear. In this review, we summarize current evidence for the role of cellular senescence of different cell types in the onset and progression of osteoarthritis. We focus on the underlying mechanisms of senescence in chondrocytes, which maintain the cartilage in joints, and review the role of the Forkhead family of transcription factors, which are involved in cartilage maintenance and osteoarthritis. Finally, we discuss the potential therapeutic value and implications of targeting senescent cells using senolytic agents or immune therapies, targeting the senescence-associated secretory phenotype of these cells using senomorphic agents, and renewing the plasticity of stem cells and chondrocytes. Our review highlights current gaps in understanding of the mechanism of senescence that may, when addressed, provided new options for modifying and treating disease in osteoarthritis.

Admasu T.D., Rae M.J., Stolzing A.

• There is no universal gene expression signature for senescent cells or the SASP. • Primary and secondary senescent cells seem to be distinct from each other in some respects. • Secondary senescence can spread via secreted molecules, extracellular vesicles, or cell-to-cell contact. • Secondary senescence contributes to the accumulation of senescent cells and is associated with the diseases of aging. Cellular senescence is a state of stable cell cycle arrest that is known to be elicited in response to different stresses or forms of damage. Senescence limits the replication of old, damaged, and precancerous cells in the short-term but is implicated in diseases and debilities of aging due to loss of regenerative reserve and secretion of a complex combination of factors called the senescence-associated secretory phenotype (SASP). More recently, investigators have discovered that senescent cells induced by these methods (what we term “primary senescent cells”) are also capable of inducing other non-senescent cells to undergo senescence — a phenomenon we call “secondary senescence.” Secondary senescence has been demonstrated to occur via two broad types of mechanisms. First, factors in the SASP have been shown to be involved in spreading senescence; we call this phenomenon “paracrine senescence.” Second, primary senescent cells can induce senescence via an additional group of mechanisms involving cell-to-cell contacts of different types; we term this phenomenon “juxtacrine senescence.” “Secondary senescence” in our definition is thus the overarching term for both paracrine and juxtacrine senescence together. By allowing cells that are inherently small in number and incapable of replication to increase in number and possibly spread to anatomically distant locations, secondary senescence allows an initially small number of senescent cells to contribute further to age-related pathologies. We propose that understanding how primary and secondary senescent cells differ from each other and the mechanisms of their spread will enable the development of new rejuvenation therapies to target different senescent cell populations and interrupt their spread, extending human health- and potentially lifespan.

Yang J., Liu M., Hong D., Zeng M., Zhang X.

Cellular senescence occurs in proliferating cells as a consequence of various triggers including telomere shortening, DNA damage, and inappropriate expression of oncogenes. The senescent state is accompanied by failure to reenter the cell cycle under mitotic stimulation, resistance to cell death and enhanced secretory phenotype. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Cellular senescence was initially described as a physiological suppressor mechanism of tumor cells, because cancer development requires cell proliferation. However, there is growing evidence that senescent cells may contribute to oncogenesis, partly in a senescence-associated secretory phenotype (SASP)-dependent manner. On the one hand, SASP prevents cell division and promotes immune clearance of damaged cells, thereby avoiding tumor development. On the other hand, SASP contributes to tumor progression and relapse through creating an immunosuppressive environment. In this review, we performed a review to summarize both bright and dark sides of senescence in cancer, and the strategies to handle senescence in cancer therapy were also discussed.

Wiley C.D., Sharma R., Davis S.S., Lopez-Dominguez J.A., Mitchell K.P., Wiley S., Alimirah F., Kim D.E., Payne T., Rosko A., Aimontche E., Deshpande S.M., Neri F., Kuehnemann C., Demaria M., et. al.

Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.

Mylonas K.J., O’Sullivan E.D., Humphries D., Baird D.P., Docherty M., Neely S.A., Krimpenfort P.J., Melk A., Schmitt R., Ferreira-Gonzalez S., Forbes S.J., Hughes J., Ferenbach D.A.

Senescent renal epithelia promote fibrosis and functional loss after injury, whereas depletion improves regeneration in aged or irradiated kidneys.

Yang D., Tian X., Ye Y., Liang Y., Zhao J., Wu T., Lu N.

Senescent cancer cells contribute to tumor refractoriness. The removal of senescent cells after chemotherapy prevents or delays cancer relapse. Our study showed that GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a potential anticancer drug, eliminated senescent MEFs (Mouse embryonic fibroblasts) and drug-induced senescent breast cancer cells. GL-V9 induced apoptosis in senescent MDA-MB-231 cells. Mechanistically, it alkalized lysosomes and increased the abundance of mitochondria as well as ROS (Reactive oxygen species). The senolytic effect of GL-V9 was also observed in epirubicin-treated mammary tumors in MMTV-PyMT mice. Our data thus indicated that GL-V9 is a promising senolytic drug which could be used to improve the outcome of cancer chemotherapy.

Cabrera-Fuentes H.A., Barreto G., Al-Suhaimi E.A., Liehn E.A.

García-Domínguez M.

Aging is a complex, progressive, and irreversible biological process that entails numerous structural and functional changes in the organism. These changes affect all bodily systems, reducing their ability to respond and adapt to the environment. Chronic inflammation is one of the key factors driving the development of age-related diseases, ultimately causing a substantial decline in the functional abilities of older individuals. This persistent inflammatory state (commonly known as “inflammaging”) is characterized by elevated levels of pro-inflammatory cytokines, an increase in oxidative stress, and a perturbation of immune homeostasis. Several factors, including cellular senescence, contribute to this inflammatory milieu, thereby amplifying conditions such as cardiovascular disease, neurodegeneration, and metabolic disorders. Exploring the mechanisms of chronic inflammation in aging is essential for developing targeted interventions aimed at promoting healthy aging. This review explains the strong connection between aging and chronic inflammation, highlighting potential therapeutic approaches like pharmacological treatments, dietary strategies, and lifestyle changes.

Wang L., Tang D.

Atasever E., Atayik M.C., Çakatay U.

Meyer M., Fourie C., van der Merwe H., Botha H., Engelbrecht A.

Pan Q., Zhu Y., Ye Z., Zhang H., Wang J., Yi G., Li Z., Xu R., Wang L., Wu Z., Qi S., Huang G., Qu S.

AbstractCellular senescence is characterized by a sustained and irreversible cessation of cell proliferation in response to diverse environmental stimuli. However, senescent cells exhibit strong metabolic activity and release a range of cytokines and inflammatory mediators into the tumor microenvironment, collectively referred to as the senescence‐associated secretory phenotype (SASP). In recent years, to develop new therapies for cancers, researchers have conducted extensive studies on the mechanism of cancer cell senescence and revealed that induction of cancer cell senescence could effectively suppress cancer progression. However, it has been documented that cellular senescence not only inhibits cancer initiation but also contributes significantly to cancer progression in some cases. Hence, it is imperative to comprehend the correlation between cellular senescence and tumorigenesis, and discuss the potential utilization of cellular senescence mechanisms to suppress cancer progression, which lays a theoretical foundation for new drugs to treat cancers. In this review, we first provide an overview of the discovery of cellular senescence and its key milestone events. Meanwhile, this review examines the major stimulus for the induction of senescence, and provides an overview of the categorization of cellular senescence. Subsequently, an examination of the primary regulatory mechanisms of cellular senescence is discussed, followed by a summary of the control of the SASP expression and its dual biological roles in cancers. Additionally, we also provide an overview of common biomarkers utilized in the identification of cellular senescence. Finally, this review investigates the efficacy of the “One‐Two punch” sequential treatment approach for cancers, and examines the emerging challenges of this novel approach.

Li S., Wang K., Wu J., Zhu Y.

Zhao X., Lin J., Liu F., Zhang Y., Shi B., Ma C., Wang Z., Xue S., Xu Q., Shao H., Yang J., Gao Y.

AbstractOsteoarthritis (OA) is an age‐related degenerative joint disease, prominently influenced by the pro‐inflammatory cytokine interleukin‐6 (IL‐6). Although elevated IL‐6 levels in joint fluid are well‐documented, the uneven cartilage degeneration observed in knee OA patients suggests additional underlying mechanisms. This study investigates the role of interleukin‐6 receptor (IL‐6R) in mediating IL‐6 signaling and its contribution to OA progression. Here, significantly elevated IL‐6R expression is identified in degenerated cartilage of OA patients. Further, in vivo experiments reveal that intra‐articular injection of recombinant IL‐6R protein or activation of gp130 (Y757F mutation) accelerates OA progression. Conversely, knockout of IL‐6R or JAK2, as well as treatment with a JAK inhibitor, alleviates OA symptoms. Mechanistically, chondrocytes derived from degenerative cartilage exhibit impaired nuclear localization of SOX9, a key regulator of cartilage homeostasis. JAK inhibition stabilizes SIRT1, reduces SOX9 acetylation, and thereby facilitates SOX9 nuclear localization, promoting cartilage repair. Additionally, the JAK inhibitor‐induced apoptosis in p21‐positive senescent cells, and their targeted clearance successfully alleviates OA in p21‐3MR mice. In conclusion, these findings reveal a novel mechanism by which inhibiting the IL‐6R/JAK2 pathway can alleviate OA. Furthermore, this study proposes targeting p21‐positive senescent cells as a new therapeutic strategy for OA.

Wnuk M., Del Sol-Fernández S., Błoniarz D., Słaby J., Szmatoła T., Żebrowski M., Martínez-Vicente P., Litwinienko G., Moros M., Lewińska A.

Zhang J., Guan X., Zhong X.

Zheng H., Wu J., Feng J., Cheng H.

Jin S., Li W., Huang Q., Zeng X., Zhang X.

Clearing senescent cells (SnCs) have emerged as a promising strategy for delaying aging and treating aging-related diseases. The combined administration of dasatinib and quercetin has been widely employed for the elimination of SnCs. However, the therapeutic effectiveness of these two drugs is restricted because they possess distinct pharmacokinetics and biodistributions in vivo. Hence, there is a pressing need to devise a strategy for the targeted synchronous delivery of these two drugs. Here, a dual-drug codelivery nanosystem (lysozyme-dasatinib and quercetin nanoparticles, L-DQ) was developed by integrating DQ through electrostatic interactions. Furthermore, the surfaces of these nanoparticles were modified with lysozyme, enhancing their ability to specifically target the kidney for efficient clearance of SnCs. Through in vivo and in vitro experiments, the effective elimination of SnCs from the kidney and accelerated recovery of renal function by L-DQ were demonstrated. This study provides a potential strategy for the treatment of multiple aging-related diseases by the targeted delivery of senolytics to specific organs.

Shao M., Qiu Y., Shen M., Liu W., Feng D., Luo Z., Zhou Y.

AbstractPulmonary fibrosis is a formidable challenge in chronic and age‐related lung diseases. Myofibroblasts secrete large amounts of extracellular matrix and induce pro‐repair responses during normal wound healing. Successful tissue repair results in termination of myofibroblast activity via apoptosis; however, some myofibroblasts exhibit a senescent phenotype and escape apoptosis, causing over‐repair that is characterized by pathological fibrotic scarring. Therefore, the removal of senescent myofibroblasts using senolytics is an important method for the treatment of pulmonary fibrosis. Procyanidin C1 (PCC1) has recently been discovered as a senolytic compound with very low toxicity and few side effects. This study aimed to determine whether PCC1 could improve lung fibrosis by promoting apoptosis in senescent myofibroblasts and to investigate the mechanisms involved. The results showed that PCC1 attenuates bleomycin (BLM)‐induced pulmonary fibrosis in mice. In addition, we found that PCC1 inhibited extracellular matrix deposition and promoted the apoptosis of senescent myofibroblasts by increasing PUMA expression and activating the BAX signaling pathway. Our findings represent a new method of pulmonary fibrosis management and emphasize the potential of PCC1 as a senotherapeutic agent for the treatment of pulmonary fibrosis, providing hope for patients with pulmonary fibrosis worldwide. Our results advance our understanding of age‐related diseases and highlight the importance of addressing cellular senescence in treatment.

Rudat R.

Störungen eines Organs oder Organsystems haben immer auch Auswirkungen auf andere Organsysteme. Dieser Artikel beschreibt das vielfach ineinandergreifende Zusammenspiel der Nieren mit anderen Organsystemen wie Herz, Lunge, Leber und Schilddrüse. Wie hängen diese physiologisch und pathogenetisch voneinander ab und welche Schlussfolgerungen kann und sollte man für die Therapie daraus schließen?

Zhang H., Xu X., Shou X., Liao W., Jin C., Chen C., Zhang C., Gao W., Zhang J., Ge W., Shi L.

AbstractCellular senescence is a significant risk factor for aging and age‐related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of the nanomaterial‐based approaches targeting SnCs, limited therapeutic effects and potential toxicity still remain a major concern. Herein, we developed a “double locks‐like” nanoplatform that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ was only released in SnCs that were featured with higher levels of β‐galactosidase (β‐gal) and low PH. Additionally, the nanoparticles were equipped with 2,2,6,6‐Tetramethylpiperidine‐1‐oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrated remarkable specificity and efficacy in eradicating SnCs, and accordingly reversed pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near‐infrared (NIR) light, the nanoparticles demonstrated to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an “On/Off” switchable nanoplatform in response to SnCs, and produces a more safe, efficient and feasible way to delay aging or alleviate age‐associated diseases.This article is protected by copyright. All rights reserved