Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy (Review).

Cellular senescence has a complex role in lymphocyte carcinogenesis and drug resistance of lymphomas. Senescent lymphoma cells combine with immunocytes to create an ageing environment that can be reprogrammed with a senescence­associated secretory phenotype, which gradually promotes therapeutic resistance. Certain signalling pathways, such as the NF­κB, Wnt and PI3K/AKT/mTOR pathways, regulate the tumour ageing microenvironment and induce the proliferation and progression of lymphoma cells. Therefore, targeting senescence­related enzymes or their signal transduction pathways may overcome radiotherapy or chemotherapy resistance and enhance the efficacy of relapsed/refractory lymphoma treatments. Mechanisms underlying drug resistance in lymphomas are complex. The ageing microenvironment is a novel factor that contributes to drug resistance in lymphomas. In terms of clinical translation, some senolytics have been used in clinical trials on patients with relapsed or refractory lymphoma. Combining immunotherapy with epigenetic drugs may achieve better therapeutic effects; however, senescent cells exhibit considerable heterogeneity and lymphoma has several subtypes. Extensive research is necessary to achieve the practical application of senolytics in relapsed or refractory lymphomas. This review summarises the mechanisms of senescence­associated drug resistance in lymphoma, as well as emerging strategies using senolytics, to overcome therapeutic resistance in lymphoma.

Therapeutic strategies targeting cellular senescence for cancer and other diseases.

Cellular senescence occurs in response to endogenous or exogenous stresses and is characterized by stable cell cycle arrest, alterations in nuclear morphology and secretion of proinflammatory factors, referred to as the senescence-associated secretory phenotype (SASP). An increase of senescent cells is associated with the development of several types of cancer and aging-related diseases. Therefore, senolytic agents that selectively remove senescent cells may offer opportunities for developing new therapeutic strategies against such cancers and aging-related diseases. This review outlines senescence inducers and the general characteristics of senescent cells. We also discuss the involvement of senescent cells in certain cancers and diseases. Finally, we describe a series of senolytic agents and their utilization in therapeutic strategies.

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions.

OBJECTIVE: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. DESIGN: To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. RESULTS: We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. CONCLUSIONS: These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

Antidiabetic Effects of the Senolytic Agent Dasatinib.

OBJECTIVE: To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus. METHODS: This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32). RESULTS: Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.06). CONCLUSION: Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties.

Senotherapeutic Drugs: A New Avenue for Skincare?

SUMMARY: Skin aging is an outward manifestation of other cellular and molecular aging processes occurring elsewhere in the body. These processes are known collectively as the "hallmarks" of aging, which are a series of basic health maintenance mechanisms that fail over time. Cellular senescence is one of the most studied of the hallmarks of aging; senescent cells accumulate over time and are major drives of the aging process. Here, we discuss the impact of cellular senescence in the context of skin aging, and discuss the emerging landscape of interventions designed for their selective removal by targeted cell death (senolytics) or rejuvenation (senomorphics). We discuss the serotherapeutic strategies that are currently under investigation for systemic aging, which may bring eventual benefits for skin health. Next, we discuss a newly discovered hallmark of aging, dysregulated mRNA processing, which can be targeted for the senomorphic effect. Finally, we highlight a new modality for manipulation of disrupted mRNA processing, oligonucleotide therapeutics. The emerging field of senotherapeutics is set to revolutionize how we view and treat skin aging, and senotherapies are now poised to become a new class of skincare interventions.

Potential Use of Senolytics for Pharmacological Targeting of Precancerous Lesions.

Senescence is a cell state that contributes to several homeostatic and pathologic processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction [oncogene-induced senescence (OIS)]. Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung. Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. Although senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This Emerging Concepts commentary will 1) summarize evidence in established models of OIS including B-Raf-induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models, as well as evidence from clinical precancerous lesions; 2) suggest that OIS is targetable; and 3) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions. SIGNIFICANCE STATEMENT: The treatment of premalignant lesions is largely based on the utilization of invasive (or minimally invasive) measures. Oncogene-induced senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. Although the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation. Accordingly, the pharmacological targeting of oncogene-induced senescent cells could potentially provide a novel, less invasive, means for the treatment of premalignant disease.

Extracellular vesicles from mesenchymal stromal cells: Therapeutic perspectives for targeting senescence in osteoarthritis.

Osteoarthritis (OA) is a common age-related disease that correlates with a high number of senescent cells in joint tissues. Senescence has been reported to be one of the main drivers of OA pathogenesis, in particular via the release of senescence-associated secretory phenotype (SASP) factors. SASP factors are secreted as single molecules and/or packaged within extracellular vesicles (EVs), thereby contributing to senescent phenotype dissemination. Targeting senescent cells using senolytics or senomorphics has therefore been tested and improvement of OA-associated features has been reported in murine models. Mesenchymal stromal cells (MSCs) and their derived EVs (MSC-EVs) are promising treatments for OA, exerting pleiotropic functions by producing a variety of factors. However, functions of MSCs and MSC-EVs are affected by aging. In this review, we discuss on the impact of the senescent environment on functions of aged MSC-EVs and on the anti-aging properties of MSC-EVs in the context of OA.