Cellular senescence (CS), a permanent and irreversible arrest of the cell cycle and proliferation leading to the degeneration of cellular structure and function, has been implicated in various key physiological and pathological processes, particularly in cancer. Initially, CS was recognized as a barrier to tumorigenesis, serving as an intrinsic defense mechanism to protect cells from malignant transformation. However, increasing evidence suggests that senescent cells can promote tumor progression to overt malignancy, primarily through a set of factors known as senescence-associated secretory phenotypes (SASPs), including chemokines, growth factors, cytokines, and stromal metalloproteinases. These factors significantly reshape the tumor microenvironment (TME), enabling tumors to evade immune destruction. Interestingly, some studies have also suggested that SASPs may impede tumor development by enhancing immunosurveillance. These opposing roles highlight the complexity and heterogeneity of CS and SASPs in diverse cancers. Consequently, there has been growing interest in pharmacological interventions targeting CS or SASPs in cancer therapy, such as senolytics and senomorphics, to either promote the clearance of senescent cells or mitigate the harmful effects of SASPs. In this review, we will interpret the concept of CS, delve into the role of SASPs in reshaping the TME, and summarize recent advances in anti-tumor strategies targeting CS or SASPs.

Drug delivery systems (DDSs) enable the controlled release of drugs in the body. DDSs have attracted increasing attention for the treatment of various disorders, including cancer, inflammatory diseases, and age-related diseases. With recent advancements in our understanding of the molecular mechanisms of aging, new target molecules and drug delivery carriers for age-related diseases have been reported. In this review, we will summarize the recent research on DDSs for age-related diseases and identify DDS strategies in the treatment of age-related diseases.

Senescent cells are characterized by multiple features such as increased expression of senescence-associated β-galactosidase activity (SA β-gal) and cell cycle inhibitors such as p21 or p16. They accumulate with tissue damage and dysregulate tissue homeostasis. In the context of skeletal muscle, it is known that agents used for chemotherapy such as Doxorubicin (Doxo) cause buildup of senescent cells, leading to the inhibition of tissue regeneration. Senescent cells influence the neighboring cells via numerous secreted factors which form the senescence-associated secreted phenotype (SASP). Lipids are emerging as a key component of SASP that can control tissue homeostasis. Arachidonic acid-derived lipids have been shown to accumulate within senescent cells, specifically 15d-PGJ2, which is an electrophilic lipid produced by the non-enzymatic dehydration of the prostaglandin PGD2. This study shows that 15d-PGJ2 is also released by Doxo-induced senescent cells as an SASP factor. Treatment of skeletal muscle myoblasts with the conditioned medium from these senescent cells inhibits myoblast fusion during differentiation. Inhibition of L-PTGDS, the enzyme that synthesizes PGD2, diminishes the release of 15d-PGJ2 by senescent cells and restores muscle differentiation. We further show that this lipid post-translationally modifies Cys184 of HRas in C2C12 mouse skeletal myoblasts, causing a reduction in the localization of HRas to the Golgi, increased HRas binding to Ras Binding Domain (RBD) of RAF Kinase (RAF-RBD), and activation of cellular Mitogen Activated Protein (MAP) kinase-Extracellular Signal Regulated Kinase (Erk) signaling (but not the Akt signaling). Mutating C184 of HRas prevents the ability of 15d-PGJ2 to inhibit the differentiation of muscle cells and control the activity of HRas. This work shows that 15d-PGJ2 released from senescent cells could be targeted to restore muscle homeostasis after chemotherapy.

Currently, there is a growing focus on aging and age-related diseases. The processes of aging are based on cell senescence, which results in changes in intercellular communications and pathological alterations in tissues. In the present study, we investigate the influence of senescent mesenchymal stem cells (MSCs) on endothelial cells (ECs). In order to induce senescence in MSCs, we employed a method of stress-induced senescence utilizing mitomycin C (MmC). Subsequent experiments involved the interaction of ECs with MSCs in a coculture or the treatment of ECs with the secretome of senescent MSCs. After 48 h, we assessed the EC state. Our findings revealed that direct interaction led to a decrease in EC proliferation and migratory activity of the coculture. Furthermore, there was an increase in the activity of the lysosomal compartment, as well as an upregulation of the genes P21, IL6, IL8, ITGA1, and ITGB1. Treatment of ECs with the \"senescent\" secretome resulted in less pronounced effects, although a decrease in proliferation and an increase in ICAM-1 expression were observed. The maintenance of high levels of typical \"senescent\" cytokines and growth factors after 48 h suggests that the addition of the \"senescent\" secretome may have a prolonged effect on the cells. It is noteworthy that in samples treated with the \"senescent\" secretome, the level of PDGF-AA was higher, which may explain some of the pro-regenerative effects of senescent cells. Therefore, the detected changes may underlie both the negative and positive effects of senescence. The findings provide insight into the effects of cell senescence in vitro, where many of the organism\'s regulatory mechanisms are absent.

Targeting senescence has emerged as a promising strategy for liver cancer treatment. However, the lack of a safe agent capable of inducing complete senescence and being combined with senolytics poses a limitation. Here, we screened a natural product library and identified tryptanthrin (TRYP) as a potent inducer of cellular senescence in liver cancer cells both in vitro and in vivo. Mechanistically, Glutathione S-transferase P1 (GSTP1), a key regulator for redox homeostasis, was identified as a target protein for TRYP-induced senescence. TRYP directly bound to GSTP1 and inhibited its enzymatic activity, mediating reactive oxygen species (ROS) accumulation, followed by DNA damage response (DDR), consequently contributing to initiating primary senescence. Furthermore, TRYP triggered DNA damage-dependent activation of NF-κB pathway, which evoked senescence-associated secretory phenotype (SASP), thereby leading to senescence reinforcement. Importantly, TRYP exposed the vulnerability of tumor cells and sensitized senescent cells to apoptosis induced by senolytic agent ABT263, a Bcl2 inhibitor. Taken together, our findings reveal that TRYP induces cellular senescence via GSTP1/ROS/DDR/NF-κB/SASP axis, providing a novel potential application in synergizing with senolytic therapy in liver cancer.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory senescence-associated secretory phenotype (SASP), is a cause of aging. In senescent cells, cytoplasmic chromatin fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. Promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA\'s localization to PML NBs. Inactivation of HIRA does not directly block expression of nuclear factor κB (NF-κB) target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in the regulation of SASP.

Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence-associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.

Senescent cells are typically characterized by a stable proliferation arrested in dividing cells accompanied with a senescence-associated secretory phenotype (SASP). Skin cellular senescence is the primary cause of skin aging, whereas the lack of identified skin senescence markers limits our understanding of the mechanisms involved in skin aging. Recent studies have revealed that intracellular calcium signaling has emerged as a key player in regulating cellular senescence and aging. However, the implication and roles of calcium signaling in skin keratinocyte senescence remain only partially understood. In this study, we developed a model for skin keratinocyte senescence using ionizing radiation (I/R) stimulation and found that the calcium-associated gene transglutaminase 2 (TGM2) was significantly induced compared with normal control. Interestingly, inhibition of TGM2 was found to delay skin keratinocyte senescence by suppressing I/R-promoted intracellular calcium signaling, accumulation of reactive oxygen species (ROS), DNA damage, as well as NF-κB-mediated SASP secretion. Taken together, our findings demonstrate that inhibition of TGM2 contributes to bypassing I/R-induced skin keratinocyte senescence and sheds light on novel strategies against skin stresses caused by I/R.

Therapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers.

BACKGROUND: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top \"hit\" was chromatin opening at H3K9ac.
METHODS: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women.
RESULTS: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women.
CONCLUSIONS: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.