Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with “senolytics” has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals’ age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.

Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of melanoma, which can induce reactive oxygen species (ROS) production and the presence of DNA damage in the cells, and results in cell senescence. As cellular senescence plays an important role in the relationship that exists between the skin aging process and the development of melanoma, the present study provides insight into the literature concerning the topic at present and discusses the relationship between skin aging and melanoma, including the mechanisms of cellular senescence that drive melanoma progression, the microenvironment in relation to skin aging and melanoma factors, and the therapeutics concerning melanoma. This review focuses on defining the role of cellular senescence in the process of melanoma carcinogenesis and discusses the targeting of senescent cells through therapeutic approaches, highlighting the areas that require more extensive research in the field.

Telomeres are nucleoprotein complexes that cap the ends of eukaryotic linear chromosomes. Telomeric DNA is bound by shelterin protein complex to prevent telomeric chromosome ends from being recognized as damaged sites for abnormal repair. To overcome the end replication problem, cancer cells mostly preserve their telomeres by reactivating telomerase, but a minority (10–15%) of cancer cells use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). Recent studies have found that shelterin components play an important role in the ALT mechanism. The binding of TRF1, TRF2, and RAP1 to telomeres attenuates ALT activation, while the maintenance of ALT telomere requires TRF1 and TRF2. POT1 and TPP1 can also influence the occurrence of ALT. The elucidation of how shelterin regulates the initiation of ALT remains elusive. This review presents a comprehensive overview of the current findings on the regulation of ALT by shelterin components, aiming to enhance the insight into the altered functions of shelterin components in ALT cells and to identify potential targets for the treatment of ALT tumor cells.

Ethnopharmacological relevance Natural medicinal plants, also named herbs, have attracted considerable research attention for their potential pharmacological activities, such as antitumor and longevity-promoting activities. Our previous review proposed that maintaining the homeostatic balance between aging and cancer may benefit organisms to enable tumor-free longevity. Congea chinensis Moldenke (CCM) is a plant species that grows on the border of Yunnan Province of China. Its medicinal value has been few reports until now. Thus, screening and extraction the ingredients from CCM that are both active tumor suppressors and TERT activators is a therapeutic strategy for improving tumor-free longevity. Aim of the study: To extract and evaluate the cytotoxic antitumor and TERT transcription-promoting activities of the plant CCM. Materials and methods The ingredients extracted from CCM were tested for transcriptional activation of p53 using pGL4-p53-GFP cells and for TERT expression using a real-time PCR assay. In vitro antitumor activity was detected by sulforhodamine B (SRB) assay and Annexin V/PI staining assay. The cell-permeable probe H₂ DCFDA was used to detect intracellular reactive oxygen species (ROS). Western blot was performed to verify predicated proteins regulated by the ingredients. RNA-sequence analysis was applied to predicate the underlying mechanism of CCM. Results: Both CCM and MPRC2-8, two novel extracts of Congea chinensis Moldenke, activated the expression of p53 and TERT and were selectively cytotoxic toward tumor cells. In addition, the cytotoxic mechanism of MPRC2-8 was identified as ROS generation-induced apoptosis. Interestingly, MPRC2-8 showed opposite regulatory effects on the SIRT1-p53 axis in A549 and HT-29 cells, which have different p53 statuses. RNA-seq analysis showed that CCM and MPRC2-8 induced the p53, apoptosis and ROS signaling pathways, consistent with the results of cellular experiments in vitro. Conclusion: Our study reveals that CCM and MPRC2-8 have two complementary activities, antitumor activity and TERT-activating activity, with potential antitumor and longevity-improving effects.

One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53^S/+) escaped HRas^V12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC–1α in late-stage p53^S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC–1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC–1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC–1α in this process.

Pathological accumulation of senescent cells (SnCs) across tissues drives aging and age-related diseases. Senolytic agents targeting senescent cell anti-apoptotic pathways (SCAPs) hold promise for treating age-related diseases, yet their efficacy is limited by the heterogeneity of SnC survival mechanisms beyond canonical BCL-2 family pathways. Here, we identify intracellular complement C3 (intC3) as a previously unrecognized determinant of senolytic responsiveness. C3 was consistently and markedly upregulated across diverse senescent cell types and aged tissues; however, its depletion via knockout (KO) or knockdown (KD) did not alter canonical senescence phenotypes. Unexpectedly, C3 KD attenuated ABT263- and bortezomib-mediated SnC apoptosis, while sustaining pro-survival AKT/S6K signaling. In aged C3-knockout (C3KO) mice, ABT263 failed to effectively eliminate SnCs, resulting in persistent senescence markers, unresolved senescence-associated secretory phenotype (SASP), and exacerbated fibrosis. Mechanistically, AKT inhibition rescued senolytic sensitivity in C3-KD SnCs, confirming AKT/S6K as the functional downstream mediator. These findings redefine intC3 as an intracellular stress sensor that sensitizes SnCs to apoptotic clearance—transcending its canonical extracellular immune role—and position the intC3–AKT axis as a potential target for overcoming senolytic resistance.