Cellular senescence is a complex process that significantly contributes to the pathogenesis of various diseases, including cancer and neurodegenerative disorders. It is characterized by permanent cell cycle arrest and morphological changes, such as cell enlargement and a decrease in lamin B levels. As organisms age, a secretory phenotype known as the senescence-associated secretory phenotype (SASP) develops, which produces pro-inflammatory factors that can impact surrounding tissues and promote disease. This article discusses the molecular mechanisms regulating senescence, notably the p53/p21 and p16INK4a/pRb pathways, which are crucial for inducing cell cycle arrest. While increased activity of cyclin inhibitors like p16 and p21 serves as a protective mechanism against cancer, their prolonged activation can lead to pathological effects. Additionally, the article examines therapies involving senolytics and senomorphics, which aim to eliminate senescent cells. Current research suggests that targeting senescence may represent a promising strategy for treating various diseases, improving health outcomes, and enhancing the overall quality of life as we age.

Cellular senescence plays a critical role in tumorigenesis and is recognized as a hallmark of colorectal cancer (CRC). Emerging evidence suggests that 5-fluorouracil (5-FU)-induced senescence may contribute to chemoresistance and tumor recurrence. Here, we investigated the effect of 5-FU on colon cancer cell senescence and whether MM-129 (pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamide) can antagonize this activity. Senescence was identified by the expression of senescence-associated β-galactosidase (SA-β-gal) and cyclin-dependent kinase inhibitor 1A (p21) using qPCR, microscopy, flow cytometry, and immunohistochemistry. We also measured interleukin 6 (IL-6) and tumor necrosis factor (TNF-α) as key SASP cytokines, along with E-cadherin (CDH1), a marker of epithelial integrity. The SIRT1/STAT3 pathway was evaluated to elucidate the mechanism of MM-129′s action. MM-129 counteracted 5-FU-induced senescence in colon cancer models, reducing p21 levels in zebrafish xenografts and the number of SA-β-gal-positive cells in vitro and in tumor tissues from DLD-1 and HT-29 mouse xenografts. MM-129 also inhibited senescence-associated responses by suppressing SASP cytokines (IL-6, TNF-α) and restoring E-cadherin (CDH1), and it modulated the SIRT1/STAT3 axis, which may underlie the observed senotherapeutic effects. In conclusion, MM-129 represents a novel senotherapeutic candidate. By modulating the SIRT1/STAT3 axis, it may suppress the SASP and weaken pro-survival signaling, thereby facilitating selective clearance of senescent cells. Integrating senotherapeutics with conventional cancer therapies may enhance efficacy and open new avenues for translational research.

Major depressive disorder (MDD) has been linked to oxidative stress, mitochondrial dysfunction, and impaired neuronal plasticity, but the reproducibility of related transcriptomic alterations across postmortem brain cohorts remains uncertain. We performed a targeted cross-platform analysis of a prespecified 14-gene panel spanning antioxidant defense, mitochondrial-redox regulation, cellular stress responses, neurotrophic signaling, synaptic plasticity, and polyamine metabolism across seven postmortem dorsolateral prefrontal cortex cohorts comprising 146 MDD cases and 179 controls. Primary support required Fisher-combined evidence, Benjamini–Hochberg correction across the panel, and concordant MDD-minus-control direction across all available cohorts. NPTX2, EGR1, VGF, BDNF, and SAT1 met these criteria, with lower expression in MDD. The same five-gene pattern was supported by weighted signed Stouffer analysis, one-stage generalized least-squares models, random-effects meta-analysis, and 200,000 disease-label permutations; none produced at least five genes meeting the complete primary-support criterion (empirical p = 5.0 × 10⁻⁶). The most robust cross-cohort finding was a convergent lower-expression pattern across genes supporting redox-linked stress adaptation, polyamine homeostasis, neurotrophic signaling, activity-dependent transcription, and synaptic plasticity. This pattern suggests impaired molecular capacity for neuronal stress resilience and adaptive plasticity in MDD.