Alam, Md Tanjim

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs.

Abstract Muscle wasting is a significant hurdle in patients due to immobilization, prolonged bed rest, and injury. In particular, the older population develops sarcopenia, characterized by progressive loss of muscle strength due to natural aging. However, there are no FDA-approved drugs for sarcopenia, and it is critical to explore novel therapeutics. Myostatin inhibition is one such strategy that has had varying degrees of success previously, yet the desired levels of muscle strength have not been achieved. Here, we employed a novel vaccine (V13) that generates anti-myostatin antibodies and another (V07) that generates anti-activin A; myostatin and activin A regulate muscle growth negatively. We administered seven doses of V13, V07, and V35 (generates both anti-myostatin and anti-activin A) to long-living, GH-deficient Ames dwarf mice (df/df) and their normal littermate controls (N/df). By week 24 post-first dose, we saw increased forelimb grip strength in V13, V07, and V35 vaccinated df/df mice and V07 and V35 vaccinated N/df mice. Additionally, almost 40% of the vaccinated df/df mice completed the accelerating rotarod trials, compared to the 20% of placebo-treated counterparts. We observed increased lean body mass and reduced fat mass in vaccinated N/df mice, yet surprisingly there were no changes in lean and fat mass in df/df mice. In summary, our results indicate that while myostatin and activin A inhibition play an intimate role in fat metabolism in the presence of GH/IGF-1, this immunization strategy improves muscle motor performance in GH/IGF-1 deficient mice providing promising treatments in older animals regardless age-associated suppression of GH/IGF-1 axis.