The interplay of cellular senescence and reprogramming shapes the biological landscape of aging and cancer revealing novel therapeutic avenues

Fuan Ding¹Ying Yu²Jiangqi Zhao³Shibo Wei⁴Yan Zhang⁴Jung Ho Han⁵Zhuo Li⁶Hong-Bo Jiang⁷Dongryeol Ryu⁴Minkyoung Cho⁸Sung-Jin Bae⁹Wonyoung Park^10,11*Ki-Tae Ha^11*Bo Gao^1*

• ¹Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, Changchun, Hebei Province, China
• ²Department of Surgery, Changchun University of Chinese Medicine, Changchun, Hebei Province, China
• ³Department of Dermatology, The Second Hospital of Jilin University,, Jilin, China
• ⁴Department of Biomedical Science and Engineering, School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, Gwangju, Republic of Korea
• ⁵Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, North Gyeongsang, Republic of Korea
• ⁶Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
• ⁷Department of Dermatology, Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, Shandong, China
• ⁸Department of Parasitology and Tropical Medicine, and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, South Gyeongsang, Republic of Korea
• ⁹Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Republic of Korea
• ¹⁰Pusan National University, Busan, Republic of Korea
• ¹¹School of Korean Medicine, Pusan National University, Busan, Busan, Republic of Korea

Cellular senescence and cellular reprogramming represent two fundamentally intertwined processes that profoundly influence aging and cancer. This paper explores how the permanent cell-cycle arrest of senescent cells and the identity-resetting capacity of reprogramming jointly shape biological outcomes in later life and tumor development. We synthesize recent findings to show that senescent cells, while halting the proliferation of damaged cells, can paradoxically promote tissue dysfunction and malignancy via their secretory phenotype. Conversely, induced reprogramming of somatic cellsexemplified by Yamanaka factors-resets cellular age and epigenetic marks, offering a potential to rejuvenate aged cells. Key findings highlight shared mechanisms (e.g. DNA damage responses and epigenetic remodeling) and bidirectional crosstalk between these processes: senescence signals can facilitate neighboring cell plasticity, whereas reprogramming attempts can trigger intrinsic senescence programs as a barrier. In aging tissues, transient (partial) reprogramming has been shown to erase senescence markers and restore cell function without inducing tumorigenesis, underlining a novel strategy to combat age-related degeneration. In cancer, we discuss how therapy-induced senescence of tumor cells may induce stem-cell-like traits in some cells and drive relapse, revealing a delicate balance between tumor suppression and tumor promotion. Understanding the interplay between senescence and reprogramming is crucial for developing innovative therapies. By targeting the senescencereprogramming axisfor instance, via senolytic drugs, SASP inhibitors, or safe reprogramming techniquesthere is significant therapeutic potential to ameliorate aging-related diseases and improve cancer treatment. Our findings underscore that carefully modulating cellular senescence and rejuvenation processes could pave the way for novel regenerative and anti-cancer strategies.