Cellular senescence: Between protection and pathologies

Area of Science:

• Cellular biology
• Molecular biology
• Aging research

Background:

• Cellular senescence is a stable, irreversible cell cycle arrest triggered by various stressors.
• It plays crucial roles in tissue homeostasis, development, aging, and disease.
• Senescence is categorized into damage-induced and developmentally programmed forms.

Purpose of the Study:

• To elucidate the dual role of cellular senescence in biological processes.
• To understand the molecular mechanisms underlying beneficial and detrimental senescence.
• To highlight the importance of distinguishing senescence types for therapeutic development.

Main Methods:

• Review of existing literature on cellular senescence.
• Analysis of molecular pathways involved in senescence, including DNA damage response (DDR), p53/p21, p16/RB, and senescence-associated secretory phenotype (SASP).
• Examination of the senescence-associated secretory phenotype (SASP) signaling pathways (NF-κB, C/EBPβ, STAT3) and their role in cancer progression.

Main Results:

• Senescence is activated by sustained DNA damage response (DDR) and involves key tumor suppressor pathways.
• Acute senescence promotes beneficial roles like tumor suppression and wound healing via transient SASP.
• Persistent senescence drives chronic inflammation, tissue dysfunction, and cancer progression, fostering EMT, invasion, and therapy resistance.

Conclusions:

• Cellular senescence presents a biological paradox, acting as both a protective mechanism and a driver of aging and malignancy.
• Therapy-induced senescence (TIS) can lead to polyploid giant cancer cells (PGCCs), promoting tumor relapse.
• Targeted senotherapies require a deep understanding of the molecular determinants distinguishing beneficial from pathological senescence.