Senescence is a complex, multi-factorial, irreversible cell cycle arrest that has tumor-suppressive effects and is a significant factor in aging and neurodegenerative diseases. Factors such as DNA damage, neuroinflammation, oxidative stress, and disrupted proteostasis contribute to senescence. DNA damage triggers the DNA damage response (DDR), which includes the formation of DNA damage foci containing activated H2AX, a key factor in cellular senescence. Oxidative stress impairs cognition, inhibits neurogenesis, and accelerates aging. Senescent cells secrete pro-inflammatory mediators known as SASP, which impact neuroinflammation, neuronal death, and cell proliferation. While neurodegenerative diseases are often viewed as manifestations of accelerated aging and senescence, this review explores the role of senescence and DDR in brain aging and neurodegeneration. Senescence is regulated by molecules such as p53, p16INK4a, and Rb. DNA damage activates DDR and the p53-p21 pathway, leading to cell cycle arrest. Epigenetic alterations via the p16-Rb pathway also cause senescence. SASP includes chemokines, cytokines, and growth factors that cause inflammation and may aid in the clearance of senescent cells. SASP is regulated by pathways such as JAK-STAT and NF-κB, which amplify inflammation and tumorigenesis. Senescent cells activate immune cells, leading to their clearance. SASP components like TLR2 and A-SAAs are sensed by TLR2 after oncogenic-induced senescence, activating p38MAPK and NF-κB pathways. Senescence is associated with cellular changes such as increased cytoplasm-to-nucleus ratio, altered metabolism, and elevated ROS production. Biomarkers of senescence include SA-βgal, p16, and p21. DDR activation involves recognition of DNA damage by sensor proteins, leading to cell cycle arrest, DNA repair, or apoptosis. p53 is a key regulator of DDR and senescence, activating cell cycle arrest and apoptosis. p16INK4a regulates the cell cycle by inhibiting CDK4 and CDK6, leading to cell cycle arrest. Telomere dysfunction is a well-established driver of cellular senescence, leading to DNA damage signals and DDR activation. LINE-1 and KAT7 play roles in cellular senescence. LINE-1 activity is linked to SASP and inflammation, while KAT7 influences chromatin structure and gene expression, contributing to senescence. DDR and epigenetic changes in senescence are interconnected, with DDR affecting DNA methylation and histone modifications. SASP components are involved in immune cell recruitment and tissue repair but can also cause chronic inflammation. Senescence in neurodegenerative diseases is linked to neuronal death, protein aggregationSenescence is a complex, multi-factorial, irreversible cell cycle arrest that has tumor-suppressive effects and is a significant factor in aging and neurodegenerative diseases. Factors such as DNA damage, neuroinflammation, oxidative stress, and disrupted proteostasis contribute to senescence. DNA damage triggers the DNA damage response (DDR), which includes the formation of DNA damage foci containing activated H2AX, a key factor in cellular senescence. Oxidative stress impairs cognition, inhibits neurogenesis, and accelerates aging. Senescent cells secrete pro-inflammatory mediators known as SASP, which impact neuroinflammation, neuronal death, and cell proliferation. While neurodegenerative diseases are often viewed as manifestations of accelerated aging and senescence, this review explores the role of senescence and DDR in brain aging and neurodegeneration. Senescence is regulated by molecules such as p53, p16INK4a, and Rb. DNA damage activates DDR and the p53-p21 pathway, leading to cell cycle arrest. Epigenetic alterations via the p16-Rb pathway also cause senescence. SASP includes chemokines, cytokines, and growth factors that cause inflammation and may aid in the clearance of senescent cells. SASP is regulated by pathways such as JAK-STAT and NF-κB, which amplify inflammation and tumorigenesis. Senescent cells activate immune cells, leading to their clearance. SASP components like TLR2 and A-SAAs are sensed by TLR2 after oncogenic-induced senescence, activating p38MAPK and NF-κB pathways. Senescence is associated with cellular changes such as increased cytoplasm-to-nucleus ratio, altered metabolism, and elevated ROS production. Biomarkers of senescence include SA-βgal, p16, and p21. DDR activation involves recognition of DNA damage by sensor proteins, leading to cell cycle arrest, DNA repair, or apoptosis. p53 is a key regulator of DDR and senescence, activating cell cycle arrest and apoptosis. p16INK4a regulates the cell cycle by inhibiting CDK4 and CDK6, leading to cell cycle arrest. Telomere dysfunction is a well-established driver of cellular senescence, leading to DNA damage signals and DDR activation. LINE-1 and KAT7 play roles in cellular senescence. LINE-1 activity is linked to SASP and inflammation, while KAT7 influences chromatin structure and gene expression, contributing to senescence. DDR and epigenetic changes in senescence are interconnected, with DDR affecting DNA methylation and histone modifications. SASP components are involved in immune cell recruitment and tissue repair but can also cause chronic inflammation. Senescence in neurodegenerative diseases is linked to neuronal death, protein aggregation