Implications of Cellular Senescence on Aging and Disease in the Brain

Abstract

Senescence is an irreversible mitotic arrest of the cell that can result from replicative aging or stressors. It can be beneficial by conferring resistance to apoptosis, or detrimental by inducing pro-inflammatory signaling in the microenvironment. Senescent cells have been observed in both aged and diseased tissue, including the brain. The aging brain undergoes changes such as cortical atrophy and increases in inflammatory and oxidative factors, with decreases in synaptic plasticity and mitochondrial function. Significant neuronal loss is observed and thought to drive the atrophy in the corresponding areas of the brain in neurodegenerative diseases (ND). Despite being terminally differentiated, a senescence-like phenotype is observed in neurons upon stress in vitro and also in neurocognitive disorders like HIV-associated dementia and Alzheimer’s disease in vivo. Aging is also associated with lower regenerative capacity of neural stem and progenitor cells (NSPC). In vivo, their neurogenerative capacity is modulated by a variety of external factors, including growth factors, diet, and inflammation. NSPC have been observed to undergo stress-induced senescence in vitro. Deregulation of other CNS cell types, including oligodendrocytes and microglia occur in aging and ND. Microglia, which are not post-mitotic, senesce in culture in response to replicative or inflammatory stress. Astrocytes, which make up half of all cells in the CNS, maintain and protect neurons. In response to insult or injury however, astrocytes undergo phenotypic changes collectively termed reactive astrogliosis. This response can be both detrimental and beneficial to the neurons, and its downregulation improves disease parameters in a mouse model of AD. We have observed astrocyte senescence in vitro in response to replicative and oxidative stress and Aβ peptides, along with accumulation of senescent astrocytes in aged and AD brain. Given that astrocytes perform a myriad of complex functions in the CNS in order to maintain homeostasis, the loss of astrocyte function or the gain of neuroinflammatory function as a result of senescence could have profound implications for aging brain and neurodegenerative disorders.