Aging, Cellular Senescence, and Alzheimer's Disease

Abstract

Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates β-amyloid (Aβ) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD.

Keywords: Alzheimer’s disease; aging; cellular senescence; late-onset Alzheimer’s disease (LOAD); neurodegeneration; oxidative stress; plasminogen activator inhibitor 1 (PAI-1); tauopathy; telomere shortening; β-amyloid peptides (Aβ).

Figure 1

Potential causes and consequences of cell senescence. Several factors have been identified to induce cell senescence, including telomere shortening, oncogene activation, DNA damage, and oxidative stress. Senescent cells, on the other hand, exhibit multiple characteristics, including growth arrest, metabolic changes, altered apoptosis sensitivity, and senescence-associated secretary phenotype (SASP).

Figure 2

Potential mechanisms underlying brain cell senescence in AD. Various types of cells, including glia, oligodendrocyte precursor cells (OPCs), neuronal stem cells (NSCs), neurons, and endothelia, have been shown to undergo senescence in AD brain and/or AD model mice. Mutations in the telomerase reverse transcriptase (TERT) gene and telomerase RNA component (TERC), which leads to telomere shortening, hyperphosphorylated tau, increased Aβ oligomers, reactive oxygen species (ROS), and plasminogen activator inhibitor 1 (PAI-1) expression, are implicated in brain cell senescence in AD. Red arrows indicate increases in the amounts of these molecules.