FIGURE 2.

Several inducers alone or in combination can trigger senescence through p16^INK4a/Rb and p53/p21 pathways. Senescence‐triggering signals may involve DNA damage (eg, telomere shortening), oncogenic mutation (eg, Myc, Ras), oxidative stress (eg, ROS), and proteotoxic stress (eg, Aβ and tau protein aggregation and protein misfolding). These senescence‐inducers contribute to chromatin remodeling and alterations in gene expression that underlie senescence‐associated cell cycle arrest and SASP. Intracellular autocrine signaling reinforces senescence and initiation of SASP. Senescence not only negatively impacts progenitor/stem cells but also contributes to tissue dysfunction, AD pathology, and subsequent cognitive decline through SASP, chronic inflammation, and loss of extracellular matrix. Aβ, amyloid beta; AD, Alzheimer's disease; ROS, reactive oxygen species; SASP, senescence‐associated secretory phenotype.