Abstract
Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.
Highlights
The risk of both neurodegenerative disease and cancer increases with advanced age due to increased damage accumulation and decreased repair capabilities; yet the relative odds of developing one or the other are inversely correlated [1,2,3,4,5]
We focus on mitotically competent brain cells; due to space considerations, the topic of postmitotic brain cellular senescence is reviewed in a separate manuscript (Sah et al, Life, in review)
Beyond theused pre-defined criteriaadditional used in this review, additional ers may be applied to supplement the characterization ofthe senescent cells
Summary
The risk of both neurodegenerative disease and cancer increases with advanced age due to increased damage accumulation and decreased repair capabilities; yet the relative odds of developing one or the other are inversely correlated [1,2,3,4,5]. SNPs in this locus were identified in the brain, as well as other tissues analyzed [8] These results point toward aberrant cell cycle, and in particular senescence, as a key age-associated molecular pathway worth further study. Senescent cell abundance increases with aging, but the relative contribution to a tissue is relatively low and may be missed in bulk analyses [16] (reviewed [11]). Several laboratories are using single cell technologies to assign cell type specificity to tissue-level observations [17], but to date these analyses have not included senescent cells in the brain. To maximize generalization and interpretation across studies, in this review we only evaluate studies which investigated cellular senescence with cell type specificity, and not bulk analyses. This review explores how the cellular senescence stress response may simultaneously distinguish and connect AD and cancer risk
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