Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives

Abstract

Along with a general decline in overall health, most chronic degenerative human diseases are inherently associated with increasing age. Age-associated cognitive impairments and neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, are potentially debilitating conditions that lack viable options for treatment, resulting in a tremendous economic and societal cost. Most high-profile clinical trials for neurodegenerative diseases have led to inefficacious results, suggesting that novel approaches to treating these pathologies are needed. Numerous recent studies have demonstrated that senescent cells, which are characterized by sustained cell cycle arrest and production of a distinct senescence-associated secretory phenotype, accumulate with age and at sites of age-related diseases throughout the body, where they actively promote tissue deterioration. Cells with features of senescence have been detected in the context of brain aging and neurodegenerative disease, suggesting that they may also promote dysfunction. Here, we discuss the evidence implicating senescent cells in neurodegenerative diseases, the mechanistic contribution of these cells that may actively drive neurodegeneration, and how these cells or their effects may be targeted therapeutically.

Figure 1. Hallmarks of senescence in CNS cells.

(A) A number of stressors, both intrinsic and extrinsic, can stimulate the conversion of otherwise normal cells into senescent cells. Once they have entered into this state, a number of distinguishing qualities can be observed. depending on the cell type and senescence-inducing stimuli. (B) Senescent cell evidence and identity are observed in neurological aging and pathology. Commonly observed features reminiscent of senescence are indicated for the various cell types. See text for extended discussion and references. SAHF, senescence-associated heterochromatin foci; NSC, neural stem cell.

Figure 2. Senescence in normal aging and CNS disease.

The molecular correlates of normal aging and CNS disease are not fully defined. Further research on the markers of senescence that distinguish healthy aging from neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease may provide insights into the role of senescent cells in disease pathogenesis.