Role of Senescence in Neurodegenerative Diseases

The risk of major neurodegenerative diseases (ND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) increases with age, however, the contribution of age to disease processes remains unknown. Cells can enter a state known as senescence upon unresolved DNA damage resulting from multiple stressors including telomere erosion, oxidative stress, and excessive mitogenic signaling. Senescence is a central hallmark of aging. It can influence other hallmarks of aging such as loss of proteostasis and mitochondrial health and also result from aging hallmarks such as DNA damage, increased reactive oxygen species production, and inflammation. Senescence increases with age in multiple tissues in mammals, including the brain, and further increases are seen in ND. Increases in senescence markers have been observed in astrocytes, oligodendrocyte precursors, and neurons in AD, PD and amyotrophic lateral sclerosis (ALS), with possible cell-specific senescence induction indicated with different pathologies (amyloid-beta vs. tau). Senescence in astrocytes has been shown to lower the expression of genes related to their functioning as modulators of neuronal homeostasis. Recovery of function and lowering of pathology after the genetic or pharmacologic removal of senescent cells in mouse models of ND points to a role for senescent cells in the pathology of these diseases. However, we do not know how senescence and its modulation affect disease progression. Possible pathways include a direct effect on neurons, however, the effect of senescence on systemic parameters also needs to be investigated. Possible contributors include metabolic dysfunction and diabetes, which increase with age, and in ND. Cardiovascular pathology is commonly observed in AD and is associated with one of the genetic risk factors for late-onset AD, apolipoprotein E4 variant. Age-associated increase in senescence and inflammation may contribute to cardiovascular amyloid pathology.

We are interested in original research studies and reviews that explore the connections between senescence and ND. Possible research topics include, but are not limited to:

1) Transcriptional and proteomics studies on changes in senescent cell types in the brain in the progression of ND in animal models.
2) Molecular pathways in different cell types and systemic parameters affected upon pharmacologic or genetic elimination of senescent cells, or other senescence-modulatory interventions, and
3) The impact of different disease-modulatory treatments in ND models on senescence parameters.
Studies using human subject material and patient-derived iPSCs/organoids are also welcome.