Parkinson’s disease (PD) is an aging-related neurodegenerative disease characterized by a progressive loss of dopamine (DA)-secreting neurons in the substantia nigra. Most of the currently available treatments attempt to alleviate the disease symptoms by increasing DA transmission in the brain and are associated with unpleasant side effects. Since there are no treatments that modify the course of PD or regenerate DA neurons, identifying therapeutic strategies that slow, stop, or reverse cell death in PD is of critical importance. Here, factors that confer vulnerability of substantia nigra DA neurons to cell death and the primary mechanisms of PD pathogenesis, including cellular senescence, a cellular stress response that elicits a stable cell cycle arrest in mitotic cells and profound phenotypic changes including the implementation of a pro-inflammatory secretome, are reviewed. Additionally, a discussion of the characteristics, mechanisms, and markers of cellular senescence and the development of approaches to target senescent cells, referred to as senotherapeutics, is included. Although the senotherapeutics curcumin, fisetin, GSK-650394, and astragaloside IV had disease-modifying effects in in vitro and in vivo models of PD, the potential long-term side effects of these compounds remain unclear. It remains to be elucidated whether their beneficial effects will translate to non-human primate models and/or human PD patients. The enhanced selectivity, safety, and/or efficacy of next generation senotherapeutic strategies including senolytic peptides, senoreverters, proteolysis-targeting chimeras, pro-drugs, immunotherapy, and nanoparticles will also be reviewed. Although these next generation senotherapeutics may have advantages, none have been tried in models of PD.

Cellular senescence is a stable, pro-inflammatory cell cycle arrest that has been recently implicated in the persistent memory deficits experienced with repetitive mild traumatic brain injury (rmTBI). Testosterone (T) treatment immediately following traumatic brain injury (TBI) mitigates cognitive deficits and cellular dysfunction known to induce cellular senescence. However, it has yet to be elucidated whether the therapeutic window for T treatment can be extended to a subacute time post-injury. This study examined the progression of hippocampal cellular senescence after rmTBI and evaluated the effects of subacute T on persistent memory deficits and cellular senescence post-injury. Changes in senescence-associated markers in the hippocampus were quantified at 5- and 9-weeks post-injury (WPI). An age-independent progressive increase in senescence-associated gene expression was observed for Cdkn2a, Cdkn1a, and p53 protein levels, along with a decrease in Sirt1 gene expression. Acute and persistent cognitive deficits were observed in the rmTBI rats as compared to sham rats. Serum T levels were significantly decreased at 4 WPI. Testosterone administration at 5 WPI ameliorated these persistent memory deficits. Moreover, subacute T treatment reduced rmTBI-induced levels of Cdkn2a 4 weeks post-treatment. This study indicates that rmTBI results in a progressive cellular senescence pathology that may contribute to the underlying mechanisms of persistent cognitive symptoms. Therapeutically targeting cellular senescence within this extended temporal window holds implications for patients dealing with the chronic cognitive ramifications of rmTBI.