Role of Cellular Senescence in Parkinson's Disease: Potential for Disease-Modification Through Senotherapy

Abstract

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.

Keywords: Parkinson’s disease; cellular senescence; neurodegeneration; pathology; therapeutics.

Figure 1

Inter-relationships between SNpc DA neurons, microglia, astrocytes, vascular endothelial cells, and T cells play a role in the pathophysiology of PD. SNpc DA neurons are vulnerable to stressors due to a state of high ATP demand, low Ca²⁺ buffering capacity, low anti-oxidant defenses, and low trophic support. ROS and DNA damage induce senescence in microglia, astrocytes, and SNpc DA neurons. Autocrine transmission of the senescence-associated secretory phenotype (SASP) by senescent microglia, astrocytes, and SNpc DA neurons reinforces the senescent phenotype. Nearby cells undergo senescence as a result of paracrine transmission of the SASP. Transmission of the SASP from senescent microglia and astrocytes to SNpc DA neurons induces senescence in those neurons and contributes to SNpc DA neuron cell death. Chronic inflammation causes endothelial cells to contract, forming gaps between these cells thereby allowing circulating T cells to infiltrate the brain. Infiltrating T cells contribute to the death of SNpc DA neurons by secreting chemokines and cytokines. In PD, astrocytes, microglia, and SNpc DA neurons exchange exosomes containing pathogenic α-syn, resulting in the formation of LBs and LB-like intracellular inclusions. This figure was created with BioRender.com by Rademacher, Exline, and Foecking, 2025. http://app.biorender.com/ (accessed on 21 May 2025).

Figure 2

Mechanisms of cell death induction of senolytics. The senolytic names are given in the red boxes. The red flat arrowheads indicate inhibition. Abbreviations: mTOR, mechanistic target of rapamycin; IL-1, interleukin-1; NF-κB, nuclear factor kappa-B; AKT, protein kinase B; Bcl-2, B-cell lymphoma-2; Bcl-xl, B-cell lymphoma-extra large; Bcl-w, B-cell lymphoma-w; 17-DMAG, 17-dimethylaminoethylamino; FoxO4, forkhead box subclass O protein 4; HSP90, heat shock protein 90; RTK, receptor tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; P, phosphorylation; Na⁺/K⁺ ATPase, sodium/potassium adenosine triphosphatase. This figure was created with BioRender.com by Rademacher, Exline, and Foecking, 2025. http://app.biorender.com/ (accessed on 21 May 2025).

Figure 3

Mechanisms of SASP modulation by senomorphics. The names of the senomorphics are given in the red boxes. The red flat arrowheads indicate inhibition. Abbreviations: SASP, senescence-associated secretory phenotype; JAK, Janus kinase; STAT, signal transducer and activation of transcription; NLRP3, NLR family pyrin domain containing 3; H₂O₂, hydrogen peroxide; mTOR, mechanistic target of rapamycin; IL-1, interleukin-1; IL-1R; interleukin-1 receptor; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; MitoQ, mitoquinone; NF-κB, nuclear factor kappa-B; cGAS, cyclic GMP-AMP synthase; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; AKT, protein kinase B; RTK, receptor tyrosine kinase; STING, stimulator of interferon genes; PI3K, phosphatidylinositol 3-kinase; P, phosphorylation. This figure was created with BioRender.com by Rademacher, Exline, and Foecking, 2025. http://app.biorender.com/ (accessed on 21 May 2025).