Fight Aging!

A growing body of evidence points to the role of senescent supporting cells in the brain as a meaningful cause of neurodegenerative conditions. In this context, a number of research groups have focused on microglia, the innate immune cells of the brain. Microglia become increasingly overactive and inflammatory with age, stimulated by features of the aged tissue environment that resemble the molecular signals of pathogens or cancerous cells. A significant number of microglia become senescent, and do so at a time when the immune system as a whole becomes less competent in its task of clearing senescent cells in a timely manner. Senescent cells secrete a pro-inflammatory mix of signals that is harmful to surrounding tissue.

Inflammation in the brain is coming to be seen as a central pillar of neurodegenerative conditions, and the research community is in the process of testing a broad range of approaches to suppression of inflammation. Most, however, involve interference in specific inflammatory signals that block both excessive and necessary inflammation, and thus reduce the efficacy of the immune response. Targeted removal of senescent cells via senolytic treatments is (more or less) the only present approach that can only eliminate the excessive and harmful inflammatory signaling. Given the animal evidence for senolytic therapies to greatly improve pathology in animal models, and the availability of cheap small molecule senolytics that cross the blood-brain barrier, far more human trials should be underway than is presently the case.

Photoinduced elimination of senescent microglia cells in vivo by chiral gold nanoparticles

Parkinson's disease (PD) is an age-related brain disease that is associated with motivation and cognitive disorders and the assembly of alpha-synuclein (α-syn); there is no effective therapeutic treatment for this condition. Along with tissue dysfunction, the typical senescence-associated secretory phenotype is significantly characterized by the generation of interleukin-6 (IL-6) and interleukin-1β (IL-1β). Indeed, the accumulation of senescent cells is associated with a range of age-related diseases as well as neurodegenerative diseases. However, it is still unclear how senescence in the brain contributes to PD and what role it might play in therapeutic strategies of PD.

It had been reported that senescent cells could give rise to local and systemic inflammation and contribute to neurodegeneration in neurodegeneration diseases like PD. In addition, direct exposure to amyloid-β (Aβ) was shown to cause senescence in oligodendrocyte precursor cells (OPCs), and the clearance of OPCs by senolytic therapy alleviated Aβ-associated inflammation and restored cognitive deficits in Alzheimer's disease mice, thus illustrating the potential for senescence clearance to be used in clinical practice. Moreover, senescent cells play a role in the initiation and progression of tau-mediated disease, and targeting of senescent cells may provide a therapeutic avenue for the treatment of such pathologies. Therefore, eliminating senescent cells may hold therapeutic promise for alleviating the symptoms of PD.

In this study, chiral gold nanoparticles (NPs) with different helical directions were synthesized to selectively induce the apoptosis of senescent cells under light illumination. By modifying anti-B2MG and anti-DCR2 antibodies, senescent microglia cells could be cleared by chiral NPs without damaging the activities of normal cells under illumination. Mechanistic studies revealed that the clearance of senescent cells was mediated by the activation of the Fas signaling pathway. The in vivo injection of chiral NPs successfully confirmed that the elimination of senescent microglia cells in the brain could further alleviate the symptoms of PD mice in which the alpha-synuclein (α-syn) in cerebrospinal fluid decreased from 83.83 ± 4.76 ng/mL to 8.66 ± 1.79 ng/mL and the pathological symptoms of the PD mice were greatly improved after two months of treatment.