Resveratrol is a natural phenolic compound with known benefits against neurodegeneration. We analyzed in vitro the protective mechanisms of resveratrol against the proinflammatory monomeric C-reactive protein (mCRP). mCRP increases the risk of AD after stroke and we previously demonstrated that intracerebral mCRP induces AD-like dementia in mice. Here, we used BV2 microglia treated with mCRP for 24 h in the presence or absence of resveratrol. Cells and conditioned media were collected for analysis. Lipopolysaccharide (LPS) has also been implicated in AD progression and so LPS was used as a resveratrol-sensitive reference agent. mCRP at the concentration of 50 µg/mL activated the nitric oxide pathway and the NLRP3 inflammasome pathway. Furthermore, mCRP induced cyclooxygenase-2 and the release of proinflammatory cytokines. Resveratrol effectively inhibited these changes and increased the expression of the antioxidant enzyme genes Cat and Sod2. As central mechanisms of defense, resveratrol activated the hub genes Sirt1 and Nfe2l2 and inhibited the nuclear translocation of the signal transducer NF-ĸB. Proinflammatory changes induced by mCRP in primary mixed glial cultures were also protected by resveratrol. This work provides a mechanistic insight into the protective benefits of resveratrol in preventing the risk of AD induced by proinflammatory agents.

Cells terminally arrested in the cell cycle that exhibit a distinct secretory phenotype are referred to as senescent. These cells play a complex role during tumor progression; they can inhibit or promote tumor growth depending on disease stage. We developed a mouse model that allows monitoring and selective elimination of cells expressing high levels of the cyclin-dependent kinase inhibitor p16 and interleukin-6. These mice, termed SuSe (suicidal senescence), were crossed with the mouse mammary tumor virus–polyomavirus middle T antigen (MMTV-PyMT) model of breast cancer. Functional characterization in SuSe/PyMT mice confirmed that depletion of senescent cells (senolysis) in early and late lesions accelerated and decelerated tumor growth and metastasis, respectively. Tumor acceleration was attributed to expansion of immunosuppressive, protumorigenic macrophages. C-C motif chemokine ligand 2 was identified as an autocrine chemokine essential for their recruitment and maintenance. Depletion of these macrophages reversed the effects of senescent cell clearance, rendering senolysis antitumorigenic even at early stages. Our results suggest that targeting immunosuppressive macrophages can preserve the benefits of senolysis while mitigating adverse effects.

The increase in antioxidant defenses mediated by physical exercise signaling is proposed to be a protective factor against brain aging and neurodegeneration. However, the processes involved, particularly the response of senescence markers and cell fitness status in the context of Alzheimer’s disease (AD) pathology, remain unclear. We analyzed male and female 5XFAD transgenic AD mice subjected to 6 months of voluntary wheel running using molecular and behavioral techniques. Levels of mRNA of selected genes, mitochondrial complex proteins, and proteasomal function, were analyzed in the cerebral cortex or hippocampus. In an exploratory translational approach, proteasomal dynamics- and senescence-related genes were analyzed in peripheral blood from middle-aged amateur sportsmen. Physical exercise increased expression of antioxidant genes and modulated epigenetic genes in 5XFAD male and female mice. An increase in protein levels of hippocampal mitochondrial complexes CIII and CV was also induced in males. Both exercised 5XFAD mice and veteran sportsmen showed improved proteasomal status and decreased expression of senescence genes. Exercised mice showed memory and behavior preservation, as well as increases in brain metabolic fitness and gene modulation. These changes may contribute to the neuroprotective effect of physical exercise.