Researchers here evaluate the flavonoid naringenin for its ability to dampen the inflammatory signaling of senescent neural cells, particularly levels of TNF-α, and increase neurogenesis in mice. This increased neurogenesis is likely a result of reduced inflammation in brain tissue, but possibly due to other, distinct mechanisms. Neurogenesis is the name given to the generation of new neurons in the brain, and their integration into existing neural circuits. Evidence suggests that increased neurogenesis is a good thing at any age, improving cognitive function and making the brain more resilient to injury. Now that the research community is paying attention to senescent cells and their signaling in the context of aging, we'll no doubt see a great many compounds classified or reclassified as senotherapeutics in the years ahead.
The use of metabolomic analysis to investigate the specific composition of Ribes meyeri anthocyanins revealed that naringenin (Nar) may be an important flavonoid metabolite. Nar has previously been reported to ameliorate myocardial cell senescence, improve the metabolic capacity of the intestinal tract, and exert anti-inflammatory and anti-cancer effects. However, the effects of Nar on neural stem cells (NSCs) during aging remains unknown.
To explore the anti-aging effects of R. meyeri anthocyanins, we conducted further studies using Nar. Treatment with 6.8 μg/mL Nar increased cell viability, reduced P16ink4a gene expression, lengthened telomeres, and promoted mouse NSC differentiation into neurons in vitro. To further assess the effects of Nar on cell proliferation, we performed immunofluorescence studies. Results indicated that Nar treatment increased both the number of Ki67-positive cells and the proportion of MAP2-positive cells, suggesting that Nar may promote neurogenesis.
Furthermore, the effects of Nar on learning and memory were also evaluated in aging mice. Morris water maze test results consistently demonstrated that Nar treatment enhances spatial learning in aging mice. Interestingly, RNA-seq analysis revealed that Nar may affect senescence via the TNF signaling pathway, especially by downregulating TNF-α expression in the blood of aging mice. ELISA assays also indicated that Nar treatment reduced plasma TNF-α levels compared with control aging mice. TNF-α is a key factor in the TNF signaling pathway and is closely related to cognitive aging. Its functions include the promotion of pathological changes in hippocampal synapses and the inhibition of precursor cell proliferation. Altered TNF levels are associated with cognitive impairment in depression, schizophrenia, bipolar disorder, and Alzheimer's disease. More specifically, TNF-α is upregulated in patients with Alzheimer's disease.
In summary, our study demonstrates that R. meyeri anthocyanins improve the effects of aging in NSCs via Nar, which downregulates TNF-α levels in vivo and improves cognition in aging mice. Collectively, our findings provide a novel strategy for the development of clinical treatments, aimed at greater realization of the medicinal value of R. meyeri anthocyanins.