Ellagic acid reveals promising anti-aging effects against d-galactose-induced aging on human neuroblastoma cell line, SH-SY5Y: A mechanistic study

Aging is a progressive, accumulative and natural phenomenon that leads to irreversible changes in all molecules, cells, tissues and organs of an organism. Previous studies have demonstrated that d-galactose (DG) imitates human natural aging. EA has also shown many pharmacological properties including anti-inflammatory and anti-oxidant activities.In the present study, we are aimed to evaluate anti-aging effects of EA (0.01-10 μM) on DG-induced aging model in SH-SY5Y human neuroblastoma cells, using assessment of cell proliferation, lipid peroxidation (MDA), intra-cellular reactive oxygen species (ROS), inflammation (TNF-α), total glutathione content (GSH), Beta-Galactosidase (β-GAL) and advanced glycation end products (AGEs) levels. Furthermore, the effects of EA were examined on HO-1 or PPAR-γ pathways using their selective inhibitors ZnPP or GW9662, respectively.The results revealed that EA (0.01-10 μM) significantly increased cell proliferation and GSH level, while decreased the levels of ROS, MDA, TNF-α, β-GAL and AGEs following DG-induced aging. Our findings also presented that pre-incubation with ZnPP exacerbates toxicity features of DG-induced aging in all measured parameters. Furthermore, we showed that pre-incubation of EA (0.1 and 1 μM) with either GW9662 or ZnPP significantly prevents the protective activities on cell proliferation, ROS, MDA, GSH and TNF-α levels following DG-induced aging (p < 0.001 for all cases). Additionally, EA (0.1 and 1 μM) along with GW9662 did not affect the levels of β-GAL and AGES in comparison to DG-induced aging group.Although we described for the first time that EA at low concentrations (0.1-1 μM) provides greater antiaging properties than both its high concentration (10 μM) and metformin (2.5 mM) probably through PPAR-γ/HO-1 signaling pathway, but additional and deeper investigations are needed to show exact involving mechanisms. It could be suggestible that EA may be as anti-aging agent at low concentrations for age-related neurological disorders such as Parkinson's and Alzheimer's diseases.