Elastin is a stable protein present in many tissues, including brain tissues, and is one of the most long-life proteins with a half-life of approximately 70 years. The peptide with a Val-Gly-Val-Ala-Pro-Gly (VGVAPG) amino acid sequence is released during elastin decay, which correlates with aging-related neurodegeneration. A recent study has shown enhanced protein expression of Sirtuin 2 (SIRT2 - one of the redox homeostatic factors) in aged rodent brains, while the correlation between VGVAPG and SIRT2 has never been evaluated so far. Therefore, the study aimed to determine the impact of the VGVAPG hexapeptide on SIRT2 and neuronal functions in differentiated SH-SY5Y cells at the gene and protein expression levels. The present results showed that VGVAPG caused a 52.69% decrease in the level of reactive oxygen species (ROS), as in the case of neurons treated with AGK2 (Sirtuin 2 inhibitor) after 24h and 48h. Furthermore, a decrease in superoxide dismutase (SOD) activity was observed. The SIRT2 gene expression was found to fluctuate after 6h and 24h as a result of the exposure to the VGVAPG peptide. In turn, a decrease in the PPARγ, P53, SOD2, and CAT mRNA expression was shown in VGVAPG-treated cells. Additionally, an increase in the Sirtuin 2 protein expression was recorded after 24h and 48h in the VGVAPG peptide-treated neurons. Last but not least, the decrease in the level of acetylation of α-tubulin after the hexapeptide treatment was correlated with shortening of neurites, which may indicate the destabilization of the microtubule and ROS-independent induction of neurodegeneration.