Sestrin2 (Sesn2) appears to mediate neuroprotection against Parkinson's disease (PD)-associated pathophysiology, however, the mechanism is unknown. This pilot study examines serum Sesn2 level in PD patients and older adult control and also interrogates the rescue effect of Syzygium aromaticum extract on the neurotoxicity by paraquat in neuroblastoma cells. The blood sample was collected from 36 PD patients and 54 older adult control and concentration of serum Sesn2 was measured by surface plasmon resonance and western blot. A significantly elevated level of Sesn2 (p < .0001) was observed in sera of PD group (15.96 ± 2.428 ng/μL) than the control (13.65 ± 2.125 ng/μL) which was further confirmed by western blotting. The receiver operating characteristic (ROC) curve (0.76) determined the threshold value of ≥14.58 ng/μL for differentiating PD from control. The S aromaticum extract exhibited the rescue effect from paraquat induced toxicity in SH-SY5Y cells. Further, these cells showed dose-dependent downregulation of p53, Sesn2, and phosphorylated-AMPK with concomitant increase in phosphorylated-p70S6K level than paraquat-treated cells. The differential level of Sesn2 in study subjects proposes its utility as one of the potential serum markers in PD. The ethanolic extract of S aromaticum may serve as a novel platform for management of PD-associated neurotoxicity.,? The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].