α- and β‑Santalols Delay Aging in Caenorhabditis elegans via Preventing Oxidative Stress and Protein Aggregation

α- and β-Santalol (santalol isomers) are the most abundant sesquiterpenoids found in sandalwood, contributing to its pleasant fragrance and wide-spectrum bioactivity. This study aimed at identifying the antiaging and antiaggregation mechanism of α- and β-santalol using the genetic tractability of an in vivo model Caenorhabditis elegans. The results showed that santalol isomers retard aging, improved health span, and inhibited the aggregation of toxic amyloid-β (Aβ1–42) and polyglutamine repeats (Q35, Q40, and HtnQ150) in C. elegans models for Alzheimer’s and Huntington’s disease, respectively. The genetic study, reporter gene expression, RNA-based reverse genetic approach (RNA interferences/RNAi), and gene expression analysis revealed that santalol isomers selectively regulate SKN-1/Nrf2 and EOR-1/PLZF transcription factors through the RTK/Ras/MAPK-dependent signaling axis that could trigger the expression of several antioxidants and protein aggregation inhibitory genes, viz., gst-4, gcs-1, gst-10, gsr-1, hsp-4, and skr-5, which extend longevity and help minimize age-induced protein oxidation and aggregation. We believe that these findings will further promote α- and β-santalol to become next-generation prolongevity and antiaggregation molecules for longer and healthier life.