Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and cardiovascular diseases, cancer, diabetes, and skeletal muscle pathologies. Key features of aging include a chronic low-grade inflammation state and a decrease of the autophagic process. The Mediterranean diet has been associated with longevity and ability to counteract the onset of age-related disorders. Extra virgin olive oil, a fundamental component of this diet, contains bioactive polyphenolic compounds as hydroxytyrosol (HTyr) and oleuropein (OLE), known for their antioxidant, anti-inflammatory, and neuroprotective properties. This review is focused on brain, skeletal muscle, and gut microbiota, as these systems are known to interact at several levels. After the description of the chemistry and pharmacokinetics of HTyr and OLE, we summarize studies reporting their effects in in vivo and in vitro models of neurodegenerative diseases of the central/peripheral nervous system, adult neurogenesis and depression, senescence and lifespan, and age-related skeletal muscle disorders, as well as their impact on the composition of the gut microbiota.

Hydroxytyrosol (HTyr), a plant-derived phenolic compound found in Olea europaea L. products and by-products, is well-known for its antioxidant activity and a wide range of biological effects, including anti-inflammatory, anticancer, antiviral, cardioprotective, neuroprotective, and antibacterial properties. However, due to its high hydrophilicity, HTyr exhibits unfavorable pharmacokinetic properties, preventing its potential therapeutic use. Various strategies can be employed to address these limitations. In this study, we evaluated the effect of two specific approaches on the HTyr antimicrobial and antioxidant activities: chemical modification of HTyr by lipophilization of the alcoholic moiety and encapsulation in liposomes. Based on our experience in the synthesis and biological activities of HTyr derivatives, the attention was focused on HTyr oleate (HTyr-OL), having a C-18 unsaturated alkylic chain responsible for an increased lipophilicity compared to HTyr. This structural feature enhanced antimicrobial activity against both tested strains of S. aureus, ATCC 25923 (wild-type strain) and ATCC 33591 (MRSA), and comparable antioxidant activity against two different radicals, Galvinoxyl radical and 1,1-diphenyl-2-picrylhydrazyl radical. Moreover, liposomes as delivery systems for HTyr and HTyr-OL were developed using both natural and synthetic amphiphiles, and the impact of encapsulation on their activities was further investigated. The experimental results showed that the antimicrobial properties of HTyr and HTyr-OL against S. aureus strains were not enhanced after encapsulation in liposomes, while the high antioxidant activity of HTyr-OL was preserved when conveyed in liposomes.

Novel lipophilic hydroxyalkyl esters were synthetized by Fischer esterification in good to excellent yields (60–96%) from a panel of hydroxyphenylacetic acids and increasing chain length (2 to 8 carbon atoms) α,ω-diols. The in vitro antioxidant activity of these compounds was evaluated by DPPH and ABTS assays. Hydroxybutyl esters and hydroxyphenylacetic acids were used as starting materials for the synthesis of novel lipophilic diesters (butyl diarylacetates) using Mitsunobu reaction. The final products were isolated in moderate to good yields (40–78%), and their structure–antioxidant activity relationships are discussed. Compounds bearing the catechol moiety on one of the two aromatic rings and high lipophilicity proved to be the strongest antioxidants and were selected for testing as antibacterials against Staphylococcus aureus and Escherichia coli, obtaining preliminary and promising results.