Sesamin Suppresses Aging-Associated Impairment of Protein Homeostasis in Adult <em>Drosophila </em>Muscles by Stimulating Autophagy

As Drosophila ages, damaged and no longer used proteins, which are ubiquitinated, accumulate in muscle. This is attributed to age-dependent impairment of protein homeostasis. Sesamin, which has antioxidant effects on cultured cells and Drosophila neurons, suppresses this muscle-aging phenotype. However, unlike in neurons, it failed to activate the transcription factor Nrf2 for antioxidant genes in muscle. The number and amount of ubiquitinated aggregates increased in the flies' muscles with aging. We investigated autophagy levels via anti-Ref(2)P immunostaining and demonstrated that autophagy in the muscle was stimulated in sesamin-fed flies. The effect on the muscle was eliminated via the administration of an autophagy inhibitor, chloroquine, and the muscle-specific depletion of Atg8, an autophagosome component. In contrast, the effect did not change via the administration of a proteasome inhibitor, bortezomib, and the depletion of proteasome components, suggesting that sesamin stimulates autophagy, but not the proteasome degradation system, to suppress the age-related impairment of protein homeostasis in muscle. Sesamin may be a useful anti-aging substance in delaying muscle aging. Another interesting finding from the study is that inhibition of the ubiquitin-proteasome system also influences autophagy in Drosophila muscles. Elucidating the mechanisms underlying sesamin's effects provides essential information related to the muscle aging process.