Quanyong Wu, Boya Ouyang, Hui Cao, Min Zhang, Mohamed A Farag, Thomas Efferth, Jesus Simal-Gandara, Jianbo Xiao
Adult supplementation exerted pronounced female-specific benefits, increasing median lifespan by 11.6%, improving locomotor activity and stress resistance, with little effect on body weight, whereas males showed little response. Notably, short-term supplementation during early adulthood produced sustained protective effects later in life. Mechanistically, luteolin enhanced antioxidant defenses, suppressed IIS/PI3K-mTOR signaling, activated AMPK/MAPK pathways, promoted autophagy and immune homeostasis, and induced metabolic remodeling associated with reduced mitochondrial stress and favorable histone modifications. In contrast, embryonic exposure shortened lifespan and disrupted endocrine and metabolic homeostasis, as evidenced by elevated juvenile hormone levels, reduced catalase activity, and dysregulated IIS signaling.
INTRODUCTION: Luteolin is a dietary flavonoid widely distributed in fruits, vegetables, and medicinal plants and is recognized for its antioxidant and health-promoting properties. However, its effects on physiological aging and the influence of developmental stage and biological sex remain poorly understood.
METHODS: In this study, Drosophila melanogaster was exposed to luteolin during either adulthood or embryonic development and evaluated for lifespan, healthspan, metabolic regulation, and aging-related molecular changes.
RESULTS: Adult supplementation exerted pronounced female-specific benefits, increasing median lifespan by 11.6%, improving locomotor activity and stress resistance, with little effect on body weight, whereas males showed little response. Notably, short-term supplementation during early adulthood produced sustained protective effects later in life. Mechanistically, luteolin enhanced antioxidant defenses, suppressed IIS/PI3K-mTOR signaling, activated AMPK/MAPK pathways, promoted autophagy and immune homeostasis, and induced metabolic remodeling associated with reduced mitochondrial stress and favorable histone modifications. In contrast, embryonic exposure shortened lifespan and disrupted endocrine and metabolic homeostasis, as evidenced by elevated juvenile hormone levels, reduced catalase activity, and dysregulated IIS signaling.
DISCUSSION: These findings suggest that the biological effects of luteolin on aging are highly dependent on developmental stage and biological sex in Drosophila. The beneficial effects observed in adult females were associated with coordinated changes in nutrient-sensing pathways, metabolism, mitochondrial function, and epigenetic regulation, whereas developmental exposure produced adverse outcomes. Collectively, this study provides new insights into the context-dependent actions of dietary flavonoids in Drosophila and highlights the importance of developmental stage and biological sex when evaluating nutritional interventions for healthy aging.