In vitro assessment of dietary bioactives for TFEB activation as a possible target to support cognitive and emotional wellbeing

Aging and chronic stress are associated with altered brain plasticity and an increased risk of developing cognitive and emotional health problems. A key cellular mechanism involved is autophagy, which is known to be important for memory encoding and information processing, and is also thought to be important for psychiatric and emotional health. Activation of the autophagic system can be established by the transcription factor EB (TFEB), which regulates both autophagosome formation and lysosomal biogenesis and function. As well-known activators of autophagy like caloric restriction, fasting, or regular exercise require intervention programs that are hard to adhere to, the search for nutritional solutions with similar effects, is increasing. We therefore evaluated pro-autophagic dietary bioactives for effects specifically through TFEB activation and assessed whether combining bioactives can lead to synergistic or additive effects. We also discuss current evidence supporting the use of these natural dietary compounds to promote cognitive and emotional wellbeing. Primary cortical astrocytes were treated with 13 different ingredients and analyzed for their effect on TFEB nuclear translocation by high content imaging. Effective ingredients were then evaluated at different concentrations for their effect on TFEB downstream signaling by analyzing mRNA levels of Beclin1, LC3, Lamp-1 and Cathepsin D. Furthermore, the synergistic effects of sub-optimal concentrations of different ingredient combinations were evaluated on the same TFEB downstream signaling markers. Potential signs of toxicity of all ingredients and their combinations were evaluated by analysis of ATP production and nuclear counts. DHA, EPA, 7,8-DHF, ellagic acid, curcumin and spermidine increased TFEB nuclear localization. DHA and spermidine exhibited the strongest effects when measuring mRNA levels of TFEB downstream signaling markers. The most significant synergies were observed when combining spermidine with ellagic acid or when combining DHA with curcumin. None of the ingredients alone or in combination presented any sign of toxicity at the concentrations tested. The results of our study show for the first time a synergistic effect of spermidine and ellagic acid and of DHA and curcumin on TFEB signaling and thus its ability to act on the autophagic system in brain cells. These combinations may hold potential as dietary promoters of cognitive and emotional wellbeing.