TFEB protein expression is reduced in aged brains and its overexpression mitigates senescence-associated biomarkers and memory deficits in mice

Identification of molecules and molecular pathways that can ameliorate aging-associated decline in cognitive function is crucial. Here we report that the protein levels of transcription factor EB (TFEB) were markedly reduced in both the cytosolic and nuclear fractions of the frontal cortex and hippocampus at 18-months of age relative to 6 months in the normal male wild-type mice. In the transgenic mice with ectopic expression of flag-TFEB in neurons, we observed that the levels of actin-normalized PGC1 a and mtTFA were significantly increased in both the cortex and the hippocampus. Additionally, we confirmed increased mitochondria numbers in the flag-TFEB mice by transmission electron microscopy. Most importantly, TFEB expression in the 18-month-old transgenic mice mitigated markers of senescence including PI6INK4a, gamma-H2AX, and lamin Bl, and improved memory skills implying that TFEB may exert an antiaging effect by modulating neuronal senescence. Taken together these data strongly support that TFEB can be a useful therapeutic target for brain senescent cells to help overcome the age-related issues in cognition and possibly, achieve healthy aging. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

TFEB protein levels decrease in aging mice, but ectopic expression of TFEB in transgenic mice leads to increased mitochondria numbers, reduced markers of senescence, improved memory skills, suggesting that TFEB may help delay neuronal aging and enhance cognitive abilities.