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

Neurobiol Aging. 2021 Oct:106:26-36. doi: 10.1016/j.neurobiolaging.2021.06.003. Epub 2021 Jun 10.

Abstract

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 PGC1α 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 P16INK4a, γ-H2AX, and lamin B1, and improved memory skills implying that TFEB may exert an anti-aging 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.

Keywords: Aging; Lamin B1; Learning and memory; Mitochondria; P16INK4a; PGC1-α; Senescence; TFEB; mtTFA; γ-H2AX.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Aging / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology
  • Biomarkers / metabolism*
  • Brain / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression / genetics*
  • Gene Expression Regulation, Developmental / genetics*
  • Histones / metabolism
  • Memory Disorders / genetics*
  • Memory Disorders / therapy
  • Mice, Transgenic
  • Molecular Targeted Therapy

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Biomarkers
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Tcfeb protein, mouse
  • gamma-H2AX protein, mouse