A protective role of SRC-1 against aging associated cognitive decline

Aging (Albany NY). 2025 Aug 27;17(8):2167-2188. doi: 10.18632/aging.206311. Epub 2025 Aug 27.

Abstract

Introduction: Research indicates a strong correlation between obesity and the risk of dementia, both are linked to steroid receptor coactivator-1 (SRC-1), a transcriptional coactivator.

Methods: We used RNA sequencing analysis (RNA-Seq) to investigate the transcriptome of SRC-1-KO mice, and identified S100 calcium-binding protein A6 (S100A6), an AD associated gene, as one target of SRC-1. We tested cognitive behaviors in SRC-1-KO mice and mice with a humanized SRC-1 mutation (SRC-1L1376P), and performed promoter luciferase assays on S100A6.

Results: Loss of SRC-1 caused alterations in gene signatures that are commonly associated with neurodegenerative diseases, including AD, and diminished the neural plasticity of the hippocampal CA1 neurons. Both SRC-1-KO and SRC-1L1376P mice displayed early signs of contextual memory impairment at 6 months of age. Mechanistically, SRC-1 significantly promoted the expression S100A6.

Conclusion: We identified a protective role of SRC1 against aging associated cognitive decline, potentially by promoting the expression of S100A6.

Keywords: S100A6; SRC-1; aging; dementia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging* / genetics
  • Aging* / metabolism
  • Animals
  • Cognitive Dysfunction* / genetics
  • Cognitive Dysfunction* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Neuronal Plasticity / genetics
  • Nuclear Receptor Coactivator 1* / genetics
  • Nuclear Receptor Coactivator 1* / metabolism
  • S100 Calcium Binding Protein A6* / genetics
  • S100 Calcium Binding Protein A6* / metabolism

Substances

  • Nuclear Receptor Coactivator 1
  • Ncoa1 protein, mouse
  • S100 Calcium Binding Protein A6