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Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2

Huan Yuan1,2, Yan Xu1,2, Yi Luo1,2

  • 1Institute of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.

Aging Cell
|August 5, 2022
PubMed

Insights

Ganoderic acid D (GA-D) delays stem cell senescence, a key aging factor. This compound protects human amniotic mesenchymal stem cells by activating the CaM/CaMKII/Nrf2 pathway, offering a potential anti-aging strategy.

Area of Science:

  • Cellular Biology
  • Gerontology
  • Molecular Medicine

Background:

  • Stem cell senescence is a significant contributor to organismal aging and age-related diseases.
  • Identifying compounds that can delay senescence is crucial for developing anti-aging interventions.
  • Ganoderma lucidum-derived compounds, like ganoderic acid D (GA-D), show potential in modulating cellular processes.

Purpose of the Study:

  • To elucidate the protective mechanism of ganoderic acid D (GA-D) against human amniotic mesenchymal stem cell (hAMSCs) senescence.
  • To investigate the role of the Ca2+/calmodulin (CaM)/CaM-dependent protein kinase II (CaMKII)/nuclear erythroid 2-related factor 2 (Nrf2) signaling axis in GA-D's anti-aging effects.
  • To evaluate the in vivo anti-aging efficacy of GA-D in a mouse model.

Main Methods:

  • hAMSCs were treated with GA-D, and senescence markers (SA-β-gal, p16, p21) and reactive oxygen species (ROS) were assessed.
  • Gene knockdown and overexpression of 14-3-3ε (YWHAE) were performed to confirm its role in GA-D's mechanism.
  • An in vivo aging model in mice induced by d-galactose was used to evaluate GA-D's systemic anti-aging effects and its impact on stem cell function.

Main Results:

  • GA-D significantly prevented hAMSCs senescence by activating the CaM/CaMKII/Nrf2 pathway, with 14-3-3ε identified as a direct target.
  • Modulating 14-3-3ε expression reversed or enhanced GA-D's anti-senescence effects, confirming its critical role.
  • In vivo, GA-D improved antioxidant capacity, reduced aging biomarkers, and delayed mesenchymal stem cell senescence in mice, mirroring the in vitro findings.

Conclusions:

  • GA-D effectively retards hAMSCs senescence by targeting 14-3-3ε and activating the CaM/CaMKII/Nrf2 signaling pathway.
  • The study provides a mechanistic understanding of GA-D's anti-aging properties at the cellular and organismal levels.
  • GA-D represents a promising therapeutic candidate for combating aging and age-associated diseases by modulating stem cell senescence.
Keywords:
14-3-3εCaM/CaMKII/Nrf2 signalingaging mouse modelanti-agingbone-marrow mesenchymal stem cellsganoderic acid Dhuman amniotic mesenchymal stem cells

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