Folic acid attenuates remodeling and dysfunction in the aging heart through the ER stress pathway

Life Sci. 2021 Jan 1:264:118718. doi: 10.1016/j.lfs.2020.118718. Epub 2020 Nov 5.


Aims: Age-related structure changes and dysfunction of heart are likely to contribute heart failure in elderly people. Recent studies have shown that folic acid supplementation effectively delays age-related declines; nevertheless, the role and mechanism of folic acid in protection against cardiac aging remain unclear. The aim of the current study was to determine whether folic acid inhibits remodeling and dysfunction during the aging process and to elucidate its underlying mechanisms.

Main methods: Male C57BL/6 mice aged 4 months (adult) and 14 months (aged) were fed a standard diet or a folic acid diet for 6 months. Echocardiograms and histological evaluations were used to detect left ventricle (LV) function, LV remodeling, cardiac fibrosis, apoptosis and oxidative stress. Senescence-associated β-galactosidase activity staining was used to detect cardiac senescence rate. Western blotting was employed to detect the levels of senescence and ER stress signaling.

Key finding: LV hypertrophy was reduced and LV function was preserved in aged mice that consumed folic acid. LV remodeling, fibrosis, apoptosis and oxidative stress were also reduced in mice that consumed folic acid. Senescence-associated β-galactosidase activity staining revealed that folic acid attenuated cardiac senescence by down-regulating p53/p21/p16 levels. Protein assays of myocardial tissue revealed that the ER stress pathway is the important underlying mechanism during cardiac senescence. The involvement of these pathways was confirmed by doxorubicin-induced H9C2 cardiomyocyte senescence.

Significance: These findings suggest that folic acid prevents age-related cardiac remodeling and dysfunction and attenuates cellular senescence. ER stress responses may be the mechanisms involved in the protective effect of folic acid against cardiac aging.

Keywords: Aging,ventricular remodeling; Cellular senescence; Endoplasmic reticulum (ER) stress; Folic acid.

MeSH terms

  • Aging / pathology*
  • Animals
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Cell Line
  • Endoplasmic Reticulum Stress / drug effects*
  • Fibrosis
  • Folic Acid / pharmacology*
  • Heart / drug effects
  • Heart / physiopathology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Hypertrophy, Left Ventricular / drug therapy
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects
  • Systole / drug effects
  • Ventricular Remodeling* / drug effects


  • Cardiotonic Agents
  • Folic Acid