Nutr Res Pract.  2025 Apr;19(2):186-199. 10.4162/nrp.2025.19.2.186.

Resveratrol attenuates aging-induced mitochondrial dysfunction and mitochondria-mediated apoptosis in the rat heart

• Choi Y
• No MH
• Heo JW
• Cho EJ
• Park DH
• Kang JH
• Kim CJ
• Seo DY
• Han J
• Kwak HB

• KMID: 2566808
• DOI: http://doi.org/10.4162/nrp.2025.19.2.186

Abstract

BACKGROUD/OBJECTIVES: Resveratrol, a natural polyphenolic compound, has potent antioxidant and anti-inflammatory properties, leading to beneficial effects against cardiovascular diseases. The purpose of this study was to determine whether resveratrol induces protective effects against aging-induced cardiac remodeling, mitochondrial dysfunction, and mitochondria-mediated apoptosis in the heart.
MATERIALS/METHODS
Thirty-two male Fischer 344 rats were divided into 4 groups: 2 groups that were orally treated with resveratrol (50 mg/kg/day) for 6 weeks (young and old resveratrol groups), and 2 control groups (young and old control groups). Mitochondrial function and mitochondria-mediated apoptotic pathway were analyzed in cardiac muscle fibers from the left ventricle.
RESULTS
Resveratrol significantly reduced cardiac hypertrophy and remodeling in aging hearts. In addition, resveratrol significantly ameliorated aging-induced mitochondrial dysfunction (e.g., decreased oxygen respiration and increased hydrogen peroxide emission) and mitochondria-dependent apoptotic signaling (the Bax/Bcl-2 ratio, mitochondrial permeability transition pore opening sensitivity, and cleaved caspase-3 protein levels). Resveratrol also significantly attenuated aging-induced apoptosis (determined via cleaved caspase-3 staining and TUNEL-positive myonuclei) in cardiac muscles.
CONCLUSION
This study demonstrates that resveratrol treatment has a beneficial effect on aging-induced cardiac remodeling by ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptosis in the heart.

Keyword

Aging; resveratrol; heart; mitochondria; oxidative stress

Figure

• 

  Fig. 1 Effects of aging and resveratrol on morphology. (A) Representative histological cross-sections of the LV tissues of rats from the YC, YR, OC, and OR groups stained with hematoxylin and eosin (magnification: 40× and scale bar: 100 μm). Unstained areas indicate the extramyocyte space. (B) Quantification of the percentage of extramyocyte space. (C) The number of myocytes per 100,000 μm2 in the LV tissues. (D) The myocyte CSA of LV tissue histological sections, in square micrometers. The scale bar indicates 100 m. In the 2-way ANOVA, significant age-by-resveratrol interactions were observed in the percentage of extramyocyte space (P < 0.05) and myocyte CSA (P < 0.05). Additionally, a significant main effect of age was observed in the number of myocytes (P < 0.001).Subjects were categorized according to age and divided into control and resveratrol-treated groups: young control (YC), young resveratrol (YR), old control (OC), and old resveratrol (OR) groups.Data are presented as the mean ± standard error of the mean.LV, left ventricle; CSA, cross-sectional area; ANOVA, analysis of variance.*P < 0.05 vs. YC; †P < 0.05 vs. YR; and ‡P < 0.05 vs. OC.

• 

  Fig. 2 Effects of aging and resveratrol on mitochondrial function in cardiac muscle. (A) In mitochondrial O2 respiration, 2-way ANOVA reveals significant age-by-resveratrol interactions at ADP stage (P < 0.05) and SUCC stage (P < 0.05), and a significant main effect of aging was observed at GM stage (P < 0.05). (B) In mitochondrial H2O2 emission, two-way ANOVA reveals significant main effects of age and resveratrol at GM+S stage (all P < 0.05) and GMS+G3P stage (all P < 0.05). (C) In mitochondrial Ca2+ retention capacity, 2-way ANOVA reveals significant main effects of age and resveratrol (all P < 0.05).Subjects were categorized according to age and divided into control and resveratrol-treated groups: young control (YC), young resveratrol (YR) treatment, old control (OC), and old resveratrol (OR) treatment groups. Mitochondrial H2O2 emission was measured during the following sequences 3 steps: basal, GM (substrates of complex I, GM) stage, SUCC (substrate of complex II, GM+S) stage, and G3P (lipid substrate, GMS+G3P) stage.Data are presented as the mean ± standard error of the mean.O2, oxygen; ANOVA, analysis of variance; ADP, adenosine diphosphate; SUCC, succinate; GM, glutamate-malate; G3P, glycerol-3 phosphate; Ca2+, calcium; H2O2, hydrogen peroxide.*P < 0.05 vs. YC; †P < 0.05 vs. YR; and ‡P < 0.05 vs. OC.

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  Fig. 3 Effects of aging and resveratrol treatment on mitochondria-mediated apoptotic signaling in cardiac muscle. Immunoblot bands of protein levels of (A) Bax, (B) Bcl-2, and (E) cleaved caspase-3. (C) Bax to Bcl-2 ratio. (D) mPTP opening. Two-way ANOVA reveals significant main effects of age and resveratrol in the protein levels of Bax, Bcl-2, and cleaved caspase-3, and Bax/Bcl-2 ratio (all P < 0.05). Additionally, a significant age-by-resveratrol interaction was observed in mPTP opening (P < 0.05). Quantification of relative western blot bands after normalization with β-actin.Subjects were categorized according to age and divided into control and resveratrol-treated groups: young control (YC), young resveratrol (YR), old control (OC), and old resveratrol (OR) groups.Data are presented as the mean ± standard error of the mean.mPTP, mitochondrial permeability transition pore; ANOVA, analysis of variance.*P < 0.05 vs. YC; †P < 0.05 vs. YR; ‡P < 0.05 vs. OC.

• 

  Fig. 4 Immunohistochemical assessment of apoptosis (cleaved caspase-3-positive cells and TUNEL-positive myonuclei) in the LV sections obtained from YC, YR, OC, and OR groups. Two-way ANOVA reveals significant age-by-resveratrol interactions in the cleaved caspase-3-positive cells (P < 0.001) and TUNEL-positive myonuclei (P < 0.01). (A) Representative photographs of LV sections immunohistochemically stained with anti-cleaved caspase-3 antibody (scale bar, 100 μm). (B) TUNEL staining photographs, in which brown-staining cells were TUNEL-positive myonuclei (magnification, 40×). Moreover, (C) quantification of cleaved caspase-3-positive cells, as assessed by immunohistochemical staining. (D) Quantification of TUNEL-positive myonuclei.Subjects were categorized according to age and divided into control and resveratrol-treated groups: young control (YC), young resveratrol (YR), old control (OC), and old resveratrol (OR) groups.Data are presented as the mean ± standard error of the mean.TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; LV, left ventricle; ANOVA, analysis of variance.*P < 0.05 vs. YC; †P < 0.05 vs. YR; ‡P < 0.05 vs. OC.

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