Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes

Area of Science:

• Cardiovascular Science
• Metabolic Science
• Aging Research

Background:

• Obesity and diabetes are epidemics linked to atherosclerosis.
• Aging populations exacerbate these metabolic and vascular risks.
• High-fat diets (HFD) and aging are key risk factors for atherosclerosis.

Purpose of the Study:

• To investigate how aging affects metabolic and vascular responses to HFD.
• To elucidate the mechanisms behind accelerated atherosclerosis in aging mice.
• To evaluate potential therapeutic interventions for age-related atherosclerosis.

Main Methods:

• Lipoprotein receptor knockout (LDLR(-/-)) mice of different ages (3-month-old vs. 12-month-old) were fed HFD.
• Metabolic syndrome, diabetes, and atherosclerosis were assessed.
• Aortic gene expression (microarray) and oxidative stress markers were analyzed.
• Mice were treated with apocynin or rosiglitazone.

Main Results:

• Middle-aged LDLR(-/-) mice exhibited significantly worse metabolic syndrome, diabetes, and atherosclerosis than young mice on HFD.
• Aging impaired the aortic antioxidant gene response to HFD, despite increased systemic oxidative stress.
• Reduced vascular expression of DJ-1 and FOXO pathways contributed to this impaired response.
• Apocynin and rosiglitazone treatments reduced oxidative stress and attenuated atherosclerosis; rosiglitazone also improved metabolic syndrome.

Conclusions:

• Aging significantly exacerbates HFD-induced metabolic and vascular dysfunction.
• Impaired antioxidant response in aging vasculature is a key mechanism for accelerated atherosclerosis.
• Targeting oxidative stress pathways offers a promising therapeutic strategy for aging vasculature.
• Rosiglitazone demonstrated a novel effect on Nrf2 activation, enhancing antioxidant defenses.