Abstract:
Obesity prevalence increases with age and is further exacerbated by consumption of a Western-style diet (WSD), which is characterized by high fat, refined sugars, processed foods, and low dietary fiber. Consistent with this, our studies show that adult/middle-aged mice develop markedly more severe diet-induced obesity (DIO) and metabolic
dysfunction than young mice when exposed to a high-fat diet that models key features of a WSD. This heightened obesity susceptibility in adult mice was associated with reduced energy expenditure and increased food intake, rather than increased nutrient absorption. Importantly, age-related DIO was accompanied by vascular inflammatory remodeling and barrier dysfunction. Furthermore, we demonstrated that gut microbiota alteration is a key driver of this age-dependent metabolic and vascular phenotype. Aging induced progressive changes in gut microbial composition, including enrichment of proinflammatory taxa and increased microbiota-derived LPS and flagellin activity. These changes were associated with increased intestinal permeability and colonic inflammatory/metabolic reprogramming. Depletion of gut microbiota with antibiotics markedly attenuated WSD-induced obesity and improved glucose metabolism in adult mice. Conversely, fecal microbiota transplantation from adult donors into young germ-free recipient mice transferred susceptibility to severe DIO, metabolic dysfunction, reduced energy expenditure, and vascular dysfunction upon WSD exposure. Together, these findings support a model in which aging promotes a pro-inflammatory gut microbiota that exacerbates WSD-induced obesity, metabolic dysfunction, and vascular barrier impairment.
