Abstract
With increases in life expectancy, it is vital to understand the dynamics of aging, their interaction with lifestyle factors, and the connections to age-related disease processes. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel anticancer and anti-obesity phenotype mediated by a brain-fat axis: the hypothalamic-sympathoneural-adipocyte (HSA) axis in young animals. Here we investigated EE effects on healthspan and lifespan when initiated after middle age. Short-term EE for six weeks activated the HSA axis in 10-month-old mice. Long-term EE for twelve months reduced adiposity, improved glucose tolerance, decreased leptin levels, enhanced motor abilities, and inhibited anxiety. In addition to adipose remodeling, EE decreased age-related liver steatosis, reduced hepatic glucose production, and increased glucose uptake by liver and adipose tissue contributing to the improved glycemic control. The EE-induced liver modulation was associated with a suppression of protein kinase Cε. Moreover, EE down-regulated the expression of inflammatory genes in the brain, adipose, and liver. EE initiated at 18-month of age significantly improved glycemic control and showed a trend of positive impact on mean lifespan. These data suggest that EE induces metabolic and behavioral adaptations that are shared by factors known to increase healthspan and lifespan.
Highlights
The incidence of age-related diseases such as cancer, cardiovascular disorders and neurodegenerative diseases rises with an increase in life expectancy
Robust reduction of adiposity was observed in EE mice in both brown adipose tissue (BAT) and three white adipose (WAT) depots: the subcutaneous inguinal WAT, abdominal retroperitoneal WAT and gonadal WAT (Figure 1C)
Insulin receptor (Insr) and leptin receptor (Lepr) expression were upregulated by EE (Figure 2A)
Summary
The incidence of age-related diseases such as cancer, cardiovascular disorders and neurodegenerative diseases rises with an increase in life expectancy. Muscle mass was increased in EE and hypothalamic BDNF overexpressing mice Both environmental and genetic activation of the HSA axis is efficient in decreasing adiposity, allowing the dissociation of fat loss from weight loss, which is difficult to achieve with other interventions [25]. The HSA axis activation alleviates obesityassociated insulin resistance, alleviates hyperglycemia and dyslipidemia [11, 12], alters adipokine levels with higher adiponectin and lowers leptin expression in adipose tissue as well as in circulating blood [10, 12], suppresses tumor progression and metastasis [10, 26], and enhances immunocompetence [10, 26, 27], all mimicking CR [1, 5, 28, 29]. We investigated the effects of EE on healthy aging and lifespan from a unique perspective of the recently characterized HSA axis
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