Abstract
Dietary restriction (DR) is a robust intervention that extends lifespan and slows the onset of age-related diseases in diverse organisms. While significant progress has been made in attempts to uncover the genetic mechanisms of DR, there are few studies on the effects of DR on the metabolome. In recent years, metabolomic profiling has emerged as a powerful technology to understand the molecular causes and consequences of natural aging and disease-associated phenotypes. Here, we use high-resolution mass spectroscopy and novel computational approaches to examine changes in the metabolome from the head, thorax, abdomen, and whole body at multiple ages in Drosophila fed either a nutrient-rich ad libitum (AL) or nutrient-restricted (DR) diet. Multivariate analysis clearly separates the metabolome by diet in different tissues and different ages. DR significantly altered the metabolome and, in particular, slowed age-related changes in the metabolome. Interestingly, we observed interacting metabolites whose correlation coefficients, but not mean levels, differed significantly between AL and DR. The number and magnitude of positively correlated metabolites was greater under a DR diet. Furthermore, there was a decrease in positive metabolite correlations as flies aged on an AL diet. Conversely, DR enhanced these correlations with age. Metabolic set enrichment analysis identified several known (e.g., amino acid and NAD metabolism) and novel metabolic pathways that may affect how DR effects aging. Our results suggest that network structure of metabolites is altered upon DR and may play an important role in preventing the decline of homeostasis with age.
Highlights
Aging is a complex biological process that results in a gradual decline in physiological function and increases the prevalence of chronic diseasesAccepted for publication 28 April 2015(Young, 1997; Kennedy et al, 2014)
Our results show that highresolution metabolomic and network analyses serve as novel, powerful models which provide insights into the mechanisms that underlie the protective effects of dietary restriction (DR) on healthspan and lifespan in diverse organisms
As seen in many previous studies, we found that DR in w1118 female mated flies extended mean and median lifespan (Fig. 1A)
Summary
Aging is a complex biological process that results in a gradual decline in physiological function and increases the prevalence of chronic diseasesAccepted for publication 28 April 2015(Young, 1997; Kennedy et al, 2014). Aging is a complex biological process that results in a gradual decline in physiological function and increases the prevalence of chronic diseases. The effects of aging on survival and pathology can be reversed through genetic, pharmacological, and environmental perturbations (Fontana et al, 2010; Kapahi et al, 2010). Researchers have proposed several biological processes to explain how DR extends lifespan. DR enhances autophagy, mitochondrial biogenesis, lipid metabolism, proteostasis, and stem cell function, while reducing oxidative stress and inflammation (Lopez-Lluch et al, 2006; Aris et al, 2013) and reversing the age-related decline in stem cell function and increase in inflammation (Horrillo et al, 2011; Cerletti et al, 2012). The TOR, Sir 2, and insulin signaling pathways have been implicated in mediating the effects of DR on lifespan (Kapahi et al, 2004; Mair & Dillin, 2008)
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