Metabolic Signalling
Scientists at the CSC and Imperial College have hit upon a collection of metabolic molecules that may provide a signature of increased longevity and healthspan. Their findings, published in the Journal of Proteome Research, reflect on the mechanisms behind ageing.
“As we live longer, there is a higher probability of age-related diseases, such as type 2 diabetes, osteoporosis, and cancer,” explains Dominic Withers (Metabolic Signalling Group) who led the study. “Understanding what underlies healthy lifespan is a challenge that could help us find new therapies to treat these diseases”.
Past research has shown that diets with reduced energy content can extend lifespan. Studies at the CSC and elsewhere have helped to identify precisely how the body adjusts to lower energy intake, uncovering potential physiological mechanisms that lead to longer life via dietary restriction. CSC researchers have also found that switching off certain genes can make animals live longer. But whether these two approaches to extend lifespan work in the same manner has yet to be established. “We were interested in defining metabolic signatures of increased lifespan in a broad spectrum approach. ” reveals Withers, “This led us to metabolic profiling using nuclear magnetic resonance (NMR). We examined the blood from three different long-lived mouse models and compared the metabolic profiles.”
Nuclear magnetic resonance is a technique used to detect and identify molecules that include hydrogen atoms. These give off signals, as unique as fingerprints, indicating the arrangement and identity of other atoms in the molecule. MRI (magnetic resonance imaging) avails of this effect to create images of the soft tissues in our bodies, which have different levels of one particular signal – that of the hydrogen atoms in water. But most molecules in our body have hydrogen atoms, and fortunately they have different NMR fingerprints. These chemical fingerprints allowed the researchers to identify key metabolites [metabolic molecules] in blood from two long-lived genetic mouse strains (Irs1 null and Ames mice) and mice undergoing dietary restriction, relative to control mice with normal longevity.
Certain metabolites were altered in the same way across the three long-lived groups, demonstrating that some specific metabolic processes underlying ageing are conserved. For example, the concentrations of specific lipids were reduced in all three models as were the metabolites choline and trimethylamine. However, certain metabolic signatures were found to be unique to each long-lived model, which is consistent with the multiple factors involved in ageing.
The research findings suggest that these distinct metabolic signatures could provide insights to the mechanisms underlying the ageing process and that metabolic profiling gives insights into the functional genotype of an organism, permitting repeated measures across its lifespan. Withers concludes that, “these metabolites could be used as biomarkers for longevity…and demonstrate that there is conservation in the metabolic processes underlying healthy lifespan.”
SJ
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NMR Metabotyping – How it works
Molecules that contain hydrogen atoms can be identified by NMR due to a consequence of quantum mechanics called spin, which makes their hydrogen nuclei susceptible to powerful magnetic fields. When a chemical sample is analysed by NMR, the nuclei line up with the field. Radio waves applied to the sample cause them to rotate, giving off a secondary radio signal that can be detected. The position of this signal is affected by electrons from other atoms in the same molecule moving around and creating their own, much smaller magnetic fields, interfering with the main magnetic field and causing a tiny ‘chemical shift’ to the normal hydrogen signal. Different atomic elements have different numbers of electrons – more electrons cause a greater shift. Other hydrogen atoms interfere and cause the signal to split up, and these two effects create a signal fingerprint that allows a picture of the molecule to be constructed. In MRI the main hydrogen-containing molecular target is water: like most life, we are awash with a sea of signals from this most familiar of fluids, and the image produced by an MRI effectively shows its varying concentration. So for their study of metabolic molecules, the CSC/Imperial team had to blank out the water signal, which would otherwise have swamped the signals they were looking for. |
Wijeyesekera, A., Selman, C., Barton, R. H. H., Holmes, E., Withers, D., Nicholson, J. K. K. (2012). Metabotyping of Long-Lived mice using 1H NMR spectroscopy. Journal of Proteome Research. Abstract
Photo by Kaushik Narasimhan (Flickr)
