Biological research now benefits from a multitude of high throughput and large-scale data gathering technologies, which together have created the current `omics' era. These tools and approaches are often used in isolation,but fields of research such as systems biology emerged to integrate all of this information. A recent study published in Molecular Systems Biology presents an impressive combination of these approaches, including genomics, metabolomics, metabolic flux modeling and whole-animal experiments;a rather daunting task! Laurence Coquin, Jacob Feala and their coworkers from the Burnham Institute and the Department of Bioengineering at the University of California San Diego used this approach to study aging in the fruit fly,focusing primarily on the effect of aging on the insect's ability to recover from hypoxic stress, a common problem in animals.
The study began by exposing two groups of flies, 3 day and 40 day old, to very low oxygen for several hours. The flies were knocked out by the severe hypoxia. The team looked at the insect's heart rate during recovery and the time it took the insects to recover and start moving again. Before, during and after the hypoxic exposure, the team measured the levels of ATP, glycogen,glucose and trehalose in the thoraxes of these flies. They also used a metabolomics approach, where they simultaneously measured the levels of 26 metabolites by proton NMR. Next, the team used available microarray data,which provides snapshots of gene expression patterns, and combined this information with a biochemical pathway database to produce a metabolic reconstruction of the thorax. Together these approaches allowed the team to pinpoint the metabolic differences between the young and old flies.
Scrutinising the metabolic results, Coquin and colleagues found that there were no differences between the young and old fruitflies during hypoxia. However, there were differences between the two age groups during their recoveries.
The young flies recovered much more quickly following a hypoxic stress. Young flies exposed to severe hypoxia for several hours recovered after approximately 30 min, while the old flies only start moving 4 h after hypoxia. Heart rate measurements during the recovery period also showed that young flies' hearts restarted beating during the first minute after oxygen was restored, while it took several minutes for the old flies' hearts to resume beating.
At the cellular level, the ATP concentration in the young flies' thoraxes was severalfold higher than in the old flies after recovery. The elderly flies' lower thorax ATP levels were also accompanied by lower levels of glycogen and trehalose, which are the main sources of fuel used to produce ATP. Monitoring the levels of anaerobic end-products generated as the flies switched to anaerobic metabolism during hypoxia, the team found that the two groups of flies accumulated anaerobic end-products to the same extent, but the old flies continued to accumulate one of the anaerobic end-products, acetate,during recovery. It was also clear from metabolic flux modelling that the old flies did not oxidise pyruvate, the main substrate used by mitochondria to produce ATP aerobically, as quickly as young flies. The pyruvate substrate was redirected towards the production of acetate, which is a much less efficient and anaerobic way to produce ATP.
The team showed that aging does not affect all aspects of cellular metabolism equally, with elderly flies taking longer to recover than youngsters. Metabolic flux models show that mitochondrial metabolism is impaired in elderly flies, making them rely more on anaerobic metabolism during recovery. The era of omics is an exciting time for integrative physiology, and we can now put these tools together and link changes in gene expression with their functional consequences on metabolic pathways.
