Reducing the activity of enzymes (or ‘downregulating’ them) in a metabolic pathway associated with aging can significantly extend lifespan in fruit flies, a study published December 15 in eLife demonstrates.
The findings suggest that the levels of enzymes in the tyrosine degradation pathway are increased (or ‘upregulated’) with age in the fruit fly Drosophila melanogaster, and that downregulating them can increase lifespan.
“Aging is the primary risk factor for major human diseases including cancer, diabetes, cardiovascular disorders and neurodegenerative diseases,” explains first author Andrey Parkhitko, who was a Postdoctoral Fellow at Harvard Medical School, Boston, US, when most of this study was carried out, and is now Assistant Professor of Medicine at the Aging Institute of the University of Pittsburgh and UPMC, US.
“Previous studies carried out in humans and other organisms have shown that aging is characterised by the extensive reprogramming of metabolic processes. This suggests that manipulating the metabolic pathways that change with age might suppress aging and extend lifespan, and we wanted to explore this idea further in fruit flies.”
To identify the metabolic pathways that are associated with lifespan and can be responsible for aging, Parkhitko and the team studied small molecules, called metabolites, in biological samples from fruit flies – an approach known as metabolomics. They searched for metabolic pathways that change differently with age between normal and long-lived flies.
The team found that, among the metabolites that change during aging, the levels of an amino acid called tyrosine are increased in long-lived flies. Additionally, they saw that the levels of enzymes in the tyrosine degradation pathway, which is responsible for the degradation or conversion of tyrosine, are decreased in long-lived flies and increase with age in normal flies.
The researchers also found that disrupting the function of mitochondria (the energy-producing components of cells) in young flies causes the same effect as aging and increases levels of enzymes in the tyrosine degradation pathway. When the team administered an FDA-approved drug called tigecycline to the flies with mitochondrial dysfunction, they found that it suppressed this upregulation.
“Altogether, our results highlight the tyrosine degradation pathway as a potential hub that links mitochondrial dysfunction, aging and the production of neurotransmitters, which allow for neuron-to-neuron communication, in fruit flies,” says senior author Norbert Perrimon, Professor of Genetics and Howard Hughes Medical Investigator at Harvard Medical School. “It will be interesting to test whether inhibiting the upregulated activity of the tyrosine degradation pathway using FDA-approved drugs can be translated to mammals and ultimately to humans to delay age-related diseases and extend health and lifespan.”
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