There are a great many ways to influence cellular metabolism to modestly slow the pace of aging, but few of them are of lll that much interest from a practical point of view, as a basis for therapies that might meaningfully extend human life spans. If an approach involves improvements in mitochondrial function and less than a 10% increase in life span in a short-lived species such as flies, as is the case here, then it is only of academic interest to scientists who closely study the intersection between metabolism and degenerative aging. Improvements in life span in short-lived species achieved in this manner, via changes in mitochondrial function, scale down dramatically when the same approach is tried in longer-lived species. Thus this method of slowing aging is unlikely to be any better for human health than the well-described outcomes of eating somewhat less or exercising somewhat more.
One approach to identify new traits responsible for aging is to compare how these traits change with age in control and long-lived animals of the same species. For example, centenarians have a distinctive epigenetic profile compared to an age-matched control population. Similarly, we previously showed that flies with increased longevity have dramatic differences in many metabolites associated with methionine metabolism even at 1 week of age when 100% of both control- and long-lived flies are still alive.
To identify novel metabolic pathways that correlate with lifespan and that can be responsible for aging, we compared the metabolome of 1-week- and 4-week-old wild-type and long-lived flies to identify changes in metabolites that correlate with lifespan and identified tyrosine as an age-dependent metabolite. We demonstrate that Drosophila has a single tyrosine aminotransferase (TAT). Whole-body or neuronal-specific downregulation of TAT as well as other downstream enzymes in the tyrosine degradation pathway significantly extend Drosophila lifespan, cause alterations of multiple metabolites associated with increased lifespan, and lead to an increase in tyrosine and tyrosine-derived neuromediators (dopamine, octopamine, and tyramine). We further demonstrate that mitochondrial dysfunction may serve as an age-dependent stimulus that redirects tyrosine from neuromediator production into mitochondrial metabolism.
In conclusion, our studies highlight the important role of the tyrosine degradation pathway and position TAT as a link between neuromediator production, dysfunctional mitochondria, and aging.