One of the side-effects of research into Parkinson's disease is that scientists are making more rapid progress in understanding the mechanisms of mitophagy than would otherwise be the case. Mitophagy is a set of quality control mechanisms that recycle mitochondria, the bacteria-like powerplants in our cells, and like the more general quality control mechanisms of autophagy it is important in aging and longevity. Boosted autophagy or mitophagy shows up in many of the genetic and metabolic alterations shown to extend life in laboratory animals, and has been shown to be required for some of them - no autophagy means no additional longevity.
This is all thought to be a matter of housekeeping: if cells and cellular components are more damaged or cluttered with waste products, then the life span of the organism is shorter as a result. If damage is reduced and more rapidly repaired when it does occur, life span lengthens. Mitochondrial damage in particular is thought to be connected to the pace of aging, by virtue of the fact that cells with damaged mitochondria can fall into malfunctioning states that export damaging reactive compounds to the surrounding tissues.
The focus on mitophagy in Parkinson's research has come about because some forms of Parkinson's are genetic in origin: the patients have a mutation in one of the proteins that form the machinery of mitophagy, making the process function less effectively. This translates to more damaged mitochondria, more cellular and mitochondrial dysfunction, and at the end of the day more dead dopamine-generating neurons. That last item, the loss of a specialized population of neurons, is the proximate cause of the symptoms of Parkinson's disease - but a range of low level biological process contribute to how exactly it happens.
I mention all of this because the research I wanted to point out today involves the protein called parkin: its association with Parkinson's disease was discovered prior to present theorizing on its involvement in mitophagy, hence the name. Researchers have now shown that more parkin means more mitophagy and longer-lived flies:
Scientists at UCLA have found a single gene that, when stimulated to be overexpressed, extends the healthy life span of fruit flies by more than 25 percent. The gene, called parkin, plays an important role in disposing of damaged proteins within a cell. Previous studies have suggested that protein build up within cells may play an important role in aging. In fruit flies, and potentially in humans, parkin "marks" damaged proteins and instructs the cell to dispose of them.
By stimulating parkin expression, thereby boosting the power of the "cellular garbage disposal," David Walker, lead author of the study, was able to keep a group of fruit flies alive much longer than normal. "In the control group, the flies are all dead by day 50. In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."
Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed.
Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored.
We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.
The theory at least is that the resulting life extension in flies is due to boosted mitophagy, and thus a greater pace of recycling of damaged mitochondria. The current understanding of the machinery involved is that parkin interacts with mitofusin to label mitochondria for destruction. Equally at this stage in the research, it might also turn out to be the case that a related but different process is adjusted by overexpressing parkin - there's still room for uncertainty, but time will tell one way or another.