Autophagy is the name given to a collection of cellular housekeeping processes that recycle damaged and unwanted proteins and structures inside a cell. Most of the means of slowing aging demonstrated in laboratory species involve increased autophagy: it is an important response to any form of stress likely to result in more damage inside the cells. The less damage there is, the better off the cells. This in turn can leads to a longer, healthier life span to some degree. It is also worthy of note that autophagy declines with age, and this is though important in a range of age-related conditions.
Autophagy enhancement therapies have been on the research community agenda for a long time now. There have been scores of papers published on this topic in the last decade alone, even putting to one side the point that all calorie restriction mimetic development is likely based on increased levels of autophagy somewhere under the hood. Unfortunately, means of directly enhancing autophagy have not as yet made it out of the lab; there has been very little progress towards the clinic. This is worth bearing in mind when reading publicity materials of the sort presented here. It is little different in tone from similar items published many years ago, and which subsequently went nowhere.
The process of autophagy involves the rounding up of misfolded proteins and obsolete organelles within a cell into vesicles called autophagosomes. The autophagosomes then fuse with a lysosome, an enzyme-containing organelle that breaks down those cellular macromolecules and converts it into components the cell can re-use. Researchers wanted to see if they could increase autophagy by manipulating a transcription factor (a protein that turns gene expression on and off) that regulates autophagic activity. In order for the transcription factor to switch autophagic activity on, it needs to be localized in the nucleus of a cell. So the team screened for genes that enhance the level of the autophagy transcription factor, known as TFEB, within nuclei.
Using the nematode C. elegans, the screen found that reducing the expression of a protein called XPO1, which transports proteins out of the nucleus, leads to nuclear accumulation of the nematode version of TFEB. That accumulation was associated with an increase in markers of autophagy, including increased autophagosome, autolysosomes as well as increased lysosome biogenesis. There was also a marked increase in lifespan among the treated nematodes of between about 15 and 45 percent.
The next step was to see if there were drugs that could mimic the effect of the gene inhibition used in the screening experiment. The researchers found that selective inhibitors of nuclear export (SINE), originally developed to inhibit XPO1 to treat cancers, had a similar effect - increasing markers of autophagy and significantly increasing lifespan in nematodes. The researchers then tested SINE on a genetically modified fruit fly that serves as a model organism for the neurodegenerative disease ALS. Those experiments showed a small but significant increase in the lifespans of the treated flies.
As a final step, the researchers set out to see if XPO1 inhibition had similar effects on autophagy in human cells as it had in the nematodes. After treating a culture of human HeLa cells with SINE, the researchers found that, indeed, TFEB concentrations in nuclei increased, as did markers of autophagic activity and lysosomal biogenesis. "Our study tells us that the regulation of the intracellular partitioning of TFEB is conserved from nematodes to humans and that SINE could stimulate autophagy in humans. SINE have been recently shown in clinical trials for cancer to be tolerated, so the potential for using SINE to treat other age-related diseases is there."