A So Far Weak Approach to Stimulating Autophagy to Slow Aging

The research materials for today offer one example of numerous parallel efforts to find a mechanism and drug candidate that can stimulate autophagy and thereby modestly slow the progression of aging. It is too early to say whether this particular mechanism is worth chasing for that part of the drug development research and development industry that sees potential in slightly slowing aging, but the initial demonstration isn't impressive. It extends mean life span in flies by about 5%, which is small enough that no-one should be holding his or her breath expecting a clear and clean replication of the results. Certainty in manipulation of the pace of aging tends to require larger gains in order for clarity to emerge across numerous studies by different research groups. Results in short-lived species like flies are rarely within a 10% of life span distance of one another from study to study and research group to research group. Statistics and chance are cruel mistresses both. It is also good to remember that short-lived species have much more plastic life spans than long-lived species. Some of the changes that extend life in flies by 30% or so do also produce benefits to health in humans, but none have such an obvious effect on life span in our species.

Autophagy is a collection of cellular housekeeping mechanisms responsible for identifying, sequestering, and removing damaged structures and proteins. The damage is contained, broken down, and the parts recycled. The more of this that takes place, the more pristine the cell, and the less time that a damaged component has to cause further problems. Many of the methods of modestly extending life in short-lived species feature enhanced autophagy, and some actually require the correct operation of autophagy in order to slow aging. Given the importance of mitochondrial damage in aging, it is reasonable to think that a large part of this results from better quality control of mitochondria. Proving which aspect of autophagy is more or less important is ever a challenge, however, as is the case for any effort to isolate just one process in the dynamic chaos of cellular biochemistry in a living individual. Everything influences everything else.

For more than a decade now, researchers been earnestly looking for drugs that can enhance autophagy to a large enough degree to make deployment as a therapy worthwhile. Some technology demonstrations suggest that there are ways to enhance autophagy greatly, and restore youthful function in at least some types of aged tissues as a result. Genetic engineering to add extra lysosomal receptors springs to mind, given its restoration of liver function in old mice. Lysosomes are the destination for structures and molecules flagged for recycling, and play an important role in the process of autophagy. Drug candidates mined from the existing catalogs are vanishingly unlikely to achieve an outcome of this magnitude, however. Given that slowed aging produced by calorie restriction has been shown to depend on autophagy to a large degree, there is the hope in some quarters that autophagy enhancement may be a path to effective calorie restriction mimetic drugs. Again, modestly slowing aging is the goal in this research.

For my part I believe that most attempts to find methods of autophagy enhancement are not useful approaches to treating aging, especially the standard drug discovery efforts. The expected gains are too small, a mere slowing of aging, in comparison to the rejuvenation that might be achieved through the repair approach espoused in the SENS research initiative. Aging is damage: researchers should be aiming to repair that damage, not to slow down its accumulation. Autophagy just isn't comprehensive enough or effective enough for this job. The types of therapy needed to repair the root cause cell and tissue damage that produces degenerative aging are no more expensive or time-consuming to develop than therapies to slow aging, but have the potential to produce rejuvenation - a much better class of outcome, a treatment that can be repeated over and again to keep producing benefits for any one individual. Unfortunately, repair as a strategy and rejuvenation as a goal is still a minority concern within the research community. Taking over the mainstream continues to be a matter of bootstrapping support, funding, and results, one small advance at a time. There is progress, certainly, and much more so in recent years, but never fast enough for my liking. The mainstream of the research community has only comparatively recently adopted the idea that aging can and should be treated as a medical condition. Most are still very fixated on the approach of altering metabolism to slightly slow aging: more radical approaches are taking time to win adoption. Time is, of course, is running out of the bottom of the hourglass for all of us, day by day. Strategy in aging research is an urgent matter precisely because this is the case. We can't aim low.

Ethanolamine: A novel anti-aging agent

Phosphatidylethanolamine (PE) is a central intermediate of lipid metabolism and a major component of biological membranes. Within cellular membranes, PE not only serves as a structural phospholipid but also regulates the tethering of proteins and fusion processes. Importantly, PE is also directly involved in the process of macroautophagy (hereafter termed autophagy), a lysosome-dependent cellular recycling mechanism that protects cells against lethal stress and extends longevity in model organisms. During autophagy, double-membraned structures that are highly abundant in PE engulf superfluous, supernumerary, or dysfunctional macromolecules or organelles contained in the cytoplasm, forming vesicles (autophagosomes). These autophagosomes then fuse with lysosomes to generate autophagolysosomes in which the luminal cargo is degraded.

Given the widespread functions of PE as a precursor of several biosynthetic pathways, there is high demand for this metabolite. A common PE pool feeds into all major cellular PE-consuming pathways, thus resulting in competition for PE between pathways. As we have recently shown, this limitation can be overcome by genetic or pharmacological interventions. External administration of ethanolamine (Etn), a precursor of PE can increase the abundance of intracellular PE. Supporting a crucial regulatory role for PE in autophagy, we observed that both external supply of PE and an increase in its internal generation similarly increased autophagic flux. Importantly, pharmacological Etn treatment extended the lifespan of yeast and fruit flies, as well as cultured mammalian cells, underlining the potential of Etn as a potent autophagy and longevity drug.

Phosphatidylethanolamine positively regulates autophagy and longevity

Autophagy is regarded as one of the major cytoprotective mechanisms during ageing, and thus is a crucial process to counteract age-associated pathologies. Age-associated neurodegenerative disorders including Alzheimer's and Parkinson's disease may be postponed or attenuated by chronic induction of autophagy, and there is substantial evidence that genetic or pharmacological induction of autophagy can increase the healthspan and lifespan of multiple model organisms including yeast, worms, flies and mice. These findings have spurred the interest in identifying novel, non-toxic pharmacological inducers of autophagy. So far, several agents have been shown to induce autophagy and increase lifespan across several species, namely rapamycin, resveratrol and spermidine. The present results suggest that ethanolamine might be yet another potent autophagy inducer that promotes longevity.

Our study provides evidence that ethanolamine-mediated autophagy induction correlates with enhanced longevity in yeast and mammalian cell culture. This is in line with a previous study in yeast demonstrating that PE is a limiting factor for autophagy. Our results demonstrate that these observations are applicable to a wild-type scenario in yeast too and can be extended to mammalian cell cultures. Still, future experiments will need to clarify if ethanolamine-induced autophagy is beneficial to higher organisms. We could indeed observe a statistically significant increase in the mean lifespan of flies upon supplementation with ethanolamine, but whether this is because of autophagy must be tackled in the follow-up studies.