Drug Discovery in Search of Ways to Boost Autophagy

There is a wealth of evidence to show that benefits to health and longevity result from increased levels of autophagy in various species. Autophagy refers to processes of cellular housekeeping that remove damaged components, and which have been found to operate with greater enthusiasm as a result of a range of different interventions in laboratory animals that increase life span and slow the progression of aging. Indeed, some researchers believe that increased autophagy is an important contribution to all of these longevity-enhancing approaches.

Given this it is surprising to see so little effort going towards drug discovery with safely increased autophagy as the primary target. As is usually the case, where drug discovery is undertaken, efforts are first focused on repurposing existing drugs that are already approved, even if the effects are marginal. This is because it costs much less to try to obtain regulatory approval for a new use of an existing drug than to push through a completely new medical technology - one of the many ways in which medical regulation distorts the research process in the direction of deliberately aiming for inferior results and slower progress towards new knowledge.

Aging has been defined as a gradually decreasing ability to maintain homeostasis and increasing risk to die. Growing evidence supports malfunctioning with age of quality control system. At an older age, accumulation of altered macromolecules and membranes may impair cell functioning; accumulation of altered mitochondria and peroxisomes may boost the yield of ROS per unit of produced energy and accelerate the aging process.

Evidence was produced that autophagy, an essential part in cell housekeeping during fasting, may help removal of altered membranes, mitochondria and peroxisomes selectively and account for the antiaging effects of caloric restriction. Stimulation of autophagy may improve innate and adaptive immunity; decrease the risk of myopathy, heart disease, liver disease, neurodegeneration and cancer; and retard aging. Functioning of autophagy may decline in well fed adults and is almost negligible at older age. Induction of autophagy may result in "cleaner cells" lower in oxidative status and more resistant to injury and disease.

The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy in a physiologically appropriate manner, to enhance submaximal antiaging effects of low level of caloric restriction, to rapidly rescue older cells from the accumulation of altered mtDNA and older peroxisomes, to increase urinary 8-OHdG levels, and counteract the age-related hypercholesterolemia in rodents. In conclusion, benefits of long-lasting stimulation of autophagy and protein and organelle turnover shows that antilipolytic drugs might find a novel therapeutic application in antiaging medicine.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24958217

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