Fight Aging!

The consensus in the scientific community is that useful therapies can be built on the safe enhancement of autophagy. This has been the case for many years now, but unfortunately, and despite a broad and ongoing range of research initiatives, there has yet to be any significant progress on the path from laboratory to clinic in this part of the field. Even simple, easily explained adjustments to the operation of metabolism turn out to be involved and costly projects. They take a long time to come to fruition, and when considered individually have poor odds of success. Look no further than the past two decades spent in search of calorie restriction mimetic drugs for proof of that point: for all the enormous sums spent and years of work this is still a field of candidate therapies characterized by marginal results, mixed evidence, and side-effects that would in any case make them impractical for widespread use. If you want to enhance the operation of autophagy, the actual practice of calorie restriction remains the only viable, reliable option at this time, and that falls far short of the level of enhancement that might be both possible and optimal when considering the bigger picture.

Why is more autophagy a good thing? Autophagy is a collection of processes responsible for recycling of damaged cellular structures and macromolecules, as well as removing some forms of unwanted metabolic waste. Damaged machinery inside the cell produces more damage the longer it is left intact; having less damaged and more functional cells at any given time throughout the body adds up over time. Many of the interventions demonstrated to slow aging in laboratory animals feature enhanced autophagy among the changes they produce in the operation of metabolism. In at least one case, that of calorie restriction, autophagy has been shown to be necessary for the health and longevity benefits observed in normal animals to take place. There is a great deal of evidence, both direct and indirect, for autophagy to one of the more important determinants of the natural pace of aging.

Given the prominent role of metabolic waste, such as amyloid aggregates, in age-related neurodegenerative conditions, it is understandable that a sizable fraction of research into autophagy is carried in the context of cellular dysfunction in neurodegeneration. Autophagy is known to decline with age, in part a consequence of the presence of hardy metabolic waste that cannot easily be broken down, and that clogs the system, reducing its effectiveness. Researchers are searching for ways to restore autophagy to youthful levels, mostly aiming for the alteration of regulatory processes or related mechanisms in order to increase autophagic activity without addressing the reasons for its decline. In fairness, this has been proven quite effective in some animal studies, but I'd still favor the approach of addressing the root causes first of all, then move on to enhancement. In this context, the open access paper here is a fairly standard overview of present thinking in the research community when it comes to autophagy and the treatment of neurodegenerative disease. That more or less amounts to more of the same work from the last twenty years, so I'd say don't hold your breath expecting stunning results any time soon on this front.

Therapeutic implication of autophagy in neurodegenerative diseases

Autophagy, a catabolic process to maintain intracellular homeostasis, has been recently focus in numerous human disease conditions, such as aging, cancer, development, immunity, longevity, and neurodegeneration. However, sustaining autophagy is essential for cell survival and dysregulation of autophagy is anticipated to speed up neurodegeneration progression; although, the actual molecular mechanism is not yet fully understood. In contrast, emerging evidence suggests that basal autophagy is necessary for removal of misfolded aggregation proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid β peptide and α-synuclein protein aggregation in Alzheimer disease and Parkinson disease, respectively. Even though autophagy could impact several facets of human biology and disease, however it functions as a clearance for toxic protein in the brain contributes us novel insight into the pathophysiological understanding of neurodegenerative disorder. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimulates autophagy which is essential in clearance amyloid-β (Aβ) and α-synuclein deposits.

As a therapeutic purpose, it has been indicated that upregulation of autophagy through mTOR complex 1-mediated pathway might be targeted to removal of aggregate protein molecules and decrease cytotoxicity in animal models. However, tauopathies, α-synucleinopathies, and other models has been implicated to treat neurodegenerative disease through this strategy. In particular, mTOR-independent autophagy inducers rapamycin analogs such as rilmenidine and trehalose drugs has been used in these diseases. On the other hand, autophagy inhibitor increases the toxicity of these protein that leads to enhance of the relevant protein during neurodegeneration. It is also mention that rapamycin and its chemically synthesized analogues such as CCI-779 are widely used potential activator of autophagy in yeast and mammalian cells in neurons as well as in vivo in mouse brain. Eventually, widespread preclinical animal model studies are required to induce autophagy in neurodegenerative disease.

Furthermore, statins, a class of lipid-lowering medications, induces autophagy in astrocytes through AMPK-mTOR mediated pathway and it has been suggested that autophagy is essential in insulin-degrading enzyme secretion, thus modulation of autophagy could provide a possible therapeutic approach in Aβ pathology by increasing clearance of extracellular Aβ. Hence, accumulation of Aβ peptide participates to the pathological condition of AD, while inhibiting Aβ production or increasing Aβ removal may be implicated in slowing the improvement of AD. In particular, the promotion of Aβ clearance is currently considered to be an additional therapeutic approach for AD. Thereby, autophagy has been found to be an important role in the clearance of Aβ under physiological conditions, for that reason it is essential to maintain Aβ homeostasis in the healthy brain. Most importantly, our current research is considerable effort directed to identify safe and more effective pharmacological inducers of autophagy in neurodegenerative diseases. Therefore, enhancement of autophagy might represent a sustainable strategy to Aβ clearance.

Even though a variety of autophagy-related proteins participate and control in autophagy pathway, several studies have been performed to explore autophagy regulation through the active ingredients of plants. Although numerous fundamental queries are essential to be further addressed before many novel agents could be useful in a clinical approaches, thus the research of interest in autophagy is developing rapidly and clinically applicable might be anticipated as soon as possible. Furthermore, it is very important to characterize dysfunctional autophagy in diverse stages of genetic and molecular subtypes in neurodegeneration. It is also necessary to study the active clinical translation of downstream autophagy regulation which proposes an exciting new era for the development of therapeutic strategies. Consequently, additional studies are required on physiological roles of modulation of brain autophagy process in neurodegenerative diseases. Finally, we would like to screen new natural compounds that modulate autophagy and identify main targets key molecular mechanisms underlying pathophysiological roles of neurodegeneration with concern for potential therapeutic drugs target.