How Far Can Boosted Autophagy Take Us?

Mitochondria in your cells damage themselves in the course of their vital, life-sustaining operations, and these damaged mitochondria contribute to aging. It's a progressive and complicated process of many steps, by which incidents of atomic-scale damage in the power plants of your cells steadily overwhelm evolved countermeasures and repair systems, corrupting a fraction of your cells and blossoming into a flow of damaged molecules throughout the body. That in turn produces the roots of atherosclerosis and many other age-related forms of degeneration and malfunction.

We would like to be able to do something about this - by hook or by crook restore the damage state of an old person's mitochondria to the way things were when he was young. There are many possible paths forward, most understood in some detail at this time, and which will either be be shown to fail or succeed within the next decade or two. The work proceeds, but very, very slowly. It's not a broad and well populated field of research, sad to say.

The importance of mitochondria is one of the reasons that autophagy is also important when it comes to the progression of aging. Autophagy is the name given to a collection of varied recycling machinery and processes that operate within cells, destroying damaged components - such as mitochondria. It shouldn't be a great leap to think that improving the recycling mechanisms might also improve the situation vis a vis malfunctioning mitochondria. This is probably the case, based on what researchers know of mitophagy, the processes of autophagy concerned with removing damaging mitochondria.

Insofar as the bottom line of health and longevity goes, there is plenty of evidence to suggest that dialing up autophagy extends life, and a further array of evidence to suggest that known life-extending techniques such as calorie restriction depend heavily on autophagy as a principle mechanism of action.

Based on what's coming out of the labs in recent years, I think the research community isn't too far away from conducting studies that will definitively show - or definitively disprove, which would be unexpected - benefits to longevity from improved mitoautophagy alone. Take this, for example:

[Researchers] have defined a specific protein complex that allows cells to rid themselves of damaged mitochondria, which are the energy producing machines of the cell. ... The study highlights the interaction between Hsp90-Cdc37 and Ulk1, a kinase that the authors show is required for the degradation and elimination of damaged mitochondria. Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn phosphorylates its substrate Atg13, which is then released from the complex. Atg13 then eliminates damaged mitochondria via the autophagy pathway. Thus, the study links Hsp90-Cdc37-Ulk1-Atg13 in a direct pathway that is essential for efficient mitochondrial clearance.

"The new study shows that the key regulatory mechanism of this process is the Hsp90-Cdc37 chaperone, which functions as an on-off switch that is critical for the correct functioning of the Ulk1 kinase," Cleveland said. "Thus, if we can control this switch, we can significantly improve the therapeutic window."

Meaning this is a target for designed drug compounds to boost autophagy specifically aimed at clearing out more of the damaged mitochondria than would otherwise be the case. How far would this get us? A good guess would be in the same ballpark as calorie restriction mimetics: it's a similar mechanism. So in other words this may do good things for health in humans, but don't expect spectacular results when it comes to life span.

The problem with attacking mitochondria by boosting autophagy is that we already know that certain forms of mitochondrial damage manage to elude autophagic processes: that's how we end up in the bad place. So boosting autophagy just slows things down, and does't solve the underlying problem. A different type of approach is needed for a real solution, one based on repair rather than slowing existing processes of damage - and as it happens making progress along the paths towards mitochondrial repair shouldn't be any harder than safely and effectively adjusting the processes of autophagy.


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