[ExI] Autophagy and Aging

[Stuart LaForge]

Rafal Smigrodzki wrote:

[snip]
> Regarding the role of autophagy - this is indeed a crucial  
> maintenance process which becomes suppressed by the continuous ad  
> lib feeding typical of modern lifestyles. Humans have not evolved  
> under conditions of continuous food availability and our metabolism  
> is not adapted to it.

Agreed. Many paleo diet practitioners put too much emphasis on eating  
what early humans ate, completely ignoring the timing of how often  
they ate it.

> However, I doubt that recycling of proteins is really what matters  
> in autophagy - my guess is that the real mechanism responsible for  
> aging retardation by fasting is actually mitophagy, or the disposal  
> of mitochondria. This process selectively removes metabolically  
> defective mitochondria and their mutated genomes that are  
> responsible for metabolic defects, thus slowing down the long-term  
> accumulation of mitochondrial mutations, which is one of the key  
> mediators of aging.

Well in the cases of age-related diseases like Alzheimer's, where  
damaged proteins (beta-amyloid plaques) are implicated, the benefit of  
protein recycling is pretty cut and dry. But the selective removal of  
defective mitochodria is certainly no less important and could very  
well be the primary anti-aging mechanism.

Fasting and autophagy have many complex downstream effects including  
cross-talk with apoptotic signalling pathways involved in tumor  
supression. Mitochondria and mitophagy might very well be one of the  
mediators of that cross-talk between the autophagic and apoptotic  
pathways.

https://www.nature.com/articles/nrm3735

Relevant portion:
"Autophagy increases the threshold of stress required for the  
induction of cell death by several mechanisms. These include the  
selective removal of damaged, potentially apoptosis-inducing  
mitochondria or that of other potentially lethal organelles, such as  
damaged zymogen granules in the exocrine pancreas. Autophagy can also  
lead to the selective elimination of pro-apoptotic signal transducers."

That passage suggests that autophagy is an attempt to directly prolong  
the life of individual cells by removing and replacing damaged  
components including mitochondria.

Stuart LaForge