Improving Lysosomal Function is a Good Thing

Lysosomes are recycling units inside cells responsible for breaking down damaged cellular components and unwanted proteins. Lysosomal function declines with age in important long-lived cells, such as those of the nervous system, as they accumulate metabolic waste products that they are unequipped by evolution to destroy. They become bloated and inefficient, and as a consequence garbage piles up in their cells harming the surrounding tissues. This is seen in diseases such as macular degeneration, in which cells of the retina are overwhelmed by certain types of metabolic waste.

The SENS rejuvenation research approach to this aspect of aging is to find ways to safely break down these waste products, thus rescuing the lysosomes. Other researchers have in past years demonstrated that there are benefits to be had from enhancing lysosomal function to at least partially compensate for the consequences of waste buildup. This paper is another in line with this latter approach:

Healthful cell maintenance requires the efficient degradative processing and removal of waste material. Retinal pigmented epithelial (RPE) cells have the onerous task of degrading both internal cellular debris generated through autophagy as well as phagocytosed photoreceptor outer segments. We propose that the inadequate processing material with the resulting accumulation of cellular waste contributes to the downstream pathologies characterized as age-related macular degeneration (AMD).

The lysosomal enzymes responsible for clearance function optimally over a narrow range of acidic pH values; elevation of lysosomal pH by compounds like chloroquine or A2E can impair degradative enzyme activity and lead to a lipofuscin-like autofluorescence. Restoring acidity to the lysosomes of RPE cells can enhance activity of multiple degradative enzymes and is therefore a logical target in early AMD.

We have identified several approaches to reacidify lysosomes of compromised RPE cells; stimulation of beta-adrenergic, A2A adenosine and D5 dopamine receptors each lowers lysosomal pH and improves degradation of outer segments. Activation of the CFTR chloride channel also reacidifies lysosomes and increases degradation. These approaches also restore the lysosomal pH of RPE cells from aged ABCA4−/− mice with chronically high levels of A2E, suggesting that functional signaling pathways to reacidify lysosomes are retained in aged cells like those in patients with AMD. Acidic nanoparticles transported to RPE lysosomes also lower pH and improve degradation of outer segments. In summary, the ability of diverse approaches to lower lysosomal pH and enhance outer segment degradation support the proposal that lysosomal acidification can prevent the accumulation of lipofuscin-like material in RPE cells.



My reading of this is that adjusting the pH in this fashion is for the most part a symptom fix: it may allow the lysosome to continue removing things for a while, but eventually the presence of indestructibles that lower the pH will dominate. The tradeoff would be a few years of better functioning for a dramatically swifter decline afterward.

Enzyme changes capable of actually breaking down things like A2E will likely be needed in the long run.

Posted by: Dennis Towne at July 6th, 2014 1:37 PM

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