How Lipofuscin Disrupts Autophagy in the Retina

One of the contributing causes of aging is the accumulation of metabolic waste products that are hard or impossible for our biochemistry to break down. Cells undertake numerous forms of housekeeping, one of which is autophagy: in this process, unwanted or damaged proteins and cellular components are tagged and shuttled to the nearest lysosome where they are broken down for recycling. Waste products that cannot be broken down remain in the lysosome, however, to form a mix of various compounds known as liposfusin. Over time the lysosomes in long-lived cells of the nervous system, such as those of the retina, become bloated and dysfunctional, and the cells begin to malfunction and die as a result.

The SENS rejuvenation research approach to this part of the aging process is the find ways to safely break down lipofuscin constituents, with a starting point of mining the natural world of bacteria to find those capable of consuming lipofuscin. It is well understood in the research community that lipofuscin accumulation is a cause of age-related retinal degeneration and consequent blindness, and so SENS researchers are far from the only people looking for ways to get rid of lipofuscin or blunt its effects. This paper looks into mechanisms involved in the disruption of autophagy caused by lipofusin and suggests one potential form of amelioration:

Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy.

We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health.



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