Removal of Lipofuscin Extends Life in Nematode Worms

Lipofuscin is a mix of many forms of persistent metabolic waste that accumulates with age in the lysosomes of long-lived cells, such as those of the central nervous system. This degrades the effectiveness of cellular recycling mechanisms, as they depend upon the delivery of materials to lysosomes, where they are broken down. A lysosome is a membrane packed with molecular tools to break down near everything a cell will encounter, but (a) it struggles with some compounds, and (b) becomes impaired in old tissues, and hence the existence of lipofuscin.

Targeted removal of lipofuscin is an important strategy in the rejuvenation toolkit. As of yet only partially effective approaches are available, unfortunately. Like the example here, these depend on adjusting metabolism in ways that provoke greater cellular housekeeping efforts, more efficient lysosomal function.

Plausibly, this will only work for some of the many different problem molecules that make up lipofuscin, those are are less resilient to being broken down, that only accumulate to cause pathology as a result of age-related declines in cellular maintenance. While we have the one impressive example of liver function rejuvenation as a result of improving lyosomal function with LAMP2A upregulation, in general the strategy of upregulating cellular maintenance doesn't work as well to extend life in long-lived species as it does in short-lived species. This is well demonstrated in the few examples we can compare directly, such as the practice of calorie restriction.

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly extended the lifespan of C. elegans compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms.

The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans.

In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.


Wouldn't it be great if someone looked at the things the ribosomes try to burh when deprived of sugar/ATP? My extremely fit 21yo son swears by the idea that his body turns to ketones, and I wonder if other things get caught up in cellular metabolism like a star that has burned all its hydrogen and turns to helium, then carbon, etc. Can't someone do advanced blood work on deeply fasting people and then compare the results to pre- and post cellular composition?

Posted by: Thomas Schaefer at May 17th, 2022 4:07 PM

Soraprazan in phase 11 clinical trial in Japan. Has been used for Stargardts disease in the eye - very useful. It is also extremely useful for gastic acid disease and likely to supercede the PPI's eg esomeprazole when licensed.
The rejuvenatory effects on large mammals will then be apparent.
Probably quite good.

Posted by: JLH at May 18th, 2022 2:22 AM

Actually, now in late phase111.

Posted by: JLH at May 18th, 2022 10:36 AM

If only the SENS RF or Methuselah Foundation for Forever Healthy Foundation could throw Underdog Therapeutics some cash to investigate using their cyclodextrans to remove some Lipofuscin components other than the oxidised cholesterol they are currently pursuing.

It would also be good if this could be done in Daphina with internal organs instead of nematode worms like C. elegans, as these may turn out to be better cheaper aging models.

Posted by: jimofoz at May 20th, 2022 10:07 AM
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