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Researchers at Brown University have discovered a way to stimulate cellular autophagy, which is a natural recycling system built into every cell in the body. This has the potential to combat many age-related neurodegenerative diseases.

What is autophagy?

Autophagy means “eating of self” (from Ancient Greek “auto” = self, “phagein” = to devour). Autophagy is how cells break down broken or dysfunctional organelles and proteins in the cell [1,2]. This essentially means that autophagy can consume organelles, such as mitochondria, peroxisomes, and the endoplasmic reticulum, as part of this process. There is also evidence to support that high levels of autophagy are linked to longevity.

The autophagy process involves collecting up the misfolded proteins and useless organelles within a cell into vesicles called autophagosomes. These autophagosomes then fuse with a lysosome, an enzyme-containing organelle that digests the unwanted garbage and recycles it into components that the cell can re-use.

Enhancing autophagy

The researchers published a study in Cell showing that their approach was able to increase the lifespan of worms and flies, and tests on human cells also suggest that this approach might potentially be used to treat age-related neurodegenerative diseases in humans [3].

During a number of age-related neurodegenerative diseases, we observe the loss of autophagy and the cell’s ability to recycle worn-out parts. Some researchers, including this team, believe that triggering autophagy via targeted drugs could be a solution to combating these diseases.

The researchers investigated boosting autophagy levels by targeting transcription factor EB (TFEB), which is responsible for regulating autophagy. For the transcription factor to activate autophagy, it needs to be localized in the cell nucleus, so the team searched for genes that increased the production of TFEB in the nuclei.

Testing on nematode worms, the team discovered that expression of the protein XP01, a protein that transports other proteins out of the nucleus, increases the TFEB in the nucleus as well as autophagic activity. The researchers also noted that the worms’ lifespan was significantly increased, leading to a 15-45 percent rise. To do this, they actually prevented the XP01 protein from leaving the nucleus by using a gene-inhibiting technique, which resulted in more autophagy and lifespan.

The next step was to see if they could identify a drug that was able to do the same as the gene-inhibiting achieved. They screened a drug library for the right compound and found that selective inhibitors of nuclear export (SINE), a class of compounds originally developed for cancer treatment, were able to do this. When they tested SINE on the worms, they found similar increases of autophagy and lifespan.

The research team then tested SINE on a fruit fly model of ALS, finding a significant increase in the lifespans of the flies. The researchers suggest that SINE was able to alleviate some of the neurodegeneration normally seen in these flies.

Finally, the researchers tested SINE on human HeLa cells, an immortalized cell line; the observed result was, again, increased levels of TFEB in the nuclei and higher levels of autophagy. This confirms that the regulation of TFEB is conserved from nematodes to humans and that SINE could be used to enhance autophagy in humans.

Conclusion

SINE has recently been shown to be well-tolerated in clinical trials for cancer, so the potential is there for treating other age-related diseases that could also benefit from increased autophagy.

Literature

[1] Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of Pathology, 221(1), 3-12. doi:10.1002/path.2697

[2] Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011). Autophagy and Aging. Cell,146(5), 682-695.

[3] Silvestrini, M. J., Johnson, J. R., Kumar, A. V., Thakurta, T. G., Blais, K., Neill, Z. A., … & Lapierre, L. R. (2018). Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. Cell Reports, 23(7), 1915-1921.

About the author

Steve Hill

As a scientific writer and a devoted advocate of healthy longevity and the technologies to promote them, Steve has provided the community with hundreds of educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).
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