Boosting Autophagy to Treat Atherosclerosis

Today, we decided that it was a good time to take a look at a new study that demonstrates that increasing autophagy is a good approach to slowing aging and could be the foundation for a variety of therapies to treat age-related diseases.

What is Autophagy?

Autophagy is an intracellular degradation system that delivers unwanted cell components to a cellular garbage disposal system known as the lysosome. The lysosome uses powerful enzymes that break down the unwanted material for recycling.

However, as we age, the lysosomes become clogged up with materials that are so fused together that not even the potent enzymes can destroy them. This causes the lysosomes to become dysfunctional, and eventually the cell dies.

This is a particular problem for long-lived cells with a very low rate of replacement, such as the heart, the back of the eyes, nerve cells, and other cells that rarely divide if at all. Ultimately, as more and more cells become dysfunctional over time due to lysosome dysfunction, tissue function becomes impaired and age-related disease sets in.

Macrophages and heart disease

Macrophages are responsible for cleaning up many kinds of cellular waste, including misfolded proteins, excess fat droplets, and dysfunctional organelles, and they are the housekeepers of the body. They protect our blood vessels from damage by the toxic byproducts of cholesterol, and they work by surrounding these toxic byproducts and breaking them down in their lysosomes into useful materials.

However, macrophages can become dysfunctional from the accumulation of lysosomal waste that they cannot break down. Over time, macrophages consume ever more amounts of toxic materials, and eventually their lysosomes become filled with insoluble waste that cannot be destroyed.

This causes the macrophages to eventually stop functioning and either become trapped and immobile in the artery wall or simply die. It is the buildup of trapped macrophages in the arterial wall that is the basis of arterial plaques, which lead to heart disease. Eventually, once the plaques grow too large, the injury swells and bursts, sending out clots that trigger strokes and heart attacks.

One of the potential ways to address this problem is by increasing autophagy in macrophages, which makes them better at dealing with the toxic waste and helps them to resist stress. It is the hope of some researchers to find ways to improve autophagy, thereby making macrophages more robust and slowing the accumulation of lysosomal waste, thus reducing the risk of heart disease.

Improving autophagy could help combat heart disease

A new study published in Nature Communications demonstrates that finding ways to make macrophages more efficient and more resistant to stress can help to slow the progression of atherosclerosis [1]. The approach also has the potential to treat other diseases, such as fatty liver disease and type 2 diabetes.

The research team found that a natural sugar known as trehalose boosts autophagy in macrophages, encouraging them to improve their housekeeping efforts. These enhanced macrophages are then better able to deal with the toxic materials and break down the atherosclerotic plaques that have built up inside arteries and cause heart disease.

In the study, the researchers showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured at the aortic root were variable, but on average, the plaque size measured 0.35 square millimeters in control mice versus 0.25 square millimeters in the mice given trehalose. This was approximately a 30 percent reduction of plaque size and is therefore statistically significant.

The effect was not observed when mice were given trehalose orally or when they were injected with other types of sugar, even ones that are structurally similar. The sugar is broken down by the digestive system when eaten, so its ability to trigger autophagy is destroyed as well.

So what is trehalose?

Trehalose is a naturally occurring sugar that consists of two glucose molecules bound together. It is approved by the Food and Drug Administration for human consumption and is commonly used as an ingredient in various pharmaceuticals.

Past work by many research groups has shown trehalose triggers autophagy [2-3]. However, exactly how it boosts autophagy has remained unknown until now. The study authors showed that trehalose activates a molecule called transcription factor EB or TFEB. TFEB is a master regulator of lysosomal biogenesis, the creation of lysosomes in the cell, as well as autophagy in mice and humans.

Once activated by trehalose, TFEB then goes into the nuclei of macrophages and binds to the DNA. When the molecule binds to the DNA, this causes various genes to be expressed, instructing the cell to create additional housekeeping components – in this case, more lysosomes to gobble up toxic waste.

So, interestingly, this process isn’t just enhancing the existing cellular machinery already in place: it actually triggers the cell to make new housekeeping machinery, boosting cellular autophagy.

The researchers are continuing to study trehalose and its potential as a therapy for heart diseases, particularly since it is safe for human consumption. The researchers are hoping to overcome the need for injections, potentially by blocking the digestive enzyme that breaks trehalose down when eaten. This would allow trehalose to retain its structure, and thus its ability to trigger autophagy, and would offer a convenient way to deliver the sugar to the macrophages.

Conclusion

It is important to note that this work is in preclinical testing and has some way to go before it could move into human phase 1 clinical trials. Certainly, if such a therapy can be translated to humans, and there is reason to be optimistic that it might, it may offer a potentially valuable approach to treating heart disease and other diseases caused by plaque accumulation, such as Alzheimer’s and Parkinson’s.

Another, more direct, approach might be to remove the toxic waste in the first place before it has a chance to accumulate to dangerous levels, and this is the approach that the SENS Research Foundation is taking with its LysoSENS program. Which of the two approaches will arrive first is anyone’s guess, but either would be a good step for treating heart disease and helping people to continue living healthy, independent, and long lives.

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Literature

[1] Sergin I, Evans TD, Zhang X, Bhattacharya S, Stokes CJ, Song E, Ali S, Dehestani B, Holloway KB, Micevych PS, Javaheri A, Crowley JR, Ballabio A, Schilling JD, Epelman S, Weihl CC, Diwan A, Fan D, Zayed MA, Razani B. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nature Communications. June 7, 2017.

[2] Sarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A., & Rubinsztein, D. C. (2007). Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. Journal of Biological Chemistry, 282(8), 5641-5652.

[3] Aguib, Y., Heiseke, A., Gilch, S., Riemer, C., Baier, M., Ertmer, A., & Schätzl, H. M. (2009). Autophagy induction by trehalose counter-acts cellular prion-infection. Autophagy, 5(3), 361-369.