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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.

CategoryNews, Research
About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. June 8, 2017

    Hmmm, trehalose is also the sugar of choice in case of desiccation-tolerant organisms. For example, the Tardigrades have the right enzyme (trahalase) to convert glucose into trehalose when their environment gets dry and as you probably know, these are some of the most extreme of the extremophiles :)

  2. January 26, 2019

    Disclaimer: I am not a scientist. Just fascinated by autophagy…I just used autophagy to get rid of my osteoarthritis pain. I’m 50 years old and found myself asking my friends, am I supposed to feel so old and achy at 50? Is this normal? My fasting regimen is fast for 3-4 days per week. Water only. After just 5 weeks, my old achy bones are young again!! Autophagy rocks! Wondering if it’s fixing my atherosclerosis…2-30%blocked arteries right now. Had a heart event and stent placed in 2013.

    • April 23, 2019

      The true power of autophagy doesn’t really start happening until about 3.5 days or more (at least for me). So the longer you fast, the more effective the autophagy actually becomes.

      You can track it with a blood glucose meter. When my BG hits about 65mg/dl, then I know I’m there (about 3.5 to 4 days without any food). So another 3+ days of fasting shows real and immediate results.

      This will not only reverse bad things like arteriosclerosis, but it is even cancer preventative. I got rid of a lipoma (fat tumor) on my elbow that I’d had for over a decade. After a week it strunk. After another 2 week fast a month later, it disappeared completely.

      BTW, it is much easier to fast if you follow a ketogenic diet, because you’re metabolism is already converted to eating fat instead of glucose as its main fuel.

      Be sure to be taking magnesium (citrate) and potassium chloride (mix it with regular salt) when doing long fasts or keto, to keep your muscles and even your heart from cramping up on you. Nu-Salt or No-salt are mostly potassium chloride. Otherwise you can inadvertently hurt yourself on long fasts, as severe lack of potassium and/or magnesium can lead to heart arrhythmias or worse.

      You’ll also want to take 50 mg a day of zinc sulfate if fasting or doing keto, to keep your hair from turning gray/falling out. Zinc sulfate does not have a protein molecule like other zinc supplements, so it won’t interfere with fasting.

      • October 9, 2019

        John… I have Cad. 5 stents. I had cardiac event two days ago . Cath reveals 3 spots . Stents would not work. They recommend bypass surgery. I’ve lost 100 lbs on loose low carb keto. I backsled a little on the carbs gained about 8 back during last 5 months. I’m scared of open heart surgery. Do you believe 3-5 day fast for a month could open up my blocked arteries?

  3. April 23, 2019

    If you want true accelerated autophagy, don’t eat for a week or more.

    This is of course easier to do when following a ketogenic diet, as your metabolism is already converted to running on ketones.

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