More Autophagy is Good, and More Resistant Macrophages Slow Atherosclerosis

This research neatly demonstrates two quite different points. Firstly, that increased autophagy in our cells is generally a good thing, and a good basis for a range of therapies. It makes cells more efficient and more resistant to stress. Secondly, that finding ways to make the immune cells known as macrophages more efficient and more resistant to stress helps to slow the progression of atherosclerosis. Macrophages are responsible for cleaning up the oxidized lipids and fatty garbage that form the atherosclerotic plaques that disrupt blood vessel structure. Unfortunately these cells are easily overwhelmed, and much of the mass of these plaques in fact consists of the debris from dead macrophages by the time the disease reaches its dangerous later stages, in which major blood vessels are vulnerable to rupture. There are other studies to show that any method of making macrophages tougher and more resilient helps. That said, I think that the best class of approach to this challenge is to find ways to break down and remove at least the most challenging of the lipids, rather than trying to engineer a better class of macrophage. The former should be easier than the latter.

Studying mice, researchers have shown that a natural sugar called trehalose revs up the immune system's cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack. "We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage - making them super-macrophages."

Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins and excess fat droplets. "In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques. Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up - dying cells, more lipids. The plaque grows and grows."

The showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study. The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.

Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown. In this study, researchers show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery - more of the organelles that function as garbage collectors and incinerators. "Trehalose is not just enhancing the housekeeping machinery that's already there. It's triggering the cell to make new machinery. This results in more autophagy - the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can't say that for sure - we're still testing that. But is it a predominant process? Yes."



Anybody got a simple method to avoid injection with this stuff? Under the tongue, maybe? Or is there a part of the digestive tract that lacks this enzyme that breaks down trehalose?

Posted by: chriszell at June 7th, 2017 11:38 AM

Consider interaction isnt just enhancing autophagy but causing the cell to create more lysosomes I think this is a very interesting line of research. Sure if LysoSENS arrives first it could be better but I will take whatever gets here first. I would also suggest that BOTH is a good idea, removing the waste and also boosting autophagy in macrophages to reduce the frequency or need of repeat therapy.

Posted by: Steve Hill at June 8th, 2017 8:10 AM

Eat sunflower seeds. There is evidence that part of trehalose enters the body.
Pagliassotti et al., have examined the unfolded protein response (UPR) and inflammatory signaling in the liver of young (~6 months) and old (~28 months) mice (n=8/group), and the ability of trehalose, a compound linked to increased protein stability and autophagy, to counteract age-induced effects on these systems. When used, trehalose was provided for 4 weeks in the DRINKING WATER (!) immediately prior to sacrifice (n=7/group). Livers from old mice were characterized by activation of the UPR, increased inflammatory signaling and indices of liver injury. Trehalose treatment reduced the activation of the UPR and inflammatory signaling, and reduced liver injury. Reductions in proteins involved in autophagy and proteasome activity observed in old mice were restored following trehalose treatment. The autophagy marker, LC3B-II, was increased in old mice treated with trehalose. Metabolomics analyses demonstrated that reductions in hexosamine biosynthetic pathway metabolites and nicotinamide in old mice were restored following trehalose treatment. Trehalose appears to be an effective intervention to reduce age-associated liver injury and mitigate the need for activation of quality control systems that respond to disruption of proteostasis. So, sunflower seeds will be useful !!!

Posted by: Dmitry Dzhagarov at June 9th, 2017 1:50 PM

Dmitry, as the press release that Reason posted indicates, the study showed that much larger doses of oral trehalose (3% w/v in drinking water) barely nudged serum trehalose levels and had no effect on atherosclerosis (and thus presumably no effect on macrophage autophagy) - see especially their Figure 9, (i) and (j). Perhaps, per your study, dietary trehalose gets into the liver, but since only a small fraction of even large doses in water ever gets into the serum and have no effect on macrophages/foam cells, one is certainly not going to get any benefit on the same outcome from the trace amounts of trehalose present in sunflower seeds.

Posted by: Michael at June 9th, 2017 5:02 PM

"When ingested, trehalose is not assimilated as a disaccharide into the blood stream. Rather, it is enzymatically hydrolyzed in the small intestine by a trehalose-specific disaccharidase into two d-glucose molecules, which are subsequently absorbed and metabolized. The same physiological processes are used to digest other common disaccharides like maltose, sucrose and lactose (Dahlqvist, 1974)."
-Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies

Posted by: Michael at June 9th, 2017 5:11 PM

Back to the original question - how to bypass trehalose being broken down. How about by enema?

Posted by: Chris Zell at June 9th, 2017 9:41 PM

Won't work: sugars (even straight glucose) aren't absorbed in the colon. You get some unusual food for your gut microbiome, and (I'm guessing) a lot of flatulence ;) .

Posted by: Michael at June 9th, 2017 10:37 PM

OK, how about enteric capsules? I understand that there is a lack of trehalase in the small intestine.

Posted by: Chris Zell at June 10th, 2017 12:39 PM

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