Linking Impaired Autophagy to Changes in Polarization of Microglia in Aging

The polarization of the immune cells known as macrophages and microglia is a topic of growing interest in the study of aging and age-related disease. A perhaps overly simplistic summary is that polarization describes the state and preferred activities of a macrophage or microglial cell, changing in response to signals and environment. The states of greatest interest are M1, inflammatory and aggressive in pursuit of pathogens, versus M2, a helper in tissue maintenance and regeneration. Both polarizations are necessary in the grand scheme of things, but in older individuals and in tissues affected by age-related disease, a an excess of M1 macrophages or microglia is a common theme. The result is a diminished capacity for regeneration and necessary processes of maintenance.

Too great a number of M1 polarized cells ties in to the chronic inflammation of aging, as inflammatory signals provoke macrophages into this polarization. In this context, researchers are investigating a range of possible strategies to override polarization, forcing immune cells back into the M2 state. Another aspect of this issue is added here in an open access paper linking the quality of autophagy to polarization. Autophagy is the name given to a collection of cell maintenance processes responsible for breaking down and recycling damaged structures and proteins. That it would be linked to immune cell polarization is most interesting, as autophagic activity is known to decline with age. Increased autophagy is associated with increased longevity in a variety of interventions examined in laboratory species, such as calorie restriction. It remains to be seen how strong this relationship is in comparison to the relationship with inflammation, but it seems that they influence one another, and are not independent.

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker expression and reduction of M2 marker expression were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α.

Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated with Atg5 knockdown in cells, but alleviated given microglia pretreatment with rapamycin, suggesting that activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

Link: https://doi.org/10.3389/fnagi.2018.00378

Comments

I think magnesium deficiency is at least one of the problems here. Magnesium deficiency is rampant in the elderly and many other middle-aged people. Magnesium is a CR mimectic and should be supplemented in those who need it.

Posted by: Biotechy Marcks at December 12th, 2018 9:48 AM

What is "CR" in "CR mimectic"?

Posted by: Tom Schaefer at December 12th, 2018 10:54 AM

@Tom Schaefer: calorie restriction.

Posted by: Reason at December 12th, 2018 11:15 AM

The first paragraph already makes one realise how complicated the relationship between the cells is, and even harder to keep that relationship balanced in the right way.
The excess of those cells is obviously bad on the one hand, but too few is also bad. Dealing with this will be a clever balancing act.
It is clear that when one tries to engineer the right balance and keep control over the situation, there is always a high risk that the balance is lost anyway. But the good news is that you will see that coming and you shoukd have enough time to find a solution. And this high risk is the case with modern technology, which will continue to evolve and become better adapted to dealing with these sort of problems.
But the point is that dealing with humam biology in such a way that we can extend healthy lifespans is incredibly complicated at a micro-level, even though the idea of removing damage is theoretically simple. My brain is working oveetime when I think of all the things we need to monitor, and knowing that such things already often go wrong in hospitals with simpler things such as preventing vitamin and mineral deficiencies, I am somewhat pessimistic humans can handle this. Perhaps AI can actually do a lot better job with this, but we can't be certain.
The problem lies in the effort required, and this will probably translate to a patient having to be his own doctor 24/7, but that also makes sense if you were going to live a thousand years or more anyway....You'd probably have learned those skills by then and you'd probably trust yourself best after a long time of experience...But that is if we assume you could survive succesfully for a long time even with sloppy and error-prone medical practices of today combinef with some really cool knowledge about life extension.
I've seen a lot of what goes wrong in hospitals, and so I tend to combine that experience with future prospects about the use of life extension technologies/therapies. A somewhat dark picture emerges, but it is not all dark, because even with our sloppy and lazy medical practices of today, we manage to save a lot of people, and so that will also translate to good results with life extension even if you do not get the 100% high-quality medical care you desperately need.
All in all, perfect medical practice will not be needed to yield some good results. Nevertheless, the complexity lies in monitoring the whole thing....There are so many age-related things to monitor. So I imagine whole departmente in future hospitals will be specialised in diffent fields related to aging and the patients will get thoroughly checked in each department....ideally...but that will probably not happen, because it is cheaper to just give patients partial treatments (treating some aspects of aging while ignoring others).
That itself is scary and could be life-threatening, but dealing with that will depend on how good a patient is at fighting for his own needs and rights. In the end, it'll be about fighting for yourself...You can't just blindly believe others will take the best care of you.
Then again, it isn't all gloomy. You just got to be constantly assertive, and you need to know your needs/rights. Modern society is like that, you got to fight for yourself.
So that's that, I was just thinking out loud and there may be some crappy thoughts in there, but I'm trying to arrive at a very nuanced view about what anti-aging treatment might look like in the future....I want to get a realistic idea about everything.

Posted by: Biological Realist at December 12th, 2018 2:19 PM

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