Behind the Study: Iron: An Underrated Factor in Aging

Dennis Mangan

Dennis Mangan from MTOR LLC in Bakersfield, California details his theory article published by Aging (Aging-US), entitled, “Iron: an underrated factor in aging.”

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Behind the Study is a series of transcribed videos from researchers elaborating on their recent studies published by Aging (Aging-US). Visit the Aging (Aging-US) YouTube channel for more insights from outstanding authors.

Dennis Mangan

Hi, my name is Dennis Mangan, and I am with MTOR LLC. I’m the author of the paper, Iron: an underrated factor in aging, which was published in the journal, Aging, late last year. The editors of Aging asked me to record a little video here talking about why I wrote this and its possible significance of this paper.

So this paper is a review paper. It contains no original research of mine. The motivation for me to write this paper goes back a few years. I wrote a book called “Dumping Iron.” This was about five years ago, and I wrote it for a lay audience. I was trying to sum up some of the research relating to iron, health, and disease. Ultimately, this research and my interest in this topic goes back to the writings of the late Jerome Sullivan, MD, who first came up with the iron hypothesis of heart disease. This was very fascinating to me. I thought that no one was really taking a deeper look at it, and so I did. I ended up writing this book, “Dumping Iron.”

Iron has been implicated in many chronic diseases, not just atherosclerosis, but cancer, Alzheimer’s, Parkinson’s disease, and many other diseases.

My motivation for writing the article, Iron: an underrated factor in aging, was because I believe this is a very overlooked area in aging research. As I mentioned, iron is implicated in many diseases and chronic health conditions, but it’s relation to aging itself I believe has been overlooked. There has been quite a bit of research in the last few years pointing in this direction that iron is very important in aging. So what I wanted to do was to try to sum up some of this research and point readers of aging and other scientists in this area hopefully to this research and to point out its importance. I don’t want to just recapitulate the whole paper here. You can read it for yourself in probably 10 minutes, but let me just highlight a few points.

One is the relation of iron to the mammalian or mechanistic target of rapamycin. mTOR, as it’s called, has been very important focus of research in aging. It has been shown that inhibition of mTOR by the drug rapamycin or by other means can extend lifespan in experimental animals. Well, it so happens that iron is involved. The iron is necessary for activation of mTOR. Chelators of iron will inhibit mTOR activation. Adding iron to the media of an organism will promote mTOR activation. So it certainly seems that iron is important in mTOR activation. That using iron, whether iron chelation or lowering iron by other means, could help extend lifespan through its inhibition of the activation of mTOR.

There are some other modalities of life extension in which iron appears to be very important, calorie restriction, for example. This is the oldest and most robust known lifespan extension intervention that’s known. This has been known for about 80 years in animals and restricting the food of animals does indeed extend their lifespan quite a bit.

There have been many, many studies trying to understand why calorie restriction extends the lifespan of animals. Some of these have pointed to insulin to adiposity to hormesis to autophagy. Many other mechanisms have been proposed. It’s possible, certainly possible, that many of these have to do with the calorie restriction effects altogether. In any case, iron is also involved. Calorie restriction prevents accumulation of iron with aging. So this could be one other important mechanism by which calorie restriction extends lifespan. If so, it follows that restricting iron could slow or conceivably reverse aging.

There have been other lifespan-extending interventions of interest that also involve iron, for example, various polyphenols and drugs. I discuss these quite a bit in the article that have iron chelating capabilities. Iron may very well be important in the mechanisms of action of these drugs and natural products that extend lifespan.

Another much more recent intervention that’s of great interest is therapeutic plasma exchange or plasma dilution. These interventions have come out of experiments in heterochronic parabiosis. In heterochronic parabiosis, it’s been found that young blood will at least partially rejuvenate an older animal. Now, the question is, why does this happen? It certainly seems that dilution of the older animal’s plasma has something to do with it since blood from an old animal actually harms a younger animal. So it doesn’t seem to be strictly speaking that the young blood is helping the older animal, although there’s certainly possibility of that being involved.

Other evidence that dilution of plasma is the major factor in this phenomenon is actually doing plasma dilution. So this has been done recently in the last just couple of years where in animals, much of the plasma has been removed. 50% of the plasma has been removed, and it’s been replaced by a saline and albumin mixture. This has been shown to be rejuvenating. This has been shown in vitro as well in where muscle cells can be rejuvenated by using plasma from humans that have undergone therapeutic plasma exchange. In therapeutic plasma exchange, this is very similar to plasma dilution, in which patients with certain illnesses have an apheresis procedure and their plasma is diluted. So this diluted plasma is rejuvenating to muscle cells of rodents.

So the question is, what is this? What is going on here exactly?

One of my suggestions is that iron is being removed. There are a number of pieces of evidence of this, and so I think this is important. People are now looking at therapeutic plasma exchange as a life-extending modality.

So in sum, I believe that iron is a very, very overlooked, underrated factor in aging, and that more people ought to be taking a look at it. Scientists should be investigating it further, and that is exactly why I wrote that paper. Thanks.

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