Executive Summary
- Surgically joining the circulatory systems of a young and an old mouse may rejuvenate the old mouse
- A new study finds that benefit to the older mouse are much smaller than harm to the younger
- In the younger animal, beta 2 microglobulin increased and brain neurogenesis decreased
- The fact that a single exposure to old blood causes harm implicates some factor in old blood
- My hypothesis is that that factor is either iron or bacterial lipopolysaccharides
Scientists have studied aging by surgically joining the circulatory systems of two mice, one young, one old, and then looking at changes in either mouse. This process, known as heterochronic parabiosis, allows the exchange of circulating blood factors between the two mice, and these factors are presumed to promote either rejuvenation or aging. A new young blood study implicates iron in aging, either directly or through bacterial lipopolysaccharides.
In previous studies, scientists have thought that delivery of a protein, GDF11, from young blood to old, causes rejuvenation of muscle in the old animals. Others have cast doubt on this, and asserted that GDF11 inhibits muscle regeneration in old mice.
Other scientists have noted that this procedure may not be solely about circulating factors. When two mice are joined together, the old mouse has access not only to the blood of the young animal, but to its organs as well, since blood circulates through them. Access to a young heart, or lungs, or other organs could have rejuvenating effects on their own.
To get around the sharing of organs and study circulating factors alone, the team of scientists headed by Irina Conboy at the University of California, Berkeley, developed a new procedure using microfluidic technology. The new procedure allows the animals to be joined for a few hours, their blood to circulate together and mix, and then the animals can be disconnected. This procedure effectively isolates blood as a source of any changes seen.
The new study, “A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood“, found that old blood was much more damaging to young mice than young blood rejuvenated old mice. Several new discoveries in this study implicate iron as one of the causative factors in old blood that damage the young mice. (The scientists don’t say this; that’s my interpretation, and I’ll explain.)
Effects on muscle
Old mice transfused with young blood showed better recovery from muscle injury. Young mice transfused with old showed worse recovery.
Young blood showed a rejuvenating effect. But — the researchers note, “The positive effects of young blood could also be explained by dilution of old blood, and not necessarily by young factors.”
If that’s correct, then there’s no rejuvenating factor in young blood, but there’s something in old blood that is associated with aging and causes harm. More on that below.
Brain effects
Genesis of new neurons in the brain, specifically in the hippocampus, was “severely” curtailed in young mice after only one transfusion of old blood, and there was no rejuvenating effect in old mice from young blood.
Increase in beta 2 microglobulin
Beta 2 microglobulin (B2M) is a protein that forms part of the major histocompatibility complex in cell membranes and as such is important in immune function. Transfusion with old blood increased B2M in young mice.
“Moreover, our studies demonstrate a rapid increase in beta-2 microglobulin (B2M) in young tissues by old blood; and this phenotype is not from elevated circulating B2M in old mice (as there is none), suggesting that another age-specific systemic molecule raises B2M in the young organs.”
This increase in B2M is an important clue as to what transfusion of old blood does and what causes it.
Potential causes: iron and lipopolysaccharides
In rats, iron accumulates in tissues with aging. Calorie restriction, which is known to extend lifespan, markedly suppresses the accumulation of iron.
Yeast (Saccharomyces cerevisiae, or brewers’ yeast) are used as a model organism to study aging, since the mechanisms of aging are evolutionarily conserved in all eukaryotic organisms. They, too, massively accumulate iron with aging, 4 to 5 times as much as when young. The increased iron is associated with damage to cellular proteins.
“The pro-oxidant effects of such increased iron concentration would account for the damage observed.”
Calorie restriction curtails both the iron and the damage. Decreased accumulation of iron could be an important way in which calorie restriction extends lifespan.
Lipopolysaccharides (LPS) are fragments of bacterial cell walls, and are extremely toxic — they’re often referred to as “endotoxins”.
In aging, the lining of the gut wall deteriorates, allowing LPS to enter the circulation, where they cause a chain reaction of deleterious events. Mice show both a change in gut microbes in aging and an increase in LPS in the circulation. This causes increased inflammation, a characteristic of aging.
Can these components of old blood, iron and LPS, cause deleterious changes when given to young animals?
Douglas Kell, an expert in this field, wrote, “…there is overwhelming evidence for the involvement of iron in this neurodegeneration [in Parkinson’s disease]”.
With regard specifically to the hippocampus, the region of the brain studied in this young-old transfusion experiment, iron accumulates in it in Alzheimer’s disease in humans and correlates highly with the severity of disease.
When a specific toxin that induces Parkinson’s disease is given to lab animals, iron chelators protect against damage. What appears to occur is that the toxin causes accumulation or iron in the brain and/or causes the release of free iron from ferritin; free iron is what causes damage, and iron chelators mop up free iron and remove it.
As for LPS, they play a central role in increasing inflammation and promoting cell death. They may come either from increased bacterial translocation from the gut or from the revival of dormant bacteria in the blood.
Bacteria, like virtually all living things, require iron; withholding iron from bacteria is one of the first lines of defense in immunity. Bacteria and primates are involved in an ongoing evolutionary arms race in a battle for iron.
Exposure to LPS increases iron levels and oxidative damage in endothelial cells, and iron chelators prevent the damage.
The Mechanism
“Given the well-established facts (i) that microbial growth in vivo is normally strongly limited by the (non-) availability of free iron, and (ii) that bacterial components such as lipopolysaccharide (LPS) are strongly inflammatory, such an analysis leads to the recognition that the iron-related inflammatory diseases also have a major microbial component involving the resuscitation of dormant organisms and their shedding of inflammatory molecules, and especially of cell wall components such as LPS.”
Older animals have higher levels of both free iron and LPS. If old blood is transfused into young animals, they receive both of these. Either the high iron in the blood of old mice revives dormant bacteria in the young animals, or the LPS in old blood causes massive inflammation in young mice, and prevents neurogenesis.
As we noted above, tissue beta 2 microglobulin increased dramatically in young animals after old blood transfusion, as much as 3-fold in brain and 8-fold in muscle.
One of the most important functions of beta 2 microglobulin is the regulation of iron. B2M knockout mice, which lack genes for B2M, become iron-overloaded and are in fact used as a mouse model of hemochromatosis, or pathological iron loading.
Increased iron or LPS in old blood could cause the rise of B2M in the tissue of young mice. That, however, is speculative, as I’ve been unable to find any data on what increases B2M in tissue. Since B2M regulates iron, it stands to reason that high iron could cause an increase in it, in order to down-regulate iron. In any case, in these young mice, something clearly increases B2M.
Important to note that, while B2M has been recognized as an important pro-aging factor that circulates in old blood, and injection of it causes cognitive deficits, the present study found no increase in circulating B2M in old blood.
Conclusion
The evidence indicates that some factor in old blood causes damage when given to young animals.
That factor may be iron and/or bacterial lipopolysaccharides.
Old blood is more harmful to young animals than young blood is a benefit to old animals.
That would seem to dash hopes of any large benefit of young blood in older people.
If my analysis is correct, it shows that controlling iron and bacterial LPS are important to aging. (We already know this; this report just supplies more evidence.)
In regard to iron, controlling both total body iron stores, as represented by ferritin, and the release of free iron, are important. The former can be controlled in a number of ways, and the latter by iron chelators.
For control of bacterial LPS, oral and gut integrity are important. Since bacteria require free iron, measures that keep it low also help prevent increased LPS.
19 Comments
Interesting, thank you for the article.
Found this:
– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784982/?tool=pubmed
The patient group with an elevated serum [ferritin] level was associated with a lower albumin level, and B2MG, BMPC, CRP, and LDH levels above the upper limits of normal, compared with the patients with a normal ferritin level.
– https://www.researchgate.net/figure/13836464_fig1_Fig-1-Time-course-of-beta-2-microglobulin-production-by-purified-monocytes-from-normal
The increased production of b -2 microglobulin release by purified monocytes stimulated with LPS was time dependent and dose-dependent ( Figure 1 )
And this:
– https://www.jbc.org/content/278/27/24438.full
Treating astrocytes isolated from the cerebral cortex, the hippocampus, and the cerebellum with LPS increased the secretion of B2MG
Ted, thanks for all of those links – I think you’re a better paper searcher than I am. Those were just what I was looking for. So, high LPS in old blood could be stimulating B2M production in young animals. High LPS in old animals could be due, at least in part, to higher levels of free iron stimulating bacterial growth.
Dental integrity can be challenge in elderly people. Most elderly have had root canals performed in their teeths. Dr. Mercola believes that root canals are the cause of many chronic diseases, including cancer. Most of his arguments are based on old research done by Dr. Weston Price. However, I’ve not been able to find any recent studies, which back up Dr. Mercola’s claims,e.g. no elevated CRP level has been found in the blood of people with root-canals.
https://www.ncbi.nlm.nih.gov/pubmed/20690397
Some historical context:
https://en.wikipedia.org/wiki/Bloodletting
While being a crude practice, note that this was rather popular, especially in older people.
Humans then obviously did not understand what was going on in a scientific way, but I guess they
knew if they felt worse or better from the procedure; maybe they even took note of life quality/ability
and death rate. The procedure would have caused additional infections, because sterilization
was unknown. Therefore, even with a higher rate of disease from uncleaned bloodletting tools,
the net benefit for people back then was probably positive, hinting at a significantly positive effect of the
procedure of removing blood/iron itself.
I find it noteworthy that we are in some kind of historic circle here: A practice of the dark ages,
abandoned over time with increasing scientific understanding for being disadvantageous, suddenly appears advantageous again with more scientific understanding and we are doing it again.
It could be worthwhile looking in other practices done hundreds and thousands of years ago that
are abandoned today.
Also, I found this website which you may find interesting:
https://www.irondisorders.org/elderly
Hi Montgomery, thanks for that. I’ve speculated over on Twitter that bloodletting survived for so long precisely because a) it worked, after a fashion, and b) There wasn’t anything else. The people who came before us weren’t stupid. On the other hand, I reflect that astrology was and is popular and exists in virtually every culture I’m aware of. And it clearly has no validity. (Hope that’s not controversial.) So maybe the argument from long use doesn’t work for phlebotomy either.
Have you contacted the authors as to ferritin, LPS, etc. serum levels in the mice?
No, I haven’t. I assume that if they had measured those, they would have published them.
(Comment too long? I experience problems posting; I hereby split my post, if there is some double posting or other ill effects, please delete)
citing P.D.Mangan:
“For control of bacterial LPS, oral and gut integrity are important.”
Gut integrity problems could shown to be caused by a lack of “dietary fiber” in the diet.
Put simply, some bacteria species of the gut microbiome are specialized to consume these
as an energy source; if there is a long-term lack of such fiber in the diet, these bacteria are stressed/starved/dying and start to consume the gut wall instead, leading to “leaky gut syndrome”-
not only are they damaging the barrier function of the gut, gut bacteria and their metabolites
can then enter the bloodstream readily, causing systemic inflammation.
https://www.cell.com/cell/fulltext/S0092-8674(16)31464-7
https://en.wikipedia.org/wiki/Gut_flora
Some more info:
https://time.com/3853618/mcdonalds-gut-bacteria/
https://www.eater.com/2015/5/11/8587327/mcdonalds-gut-bacteria-college-kid-study-scary-fast-food
https://articles.mercola.com/sites/articles/archive/2015/05/27/processed-foods-gut-microbes.aspx
https://www.telegraph.co.uk/foodanddrink/11595559/Junk-food-kills-bacteria-that-protect-against-obesity-heart-disease-and-cancer-study-finds.html
Eating only fast food for some time leads to a marked decrease in the number of bacteria species
in the gut. Good gut health is associated with a high diversity, bowel problems are associated
with a low diversity of gut bacteria species. In the most extreme cases of gut inflammation diseases
only around 10 different species of bacteria were found in the gut (such patients die off in mere days);
a healthy gut microbiome contains thousands of bacteria species, up to 4000 or so.
The point is that the gut is a bacteria ecosystem: Different bacteria help us process different
kinds of food; when the food we eat is “too good”, too simply digestible, too energy-dense,
then bacteria species that are specialized to process this thrive, while species that are
specialized to process “difficult” food and to release nutrients from them to their human host
first starve and then die – from starvation, and from competitive displacement of the bacteria that
are specialized to process the “fast food”, that is, the food with quick-and-easy-release nutrients.
More than 2 links requires me to approve the comment first before it appears, which is why it didn’t post for you.
https://www.newscientist.com/article/2104864-bacteria-lurking-in-blood-could-be-culprit-in-countless-diseases/2 very relevant articles imo:
About lps, iron, blodclotting and aging:
and abouhttps://www.newscientist.com/article/dn27557-iron-levels-in-brain-predict-when-people-will-get-alzheimers/?cmpid=ILC|NSNS|2016-GLOBAL-inlinelink&utm_medium=ILC&utm_source=NSNS&utm_campaign=inlinelink iron and Alzheimers, this one is esp. relevant to your writings, PD:
Nice finds there, ted. In fact, this study (a link from your 2nd link) is the best evidence I’ve seen yet that there’s a causative link between iron levels and Alzheimer’s: https://www.ncbi.nlm.nih.gov/pubmed/1674295
Sorry for link grammar, mobile
I donated blood last week for the fist time in a decade. Based on the info I found on your website.
PD do you know if there is a way to measure free iron in tissues? As far as I understand, free iron does most of the damage, and ferritin-bound iron is safer than free iron.
Also, does blood donation decrease free iron in tissues?
A serum iron test measures total serum iron, including ferritin. As for a measure of free iron only, and in a tissue other than blood, that’s going to be a complex test done only experimentally. So, that’s a long way of saying no. You are correct that free iron is what’s causing damage. Blood donation mainly lowers ferritin (bound iron), but since free iron is normally some function (varying in different people) of ferritin, then lowering ferritin ultimately lowers free iron. Basically, keeping ferritin low will be the best way to ensure that free iron stays low. Iron chelators (whether drugs or natural) do lower free iron directly by binding and removing it. Slower process than blood donation though.
PD – interesting article on copper. Says copper determines where absorbed iron goes. Low copper may mean iron is stored in tissues/organs, copper is required to send iron to bone marrow to produce blood cells.
https://www.globalhealingcenter.com/natural-health/copper-deficient/
So maybe copper gets a bad rep undeservedly?
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