Diluting blood plasma rejuvenates tissue, reverses aging in mice | Hacker News Reader

Diluting blood plasma rejuvenates tissue, reverses aging in mice

news.berkeley.edu

147 pointshirundo102 comments

Maybe "old blood" has a lot of immune signalling volume going on? Elevated cytokine/chemokine production, elevated counts of immune cells that recognize more of the environment than a naive, under-exposed body? Inflammation.

Maybe part of aging is an auto-immune dysfunction?

Granted, this is a very dynamical system. The immune system clears cancers that are constantly popping up and prevents infections from taking hold.

(This is all unscientific pontificating. I had an undergrad in biochem, but I don't follow the relevant research.)

Edit: I'm getting downvoted for stating that this is just a theory based on my undergrad understanding. Does that add too much noise to the conversation? I wanted to foster discussion. I'm also willing to longbets this one. We're starting to see the immune system implicated for roles in diseases such as Alzheimer's, for instance. It's complicated machinery.

Aging has many causes. Oxidative stress is one. Over-stimulation of the immune system could play a direct role and seems like it's worth exploring, and I'd bet real money on it.

Meanwhile, this paper has also just come out, which looks at whether such effects are due to factors coming in from the young animals or things being removed from the old ones. The authors, from UC-Berkeley and the California Pacific Medical Center, are looking at what they call a “neutral blood exchange”. They replace half the blood volume in mice (both young and old) with isotonic saline plus added albumin protein. The effect of this on the older animals was also significant, with noticeable improvements in wound-healing ability, neurogenesis, and fibrosis/fatty deposits in the liver. The younger mice were not really changed by the treatment. The authors tried several control experiments to make sure that this wasn’t an effect being driven by added albumin protein, and it apparently isn’t. They conclude that removal and substitution of old plasma “is sufficient for most if not all observed positive effects on muscle, brain and liver” in parabiosis-type experiments. It doesn’t exclude the idea of there being beneficial factors in young plasma, but suggests that this is not the driver of many of the results seen. (It would be very interesting to check the DNA methylation status of various tissues before and after this treatment!)

The paper wastes no time in noting that therapeutic plasma exchange (TPE) is already an FDA-approved process (as witness convalescent plasma treatment in the current coronavirus epidemic), and it says that Phase II and III human trials are being planned on the basis of these results. That will be quite interesting to watch, says the 58-year-old dude writing this blog. Overall, I still find such results hard to believe, but at the same time they seem to be showing up from multiple experiments. This second paper especially seems to be a very testable hypothesis indeed. That’s a good thing, because in the end, it’s going to be reproducible human clinical data that decide whether this is real or not – so I’m glad that feasible experiments will allow such data to be collected. Something to watch. . .

https://blogs.sciencemag.org/pipeline/archives/2020/06/12/yo...

Post-hoc "evolutionary just-so story" of the day: animals evolved under conditions of predation, where they'd tend to lose blood regularly, either in the process of fighting off/getting away from predators, or in the process of attacking prey with violent defenses. A species that goes years without losing any blood, is effectively operating its body in an evolutionary out-of-spec configuration. It might work, for a while; but it wasn't heavily optimized for.

A testable hypothesis for this: if you count only the animals that survive long-enough to die by degenerative disease, then animals that get regularly bloodied by their predators or prey species should have longer average lifespans; while animals who don't (e.g. because they have no natural predators; because they're herbivores; because they prey only upon species with no violent defenses) should have shorter average lifespans. This shouldn't be purely a per-species effect, but should also be seen in a lifespan difference between e.g. wild and zoo animals, if the wild animals engage in bloody conflict that the zoo animals don't.

Does anyone know if that hypothesis holds up at all? (Maybe/especially if the question is phrased in terms of heartbeats† rather than years?)

† http://robdunnlab.com/projects/beats-per-life/

A testable hypothesis for your idea: do women age slower than men.

Good luck getting rid of all the confounders involved in testing that hypothesis. Men and women are much more different than in that one sex may lose more blood throughout their lifetime.

They certainly live longer

The way to test this is to follow all people that donate blood.

> A species that goes years without losing any blood, is effectively operating its body in an evolutionary out-of-spec configuration. It might work, for a while; but it wasn't heavily optimized for.

I think your/the hypothesis fails...take certain species of jellyfish that are biologically immortal, they don’t have blood at all.

Coincidentally they are considered top of the food chain, so another knock to the hypothesis.

> they don't have blood at all

Then that would be an evolutionary in-spec configuration, since Cnidaria-phylum species have evolved under selection pressure for hundreds of millions of years in that "never losing blood, because it doesn't have any" configuration.

For a similar reason, you wouldn't expect most plants to be troubled/benefited by the loss of solutes (= sap); a maple tree should probably live about the same lifetime whether it's tapped or not, because maple trees evolved mostly without predation. But for plants that have evolved over eons entirely under conditions of predation (e.g. where they're a primary ecological water source, like cacti in the desert—observable by the fact that they possess defenses to predation), you would expect a difference in longevity between those that lose transported solutes to predation, vs. those who don't.

I think she/he/it was referring more specifically to mammals and other animals with blood.

Why would you think they were referring specifically to mammals? Mammals isn’t mentioned once whereas species/animals is used very broadly In the context of very broad ideas of evolution.

In either case, the hypothesis suggests animals should live longer in the wild than in captivity. So let’s take the only mammal that isn’t more likely to die from age/don’t die from old age, the naked mole rat. We don’t understand why they die and any given day there is a 1 in 10,000 chance they die at any age. In captivity they should have the same lifespan as lab rats (6 years); however, in the wild the have an average lifespan of 17 years and in captivity that expands to 30 years (again in contrast to the hypothesis where wild animals of the same species should live longer than those in captivity).

I don't know but since I was young it always seemed intuitive that blood-letting ought to have some good effects. If xyz bad things buildup (say, heavy metals) exist in the blood stream, and you remove a few % of your blood stream to make new blood, haven't you removed some xyz bad buildup?

Yeah, but you've weakened your body's ability to manage whatever xyz bad buildup and are now asking it to produce more blood as well. IANAD, but I'm pretty sure the medical consensus is that it's a net negative stress on the body.

That sounds more like an argument in favor of having kidneys than anything else...

Yeah definitely. It's good to have an oil filter.

But what if you also change the oil?

Touché!

Make bloodletting trendy again!

Blood donors?

https://sciencenordic.com/body-death-denmark/frequent-blood-...

There is another than menstruating women group of people losing blood: blood donors.

If I remember correctly, it is beneficial for your health to donate blood if you have some predisposition for Fe accumulation (hemochromatosis in the severe form.

Here's a good-ish article on bloodletting in the modern age: https://www.artofmanliness.com/articles/the-potential-benefi...

TLDR: There are correlations that it reduces circulating iron, circulating cancer cells, arterial hardening, decrease insulin sensitivity, and it increased metabolism. Not a lot of super firm evidence though

Interview with the authors about the results:

https://www.lifespan.io/news/diluting-blood-plasma-rejuvenat...

An interesting blog post about the same paper:

https://joshmitteldorf.scienceblog.com/2020/06/08/out-with-t...

Thank you for sharing Josh Mitteldorf's blog on this paper. I think that he has some useful ideas on how to interpret this in light of Harold Katcher's work.

The implication is not that young blood has specific positive properties, but that old blood has specific negative properties. Simply removing some of the "bad old blood" is already enough to measurably improve biomarkers. Identifying the bad stuff may go a long way to counteracting it in a more targeted way.

> Simply removing some of the "bad old blood" is already enough to measurably improve biomarkers.

God damn it, those blood letters were onto something!

Haha, yes. Probably not a great idea to start blood-letting while fighting an infection, but as a prophylactic, it looks promising.

>Simply removing some of the "bad old blood"

well, that is in some sense that kidney and liver do, and when kidney and liver slow down then the "old blood" may be becoming "bad" (say like with bad oil or fuel filter in the car). Just adding saline water for example improves PH (as older body runs more acidic) and that has a lot of net positive effects.

https://academic.oup.com/biomedgerontology/article-pdf/51A/1...

" with increasing age, thereis a significant increase in the steady-state blood [H+] (p < .001), and reduction in steady-state plasma [HCOj] fp <.001), indicative of a progressively worsening low-level metabolic acidosis"

and on effects of increased acidity for example:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566456/

Any research saying how much and often you would need to "remove" (donate) blood to see a difference?

There's a Spanish pharma company (Grifols) that has been experimenting for years with plasma replacement to slow down or stop Alzheimer's disease progression. The first results of the therapy called AMBAR (Alzheimer's disease Management by Albumin Replacement) seem to be a slow down of the progression of the disease by 71% in moderate cases:

"The CDR-Sb scale – which assesses memory, orientation, judgment, community affairs, home and hobbies, and personal care – showed a 71% reduction in clinical decline with respect to placebo in patients treated as a whole and in all three clinical trial treatment arms analyzed separately."

https://www.webwire.com/ViewPressRel.asp?aId=251270

Which is interesting because it seems they might have stumbled on a side effect of something bigger... And it could be possible to check the participants to the trial for other effects as well.

Seems like the conspiracy theories that the rich and global elite harvest the blood of the young and innocent to rejuvenate them isn't as false as we once thought... /s

Sometimes I wish we had a medical system where whoever wanted to be a test patient for whatever reason could sign on the dotted line once advised of the potential downsides (up to and including death assumedly) so we could advance medical science faster. Maybe we'd find out things a lot faster than we currently do.

From interview with the authors, why you should be a bit careful with just going ahead and trying this out

"This is a somewhat invasive procedure where your whole blood goes through a machine and the cells are returned to you and the plasma is diluted. It is not completely benign, and you cannot just keep doing it every day. So, to know how long the effects last and to know it for each individual is an additional know-how part that we found out from a couple of years of research and are studying further. I’m sure there will be competition, but I just want to warn everybody, do not go somewhere and get your blood replaced with saline. Wait until there are reputable clinical trials and people know a little bit more."

> do not go somewhere and get your blood replaced with saline

I just did that this morning when I donated blood. They said they needed the plasma badly, so they took the red blood cells and the plasma, and returned a saline solution.

So maybe you just need to donate blood/plasma often to stay young?

study shows that people, who donate a lot of blood, suffer no serious ill effects and may even live longer than less frequent donors.

https://sciencenordic.com/body-death-denmark/frequent-blood-...

Unfortunately they don't give any details on what constitutes more frequent and less frequent. For example once a month vs once a year or once very 2 weeks vs once every 2 years, etc.

Whole blood donation generally is only allowed every 8 weeks. Double-red blood cell donation is allowed every 16 weeks up to a maximum amount per 12-month period. I believe Plasma can be safely donated every 4 weeks. Doesn't tell you specifics about the study, but know there are different kinds of blood donation and different frequencies that are permitted for each.

I think it's common for regular donors to donate almost as often as is recommended.

Some conspiracy theory, they have a price list. https://www.ambrosiaplasma.com/

Boy, wait until those customers find out they paid all that money for young plasma when all they needed was a saline and albumin solution.

$8,000 for 2 liters. I knew it would be expensive, but that's bonkers.

this is amazing. how did you find this, and do you know of any other health/longevity tips?

Nope, I just heard about it in the news a while back.

I think you missed the point... this article shows that the blood of the innocent is overrated and saline can be used in its place. If we're going with vampire conspiracies, they no longer need mortal donors, and can now exterminate us all with no consequence.

That's a silly conspiracy theory. Why steal it when you can pay a poor a pittance?

The point of this paper is no harvesting needed.

the link pretty much dismissed that whole theory.

Wouldn't call it a conspiracy, the show Silicon Valley was mocking those who do it years ago.

https://www.youtube.com/watch?v=hBA0AH-LSbo

What no one has yet discussed is being a plasma donor to keep the bad proteins down that have accumulated over time. You can donate 1 pint plasma up to twice a week, they replace it with saline and return the red cells to you. If someone went weekly, say, they would sooner or later have removed all the old plasma by dilution with the new plasma that replaces it - I dont have any data on how many donations it would take to remove 95% of the old plasma. No albumin is needed since you are only removing 1 unit and the body can replace it quickly, not like removing half the blood volume at once. Plus, they pay you to donate. - Jay Caplan

O- donors have the opposite option: The machine is configured to remove red cells and return plasma diluted with saline.

And do you feel rejuvinated?

I just gave blood today. I have been trying to give blood as often as possible (once every eight weeks) to help keep cholesterol and iron low. Now, of course, I'm getting a free COVID-19 antibody test out of the deal. I'm wondering if this frequency of blood donations has a similar effect.

> "They replace half the blood volume in mice"

I'd speculate the difference in volume is too great, having half your blood replaced with saline solution must feel awful.

Not really the same thing but I'm blood type O- and do the "Power Red" donation at Red Cross events. I have two units of blood taken out and the red cells and plasma are separated so the plasma can be returned along with saline to make up the difference in volume. I don't notice much of a difference besides feeling a little cold since the saline is at room temperature. However in that case I believe I'd only have ~10% of my blood volume replaced with saline.

« I don't notice much of a difference besides feeling a little cold since the saline is at room temperature. »

I've always wondered: Why don't they warm it up?!

"half of the blood plasma" Important difference.

Interesting point by aomix about the temperature, but that could be compensated for if it was needed.

I haven't donated plasma in a long time, but pretty much the only thing I felt when the blood cells and platelets were returned was a light tickling near the needle and sometimes a faint chemical taste or smell, presumably from some component in the replacement fluid. Exchanging several liters would take time, certainly, but it doesn't seem at all a given that it would be very disagreeable in the immediate term.

Slightly longer term, one might certainly wonder about the comfort effects of having stuff like hormones and cytokines, circulating antibodies, clotting factors, etcetera rapidly halved. That ought to jolt the homeostatic controllers good, and that could well be one of the reasons for the beneficial effects. And halving blood glucose should be potentially unpleasant, but I suspect the compensation would be very fast.

> That ought to jolt the homeostatic controllers good, and that could well be one of the reasons for the beneficial effects

Indeed, I'm wondering if this is yet another example of eustress. Other examples of eustress are exercise, sauna, and cryotherapy.

Eustress, that's a new one. I thought that was called hormesis.

Ah thank you, I came across the term hormesis from Dr Rhonda Patrick’s work

Aside from the altruistic aspect, I had extra motivation to give blood from an unfounded pet theory that the body isn't capable of removing all bad products that ends up in the bloodstream. Giving blood seemed like a safer way to purge some of these products than diy at-home phlebotomy. It's nice to finally have some research supporting this guess.

I was wondering that too. But donating only takes about 10% of your blood. So maybe not enough for any effect?

So, blood-letting[1] works?

[1] https://www.history.com/news/a-brief-history-of-bloodletting

Lovely anecdote:

A relative of mine has seasonal headaches that they experience, and they have told me that the way they relieve them is to go and donate blood.

Works every time, without a hitch.

I wouldn't be surprised if there is at least one study out there (or maybe even a wikipedia page) that attests to this phenomenon.

The article mentions plasmapheresis, therapeutic plasma exchange, so the posted article itself attests to this phenomenon.

Same, my hematocrit gets high during seasonal allergies. Donating blood clears this up.

How is this different than donating plasma?

This may go part of the way to explaining why women have a longer life span then men, they're constantly having to manufacture new blood. Men only have to create new blood if they donate or suffer some injury, but women's bodies are generating new blood all the time.

Everyone generates new blood all the time. There's nothing gender specific about this. Our blood cells are completely replaced over a cycle of something like 4 months.

And this study is about plasma and albumin specifically.

i think OP is referring to the monthly blood loss women experience.

There's some research (which I won't dig up at the moment; google "iron longevity" for a start) indicating that it's actually iron/heme which is bad. Women can get rid of it, at least while their fertility lasts. Men can't.

Except that increased female longevity is a trend that carries through many different mammal species. [0] Not all mammals menstruate in the same manner as humans. They all have a menstrual cycle, but many have a thin menstrual lining that's simple reabsorbed by the body rather than being shed in the form of menses.

---

[0]: https://www.smithsonianmag.com/smart-news/females-live-longe....

Men can't... unless they donate whole blood regularly, which is a pretty easy way to reduce iron load.

(And, in fact, donating blood regularly or even more often than usually recommended is the standard treatment for hemochromatosis, an inherited condition where too much iron is retained.)

I always assumed this was in part related to socio-economic reasons (men on average do jobs with much higher death rates) as well as the effects of pregnancy, where the mothers body can be healed when pregnant due to migration of stem cells. Wild speculation on that last one impacting the life span, but there is evidence for it.

https://www.newscientist.com/article/dn21185-fetus-donates-s...

I think popular press of animal studies is mostly clickbait, especially aging studies.

The lifetimes of mice are so small compared to humans that you have to apply large scaling factors. An old mouse would be a very young human. How valid the scaling factors are is a different story.

In this study they didn't look at the lifespans of the mice, they looked at markers of the health of different types of tissues. A lot of the time when something is about "reversing aging" it's about improving health so that organs of the old work more like those of the young or curing diseases of old age and not necessarily about increasing lifespan.

Maybe I should get some pet leeches.

I don't know if Google's search results are accurate but I watched The African Queen recently and when Bogart gets leeches I googled if they are harmful and the first results said "No"

There are various blood removal method, one of method that I’ve seen and commonly used is Hijamaz/Bekam. A small incision is made on the skin (usually the back); then a suction cup is used to draw the blood out. It is widely popular in Asia, I usually see it done by Moslem as they are recommended by their prophet to do so. Make sure the method is correct and that the equipment is sterile though.

Is this technically unani tibb

Scientifically interesting. A lot of people that have acquired the wisdom of experience would probably shudder at the thought of living 500 years, though.

But to no small extent because of people who have not yet acquired the wisdom of experience. It would be interesting to see the societal effects of a larger fraction of the population having grown up.

And one could always opt out...

> making conjoined twins out of young and old mice — such that they share blood and organs

That sent chills down my spine.

Now realize that the young mouse would have to be a clone of the old mouse, to prevent rejection.

Donate blood, live forever, anti-vampire!

(Sorry, I've been on twitter recently and it's rotting my brain.)

This seems like a simple thing to test. It is just you need some time to see if it works.

Would we see the same effects from donating blood?

Seems there may be some effect at least

https://sciencenordic.com/body-death-denmark/frequent-blood-...

Implications for recruiting plasma donors?

Ought to become easier? I'm already feeling motivated to consider getting going again.

No plasma donors. Old plasma is replaced with saline and albumin.

In this study, 50% of a body's old plasma is replaced with saline & albumin.

In plasma donation – which can be done in return for cash compensation in the USA! – 20% of a body's plasma is replaced with saline solution (no albumin).

Plasma donation might plausibly approximate this study's effects, at a lesser level.

Generally plasma donation is allowed every 28 days, though in some cases 3 donations over 8 weeks (or about once every 12 days) is allowed.

are there any actions we can take to make use of this new information?

Basically, stay hydrated? :)

This is getting flagged down as a dumb joke, but for those in the cheap seats, it's not entirely clear exactly how this differs. Presumably adding "adding albumin and water" is different than just "adding water". But why, exactly? And so on.

It differs because everything except saline and albumin is filtered out. The point is to show that some markers of aging are harmful byproducts in your blood, and filtering them out can have positive effects.

Actually, albumin seems to be filtered out as well and replaced. If I understand correctly, albumin is a transport protein, so it carries around a lot of stuff. When it gets replaced, it is replaced with a "blank" version.

It seems kind of unsurprising to me, given dialysis is a thing.

Actually, now I'm wondering, could this be a simpler substitute for dialysis in some cases?

Therapeutic plasma exchange is use in cases of renal disorder: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521768/

It's surprising in the sense that even people with fully functioning kidneys could benefit from it.

I would say that it's unsurprising that our organs are less than perfect at doing their jobs, given that they operate under various constraints (e.g. running under an ATP power budget, one tuned for an ancestral environment where dying of hunger was a real concern; being only able to eliminate metabolic waste at the rate blood flow can take it away; having to avoid strategies that lead to DNA damage, like running anaerobically for long periods; etc.)

Therefore, it's also unsurprising that external devices can do some of an organ's jobs "better" than the organ itself can. They devices don't have the same constraints our organs do.

This effect is already very clear for pacemakers: hearts are very bad at keeping themselves going in oxygen-poor conditions (as they effectively have a circular dependency—a heart can't beat without flowing oxygenated blood); but electronic pacemakers don't need oxygen, and so keep the heart going under such conditions, until oxygen-rich blood can return.

Once we perfect stem-cell organ synthesis, it'd be intriguing to know whether "untethered" human longevity could be increased just by sticking "moar kidney" and "moar liver" into the body, than the human body-plan calls for by default.

If you’ve never encountered someone with low blood albumin, it is a very serious problem. You get terrible edema all over. Albumin helps you not retain the water in your cells, and instead to get the fluid back into your bloodstream for excretion.

I haven't. But the idiot in me wants to ask whether I could just drink loads of albumin in water and "dilute" myself that way, without all of this weird dialysis, etc. Presumably not, but why not, exactly?

is there a way to supplement it, such as milk or egg whites?

https://en.wikipedia.org/wiki/Hypoalbuminemia

If your albumin levels are low, then you probably have more serious problems than your albumin levels being low, so you'd want to treat the underlying condition.

Yeah - the person I knew who had it had cancer, and was dying of it. It is not common, and speaks of major organ failure.

Reminds me of the joke:

What do you tell a mouse that has cancer or diabetes?

"You need a new agent!"

Reply on news.ycombinator.com