Rejuvenation Via Plasma Dilution, Parabiosis & Neutral Blood Exchange | Dr. Irina & Michael Conboy
Live Longer World Podcast #9
Live Longer World Podcast Episode #9 has been released!
My guests in today's episode are Dr. Irina and Michael Conboy of the Department of Bioengineering at the University of California Berkeley.
Their groundbreaking research focuses on tissue rejuvenation via plasma dilution and heterochronic parabiosis, where the Conboys took a young mouse and an older mouse and sutured them together, such that the animals shared blood and environment. The old mice became rejuvenated & younger.
They’ve also pioneered a process called the Neutral Blood Exchange or Therapeutic Blood Exchange, through which dilution of old blood plasma can lead to true rejuvenation in the brain & other tissues of mice to a younger state!
Further, we touch upon Irina's work showing how decreased Oxytocin levels with age contributes to poor muscle function. Their research is incredibly exciting and we discuss all about it in today’s episode.
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00:00 Live Longer World Intro
00:35 Irina & Michael Conboy Intro
1:08 Aging is slowdown in our repair machinery
2:55 Naked Mole Rats not extreme model for longevity
5:37 Heterochronic Parabiosis
16:00 Young Blood to Old Blood Exchange
19:19 Rejuvenation via Neutral Blood Exchange (NBE)
22:56 Old Blood Degenerates Young Mice
25:29 Rejuvenation Effects on Brain, Liver, Muscle through NBE
27:16 How long do effects of NBE last?
30:15 How is NBE working mechanistically? 2 waves of rejuvenation
33:38 Inhibiting TGF-beta & Increasing Oxytocin is rejuvenative
38:12 NBE vs. Senolytics
40:53 Unanswered Questions on NBE
43:13 Oxytocin & Muscle Functioning; Notch Signaling
48:12 Chickens & Ravens as Pets!
Extensive Show Notes & Transcript:
You’ve often spoken about aging as not necessarily an increase in the rate of damage itself, but a decline in the capacity to repair damage with time. There is a subtle difference there. Can you elaborate on what makes you think of aging this way?
I give the example of squirrel and rat. They are similar animals with similar size and metabolism. Squirrels live between 20-30 years whereas rats live only 3 years
This shows that aging is not simply wear and tear and damage but its a balance between damage and repair. So those who can repair the damage better live better
Some people think naked mole rats live are the model animals for longevity but that is not the case. Squirrels most likely outlive naked mole rat so not sure why they’ve come to be the model for longevity
They are colonial organisms so it’s not that all of them live long, it’s the matriach that lives long, so there can be numerous reasons
DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders: https://www.nature.com/articles/s43587-021-00152-1
Naked mole rat is not an exceptional model, there are other models that also live as long, but that is not to say that they don’t live long
The capacity to repair the damage is causing aging at different rate
I believe your work around neutral blood exchange and plasma dilution, which we will get to later, began with experiments around heterochronic parabiosis. Can you explain what that is?
25 years ago, we had discussions around aging and why we age
The question was why is it that all the organs and tissues tend to age together. Usually everything is aging together
So we had a hypothesis that maybe there is something that connects all the tissues and coordinates. What could coordinate from the outside, inside and middle?
The nervous system coordinates everywhere
The blood flows everywhere
The blood vasculature carries the blood everywhere
This would be everything and if we could do an experiment to transplant the nervous system or vasculature system from young animal to old animal but we didn’t know how to do that
But blood was something we knew
In 2003, Irina presented a paper in Journal Club and she described an experiment done by Irv Weissman’s lab where they were looking at: Can stem cells from one tissue type contribute to another tissue like nervous system or muscle
To answer the question, they used this technique called parabiosis
They took one animal where all of its cells were green and stitched it to another animal that did not have green cells
You cut one side of one animal and another side of another animal and stitch the skin around both of them. So the skin grows together and the blood vessels in the skin also grow together
Blood will flow from one animal to another and they used this to show that the blood cells did not contribute to anything outside of blood
This made Mike think that the parabiosis technique can answer the question around the blood: whether blood could be the connecting tissue for aging
By that time, they had done experiments with cells and culture. We would take young stem cells and put them in old blood serum and they would become old. And if we took old stem cells and put them in young blood serum, they would differentiate into muscle, and divide and recover better. So we had this idea that aging and rejuvenation is systemic but didn’t have a way to prove it in animals until Mike had the breakthrough in the Journal club
Irina asked Irv Weisman: What if we connected a young mouse with an old mouse? Even before she completed her sentence, Irv said it was a great idea and connected her to Amy Wagers, postdoc in Irv’s lab and she taught them how to connect young rat to old rat. This also spearheaded Amy’s career in aging
What were the results of the heterochronic parabiosis study?
Looked at 3 different tissues: brain, liver and muscle
In old animals, all 3 tissues were rejuvenated
Young animals showed decrease in performance in those tissues
They’ve seen it again and again from parabiosis to blood exchange to neutral blood exchange
At that time they weren’t sure whether it was bad stuff in old blood or good stuff in young blood so when they were writing the paper they were careful about it
Everybody was focused on the fact that there was only good stuff in young blood but that was an overly simplistic story