Junges Blut - 3

http://suppversity.blogspot.de/2018/04/t...vity-young.html

Heute (Donnerstag) um 20:15 in 3sat
http://www.3sat.de/page/?source=/wissens...6487/index.html

Rumors of Age Reversal: The Plasma Fraction Cure
https://joshmitteldorf.scienceblog.com/2...-fraction-cure/

Das wird eine elitäre Jungkur bleiben, aber wer weiß, vielleicht lockt auch der Profit des Massenverkaufs.
Steigt bei den Ratten die max. Lebensspanne?

Mein Wissensstand ist, das auch Bluttransfusionen, also Fremdblut vom Körper wie ein Eindringling wahr genommen wird. Nach einer Bluttransfusion steigt das Risiko an Infektionserkrankungen und auch an Krebs zu erkranken. https://www.stern.de/gesundheit/bluttran...bt-7321296.html

Also wenn ich Lebensgefährlich verletzt bin und einen hohen Blutverlust hatte, freue ich mich über eine Bluttransfusion. Aber um eventuell das Altern zu verzögern, würde ich das Risiko nicht eingehen. Auch mein Bauchgefühl sagt mir das Fremdblut in die Adern nicht gut sein kann.

How Young Blood Rejuvenates an Old Animal’s Brain
Blocking an immune-related protein lodged in blood vessels reverses cognitive decline

Zitat

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To investigate, Wyss-Coray’s team tried a new approach in their latest study, published May 13 in Nature Medicine. “We reasoned that the most obvious way plasma would interact with the brain is through blood vessels,” Wyss-Coray says. “So, we looked at proteins that change with age and had something to do with the vasculature.” One protein that becomes more abundant with age, VCAM1, stood out, and the team showed that it appears to play a pivotal role in the effects of aged blood on the brain. Biological and cognitive measures alike indicated that blocking VCAM1 not only prevents old plasma from damaging young mouse brains but can even reverse deficits in old mice. The work has important implications for age-related cognitive decline and brain diseases. “Cognitive dysfunction in aging is one of our biggest biomedical challenges, and we have no effective medical therapies. None,” says neuroscientist Dena Dubal, of the University of California, San Francisco, who was not involved in the study. “It’s such an important line of investigation; it has tremendous implications.”

VCAM1 (Vascular Cell Adhesion Molecule–1) is a protein that protrudes from the endothelial cells lining the walls of blood vessels and latches on to circulating immune cells (white blood cells, or “leukocytes”). It responds to injury or infection by increasing in number and triggering immune responses. An enzyme shears VCAM1 off endothelial cells at roughly the same rate it is produced, so the total amount in cells stays fairly stable and the amount in circulation is a good proxy for this.

The researchers first checked whether the increase in circulating VCAM1 with age was also accompanied by more of the protein bound to the cells, which they found to be the case for about 5 percent of brain endothelial cells.

They then used cutting-edge “single cell” genetic sequencing technology to inspect these rare cells, finding that they contain many receptors for pro-inflammatory proteins, known as cytokines. “It’s like these cells that express VCAM1 are a type of sensor of the blood environment,” Wyss-Coray says.

The researchers wanted to know whether this increase in VCAM1 attached to cells merely accompanies signs of brain aging, or whether it actually helps cause the damage. One sign that a brain is getting older is widespread activation of its immune cells, called microglia. These cellular housekeepers, which normally perform routine housekeeping functions, enter an inflammatory state, releasing cytokines and free radicals. “So, they’re not cleaning the house, they’re messing it up,” Wyss-Coray says. “They really trash the place.”

Another indicator is a decline in activity related to the formation of new brain cells in the hippocampus, a brain region involved in memory and one of few regions thought to produce new cells in adulthood. The team used two techniques to block VCAM1: One of them genetically deleted the protein from the mice’s brains. Another injected an antibody that binds to it to stop anything else attaching. Both methods prevented signs of brain aging in young mice infused with old plasma and reversed existing markers in elderly mice brains. The researchers then gave the mice learning and memory tests. In one, which involves remembering which of several holes is safe to drop through, treated elderly mice performed as well as youngsters once fully trained. “The aged mice looked like they were young again in terms of their ability to learn and remember,” Dubal says. “It’s remarkable.”

The researchers’ working theory for what happens, is that cytokines in aged blood first trigger brain endothelial cells to produce more VCAM1. When leukocytes then attach to the protein, the cells signal the brain to activate microglia. This creates an inflamed environment that puts dampers on the stem cells involved in new neuron formation. “What they’re showing here, is the blood-brain barrier’s not static, and can sense changes in the blood, then relay those signals to the brain, telling it to become more inflamed, explains Richard Daneman a neuropharmacologist specializing in the blood-brain barrier at the University of California, San Diego.

Stopping leukocytes from interacting with VCAM1 prevents this signaling and thus protects against or even reverses the effects of old blood. “One really has the feeling reading through this, that a major leap has been made [not only] in basic science discovery but also [in pointing to] a new therapeutic pathway for one of our most devastating problems,” Dubal contends. The precise molecular details of this pathway remain to be determined, Wyss-Coray says. “Is VCAM1 signalling into the cell, or are immune cells releasing toxic factors?” he asks. “We need to understand, at the molecular level, how this works.”

Treatments based on these findings would not necessarily have to cross the blood-brain barrier. “One of our biggest challenges is how do we get treatments into the brain given this fortress wall?” Dubal says. But VCAM1 is on the blood side of that wall. A downside is that blocking a component of the immune system could have side effects. A drug, called Tysabri that binds to leukocytes, stopping them attaching to VCAM1, is already used for treating multiple sclerosis. Problems arose shortly after its approval as some patients harbored a virus before treatment that then ran rampant.

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https://www.scientificamerican.com/artic...-animals-brain/


By disabling a protein in the brain’s blood vessels, researchers ease age-related deterioration in mice

Zitat

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What they don’t know, however, is what makes those transformations occur. On Monday, scientists reported they had latched on to a protein made by the blood vessels as a key player in how older blood seems to induce cellular damage inside the brain.

What’s more, they found that disabling the protein in older mice improved the function of their brain cells and the mice’s performance on cognitive tests. Their study, published in the journal Nature Medicine, points to the protein, called VCAM1, as a possible target for a therapy for neurocognitive disorders.

As both humans and mice get older, cells in the brain called microglia — a type of nervous system immune cell — become more active, producing neuroinflammation. At the same time, the activity of neural stem cells, which are involved in making more neurons, gets tamped down. Together, these two shifts are thought to play a key role in the structural and functional deterioration that happens as we age.

Injecting blood from an old mouse into a young mouse triggers these same cellular responses to aging, suggesting that certain factors in the plasma — the protein-rich, fluid part of blood — signal for these changes to happen inside the brain. But unlike other organs, a healthy brain is sealed off from the blood by a barrier, leaving open the question of how the components of blood can influence what’s going on inside the brain.

“What was completely not understood was how circulating factors in the blood can communicate given that we have an intact blood-brain barrier,” said Hanadie Yousef, the lead author of the paper, who conducted the study as a postdoctoral researcher at Stanford.

For the study, Yousef and her colleagues turned to brain endothelial cells — those that make up the blood vessels that run along the brain. They focused on the cells in the hippocampus, a region of the brain key to learning and memory. They figured that these cells, which help make up the blood-brain barrier, might act as intermediaries in the interplay between the two sides. And when they looked at the levels of different proteins in people as they aged, they discovered that the one that increased the most over time was VCAM1, which is made by and found on the surface of these endothelial cells.

Endothelial cells throughout the body express the protein VCAM1, which lassos immune cells circulating in the blood and helps escort them into a tissue when it is damaged or injured. Their directive is different in the endothelial cells in the brain. Here, they similarly tether immune cells, but the cells can’t cross into the brain because of the barrier. But through different signals, that binding still sets off the brain’s immune response.

Researchers have noticed, however, that too much VCAM1 might be a sign of or be involved in a waning brain. In one study of almost 700 older adults, a team found that higher VCAM1 levels correlated to worse cognitive impairment.

In the new study in mice, the researchers dismantled VCAM1 in two ways to figure out whether the high levels of the protein helped cause cognitive impairment, or whether they were simply a byproduct of aging.

First, they deleted the gene (called Vcam1) that encodes the protein, and found that these mice were protected against the effects of the transferred aged blood.

They also blocked VCAM1 with an antibody, leaving immune cells in the blood unable to tether to the endothelial cells. These older mice had more neural stem cell activity and reduced microglial activity than untreated older mice, demonstrated improvement on cognitive measures, and solved a maze test as if they were spring chickens.

“In old mice, if we gave them the antibody against VCAM1 or deleted Vcam1 for most of their lifetimes, it basically blocks the bad effects of this aged plasma,” said Tony Wyss-Coray, a professor of neurology and neurological sciences at Stanford and senior author of the paper.

The researchers don’t know exactly what was occurring, but they propose that certain components in older plasma promote the expression of VCAM1. With more VCAM1 on the surface of the endothelial cells, there’s more tethering of immune cells to the blood brain barrier. That in turn produces signals that promote inflammation and the other cellular — and, eventually, cognitive — problems associated with aging.

Julie Andersen, a neuroscientist at the Buck Institute, who was not involved in the work, said she thought it was significant that the Stanford researchers had identified something in the endothelial cells that appears to be involved in the mechanisms of aging. Oftentimes, she said, research tends to overlook these cells.

She raised the question, though, about whether the process described in the paper might just be one way aging wears on a brain. If, for example, the blood-brain barrier starts to “leak” a bit over time — if it allows cells or proteins into the brain that shouldn’t be there — then that might be another aging process that hurts the brain. Just targeting VCAM1 might not be able to overcome that and the other ways time erodes the health of the brain.

“Clearly this is a potential mechanism that can play a role in the impact you see in terms of microglial activation and reduction in stem cell proliferation, but I would contend in aging, there are other things that could be at play here,” Andersen said. “But I do think that this is cool that they’ve actually identified an endothelial cell marker that’s altering with age and really have come up with a viable hypothesis for how the increase in that marker could be driving some of these age-related phenomena, and how the use of an antibody can restore some of the changes.”

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https://infosurhoy.com/cocoon/saii/xhtml...ration-in-mice/

Young blood cocktail stops Alzheimer's decline, early clinical trial reports
https://newatlas.com/alkahest-young-bloo...6SNfyQ2k8Ormc3Y

Zitat von Prometheus im Beitrag #60

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Und vor allem: Basierend auf dem aktuellen Wissensstand werden auch Ansätze zur Verjüngung geschildert. Interessiert?

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Age Reduction Breakthrough
by Josh Mitteldorf
If you eschew hyperbole and hang in for the long haul, maintaining a discipline of understatement in the midst of a flashy neon world, you may be offered a modicum of credence when you make an extraordinary announcement. No one is entitled to this courtesy twice. If the news that you trumpet to the moon does not pan out, your readers will be justified in discounting everything you say thereafter.

Here goes.

I believe major rejuvenation has been achieved in a mammal, using a relatively benign intervention that shows promise of scaling up to humans. I’m going to stake my reputation on it.


Cartoon by Maddy Ballard

In the race to effect substantial, system-wide rejuvenation, Harold Katcher is a dark horse. He has the right academic credentials and a solid history of research. In fact, in earlier life he was part of a team that discovered the breast cancer gene, brca1. I asked Harold for a biographical sketch, and have printed it in a box at the end of this posting.

But Katcher has no research grants or university lab or venture capital funding, no team of grad students mining databases and screening chemicals in the back room.

One thing Katcher has going for him is the correct theory. Most of the explosion in aging research (and virtually all the venture capital startups) are looking to treat aging at the cellular level. Their paradigm is that aging is an accumulation of molecular damage, and they see their job as engineering of appropriate repair mechanisms.

The truth, as Katcher understands it, is that, to a large extent, aging is coordinated system-wide via signal molecules in the blood. It was our common realization of this vision that brought Katcher and me together more than a decade ago. Katcher briefly describes his 2009 epiphany below. It was the source of his 2013 essay (it took a few years to get it into print) on the significance of parabiosis experiments for the future of aging science.

Of course, Katcher was not the only one to get the message about the power of signal molecules in the blood to reprogram tissues to a younger state throughout the body. The problem is that there are thousands of constituents represented in tiny concentrations in blood plasma, but conveying messages that cells read. Which of these are responsible for aging? A small number of labs, including the Conboys at Berkeley, Amy Wager at Harvard, and Tony Wyss-Coray at Stanford have been searching for the answer over the last decade and more.

Katcher has been able to guess or intuit or experimentally determine the answer to this question. With seed funding from Akshay Sanghavi, he set up a lab in Bangalore two years ago, and tried to rejuvenate old lab rats, using a fraction extracted from the blood of younger rats. The first round of experiments were encouraging, published in this space a year ago. He obtained the next round of funding from a reader of this blog, and had enough rats to titrate dosages experimentally, and to see if treated rats who aged again over time could be re-treated successfully.

There is a hole in this story that awaits the resolution of intellectual property rights. Katcher and Sanghvi have not applied for patents and have not yet found a suitable partner to provide financing for human trials. They have not revealed any details of the treatment, besides the fact that it is in four intravenous doses, and that it is derived from a fraction of blood plasma. Katcher thinks that the molecules involved will not be difficult to manufacture, so that when a product is eventually commercialized, it will not require extraction from the blood of live subjects, rodent or human.

We’re still waiting for longevity curves of these treated rats. In the meantime, the best available surrogate measure of age comes from methylation clocks, as developed by Steve Horvath at UCLA, and other scientists as well. Crucially, Katcher found an ally in Horvath, who didn’t just test his rejuvenated rats, but did the needed statistical analysis to develop a set of six methylation clocks specialized to rats. FIve of the clocks are optimized for different tissues, and one is calibrated across species, so that it can measure age in humans as well as corresponding age in “rat years” (about 1/40 human year). The two-species clock was a significant innovation, a first bridge for translating results from an animal model into their probable equivalent in humans.

In a paper posted to BioRxiv on Friday, Katcher and Horvath report results of the methylation measurements in rejuvenated rats. “Crucially, plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]....According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age.”


Human-rat clock measure of relative age defined as age/maximum species lifespan.

Besides the methylation clock, the paper presents evidence of rejuvenation by many other measures. For example:

IL-6, a marker of inflammation, was restored to low youthful levels
Glutathione (GSH), superoxide dismutase (SOD), and other anti-oxidants were restored to youthful levels
In tests of cognitive function (Barnes maze), treated rats scored better than old rats, but not as well as young rats.
Blood triglycerides were brought down to youthful levels
HDL cholesterol rose to youthful levels
Blood glucose fell toward youthful levels
A major question in blood plasma rejuvenation experiments has been how often the cure must be administered. Many of the components of blood plasma are short-lived, secreted into the blood and absorbed continuously throughout the day. The good news from Katcher’s results is that it seems only four injections are needed in order to achieve rejuvenation.

A second question which these experiments resolve is whether rejuvenation requires both adding and removing molecular species from the blood plasma. For example, pro-inflammatory cytokines are found in old blood at much higher levels. Irina and Mike Conboy, people who I regard as most credible in the field, have said that removing bad actors from the blood is probably more important than restoring youthful levels of beneficial signals. They were grad students at Stanford 15 years ago, when the modern wave of parabiosis science was initiated, and have pursued the subject continuously ever since. Katcher’s experiments have achieved their results only by adding blood components, not by removing or even neutralizing others.

In Katcher's experiments, molecular species were added, but nothing was removed. This suggests that he has found the necessary formula for re-programming epigenetics, so that lower levels of the bad actors occur as a result. But it remains to be seen whether even better results can be obtained if some plasma constituents are removed.

A question that remains unresolved concerns the location and mechanism of the aging clock. I have been undecided over the years between two models:

There is a central aging clock, perhaps in the hypothalamus, which keeps its own time and transmits signals throughout the body that coordinate methylation state of dispersed tissues
Information about epigenetic age is dispersed through the body, and the body's clock is a feedback loop that is continually updating methylation age locally in response to signals received about the methylation age globally.
There is a suggestion in the data that the hypothalamus may be more difficult to rejuvenate than other tissues. Does it play a more important role than other tissues in coordinating the age of the entire body? Horvath (personal communication) counsels caution in drawing this inference until measurements are corroborated and more experiments are done.

The Bottom Line

These results bring together three threads that have been gaining credibility over the last decade. Mutually reinforcing, the three have a strength that none of them could offer separately.

The root cause of aging is epigenetic progression = changes in gene expression over a lifetime.
Methylation patterns in nuclear DNA are not merely a marker of aging, but its primary source. Thus aging can be reversed by reprogramming DNA methylation.
Information about the body’s age state is transmitted system-wide via signal molecules in the blood. Locally, tissues respond to these signals and adopt a young or an old cellular phenotype as they are directed.
Harold Katcher, Biographical Sketch

So, you might consider me a late bloomer. While I have thousands of citations in the literature, with publications ranging from the discovery of the human ‘breast cancer gene’, to protein structure, bacteriology, biotechnology, bioinformatics, and biochemistry, there was no center or direction to my work as I had given up my personal goal of solving/curing aging when I learned that ‘wear and tear’ was the cause of it. Yet something happened in year 1985 when I was in California working with Michael Waterman and Temple Smith (fathers of bioinformatics) that is inexplicable: I found myself in Intensive Care with a tube inserted into my trachea and the knowledge that I might not live. And then I had a dream: I dreamed that somehow in the far future (and on another world), I was being feted for ‘bringing immortality to mankind’. Clearly, I survived that incident (started with an infected tooth). I lived a wonderful life – becoming a computer programmer (which I loved), leaving that for the University of Maryland’s Asian division, becoming a full professor and then the Academic Director for the Sciences, in Tokyo, Japan. By the time I left Japan in 2004, (my daughter Sasha was a fourth-grader, (yonensei), in the Japanese school system), I was teaching for U of M online – somewhat retired, and looking forwards to writing computer programs for fun and profit. Yet I never ever forgot that dream. It was clearly impossible; I had no lab – and really, there was no way to repair all damaged cells – it’d be like sweeping back the ocean. And then, in 2009, I read an old paper from 2005, a paper written by the Conboys, (Michael and Irina), Tom Rando and others, coming from Irv Weisman’s lab, that completely changed my life; that showed me that everything I believed about aging was wrong – that aging occurred at the organismic level, not at the cellular level and could be reversed. Well, the rest of the story is about persistence and the blessed intervention of Akshay Sanghvi who too saw there was another way and provided the structural, monetary, and emotional support (and some good ideas) that had me start a new career at age 72 in Mumbai, India. I feel twenty years younger than I did three years ago, I guess that’s another hint about aging. Now the ‘mystical’ dream? It wouldn’t be the first time in history that that happened – take that as a datum.


https://joshmitteldorf.scienceblog.com/2...hrough/#respond

Out With the Old Blood
Posted on June 8, 2020
There is great promise in 2020 that we might be able to make our bodies young without having to explicitly repair molecular damage, but just by changing the signaling environment.

Do we need to add signals that say “young” or remove signals that say “old”?

Does infusion of biochemical signals from young blood plasma rejuvenate tissues of an old animal? Or are there dissolved signal proteins in old animals that must be removed?

For a decade, Irena and Mike Conboy have been telling us removal of bad actors is more important. But just last month, Harold Katcher reported spectacular success by infusing a plasma fraction while taking away nothing. Then, last week, the Conboys came back with a demonstration of the rejuvenating power of simple dilution. [Link to their new paper]

Dilution procedure

They simply replaced half of the blood plasma in 2-year-old mice with a saline solution containing 5% albumin. What is albumin? Blood plasma is chock full of dissolved proteins, about 10% by weight. About half of these are termed albumin. Albumin is the generic portion. It doesn’t change through the lifetime. It doesn’t carry information by itself. But albumin transports nutrients and minerals through the body.

The Conboys took care to show that albumin has no rejuvenation power on its own, and had nothing to do with their experimental results. Rather, they had to replenish albumin in diluting blood, because the animals would be sickened if half their albumin were removed. Replacing the albumin in a transfusion is akin to replacing the volume of water or maintaining the salinity.

In preparation for this experiment, the Conboys have invested years in miniaturizing the technology for blood transfusions, so that mice can be subjected to the same procedures that are commonplace in human hospitals.

Dose-Response

The Conboy lab replaced 50% of mouse blood plasma. They got spectacular results with a single treatment, based on a lucky guess. They have not yet experimented with 30% or 70%. They don’t know yet how long the treatment will last and how long it needs to be repeated.

Evidence of rejuvenation

As with previous papers from the Conboy lab, the group focused on repair and stem cell activity as evidence of a more youthful state. Three separate tissue samples were taken from liver, muscle, and brain.

“Muscle repair was improved, fibrosis was attenuated, and inhibition of myogenic proliferation was switched to enhancement; liver adiposity and fibrosis were reduced; and hippocampal neurogenesis was increased.”

They measured nerve growth factors in the brain, and detected a more robust response, typical of young mice
They lacerated muscles and showed repair rates typical of much younger animals
They examined microscope slides of liver tissue, and showed that it is less fatty and striated than is typical of older mice



Figure 2. Rejuvenation of adult myogenesis, and albumin-independent effects of TPE. One day after the NBE, muscle was injured at two sites per TA by cardiotoxin; 5 days later muscle was isolated and cryosectioned at 10 µm. (A) Representative H&E and eMyHC IF images of the injury site. Scale bar = 50 µm. (B) Regenerative index: the number of centrally nucleated myofibers per total nuclei. OO vs.ONBE p = 0.000001, YY vs ONBE non-significant p = 0.4014; Fibrotic index: white devoid of myofibers areas. OO vs ONBE p = 0.000048, YY vs YNBE non-significant p = 0.1712. Minimal Feret diameter of eMyHC+ myofibers is normalized to the mean of YY [9]. OO vs. ONBE p=3.04346E-05, YY vs. YNBE p=0.009. Data-points are TA injury sites of 4-5 YNBE and 5 ONBE animals. Young and Old levels (detailed in Supplementary Figure 1) are dashed lines. Representative images for YY versus YNBE cohorts are shown in Supplementary Figure 6. (C) Automated microscopy quantification of HSA dose response, as fold difference in BrdU+ cells from OPTI-MEM alone (0 HSA). There was no enhancement of myogenic proliferation at 1-16% HSA. N=6. (D) Meta-Express quantification of BrdU+ cells by automated high throughput microscopy for myoblasts cultured with 4% PreTPE versus PostTPE serum and (E) for these cells cultured with 4% of each: PreTPE serum + HSA or PostTPE serum + HSA. Significant increase in BrdU positive cells is detected in every subject 1, 2, 3, and 4 for TPE-treated serum (p=0.011, <0.0001, <0.0001, 0.0039, respectively), as well as for TPE-treated serum when 4%HSA is present (p<0.0001, <0.0001, <0.0001, =0.009 respectively). N=6. (F) Scatter plot with Means and SEM of all Pre-TPE, Post-TPE, +/- HSA cohorts shows significant improvement in proliferation in Pre TPE as compared to and Post TPE cohorts (p*=0.033), as well as Pre+HSA and Post+HSA cohorts (p*=0.0116). In contrast, no significant change was observed when comparing Pre with Pre+HSA (p=0.744) or Post with Post+HSA (p=0.9733). N=4 subjects X 6 independent assays for each, at each condition. (G) Representative BrdU IF and Hoechst staining in sub-regions of one of the 9 sites that were captured by the automated microscopy. Blood serum from old individuals diminished myogenic cell proliferation with very few BrdU+ cells being visible (illustrated by one positive cell in Pre-TPE and arrowhead pointing to the corresponding nucleus); TPE abrogated this inhibition but HSA did not have a discernable effect.

What’s missing? They did not test any measures of physical or cognitive performance at the level of the organism.
Evidence of behavioral changes (learning and memory, endurance, strength)
Inflammatory markers
Blood lipids
Methylation clock (Horvath, UCLA) or proteomic clock (Lehallier, Stanford)
Some of this is planned for future research. Mike and Irina plan to submit tissue samples for analysis by the Horvath mouse methylation clock.

Clock?

I am a committed enthusiast for the methylation and proteomic clocks that are the best surrogates we have for aging. These technologies can tell us whether anti-aging interventions have been effective without having to wait for animals (or humans) to die before reporting results. But the Conboys still regard these technologies as unproven, and they bristle at the word “clock”. The closest they come is to catalog the entire proteome of treated mice, comparing it to untreated young and old mice.

Multi-dimensional t-SNE analyses and Heatmapping of these data revealed that the ONBE proteome became significantly different from OO and regained some similarities to the YY proteome. Supplementary Figure 4 confirms the statistical significance of this comparative proteomics through Power Analysis, and shows the YY vs. OO Heatmap, where the age-specific differences are less pronounced than those between OO vs. ONBE, again emphasizing the robust effect of NBE on the molecular composition of the systemic milieu.

Translation: As controls, they had mice that underwent plasma exchange with mice of similar age. YY were young, positive controls, and OO were old, negative controls. Treated mice were ONBE=”Old—Neutral Blood Exchange”. Rather than relying on “clock” algorithms that compute an age from the proteome, they compared the entire proteomes of test animals with those of old and young animals, and foud that they resembled the young animals more closely.

Aging and epigenetics

I was an early advocate of the theory that aging is driven primarily by changes in epigenetics. Other proponents include Johnson, Rando, and Horvath. This theory is now mainstream, though its acceptance is far from universal. (The main reason people have difficulty with the idea is the question, “why would the body evolve to destroy itself?” I present a comprehensive answer in my popular book and my academic book.)

On the face of it, the new Conboy result is powerful evidence for the epigenetic theory. They have shown that there are proteins in the blood that actively retard growth and healing. Remove half theses proteins and the animals are able to grow youthful tissues and to heal better. The obvious conclusion is that, with age, there are signaling changes in the blood that weaken the animal and inhibit repair.

There are, however, other ways to interpret the changes. Aubrey de Grey has said (personal communication)

“When everything in the blood except the cells and the albumin is replaced by water, the body will definitely respond by synthesising and secreting everything that it detects a shortage of, whereas the bad stuff will not be so rapidly replaced, since by and large it was only there in the first place as a result of impaired excretion/degradation.”

The Conboys don’t embrace the programmed aging perspective, but neither is their understanding of what they see the same as Aubrey’s. The way Irina explained it to me is that the age of the biological of the body is simply a measure of how much damage has accumulated, but that cycles of epigenetics and catalysis are self-reinforcing.

“Epigenetic, mRNA, and protein are steps of one process, regulation of gene expression. And none of these steps are permanent they all actively and constantly respond to cell environment — tissue and systemic milieu…With aging there is a drift which is re-calibrated by a number of rejuvenation approaches…When an auto-inductive age-elevated ligand is diluted, it cannot activate its own receptor and induce its own mRNA, so ligand levels diminish to their younger states for prolonged time.”

The Conboys theorize that these harmful proteins are part of a positive feedback loop, in other words, a cycle that is self-sustaining

epigenetic state ⇒ gene expression ⇒ translation to circulating proteins ⇒ feedback that alters the epigenetic state

With age, the body has slipped into a dysfunctional, self-sustaining cycle, and with the shock of disruption, they are able to nudge it back into a more robust and youthful cycle, also self-sustaining.


Figure 6. Model of the dilution effect in resetting of circulatory proteome. System: A induces itself (A, red), and C (blue); A represses B (green), C represses A. A dilution of an age-elevated protein (A, at D1: initial dilution event), breaks the autoinduction and diminishes the levels of A (event 1, red arrow); the secondary target of A (B, at event 2 green arrow), then becomes de-repressed and elevated (B induces B is postulated); the attenuator of A (C, at event 3 blue arrow), has a time-delay (TD) of being diminished, as it is intracellular and was not immediately diluted, and some protein levels persist even after the lower induction of C by A. C decreases (no longer induced by A), and a re-boot of A results in the re-induction of C by A (event 4 blue arrow) leading to the secondary decrease of A signaling intensity/autoinduction, and a secondary upward wave of B (events 5 red arrow and 6 green arrow, respectively). alpha = 0.01, kc = 0.01, beta = 0.05, epsilon = 0.1, ka = 0.1. Protein removal rates from system: removalA = 0.01, removalB = 0.1, removalC = 0.01, Initial values: initialA = 1000, initialB = 400, initialC. = 700

For me, the surprising thing in Irina’s account is that there is no hysteresis in this system. The reprogramming responds to changes in the blood levels of signals within minutes. There is no homeostasis in such a system. I wonder how that can be. Life is all about homeostasis, and intuitively, we all imagine that negative feedback loops are more common than positive feedback loops. (Negative feedback loops lead to homeostasis; positive feedback loops lead to runaway, exponential change.)

Is there a clock somewhere? Is the brain special?

In the Conboy view, signals in the blood are emitted from all over the body, and not especially from the hypothalamus. If brain tissue responds in a seemingly exceptional way to proteins in the blood, it is because of selective passage of those proteins by the blood-brain barrier.

The authors remind us that in past parabiosis experiments (where blood is exchanged between old and young mice), the brain tissue of the young mice grew older but brains of the old mice didn’t get younger. This was an indication that brain aging is caused by affirmative action of “bad actors” in the plasma, and that these are able to penetrate the blood-brain barrier. This observation was part of the inspiration for the current experiments.

The corresponding procedure in humans is already FDA approved

Therapeutic Plasma Exchange (TPE) is a well-established medical procedure, and has already been performed on an experimental basis by co-author Dobri Kiprov. There is anecotal history of suggestive results, which I will write about in my next post.

Comparison with Katcher’s Elixir

This week’s announcement from the Conboys and last month’s preprint from Katcher/Horvath come from the same school of thought: that aging is coordinated through the body by signal molecules in the blood. Both demonstrated dramatic rejuvenation in rodents based on a short-term intervention, and both have plans for commercialization and human trials to begin ASAP.

So it is curious that in other ways, the programs of Katcher and Conboy are so different.

While both approaches are rooted in differing compositions of blood plasma between young and old, the Conboys focus exclusively on removing species that are inhibiting youthful regeneration, while Katcher’s approach is to add back the proteins that formerly kept the animal young.
The Conboys have fully disclosed all aspects of their experimental protocol, whereas the content of Katcher’s elixir remains a trade secret.
Katcher is on the fringe of academic research, and the Conboys’ lab is at one of the premier academic institutions in the world.
Katcher is a year further along, having experimented with different dosages and timings. Neither Katcher nor the Conboy lab has yet demonstrated life extension.
The Conboys demonstrate rejuvenation with wound healing, tissue structure, and renewal of nerve growth. Katcher’s claim is based on physiology (especially inflammation), cognitive performance, and methylation clock algorithms.
In fact, Katcher regards restoration of youthful methylation patterns as the best evidence he could offer for rejuvenation (I agree), while the Conboys are reserving judgment about the importance of methylation, and bristle at the language of a methylation “clock”.
Katcher understands the effects of plasma transfusions in terms of a broad theory (which I support). Aging is an epigenetic program, governed and enforced by a “clock” that operates via a feedback loop between circulating proteins that govern gene expression and gene expression that generate those proteins. The Conboys recognize they are working this feedback loop (their Fig 6) but they resist the theory that it is the essential cause of aging.
My guess is that a combination of their two approaches will be necessary for full remediation of aging, and that a combination of their resources, credibility, theoretical foundations, and contacts would be a transformative event for medical science, for biotech industry, and for biological theory. It is my fervent hope that Katcher and the Conboys might work together.

https://joshmitteldorf.scienceblog.com/2...blood/#comments

Zitat von Prometheus im Beitrag #68

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Gut, dann diskutiere ich hier mal alleine weiter...

These: Im Blutplasma existieren Signalstoffe, die den Zellen signalisieren, wie alt sie sich zu verhalten haben.

Etwas korrekter formuliert: Die Epigenetik der Zellen wird von Signalstoffen aus dem Blutplasma beeinflusst. Im alten Organismus zirkulieren also Botenstoffe, die die epigenetische Uhr der Zellen auf "alt" programmieren.

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Zitat von Prometheus im Beitrag #68

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Einige dieser Signalstoffe sind bereits bekannt. Josh Mitteldorf hat sie vor ca 7 Jahren mal in seinem Blog übersichtlich aufgelistet:

Molecules in the Blood that Signal Self-Destruction

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Zitat

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Ich sag's mal so, Prometheus. Wenn 2 Profis wie wir zusammenarbeiten, haben wir spätestens in 2 Jahren die wichtigsten Zellkernhormone aufgelistet und können uns an die Verjüngung machen.

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Jo, Ihr Superkerle, dann legt mal los, damit wir alle noch was davon haben

Frage:
Joker, warum gehst Du davon aus, dass die Zellkernhormone andere sind, als die, die wir schon kennen?
Sind es vielleicht eher die Mengen, die vorhanden sind?
Oder irgend welche Metaboliten der bekannten Hormone?

<ignore nurdug>

???
Was meinst Du damit?

Zitat von Prometheus im Beitrag #73

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Hier ein Überblick über die Kernrezeptoren:

https://de.wikipedia.org/wiki/Kernrezeptoren


@Joker
Ja, ich sehe da auch ein großes Potential... Neues Thread?

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#66
Aderlass war nicht ganz verkehrt :)
hätten halt wieder auffüllen müssen ;)

Naja, ob so eine Blutspendemaus wirklich älter wird? Mir reicht schon eine Blutentnahme und ich liege am Boden.