$36,000
$25,176

An Effort to Obtain More Human Data on Plasma Transfusion from Young to Old

Here I'll link to a recent press article on Ambrosia, a company currently working to obtain more human data on the effects of transfusing young blood plasma into old individuals. The aim is to see whether or not this can usefully change the balance of signaling molecules to, say, spur greater stem cell activity. There has been a trial in Alzheimer's patients, but some signs in animal studies that transfusions from young to old don't do much. It seems useful to speed up the process of determining whether or not transfusions are an interesting line of research, or something that only looked promising. That means more patients and larger trial populations, which Ambrosia is working on.

These transfusion initiatives are one of a number of outgrowths of parabiosis research in mice. Heterochronic parabiosis is the name given to connecting the circulatory systems of an old and a young individual. The older mouse shows a modest rejuvenation in a number of measures of aging, and the younger mouse shows some greater signs of aging - though most of the focus here has been on the old mouse. In recent years this technique has been used to search for potentially actionable differences in levels of specific signal molecules circulating in the bloodstream. For example, stem cell activity declines with aging, and this is likely governed by signaling processes. If levels of the most relevant molecules could be adjusted in old individuals, it might be possible to produce benefits that look quite similar to those of stem cell therapies: increased regeneration and tissue maintenance. This class of approach puts damaged, aged cells back to work, and does little to address causes of aging based on accumulation of metabolic waste, such as cross-links that stiffen blood vessels, but to the degree that it can improve health it is probably worthy of further investigation in the same way as stem cell therapy was back in the day.

One potential shortcut to the production of therapies is to perform transfusions: deliver young blood or young plasma to old individuals. I call this a potential shortcut because it really is still very uncertain as to (a) whether or not the whole process works in humans anywhere near as well as it works in mice, and (b) whether or not transfusions will recapture the effects of parabiosis to a useful degree. The evidence in mice suggests so far that it may not. It is possible to paint all sorts of scenarios in which the fact that old and young cells are in contact, feeding signals to one another in a feedback loop, is necessary to produce beneficial changes in the old individual. It is also possible to imagine signals with a short half-life, that won't be recaptured in transfusions, or changes in the old environment that are based on an increased level of specific signal molecules. That increased level won't be changed in the slightest by the arrival of some amount of young blood plasma. Only reduced levels are likely to be impacted that way.

In any case, testing and perhaps ruling out the fast path of transfusions seems like a fair plan. If it works, it will draw in more funding to build the better option of manipulating signal molecule levels directly. It if doesn't work, that result will direct scientists to focus on more productive lines of research and development. There is some grumbling from the expected quarters over the structuring of this present initiative by Ambrosia, but getting it done is better than not getting it done. The data will be useful in the sense that only sizable effects are interesting, and thus before and after data for participants will be convincing. Marginal effects, of the sort in which it would have been useful to have a control group to establish whether or not any benefits actually resulted, would mean that this probably isn't worth further exploration. Still, this well demonstrates the fact that many scientists who work within the heavily regulated, slow, and repressive system of medical development really don't like it when people try to get things done more rapidly and more inventively. To the extent that it closes down productive avenues, this is a dangerous attitude.

Young blood antiaging trial raises questions

It was one of most mind-bending scientific reports in 2014: Injecting old mice with the plasma portion of blood from young mice seemed to improve the elderly rodents' memory and ability to learn. Inspired by such findings, a startup company has now launched the first clinical trial in the United States to test the antiaging benefits of young blood in relatively healthy people. But there's a big caveat: It's a pay-to-participate trial, a type that has raised ethical concerns before, most recently in the stem cell field. The firm's co-founder and trial principal investigator is a 31-year-old physician named Jesse Karmazin. His company, Ambrosia in Monterey, California, plans to charge participants $8000 for lab tests and a one-time treatment with young plasma. The volunteers don't have to be sick or even particularly aged - the trial is open to anyone 35 and older. Karmazin notes that the study passed ethical review and argues that it's not that unusual to charge people to participate in clinical trials.

"There's just no clinical evidence [that the treatment will be beneficial], and you're basically abusing people's trust and the public excitement around this," says neuroscientist Tony Wyss-Coray of Stanford University in Palo Alto, California, who led the 2014 young plasma study in mice. Wyss-Coray has since started a company, Alkahest, that, with Stanford, has launched a study of young plasma in 18 people with Alzheimer's disease, evaluating its safety and monitoring whether the treatment relieves any cognitive problems or other symptoms. The company covers the participants' costs. Wyss-Coray expects results by the end of this year.

In Ambrosia's trial, 600 people age 35 and older would receive plasma from a donor under age 25, according to the description registered on ClinicalTrials.gov, the federal website intended to track human trials and their results. Karmazin says each person will receive roughly 1.5 liters over 2 days. Before the infusions and 1 month after, their blood will be tested for more than 100 biomarkers that may vary with age, from hemoglobin level to inflammation markers. The $8000 fee will cover costs such as plasma from a blood bank, lab tests, the ethics review, insurance, and an administrative fee, Karmazin says. "It adds up fairly quickly."

The scientific design of the trial is drawing concerns as well. "I don't see how it will be in any way informative or convincing," says aging biologist Matt Kaeberlein of the University of Washington, Seattle. The participants won't necessarily be elderly, making it hard to see any effects, and there are no well-accepted biomarkers of aging in blood, he says. "If you're interested in science," Wyss-Coray adds, why doesn't such a large trial include a placebo arm? Karmazin says he can't expect people to pay knowing they may get a placebo. With physiological measurements taken before and after treatment, each person will serve as their own control, he explains. Doubts aside, Ambrosia's trial has already attracted attention from the investment company of billionaire Peter Thiel.

Comments

Circulating Proteomic Signatures of Chronological Age (http://biomedgerontology.oxfordjournals.org/content/70/7/809.short) revealed in blood samples two most strongly age associated proteins: chordin-like protein 1 (BMP signaling antagonist) and Pleiotrophin - a secreted growth factor with a plethora of functions known to be a marker for cardiovascular risk and osteoporosis (involved in bone formation, neurite outgrowth, and
angiogenesis also regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow; and it has also been implicated in learning and memory). Absence of Pleiotrophin affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro (http://www.sciencedirect.com/science/article/pii/S1044743116300811)
It is strange why no one has studied the effect on the rejuvenation of these blood factors?

Posted by: Dmitry Dzhagarov at August 2nd, 2016 11:06 PM

There are two scenarios how parabiosis works.
1. It is a closed loop system, where old or sick organism transmits "help me" signals and young healthy organism makes factors in response to these signals. In that case no practical therapies are on the horizon.
2. Young blood simply contains beneficious factors all the time. In that case many blood samples can be compared with all equipments we have and feed supercomputers with these data. Studying samples would give more informations than a frankenstein-like experiment.

Posted by: Martin S. at August 3rd, 2016 12:10 AM

I completely agree with Reason, here. It is a swift, clever, and self-funding experiment that blows past the usual research barriers to give us a quick and dirty answer. If a large effect is noticed, better funded and more careful research will surely follow. If there is a mild, mixed result, then it is probably not worth researching further.

The one large BUT in all this is just what Martin S. posted--these are transfusions, not parabiosis. If a young system needs to be linked to an old system so that the young system can help the old system (at some cost to itself) then this experiment will not show good results.

And if further experimentation shows parabiosis works but transfusions do not, then we are probably done here. That, or we have finally found a real use for all these damn teenagers running around...

Posted by: Paul at August 3rd, 2016 1:13 AM

I feel like Wyss Coray is being a "tiny" bit hypocritical.
He started a company before he knew if it works as well.

Posted by: Anonymoose at August 3rd, 2016 11:29 AM

I like Dr Karmazin's study and its design. It is a good study and yes, it will give us a "quick and dirty" answer. There is no need to include a placebo arm as Dr. Wyss-Coray suggests. We all know what placebo does. Studying placebo effects on aging is useless - aging kills, we all know that without studying. Including individuals of different ages brings the study design closer to real life conditions.

Posted by: Shoshnik Bahoon at August 7th, 2016 12:19 PM

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