Where are the bloody entrepreneurs?

For many years’ scientists have researched Parabiosis (transfusing young blood into aging animals) to bring stem cells throughout the body back to life, helping to heal damage, replace cells, and increase organ function. 

Medical overview found here.

Many interesting findings resulted from the research such as:

• 2005: Thomas Rando’s (Stanford University) research showed that older tissue seemed to contain the same amount of stem cells as younger tissue. Rando swapped the blood of young and old mice. After five weeks, Rando found an astonishing reversal: The younger mice had started aging, their stem cells lagging and their muscles dragging. The older mice, however, were hyped up on new cells that made their livers youthful, their hearts stronger, and practically reversed aging.
• 2013: Amy Wagers and Richard Lee found that a protein from the blood of young mice can reverse the symptoms of heart failure in older mice. They showed that the protein GDF 11 appeared to act on skeletal muscle stem cells and enhance muscle repair. (this study disagrees)
• 2014: Researchers found that higher levels of the hormone oxytocin in young blood stimulate muscle growth. Factors in the blood also seem to stimulate stem cells in many organs to start dividing again. This in effect, brings stem cells throughout the body back to life, helping to heal damage, replace cells, and increase organ function.
• 2014: Saul Villeda, Tony Wyss-Coray and their team found that exposing an old mouse to young blood can decrease apparent brain age. The effects were seen not only at the molecular level, but also in the structures of the brain, and in several measures of learning and memory. In this case, the effects were controlled by a specific protein in the brain known as Creb (cyclic AMP response binding element), although the stimulating factor in the blood was not identified.
• 2016: Irina Conboy’s research team used a blood exchange technique between old and young mice, without surgically joining them. When they received old blood, the muscle strength of young mice decreased, and the growth of their brain cells slowed down. A protein known as B2M (beta-2-macroglobulin) may be involved in this process, although it does not appear to be elevated with age-possibly acted on by another signal from the older blood.
• 2017: Hanadie Yousef at Stanford University identified a protein called VCAM1 that increases with age and causes signs of aging when injected into young mice.
• 2017: (study) A protein in the brain, Tet2, declines with age, but mice whose brains have been given a boost of Tet2 are able to grow new brain cells and they improve at mouse-learning tasks.  Such a boost in Tet2 can be provided by the presence of young blood because in these experiments, old mice who are joined to young mice in a parabiosis have an increase in Tet2 in their brain.

So, if it works in mice, what about humans? This is a little trickier because of the lack of research, risks and, regulatory challenges that we will get into, but 2 companies are pioneers in the field:

• Alkahest (http://www.alkahest.com ) – Tony Wyss-Coray (board member), a neurobiologist studying Alzheimer’s disease at Stanford University has done research where plasma from young donors (aged 18-30) was transfused into patients with dementia (results of a trial).  Alkahest announced in 2016 that it had used human teen blood, injected it into old mouse blood, and remarkably reversed aging. From tired, slow, and decrepit, the elderly mice suddenly had sharp memories, renewed cognition, and were exercising with the vigor of youth. “Wyss-Coray’s lab analyzed many of the 700 protein factors circulating in the blood to determine how such factors could affect stem cell function over time. They found that they could determine a person’s relative age by analyzing these factors.” (more).
• Ambrosia Plasma (https://www.ambrosiaplasma.com) – Jesse Karmazin’s company Ambrosia is transfusing plasma from people aged 16-25 into people aged 35-92. They found that those who had been treated with young blood had lower levels of several proteins known to be involved in disease, namely carcinoembryonic antigens (which increase in cancer patients) and amyloid (which forms plaques in the brain in Alzheimer’s disease patients). Ambrosia transfuses plasma into patients for a ~8k price (here). Video (here)–From the video you can glean that this takes ~2 hours and they have found after 1 treatment a 20% reduction in amyloid (a starch like protein that is deposited in the liver, kidneys, spleen, or other tissues in certain disease) + lower cholesterol and lower inflammation biomarkers.  That being said, an update posted here reported that “…none of the results so far are either large enough or extensive enough to definitively be something other than the placebo effect, chance, or other items such as a patient making lifestyle changes”.

Beyond Wyss-Coray and Karmazin there are several others doing incredible research in this area.   Here are just a few and their referenced papers:

• Conboy IM, Conboy MJ, Wagers AJ, et al. (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760-764.
• Brack AS, Conboy MJ, Roy S, et al. (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 317:807-810.
• Villeda SA, Luo J, Mosher KI, et al. (2011) The aging systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90-94.
• Vileda SA, Wyss-Coray T (2013) The circulatory systemic environment as a modulator of neurogenesis in brain aging. Autoimmunity Reviews 12:674-677
• Villeda SA, Plambeck KE, Middeldorp J, et al. (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 20:659-663.
• Smith LK, et al. (2015) Beta-2 microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nature Medicine 8:9320937
• Kanya Honoki, (2017) Preventing aging with stem cell rejuvenation: Feasible or infeasible? NIH
• Castellano JM, et al. (2017) Human umbilical plasma proteins revitalize hippocampal function in aged mice. Nature 544:488–492

So, if there is both proof and pioneers pushing the envelope why is not more being done given the importance of the subject? Basically, it comes down to the science is still not well understood however what is not apparent is why there seem to be very little dollars available for research.

You would also think that there would be more entrepreneurs pushing into this area given that it’s a classic marketplace problem that is well understood.   Find and pay young 20 somethings to donate blood/plasma (they need money) and then find wealthy 70 somethings to purchase the blood/plasma transfusions.   The lack of interest may be due to the risks such as:

• Complications: Blood transfusions are generally considered safe, but there is some risk of complications. Mild complications and rarely severe ones can occur during the transfusion or several days or more after. Reactions include:
  • Allergic reaction – which might cause hives and itching, and fever.
  • Infections – Blood banks screen donors and test donated blood to reduce the risk of transfusion-related infections, so infections, such as HIV or hepatitis B or C, are extremely rare.
  • Acute immune hemolytic reaction – Your immune system attacks the transfused red blood cells because the donor blood type is not a good match. The attacked cells release a substance into your blood that harms your kidneys.
  • Delayed hemolytic reaction – Similar to an acute immune hemolytic reaction, this reaction occurs more slowly. It can take one to four weeks to notice a decrease in red blood cell levels.
  • Graft-versus-host disease – In this condition, transfused white blood cells attack your bone marrow. Usually fatal, it’s more likely to affect people with severely weakened immune systems, such as those being treated for leukemia or lymphoma.
• Mortality: A Canadian study published in the July 11 JAMA Internal Medicine found an elevated risk of mortality from blood donated from young (17-20) and female donors–About an 8% increased risk of death from any cause.
• Disease: Irina Conboy, a neurologist at the University of California, Berkeley and who’s research is mentioned above, says that frequently exposing older people to foreign plasma may be unsafe because hyperactivation of their immune systems could lead to autoimmune or inflammatory disease. (more)
• Cancer: Higher stem cell replication rates also bear the risk of cancer. (more)

After all, most tech entrepreneurs don’t want to be responsible for hurting anyone (i.e. Silicon Valley’s ‘do good’ mantra).

The second reason entrepreneurs probably don’t push into this area is due to the PR backlash.  Mario Macis, an economist at the Johns Hopkins Carey Business School who has studied incentives for blood donation said: “Even though it’s legal, it’s still considered not totally moral or ethical to pay cash to blood donors.” It’s like handing out blood money and the FDA worries that paying donors would jeopardize the safety of the blood supply. If money were on the line, donors may lie about their health or their risky behaviors.   Here is just one of many examples that Ambrosia Plasma has had to endure since its founding: (example).  Several countries such as Australia, France, the UK, Japan, and New Zealand all have made compensation for blood donation illegal (more).

The third reason entrepreneurs may not be interested in this space is the fact that advertising is prohibited.   A spokeswoman for the Food and Drug Administration says the agency “regulates the collection and manufacture of blood and blood components to help protect the health of the blood donor and to ensure the safety, purity, and potency of the blood product.” While it’s not approved specifically for anti-aging treatments, like other drugs, it can be prescribed for so-called off-label uses as long as there are no advertising or efficacy claims involved.

Ambrosia Plasma purchases their plasma but to do this at scale a company would need to create their own blood bank (that adheres to the WHO guidelines), hire a knowledgeable physician (plasma is a prescription drug) several nurses and a research staff. Link to how to start a blood bank and the associated business plan. To get such a startup off the ground would require several million dollars and as noted above much more risk than most venture capitalists would care to accept.

After looking into the subject for some time I am left to wonder 2 things.  1.  Why isn’t more government/corporate research money going into such an important subject? and 2. What if matching the age of the donor and the end recipient is super important? Could we be currently harming young people that receive blood from an older donor?

Update: FDA puts out warning. (here)