Kelly Chen
Birmingham, Alabama, United States

Two mice waddle in unison. They eat together, drink together, and nest together. Their closeness is no act of nature—for on closer inspection a delicate line of sutures is seen connecting them from forelimb to hindlimb. They are linked by parabiosis, the surgical joining of two organisms.

Parabiosis was first described by physiologist Paul Bert in 1864, who stitched two rats together in the hope of forming a shared circulatory system.¹ After the wounds healed, Bert proved that blood flowed as freely between the two animals as if they were conjoined twins.

Bert had established a powerful way to test what happens when blood from one animal enters another. The effects of molecules in the blood could be observed for as long as the animals lived, unlike the transient nature of blood transfusions. Nearly 150 years after its first use, parabiosis would spawn the industry of young blood therapeutics, raising entirely new questions about the understanding and ethics of medicine.

Building on Bert’s success, modern-day scientists have used parabiosis to study healing and rejuvenation. By joining a diseased animal with a healthy animal, researchers could monitor any resulting physiological and pathological changes. Unsurprisingly, healthy animals often became sick when joined with a sick partner. Intriguingly, scientists also noticed that diseased animals often lived longer when connected to a healthy animal than if they had been separated. For example, mice with muscular dystrophy had a longer lifespan when parabiosed to a healthy partner.² It seemed as if sharing a circulatory system could not only make a healthy mouse sick, but also a sick mouse healthier.

Extending this idea, scientists have focused most recently on what happens when two mice—one young and one old, but both healthy—are joined. What would be the effect of an old mouse’s blood on a young mouse? And more intriguingly, the inverse: Could the blood of young mice reverse age-related changes in old mice? What seemed like a wild hypothesis may not be so far-fetched: aging affects all body systems, and blood is what links and supports all the organ systems of the body.

Professor Tony Wyss-Coray of the Department of Neurology at Stanford University was the first to use parabiosis in extensive study of the brain. No one knows exactly why, but the brain’s ability to form new neurons sharply declines with age, impairing memory and thinking as we get older. One clue may come from the blood vessels in the brain, which are the strictest of the body in terms of what molecules they allow in and out. This blood-brain-barrier is a double-edged sword: it protects the brain from potentially harmful toxins in the blood stream, but also makes it very difficult for potentially beneficial blood factors to reach the brain. Wyss-Coray hypothesized that something in blood could cross the blood-brain-barrier and deliver external cues to the brain and affect neuronal stem cells.³ Parabiosis could test this idea.

The results were astonishing. After a young mouse and an old mouse were joined, the old mouse showed an increase of new neurons.³ Even simply injecting young mouse plasma (the liquid component of blood after red and white blood cells are removed) into older mice led to improved memory. Old mice injected with the plasma of young mice could solve a maze as well as mice six times younger.⁴ It was as if their old brains had been revived by young blood, a sign that some age-related cognitive decline was reversible.

In another giant leap forward, Wyss-Coray showed that injecting young human plasma into old mice led to similar effects.⁵ This result meant that human blood, like mouse blood, had some rejuvenating factors. These factors could be of high translational value for targeting Alzheimer’s disease or the general cognitive decline seen in the elderly. The science had moved from mice to men.

Unfortunately, the caution implicit in such revolutionary research was lost in translation when the public caught wind of the study. Several news outlets sensationalized the results with headlines proclaiming “eternal youth,” “the vampire molecule,” and “young blood elixir.”⁶ Studies have been grossly exaggerated on The Late Show with Stephen Colbert and turned into a television episode titled “Blood Boy” on HBO’s Silicon Valley.⁶ Somehow, the studies’ results had turned into a prescription for humans to preserve their youth by drinking young blood. In an interview, Wyss-Coray alarmingly noted the flood of emails he received in the aftermath, many from aged billionaires inquiring about injections and inviting him to lavish parties.⁷ Forget replication studies and clinical trials—a few studies in mice and some news reports surely proved their safety and efficacy.

Understandably, the fight against aging has long captured our attention. From Ponce de León’s quest for the Fountain of Youth to the modern telomerase theory of aging, medicine does not yet know how to prevent our eyes from failing and our bones from aching. Parabiosis studies had suggested the potential not only for longer lifespan, but a longer length of disease-free life (in mice, anyway). The promise of parabiosis catalyzed public excitement into a flood of resources toward young blood therapeutics.

With the help of a $50 million investment, Wyss-Coray formed the company Alkahest.⁷ Alkahest’s goal is to find which specific proteins, of the more than 10,000 proteins found in blood plasma, are causing aging and age-related diseases.⁸ Alkahest emphasizes the potential of using young blood plasma to improve cognitive dysfunction and dementia.⁸ The company’s first clinical trial tested the safety of young plasma for treating Alzheimer’s.⁷ In this trial, Plasma for Alzheimer’s Symptom Amelioration (PLASMA), plasma from young donors was infused for four weeks into eighteen patients with mild to moderate Alzheimer’s disease.⁹ PLASMA confirmed the safety of the plasma infusions and even reported improvement in patients’ capacity to perform basic daily life tasks, such as remembering to take medications and preparing meals.⁹ Still, the study was small, and larger trials are needed before concluding anything about the infusions’ efficacy.

Wyss-Coray was also quick to temper his enthusiasm with a scientist’s skepticism. He says, “People always joke: if you’re a mouse and you have Alzheimer’s, we can cure you, no problem. For humans, however, nothing so far has worked.”⁷ He would later also caution that “. . . we don’t understand the mechanism of how mice look younger.”¹⁰ The science is simply not conclusive, and it is too soon to raise patient hopes. Alkahest, now one of several companies investigating the potential of young blood therapeutics, continues to search for the right combination of blood plasma proteins to treat age-related decline. In the works, for instance, is ALK6019, a cocktail of human plasma proteins optimized to improve learning and memory.⁸

Ultimately, we must prioritize patient safety in the new era of young blood therapeutics. Short-term blood transfusions are common and one of the safest procedures we have; however, there may be complications related to long-term exposure to young plasma, including iron accumulation, development of auto-antibodies, and transmitted infections.¹¹

Provided that young blood plasma is proven to medically benefit the elderly, new ethical concerns arise. According to the American Association of Blood Banks, only 27.5% of blood donations come from people under the age of thirty.¹² Should demand be great enough, a black market could emerge. The legal market would need to recruit more young donors to prevent exploitation. The sale of plasma is legal, and the body can regenerate the amount of plasma given in a typical donation in about a week. Still, it is hard to imagine supplying the amount of plasma needed to sustain entire populations. Medical providers and blood donation agencies would grapple with issues of consent, equal access, and the growing issue of the affluent turning to the needy for blood products.

Overall, the stunning results of young blood studies is faced with a staggering number of scientific and ethical considerations. Researchers race towards clarity each day, but we should be cautious as new findings arise. At times, it may be hard to quell our optimism at the promise of more healthy years to do what we love and be with those we love. But we should remain rational to dispel misinformation and expectations about young blood science.

Young blood therapy, in time, may touch all aspects of medicine. From diagnostics to treatment, such a breakthrough would come at a crucial time as the world population ages. Will there one day be an “aging panel” similar to the comprehensive metabolic panel used commonly today? Will our target be reversing or preventing aging? The major goal of medicine may eventually move from treating disease to promoting wellbeing thanks to young blood. The chance of such a change warrants thorough and lasting reflection so that we are prepared if this reality is fulfilled.

References

1. Bert P. Expériences et Considérations Sur la Greffe Animale. J Anatomie Physiologie. 1864;1:69–87.
2. Hall CE, Hall O, Nevis AH. Prolongation of survival by parabiosis in strain 129 dystrophic mice. Am J Physiol. 1959 Jan; 196(1):110-2.
3. Villeda SA, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–94.
4. Villeda S.A, et al. Wyss‐Coray T. (2014). Young blood reverses age‐related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine, 20, 659–663. 10.1038/nm.3569
5. Castellano J. M., Mosher K. I., Abbey R. J., McBride A. A., James M. L., Berdnik D., et al. . (2017). Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492. 10.1038/nature22067
6. CBC Radio. “The vampire molecule: scientists discover why young blood helps reverse aging.” CBCnews. March 02, 2018. https://www.cbc.ca/radio/quirks/march-3-2018-detecting-the-first-stars-young-blood-rejuvenation-acoustic-tractor-beam-more-1.4557129/the-vampire-molecule-scientists-discover-why-young-blood-helps-reverse-aging-1.4557132. October 16, 2018.
7. Sample, Ian. “Can we reverse the ageing process by putting young blood into older people?” The Guardian. August 04, 2015. https://www.theguardian.com/science/2015/aug/04/can-we-reverse-ageing-process-young-blood-older-people. October 14, 2018.
8. General information on Alkahest. Alkahest. http://www.alkahest.com/. October 05, 2018.
9. “The PLasma for Alzheimer SymptoM Amelioration (PLASMA) Study (PLASMA).” U.S. National Library of Medicine. October 10, 2017.
10. Maxmen, Amy. “Questionable “Young Blood” Transfusions Offered in U.S. as Anti-Aging Remedy.” MIT Technology Review. January 13, 2017. https://www.technologyreview.com/s/603242/questionable-young-blood-transfusions-offered-in-us-as-anti-aging-remedy/. October 12, 2018.
11. Chute RN, Sommers SC. Hemolytic disease and polycythemia in parabiosis intoxication. Blood. 1952 Oct; 7(10):1005-16.
12. Land K, et al. “2012 AABB United States Donor Hemovigilance Report.” AABB, 2012, www.aabb.org/research/hemovigilance/Documents/aabb-donor-hemovigilance-report-2012.pdf. October 17, 2018.