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by Alexandra Taylor Published on 24th Sep 2015
by Alexandra Taylor Published on 24th September 2015
On September 21, World Alzheimer’s Day, Alzheimer’s Research UK released a chilling statistic: one in three people born in the UK will develop dementia in their lifetime. As human lifespan increases, so unfortunately, does the prevalence of age-related chronic conditions. In 2014, the World Health Organization estimated that the number of dementia sufferers worldwide will increase by over 300% by 2050. Scientists are working feverishly to combat this looming public health crisis. News on this topic is not all bad, however. Last year, researchers in California, led by Stanford neurologist Tony Wyss-Coray, published some startling (and heartening) findings. After adding blood from a young mouse to the circulatory system of an old mouse, researchers observed a significant increase in tissue function. Brain tissue was among the areas showing improvement, making this a plausible area for Alzheimer’s research. While the results are exciting, the methods by which Wyss-Coray’s lab arrived at them are a little shocking. The researchers sewed together pairs of mice of differing ages, and allowed their circulatory systems to fuse, a technique known as parabiosis. They then studied the effects that intermingling blood had on the two mice. The technique has since been refined and can now be completed via injection, opening the doors for potential therapeutic uses in humans. Restoration Breakthrough In the human brain, one of the first regions to decline with age is the hippocampus, which is responsible for both learning and memory. This is partially due to a decline in stem cells, which give rise to new cells throughout the body. 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. What is even more exciting is that their research on mice has shown that tissues can recoup some age-related loss of function when infused with blood from a younger animal. “This opens an entirely new field. It tells us that the age of an organism, or an organ like the brain, is not written in stone. It is malleable. You can move it in one direction or the other,” Wyss-Coray told the Guardian. “It’s almost mythological that something in young organisms can maintain youthfulness, and it’s probably true.” History of Parabiosis One surprising aspect of this discovery is that the technology has been available for so long. It did not require the highly sophisticated (yet still woefully incomplete) knowledge of the human brain that we have today. This study could have been performed decades ago. As a technique, parabiosis has been around since at least the 1600s. Methods of conjoining have much improved since those times, but the process is still gruesome. It was not until 2008, however, that scientists began to uncover its potential for studying age-related changes in learning and memory.In 2011, Wyss-Coray’s team found that when mice of different ages were conjoined, the younger mouse could not develop as many new neurons. A later study, published in Nature Medicine in May 2014, focused more on the behavioral effects of commingling. In order to test for behavior the mice could not be conjoined, so the lab streamlined a process for injection. Whereas before the younger mice had suffered adverse effects from old blood exposure, this risk could now be circumvented. These developments paved the way for human trials. The study in Nature Medicine showed the old mice injected with young plasma did better on classic behavioral tests, such as the maze water test. Researchers observed positive structural changes in their brains, including a 20-50% increase in the neuroplasticity network. If these findings can be reproduced in humans, this technique could be used to treat a host of age-related diseases. The scientific community has taken notice: last year, Science named Wyss-Coray’s work one of the top breakthroughs of the year. Human Trials Human trials testing the efficacy of young-to-old blood transfusions are currently underway in the US. The randomized, double-blind study involves 18 people aged 50-90 with moderate to severe Alzheimer’s. For one month each patient will receive a weekly plasma injection from donors aged 30 and under, in addition to a four-week course of saline as a placebo, with six weeks between the treatments. They will then be subjected to multiple rounds of testing for mental acuity, and their caregivers will watch them closely for behavioral changes. Because blood transfusion is already an established process, the team was able to skip the traditional animal testing phase and jump right to human trials. The results are expected at the end of this year. Wyss-Coray and others have set up a private company, Alkahest, in order to fund such studies. Much of the money for the initial trial was donated by the family of a Chinese billionaire, who suffered from Alzheimer’s and appeared to improve temporarily after receiving a blood transfusion. Alkahest hopes to separate out factors related to healthy stem cell function and mix them into a “cocktail” to inject into aging patients. It is estimated that this goal could take about 10-15 years. Despite the optimism of those involved in this venture, this area of study is still very new. The existence of a private company does not mean the results are guaranteed. Parallel WorkScientists other than Wyss-Coray are doing significant research in this field. Two researchers at the Harvard Stem Cell Institute, Dr. Lee Rubin and Dr. Amy Wagers, published separate papers on growth differentiation factor-11 (GDF-11) in Science last May. By injecting GDF-11, a circulating protein, into the blood of older mice, they found they were able to exercise longer and better differentiate between smells. Dr. Rubin’s mice developed more blood vessels and neural stem cells, while Dr. Wager’s team found improved muscle stem cell function. It is estimated that many blood factors besides GDF-11 could have this effect. Both studies illustrate the potential scope of this type of work. Measured Enthusiasm Scientists working in this field are quick to caution that while young-to-old plasma transfusions could improve health later in life, there is no evidence that it could prolong the lifespan of mice or humans. The technique is not a way to turn back the clock, but rather to restore some function to worn-out tissues. Furthermore, as with other techniques that involve stem cell stimulation, there is also a risk of uncontrolled cell division leading to cancer. Ultimately, the Stanford trial may find the transfusions have little to no effect on the subjects. Humans live long lives in complex environments, and the results of the mice studies may not carry over. Wyss-Coray and others have noted that the “cocktail” approach—mixing known factors for injection—may be more effective in a human trial setting. The development of synthetics would be a necessary step for widespread therapeutic benefit, as human plasma is in limited supply. While the results of this trial may send scientists back to the drawing board, they are nonetheless eagerly awaited.