动物造模 z-bio 2022-09-30 944

　　Xenosymbiosis is a 150-year-old surgical technique that connects the vasculature of two living animals. It mimics natural instances of shared blood supply, such as conjoined twins or animals sharing the same placenta in the womb.

　　In the lab, xenobiotic symbiosis offers a rare opportunity to test what circulating factors in one animal's blood do when it enters other animals. Experiments with symbiotic dentate species have led to numerous breakthroughs in endocrinology, tumor biology, and immunology, but most of the discoveries occurred 35 years ago. For reasons that are not yet clear, the technology was gradually buried after the 1970s.

　　However, in the past few years, a small number of laboratories have begun to resume xenobiotic research, especially in the field of aging research. By linking the circulatory systems of an old mouse and a young mouse, scientists have achieved some striking results. In the heart, brain, muscle, and nearly every tissue studied, the blood of young mice appears to bring new life to aging organs, making older mice stronger, smarter and healthier, and even giving them hair become more glossy. Now, these labs have begun to identify the components of young blood responsible for these changes. Last September, a clinical trial in California began testing the benefits of young blood in elderly patients with Alzheimer's for the first time.

　　The power of symbiosis

　　In 1864, the physiologist Paul Bert conducted the earliest documented experiments of xenobiotic symbiosis. At the time, he removed the skin of the flanks and abdomens of two white mice and sewed the animals together in hopes of creating a shared circulatory system. Biology did the rest: Natural wound healing joined the circulatory systems of the two animals together as capillaries regrowed at the sutured intersection. Bert found that fluid injected into one mouse's blood vessels could easily flow into another. This work earned it an award from the French Academy of Sciences in 1866.

　　That process hasn't changed much since Bert's initial experiments. The technique has been used in experiments with hydras, frogs and insects, but has performed best in rodents. By the mid-20th century, scientists had studied a range of phenomena using xenobiotic mice or rats. For example, one team rejected the idea that tooth decay is caused by sugar in the blood by using a pair of xenobiotic rats. Of the two rats, only one was fed glucose daily. But because of the shared circulatory system, they have similar blood sugar levels. However, only the rats that actually consumed the glucose developed dental caries.

　　Cornell biochemist and geriatrician Clive McCay was the first to apply xenobiosis to aging research. In 1956, his team joined 69 pairs of symbiotic rats of nearly all ages. The spliced rats included a one-and-a-half-month-old pair and a 16-month-old pair, the equivalent of 5 and 47 years old in humans, respectively. "If two rats couldn't adapt to each other, one would nibble on the other's head until the latter died," the researchers wrote in a description of their work. Of the 69 pairs of symbiotic rats, there were 11 pairs died from a mysterious commensal disease that may have been tissue rejection.

　　In McCay's first xenobiotic aging trial, 9 to 18 months after young and aged rats were joined together, the bones of aged rats were similar in weight and density to their younger counterparts. In 1972, two scientists from the University of California studied the lifespan of aged and young symbiotic rats. Aged rats survived four to five months longer than controls, suggesting for the first time that the circulation of young blood may affect lifespan.

　　Despite these striking findings, xenobiotic research has been gradually abandoned. Either the researchers think they have learned everything from it, or the threshold for applying to the relevant agency for xenobiotic research is too high, according to experts who study the history of the technology. Whatever the reason, the trial was interrupted. Until a stem cell biologist named Irving Weissman reborn xenobiotic research.

　　Tracing the source

　　In 1955, 16-year-old Weissman learned to splice mice together under the tutelage of a pathologist at a small-town hospital in Great Falls, Montana. He remembers adding a fluorescent tracer to the blood of a symbiotic mouse and watching it flow back and forth between the two animals. "It's just amazing," Weissman said.

　　For the next 30 years, he continued his research on stem cells and regeneration using the natural symbiont, the sea squirt. In 1999, when Wagers was a newly recruited postdoc in Weissman's lab at Stanford University, she proposed to study the movement and fate of blood stem cells. Weissman suggested she use symbiotic mice and use fluorescent markers to track cells in one of the mice. Wagers' experiments soon led to two discoveries about the properties and migration of hematopoietic stem cells. It also inspired her friends at Stanford University.

　　In 2002, Irina Conboy, a postdoc in Rando's lab, presented a paper by Wagers at a journal club meeting. At the time, Irina's husband, Michael Conboy, a postdoc in the same lab, was sleeping in the back of the conference room. When it came to stitching the mice together, he was startled. "What we've been talking about for years is that aging seems to be about all the cells in the body, and the whole tissue seems to decline rapidly together," says Michael. However, they were unable to come up with a realistic experiment to study what exactly regulates physical aging.

　　"I was like, 'Hey, wait, these groups are sharing blood,'" Michael said, answering a question they've had for years. At the end of the speech, he rushed to Irina and Rando. However, before Michael had finished explaining his thoughts, Rando said, "Let's do it together."

　　They teamed up with Wagers, who experimented with suturing in aged-young symbiotic mice, and taught Michael the technique. After five weeks, the young blood repaired muscle and liver cells in the aged mice, largely by triggering senescent stem cells to start dividing again.

　　The team also found that young blood accelerated the growth of brain cells in aged mice, although the work was not mentioned in a 2005 paper describing their results. Taken together, the findings suggest that blood contains a number of elusive factors that regulate the rhythm of aging in different tissues.

　　In 2008, Irina and Michael, already at the University of California, Berkeley, linked muscle regeneration to the activation of the Notch signaling pathway, which drives cell division, or the inactivation of transforming growth factor-beta, which prevents cell division. In 2014, they identified an anti-aging factor circulating in the blood: oxytocin. It's a hormone known for its involvement in labor and its use as a binder, and it's a drug approved by the U.S. Food and Drug Administration to induce labor. Oxytocin levels decline with age in both men and women. When injected into aged mice, the hormone quickly rejuvenated muscles by activating muscle stem cells.

　　Wagers has been conducting anti-aging research at Harvard University and established his own lab in 2004. She recruited experts who study different organ systems to help them study the anti-aging effects of young blood on various organs. With the help of colleagues, Wagers set out to screen for proteins that were abundant in young blood but not in older blood. One jumped into their eyes: growth differentiation factor-11 (GDF11). Wagers et al. found that direct infusion of GDF11 alone was sufficient to increase muscle strength and vitality and reverse DNA damage in muscle stem cells.

　　Human trials must be cautious

　　Of course, there are some lingering doubts about whether activating stem cells (which is often what young blood does) over an extended period of time can lead to too many cell divisions. "My suspicion is that long-term treatments to regenerate cells in aged animals, whether it's plasma or drugs, will lead to an increase in cancer." Rando said that even as people learn how to make cells younger, some things have to be done with caution.

　　Michael Conboy is worried about another thing: He has seen many symbiotic mice die from symbiotic diseases, so testing xenobiotic technology in humans must be very cautious. "I would be very careful with any experiment in which large amounts of blood or plasma are regularly transfused into elderly people."

　　In this regard, Karoly Nikolich, CEO of California-based startup Alkahest, said he understood these safety considerations, but emphasized that millions of blood and plasma transfusions have been safely carried out in humans so far. A preliminary study by Alkahest is expected to be completed by the end of this year. The company plans to initiate more in-depth studies to test the role of young plasma in treating different types of dementia and age-related diseases.

　　All the caveats about young blood are justified, given the dashed hopes in the anti-aging field. Over the past 20 years, researchers have identified the anti-aging properties of numerous treatments, including calorie-restricted diets, the chemical resveratrol found in grape skins, telomerase, which protects chromosome integrity, and the ability to prolong The immunosuppressive drug rapamycin for longevity in mice and stem cells whose function and number decline as humans age.

　　However, only two modalities, caloric restriction and rapamycin, have been shown to actually delay or reverse the effects of aging in many different mammalian tissues, and neither has been translated into anti-aging therapy. The former produced conflicting results in primates, while the latter had toxic side effects.

　　In contrast, young blood appears to reverse the effects of aging, and there may be few known safety concerns in humans. At the same time, the related results have been confirmed in the xenobiotic aging research carried out in multiple laboratories so far. Still, scientists and ethicists remain concerned that human trials will be conducted outside of approved clinical trials until evidence of the therapy's safety and efficacy emerges. Unlicensed stem cell transplants have become a nascent industry, and unrestricted transfusions of young blood will become easier, experts warn.