Fight Aging!

The popular science article I'll point out today does a fair job of following the past decade or so of work arising from heterochronic parabiosis, in which the circulatory systems of a young animal and an old animal are joined. The young animal exhibits some degree of accelerated aging, while the old animal exhibits some degree of rejuvenated function. The question all along has been why exactly this happens: what are the underlying mechanisms, and can they be replicated as a basis for therapy.

The obvious first approach was to transfuse young donor blood into old recipients, as positive results would mean that the existing blood transfusion infrastructure could be used to provide a relatively low cost therapy to large number of older people. Unfortunately, this doesn't work. The results from animal studies and human trials indicate that if there are benefits, they are too small and unreliable to care about. There is something about parabiosis that isn't captured by transfusion.

Otherwise, initial research focused on factors in young blood that might be beneficial. This gave rise to the identification of GDF11 as one such factor, followed by considerable debate over whether this work was flawed, in parallel to the establishment of Elevian, a company that continues to work on therapies based on delivery or upregulation of GDF11. Researchers later provided compelling proof that the effect of beneficial factors in young blood is small in comparison to the effect of harmful factors in old blood, and from there identified TGF-β as one such problem factor. The suggestion here is that parabiosis works via a dilution of harmful factors, not via introduction of youthful factors.

Experiments in diluting blood in old animals with saline, while adding significant amounts of albumin because it cannot be diluted in the bloodstream without severe consequences, seemed to bear out this viewpoint. Animals exhibited similar benefits to those undergoing parabiosis. And yet, is the real signal in the albumin, and not in the dilution? Recently, researchers have delivered albumin to old animals without dilution of blood, and this also produces benefits. So is this a case of albumin becoming modified or damaged in increasing proportions in the bloodstream with advancing age, while cells are very sensitive to that form of damage? This is but the latest twist in this ongoing saga, so perhaps, or perhaps not. Give it a few years, and there may be another chapter to come.

Has the fountain of youth been in our blood all along?

In a series of studies over the last 15 years, researchers have shown that, when infused with blood from young mice, old ones heal faster, move quicker, think better, remember more. The experiments reverse almost every indicator of aging the teams have probed so far: It fixes signs of heart failure, improves bone healing, regrows pancreatic cells, and speeds spinal cord repair. It sounds sensational, almost like pseudoscience. It's some of the most provocative aging research in decades. These studies, which use a peculiar surgical method called parabiosis that turns mice into literal blood brothers, show that aging is not inevitable. It is not time's arrow. It's biology, and therefore something we could theoretically change.

Blood itself will not become a treatment for old age. It's too messy, too complicated, too dangerous. But because of these labs' findings, we know that somewhere swirling around in young veins are signals that awaken the natural mechanisms to repair and restore the body. These mystery factors, once researchers can identify and fine-tune them, could become precious medicine. Heterochronic parabiosis, in which researchers pair two animals at different points in the lifespan, was first used to study aging in the 1950s. But by the 1990s, it was largely forgotten - until more recent studies put it back on the map.

On the theory that blood-borne factors might orchestrate the transitions of aging, researchers turned to heterochronic parabiosis. The team's 2005 findings caused a stir. If an older mouse's leg gets frozen with a piece of dry ice, the cells in charge of muscle repair don't respond much; the number of active cells increases by just 10 percent or so. But after heterochronic parabiosis, twice as many cells activate in response to injury - a reaction like that of a young animal. Older mouse livers demonstrate a similarly sprightly cellular turnover. Longevity enthusiasts eagerly discussed the findings, even though there is little evidence that heterochronic parabiosis extends life; even in rodents, all we know for sure is that it undoes some late-in-life decay.

Meanwhile, a cottage industry began selling young plasma. Around 2016, Ambrosia, a California company, offered to infuse customers as part of a clinical trial that charged participants $8,000 to join. (So far, the team has not published any findings in the scientific literature.) Other entities and individuals launched similar efforts, such as a proposed study that would charge large sums to frail elderly people for doses of young plasma. This "therapeutic plasma exchange" is a legitimate treatment for certain rare autoimmune diseases and problems with coagulation, so these providers are not necessarily required to obtain explicit approval from the Food and Drug Administration so long as they make no unsubstantiated health claims about their regimen. But, of course, they did: Companies marketed benefits for people with memory loss, heart disease, and even Parkinson's. The FDA, now stepping into the regulatory role of the 17th-century pope, released a stern memo in 2019 that curbed the trend.

The most straightforward path to a therapy would be to pinpoint a pro-aging factor in old blood, mouse and human, that a drug could block. Many groups have identified such elements. One has found that a protein called CCL11 increases in aged humans and mice and is correlated with reduced brain cell birth. The other obvious tactic is to identify youthful plasma's secret formula and optimize it. Some research suggests the hormone oxytocin might be a candidate; other work has identified the protein GDF11. Combination therapies are also under consideration; a biotech company is exploring mixtures of hundreds of blood-borne proteins as therapies for a variety of age-related diseases.

It's also possible that the rejuvenating effects seen in experiments don't arise from one magic ingredient, or even from some combination of a dozen or a hundred compounds, but happen simply because the procedure dilutes some unknown harmful substances that accumulate in old blood. From this perspective, there's no particular need for young stuff: Any form of plasma replacement will do. It's sort of like changing the oil in your car. One research group is starting a company and are aiming for human clinical trials to determine if simply flushing out the bloodstream can help with problems like frailty and declining cognition.