Parabiosis

Stories of the surgical separation of conjoined twins—the medical feat of separating two beings previously living as one—often makes the news. In that light, the science of connecting two beings, or parabiosis, might sound more Frankenstein than medical advancement.

Parabiosis studies in mice, however, have been central to rejuvenation research. Stitching together two beings, one old and one young, offers scientists a unique vantage point from which to study the process of aging to the end of extending longevity and even reversing decline.

Here’s why parabiosis matters to longevity and the future science of aging.

What Is Parabiosis?

The word parabiosis is derived from the Greek words, para “besides” and bios “life.” Parabiosis is the physical joining of two living organisms together via surgical procedure such that they share one physiological system. Parabiosis mimics the shared blood supply that naturally occurs in conjoined twins and offers a “transformative experimental paradigm” for the study of age-related chronic diseases.

Parabiosis and Aging: What is Heterochronic Parabiosis?

Parabiosis was first invented in 1864 by physiologist Paul Bert who joined two mice together to test whether they could share one circulatory system. While Bert’s experiments were a bit of a novelty at the time, his research was later picked up in the 1950s by Clive McCay, a biochemist and gerontologist at Cornell University known for his studies on caloric restriction and longevity.

McCay applied parabiosis to longevity by connecting a young mouse to an older mouse. His study demonstrated the phenomenon of heterochronic parabiosis, or that when a young animal is joined to an older animal, the older animal “recovers some features of youth, while the young animal becomes functionally older.” In the 1970s, however, research went dormant after rats began to die a week or two following surgeries. (Termed ‘parabiotic disease’ at the time, the deaths may have actually resulted from tissue rejection.)

Studies on heterochronic parabiosis were later picked up in the early 2000s. Most notably, in 2005, Irina and Mike Conboy at Berkeley published a study demonstrating that “exposure to the young animal’s circulation dramatically improved the older parabiont’s regenerative response to injury.” This revived interest in the study of parabiosis, aging, and the potential for rejuvenation.

The Basics of Aging and Cell Health

In the basic science of aging, stem cells gradually lose their ability to renew and differentiate as they age. Skeletal muscle satellite cells specifically are crucial to muscle fiber maintenance, repair and remodeling. As satellite cells age, their regenerative potential declines. This is in part because Notch signaling, essential to satellite cell maintenance, also declines with age.

In their 2005 study, Irina and Michael Conboy paired young mice with old mice to find that heterochronic parabiosis specifically restored the activation of Notch signaling as well as the proliferation and regenerative capacity of aged satellite cells. These results suggested that the age-related decline of cell activity could be modulated by systemic factors that change with age.

What Has Parabiosis in Mice Proven?

Since Bert pioneered the practice, over 1700 articles related to parabiosis have been published.

Notably, in 1969 Douglas Coleman joined a diabetic mouse with a non-diabetic mouse via parabiosis. While the disease did not improve in the diabetic mouse, “the normal partners lost weight, became hypoglycemic, and died of apparent starvation within 50 days after surgery. In contrast, the diabetic partners gained weight rapidly and remained diabetic.”

At first Coleman blamed the deaths on his surgical ability, but later, studies proved that diabetic mice “produced a blood-borne chemical so powerful that it could fatally starve the normal partners.” Dr. Coleman theorized that while blood-borne factors helped prevent obesity and speculated that blood-borne factors might also help cause obesity. His research led to the later (90s era) discovery of leptin, a key regulator of body weight and energy homeostasis.

Also in 1969, a separate parabiosis study performed on rats linked kidneys, hypertension, and genetic determinants.

Then, in 2005, a group of Stanford researchers connected young mice and older mice confirming that the stem cells of the older mice worked more effectively in their younger mates. The takeaway: the functionality of stem cells is tied more closely to their surrounding environment than their age.

A few years later researchers paired more mice (young with old) and determined that the infusion of young blood boosted cognitive function on the older partner and the infusion of older blood impaired spatial learning and memory for the younger mates.

The science in mice is clear: there’s much more that parabiosis can teach us about how aging occurs, and we are perhaps just at the forefront.

Startup company Elevian is one entity exploring the potential of parabiosis to reframe how scientists approach aging, targeting the aging process itself instead of cancer, dementia, and other age-related impairments that accompany decline. Their focus is how the single protein Growth Differentiation Factor 11 (GDF11) changes with age.

Researchers found that injecting just GDF11 using parabiosis provided many health benefits to the aging animal. These results are “really strong proof that circulating factors regulate aging,” according to Mark Allen, Elevian CEO.  Another study published in March 2020, indicates that GDF11 was shown to “significantly improve glucose tolerance in aged mice.”  Still, researchers warn that not all effects in mice, specifically that of GDF11 studies, translate to humans.

Are Scientists Experimenting Parabiosis on Humans?

No two people are being stitched together just yet, but plasma injections are happening.

After neuroscientist Tony Wyss-Coray’s lab at Stanford University found that injecting plasma from young mice into old mice improved cognitive function in the older mice, a 2017 study injecting plasma from young people into older people with Alzheimer’s indicated some improvement on functional ability.

Then in 2018, Ambrosia, a controversial start-up company opened a clinic in San Francisco and began offering infusions of young blood plasma from young donors to people aged 30 and older with the promise of improving “biomarkers related to Alzheimer’s disease, cancer, inflammation, and stem cells after a single treatment.” In 2019, the FDA briefly shut down Ambrosia’s clinic operation, issuing a warning to consumers about the lack of proven benefit. Ambrosia has since restarted operations and continues to offer blood products for sale today.

While parabiosis offers a new frontier into aging and rejuvenation, results from experiments on mice are not guaranteed to translate to humans, and the exchange of plasma and cells is not quite the same as stitching beings together. But, just like Bert’s original discovery wasn’t applied to aging until a century later, the science extending from parabiosis will no doubt offer many more insights into longevity in the decades to come.