SENS Research Foundation on Recent Plasma Dilution Research

The SENS Research Foundation scientific staff here discuss the recent results demonstrating benefits to an aged metabolism resulting from dilution of blood plasma. Plasma dilution is a comparatively simple process, straightforward enough that self-experimenters with the support of physicians recently replicated the animal study protocol in a few human volunteers. Dilution of blood plasma also dilutes harmful signal molecules present in an aged body, such as those generated by an increased burden of lingering senescent cells. This reduces chronic inflammation and improves tissue function in older individuals.

When researchers surgically conjoin the circulatory systems of a young and an old animal, something remarkable happens: the older animal recovers some features of youth, while the young animal becomes functionally older. This phenomenon is called heterochronic parabiosis. A possible player in the pro-aging/rejuvenating effects of parabiosis that has been largely ignored until recently is the potential role of metabolic toxins and wastes. In addition to the cellular and molecular damage of aging that accumulates in our bodies over time, the body's normal metabolic processes also produce an enormous amount of more transient metabolic waste every day. In youth, much of what could go to waste is instead reprocessed and reused, and the rest is detoxified and excreted.

As we age, however, the organs responsible for detoxifying and eliminating these wastes - the kidneys, the liver, and to a lesser extent the lungs - age along with the rest of us, and their ability to remove these wastes progressively degrades. As a result, waste levels in blood circulation rise with age. These metabolic toxins are definitely bad for us - just ask a patient waiting for a liver transplant or on haemodialysis. Consistent with this, a biomarker called cystatin C, the most reliable marker of loss of kidney function, is a powerful predictor of broader age-related decline.

At the urging of SENS Research Foundation CSO Aubrey de Grey, and with SRF funding, pioneering parabiotic researchers Michael and Irina Conboy conducted a study to tease out the role of access to a young animal's organs in the parabiosis effect in 2015. Researchers built a machine capable of exchanging volumes of blood at will, replacing them with equal volumes of blood (or plasma, or other substitute fluid). They found that the benefits of directly trading old blood for young were dramatically less impressive than the effects of full-on parabiosis complete with the filtering and detoxification services provided by young liver and kidney function.

On the other hand, receipt of young blood did enhance the repair of old animals' muscles after injury, although the effects were less impressive than what's seen in parabiosis - and in this case, there was no inhibitory effect on the muscles of young animals exposed to old blood. Similarly, the ability of an old animal's injured liver to regenerate was enhanced by young blood, and existing age-related fibrosis improved. These experiments show that these health effects are not mediated primarily by removal of metabolic wastes, though certainly they could still be mediated by dilution effects rather than true active-factor transfers.

By this point, a direct test of the dilution hypothesis would seem to be in order - and recently the Conboys ran one. With the blood-replacement machine up and running, they replaced half the blood of old mice - not with young blood, but with saline solution, plus an amount of the albumin protein family equivalent to that in blood, to avoid losing albumin's important non-signaling functions in transporting different substances around the body. Like young blood itself, this "neutral blood exchange" (NBE) substitute (as they called it) would lack all of the pro-aging factors that an old mouse's blood would contain (as well as the metabolic sludge its aging organs would have failed to remove) - but, importantly, would not contain any of the pro-youth molecules that some think are responsible for the effects of heterochronic parabiosis.

Remarkably, a single NBE treatment rejuvenated muscle repair capacity of old mice to equivalent levels of quite young control animals, including major improvements in the number of muscle stem cells engaged to regenerate the damaged muscle, the area of muscle where such cells were active, and in the level of fibrosis left behind. NBE also significantly improved liver health in old animals, partially reversing their fibrosis and reducing the pathological fat deposits in the organ.