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Young Blood Plasma Makes Old Rats Young Again – But Is It Too Good To Be True?

Posted on 5 September 2023

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The association of blood with youthfulness and strength dates from long before the advent of modern science. Roman historian Pliny the Elder describes how spectators would sometimes rush to drink the blood of fallen gladiators. In 1492, dying Pope Innocent VIII was supposedly given the blood of three children in an attempt to revitalise him, although medical historians doubt this actually happened. The point is that the idea that blood could contain some ‘youthful essence’ of its originator has been around for a long time, but only relatively recently has there been any scientific evidence that it might actually be true.

A Brief History Of Blood Plasma And Rejuvenation

The first evidence came in the 1970s from studies of parabiosis – an experiment in which two mice have their circulatory systems joined together, allowing them to share blood. Remarkably, these experiments showed that an old mouse receiving blood from a young mouse would be rejuvenated. Later experiments suggested that the reverse was also true – the young mouse in the pair would experience signs of ageing. This led to a quest to figure out what underlying process was responsible, which you can read more about here. In short, this rejuvenating effect seems to be down in part to some unidentified beneficial molecules in ‘young’ blood, and also because harmful molecules in ‘old’ blood are diluted.

These findings have driven a search for exactly which molecules in the blood plasma (the non-cellular portion of the blood) are responsible for the rejuvenating effects, as well as a deeper investigation into their mechanisms. One prominent scientist involved in developing and testing blood plasma fractions for the purpose of rejuvenation is Harold Katcher. In a paper that recently entered preprint, he and his colleagues set out to investigate the effects of their piglet-derived plasma fraction, called E5, on old rats. Specifically, they were interested in the effects of E5 on the epigenetic clock, a method used by scientists to accurately estimate the biological age of an organism – more on this later.

The Experiment

In the study, researchers used a fraction of the blood plasma they called E5. Two things make E5 stand out from most previous experiments. The first is that instead of using whole plasma (that is to say, everything that is in the blood, minus the cells), E5 was made from the fraction of the plasma containing exosomes. Exosomes are small packages containing signalling molecules and genetic material that are released by cells into the bloodstream. The second is that E5 was extracted from piglets, rather than from young rats. 

Researchers then took 18 rats and divided them into three groups of 6. One group contained young 30 week-old rats and the other two contained older 109 week old rats. For reference, a rat might expect to live roughly 160 weeks or about three years.

One of the groups containing old rats received 4 injections of E5 at the start of the study, then another series of 4 injections after 95 days. The other old rats received identical treatment with saline solution as a control. The study lasted 155 days in total, and researchers drew blood and assessed the physical and cognitive performance of the rats at various intervals.

Measuring Epigenetic Age

Scientists can estimate what the true biological age of an organism is by looking at epigenetic modifications. These are chemical changes to the DNA that don’t alter the genetic code itself, but change the way in which it is read. To make these estimates, scientists develop epigenetic clocks, which are essentially machine learning algorithms that have been trained on epigenetic data from organisms whose age is known. They can then use this data to estimate the age of an organism based on epigenetic data alone.

Researchers developed six different epigenetic clocks using different training data: three tissue-specific clocks tailor-made for the brain, liver and blood, one clock that was designed to work on any rat tissue, and two clocks that were trained using both rat and human data. These clocks specifically used DNA methylation to estimate age. DNA methylation is a process in which molecular ‘tags’ called methyl groups are added to the DNA molecule in order to change the activity of genes. The addition and removal of methyl groups from certain key sites can be used to estimate age very reliably.

The Results

Regardless of which epigenetic clock was used, E5 treatment was associated with reduced epigenetic age in old rat hearts, livers and blood by a substantial amount. For example, when using the epigenetic clock designed to work on any rat tissue, treatment was associated with a roughly 50% reduction in epigenetic age in the blood and heart, and an over 75% reduction in the liver. This left treated rats with epigenetic ages comparable to those of the young rats in these tissues. Though not as substantial, there was also a significant reduction in the epigenetic age of the hypothalamus (a brain region with a variety of functions including maintaining body temperature).

DNA methylation age in years (as measured by the clock designed to work in multiple rat tissues) for the old rat control group (red), young rat group (blue) and old rat treated group (orange).
Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

So, E5 treatment appeared to reverse the epigenetic changes that occur with ageing, but did this reversal actually rejuvenate the treated rats? The answer appears to be yes, and in more ways than one. E5 treatment was associated with significant improvements in the rats’ grip strengths, and 30 days post-treatment, grip strength was indistinguishable from that of the young rat group. Treatment didn’t seem to negatively impact the rats’ health or behaviour in any way.

The researchers also found that as time went on, markers of ageing in the blood of the treated old rats started to resemble those of the young rats more and more, in some cases becoming indistinguishable. Treated rats also showed reduced levels of inflammation and oxidative stress.

Changes in blood markers over time in the three groups. SPGT and SGOT are markers of liver health (high is bad). BUN is a marker of kidney health (high is bad).
Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

Finally, the rats displayed signs of improved cognitive function – it took treated rats less time to learn how to escape a box than their untreated counterparts, suggesting improved learning and memory.

Time taken in seconds (latency) for rats to escape a box using the correct path.
Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

The Implications

Is all this a little too good to be true? Rewinding the epigenetic clock of an old rat so that it is indistinguishable from that of a young one is an impressive feat, especially with such a simple treatment. The fact that old rats benefited from improved physical and cognitive function suggests that this epigenetic age reduction also translated into health benefits, though we don’t know if the treated rats would have lived any longer than the controls. 

Since E5 was derived from piglets, this research suggests that whatever mechanisms are responsible are conserved between mammalian species to some extent. This bodes well for humans, both because it increases the plausibility of an E5-like treatment working, and because it means that such a treatment might not need to come from human blood. 

There are a few reasons why you might wish to view these results with scepticism, however. The first is that this study is in preprint, which means that it hasn’t yet been peer-reviewed by other scientists. The second is that several authors of this study are either owners, founders or employees of Yuvan Research, the company that will commercialise E5 if it proves successful in human trials. There is therefore a potential conflict of interest.

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    Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

    Title image by engin akyurt, Upslash

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