Longevity Briefs: Can ‘Diluting’ The Blood Slow Ageing?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Whether it’s fictional vampires drinking blood to maintain their immortality or the supposed healing properties of Roman gladiator blood, humanity clearly has a fascination with the idea that this red substance in our veins is somehow related to youth and health. Thanks to modern science, we now know that there is some truth to this idea. Experiments show that when two mice – one old and one young – are stitched together so that they share the same blood, the older of the two animals appears to age more slowly while ageing in the younger animal is accelerated.

Why does this happen? Over the years, experiments have provided two explanations. ‘Diluting’ the blood by replacing the blood plasma (the fraction of the blood that doesn’t include the blood cells) with a saline solution reproduces the benefits of blood sharing experiments. This suggests that there are some harmful factors in the blood of older organisms that can be removed to slow ageing and improve health. However, collecting blood plasma from young organisms and injecting it into older organisms also has beneficial effects, suggesting that there are additional beneficial components of ‘young’ plasma that diminish with age and can be restored.

Since these discoveries were made, researchers have been trying to figure out which specific components of the plasma are responsible for these effects. There have also been some tentative human trials to test whether blood dilution (which is considered safer than introducing new compounds into the blood) might have some general health benefits. In this study, researchers provide the first evidence that therapeutic plasma exchange (TPE) may slow epigenetic ageing in healthy adults. TPE is a therapy approved for the treatment of some neurological diseases and in which the patient’s plasma is separated from their blood cells by a machine. Replacement plasma, usually a saline solution containing albumin (the most common protein in the blood), is then returned to the patient alongside their blood cells.

The discovery:

Researchers recruited 42 healthy adults over the age of 50 and randomly assigned them to one of four groups. One group received TPE twice in the first week of each month lasting for three months. Another group received the same treatment, except this group also received intravenous immunoglobulin (IVIG). These are antibodies collected from pooled blood plasma from many human donors. A third group received only TPE, this time as a single monthly treatment for six months, while the final group was a control group that underwent a placebo TPE treatment.

Researchers then used 36 different epigenetic clocks to measure changes in participants’ biological age. These are machine learning algorithms that estimate how quickly someone is ageing by comparing molecular alterations to their DNA (called epigenetic modifications) against the population average. If a 50 year-old has epigenetic modifications comparable to those of the average 40 year-old, this suggests that they may be ageing more slowly than average. Such measurements will vary between different tissues – in this study, biological age measurements were based on blood cells.

Not only were the TPE treatments found to be safe, but they were also associated with significantly reduced biological age according to 15 of the epigenetic clocks. When combining these measurements together, the TPE with added IVIG was the most effective, leading to an average biological age reduction of 2.61 years after one month, however, this benefit fell of sharply after two months. The TPE-only treatments were also associated with significant biological age reductions at first, but these too were diminished later on during the study.

The researchers didn’t just measure epigenetic ageing, but also the protein and cell content of the participants’ blood. They found that the TPE+IVIG recipients specifically had signs of improved immune function – the counts for immune cells that typically decline with age, like T cells, increased. Meanwhile, proteins associated with inflammation, senescence and other hallmarks of ageing decreased.

The implications:

This is the first study to demonstrate a reduction in epigenetic age after TPE in humans, although previous studies have shown that multiple rounds of TPE can shift the proteins in the blood towards levels characteristic of a younger person. The present study additionally shows that treatment with immunoglobulins roughly doubles the epigenetic age reduction from TPE and also improves markers of immune function. Why the reduction in epigenetic age was diminished as time went on will need to be investigated further – previous studies looking at proteins in the blood suggested that benefits increased steadily across multiple rounds of TPE. The authors caution that due to the relatively small sample sizes, the results should be considered ‘hypothesis generating’ rather than conclusive proof that TPE and IVIG delays biological ageing. So, what hypotheses can we generate?

As the immune system ages, the white blood cells (such as T and B cells) involved in mounting targeted immune responses against specific pathogens decrease in number. This weakens the immune system’s ability to deal with new threats or to target cancer cells. Meanwhile, there’s a rise in circulating inflammatory molecules, leading to widespread chronic inflammation known as ‘inflammageing’ and promoting many age-related diseases. TPE essentially replaces the portion of the blood that contains all of these molecules, offering an at least temporary reprieve and potentially allowing some cells to repair damage and reverse epigenetic ageing somewhat. IVIG, on the other hand, is known to modulate the immune system and, when combined with TPE, may actually improve the counts of certain cells that are vital to immune defence.

TPE is a relatively inexpensive and safe treatment, making it a compelling target for investigation. However, we still don’t know whether any of the benefits to blood markers observed in this study or others would actually translate into real health improvements for healthy humans. Until such benefits are demonstrated, we ought to remain cautiously optimistic.