Harold Katcher’s rejuvenation experiments using young plasma fraction
(Note that I originally wrote this in May 2020)
Just recently a preprint of a study was published on a potential breakthrough treatment for aging. (1) In fact I think I haven't seen anything so exciting in the field since I got interested in aging 16 years ago!
In short, Dr Harold Katcher and his partner Akshay Sanghvi treated a group of old rats with a chemical mixture designed from chemicals isolated from the plasma of rats. They call this isolated fraction elixir. Treatment with the elixir resulted in a major reduction in the epigenetic age of several organs of the rats and of various other parameters. What does this mean and why is it important?
The study is built on previous experiments on heterochromic parabiosis. Heterochromic parabiosis is the process of pairing animals surgically such that their circulatory systems are joined so they share the same blood but not their organs. When this is done with two mice, one being old and the other one being young, the old mouse commonly experiences beneficial effects such as an increase in stem cell regenerative capacity. Basically from being exposed to blood from the young mouse the stem cells of the old mouse get healthier and start behaving more as if they were younger. (2) These effects might result from dilution of harmful factors in the blood of old mice or exposure of the old mice to some rejuvenating factors found in the blood of the young mice. If such factors can be identified then they may be produced or isolated and administered to animals and have rejuvenating effects on the animals without needing to join their circulation systems or give them blood transfusions from young animals. This is what Harold set out to do, to identify the factors in the blood of young animals that decline with age and have benefits when given to old animals, and then to produce these factors and give them to animals directly to rejuvenate them.
According to their report, Harold and his team have found molecules isolated from the plasma fraction of blood that appear to be responsible for much of the benefits of young blood on the health of older animals. In a preprint study (it has yet to be peer reviewed) just published they report on a study where they used this plasma fraction (which they named elixir) on rats. They gave old rats just a few injections of the elixir and the results were quite amazing. Firstly the epigenetic age of the rats, measured in different organs, was markedly reduced by an average of around 50% (more on why this is important below). Secondly when they tested a whole bunch of biomarkers associated with aging, and tested the cognitive function of the animals, they found marked rejuvenation with almost all the biomarkers (such as inflammation and oxidative stress markers) being restored to the levels of the young rats. The rats given the mixture also had greatly improved cognitive function and performed just as well as young mice on cognitive tests meaning their brains were performing much like the brains of young rats. Importantly the control group did not experience any of these benefits.
The treatment also markedly reduced the epigenetic age of several tissues in the rats. This epigenetic age is based on a clock developed to predict the age of animals based on their gene expression profile (also called epigenetic signature). The gene expression of the various cells of the body of animals changes with time and these changes correlate with age to a high enough degree that they can be used to predict the age of animals (including humans) with a surprisingly decent amount of accuracy. A halving of the epigenetic age of the rats given the elixir is quite amazing and means their epigenetic signature was reverted back to that of rats that were far younger. In other words this means the expression of their genes was changed to a much more youthful one. This in turn may be responsible for the major improvements in various biomarkers and cognitive function. Basically if you change the gene expression back to what it was when the animal was much younger the cells start behaving like they are much younger and get much healthier which then could cause the dramatic health benefits seen in the rats. Gene expression controls what genes are turned on and off and when animals get older a lot of genes that protect them and are beneficial for health get turned off. While such changes in gene expression do not cause aging they can contribute to aging and reversing them can be beneficial.
If the above results are found to be true and replicable and to be translatable to humans then this has potential to be the biggest breakthrough in medicine and longevity for decades!
Now of course this should be taken with a grain of salt because the results have yet to be peer reviewed and to be replicated. Also even if it works in rats it still has to be proven to work in humans and if it works in humans I would expect the results to be not quite as dramatic for humans as for the rats. But still if this works in humans then this has potential to be a major breakthrough.
I think it is entirely reasonable that this can work and also in humans. Why? Because the principle behind it is sound. If you look into studies on cellular reprogramming and induced pluripotent stem cell creation you will find a whole bunch of studies showing that you can take a cell from human adults and treat them in cell culture with certain reprogramming factors or specific small molecules resulting in their gene expression being reverted not just back to a cell that is 50% younger but all the way down to a primitive stem cell of an embryo. When doing so the cell also becomes rejuvenated and behaves and is in most ways indistinguishable from a younger cell. In fact it's even possible to take a cell of a 100 year old person and reprogram the gene expression to reverse the epigenetic age towards a young one. The elixir, if it works, seems to do this to a smaller degree on a systemic level, that is revert back the epigenetic age of the cells leading to them being rejuvenated.
Note that even if you can make the cells rejuvenated to be much younger that doesn't mean the whole body will get younger. The body isn't just made of cells and there are a lot of problems that cellular rejuvenation won't fix. But it is still a very important step in rejuvenation therapies and has great potential as a rejuvenation therapy.
The good news is they are planning more studies including studies on whether the elixir makes the rats live longer (such a study takes a longer time) and human studies are also in the pipeline later. I'm very excited to see more about this and hope it actually turns out to work. If it does then we will still have to wait several years for this to hit the market because the clinical trial process is so slow but lets hope for the best.
References
1. Horvath S, Singh K, Raj K, Khairnar S, Sanghavi A, et al. Reversing age: dual species measurement of epigenetic age with a single clock. Science. 2019 Dec 13;366(6471):eaan4673. doi: 10.1126/science.aan4673. PMID: 31831640.
2. Conese M, Carbone A, Beccia E, Angiolillo A. The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation. Open Med (Wars). 2017 Oct 28;12:376-383. doi: 10.1515/med-2017-0053. PMID: 29104943; PMCID: PMC5662775.