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              Advocacy & Research for Unlimited Lifespans

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'Nugenics' - breakthrough rejuvenation?

Discussion of a recent preprint by Horvath/Katcher et al. reporting rejuvenation in mice with an undisclosed blood component.

On May 7, a study was posted on bioRxiv that has all the apprearance of a potential major breakthrough in anti-aging research. The researchers claim they've made a mammal 54% younger with a few simple injections. The internet has been buzzing about the news ever since, with Josh Mitteldorf, who has written two books on aging, writing, "I believe major rejuvenation has been achieved in a mammal, using a relatively benign intervention that shows promise of scaling up to humans. I'm going to stake my reputation on it."
The paper describes treating old rats with injections derived from the blood plasma of young rats. As a result, the old rats showed DNA methylation clocks more typical of younger rats.
bioRxiv is a site for publishing pre-print scientific papers, that is to say, ones that have not finished the process of peer-review. The authors aim to publish the paper in a peer-reviewed journal. In its current form, the paper is missing important data and the experiment cannot be reproduced.
Methylation patterns were rolled back 75% in liver tissue, 66% in blood, 57% in heart tissue, and 19% in the hypothalamus: an average rejuvenation of 54.2% across four tissues. It is notable that not all tissues showed equal improvement on the methylation clock. In particular, the hypothalamus seemed stubborn. However, the treated rats "learned and remembered better" than the controls. Strength was up, fat was down, good cholesterol up, bad cholesterol down, and the biomarkers measured in the blood "were altered towards the values of young rats, without exception."
David Sinclair, a tenured professor at Harvard genetics department and a regular in the media, commented favourably on the paper, saying, "So are the result believable? I see nothing wrong with the epigenetic clock analyses, the stats "Horvath is the best there is. It's also hard to see how the other measures could be messed up."
So far it sounds like we should get pretty excited. Let's take a look at what the theoretical basis of the research, the empirical results, and the pathway from here to human rejuvenation. 

Methylation theory
The researcher, Harold Katcher, made his name as co-discoverer of the breast cancer gene, brca1, in 1994 and has published actively since then. He writes, "I have thousands of citations in the literature, with publications ranging from the discovery of the human 'breast cancer gene', to protein structure, bacteriology, biotechnology, bioinformatics, and biochemistry". 
Another co-author is Steve Horvath, the developer of 'Horvath's clock', a way of measuring the biological age of tissues based on which genes are active, versus which genes have methyl locks on them.
The team and their research represents a mild rebellion in the ranks of aging research. The dominant theory about biological aging  --
but not the only respectable one -- is about damage. The body, in its day-to-day running, accumulates damage, much like wear on machine parts. Over time the damage builds up, causing what we know as old age.
Katcher (along with Tom Rando, Michael and Irina Conboy, and others) believe something different. Molecules in the blood give instructions to cells telling them to act young or old, and part of what it means to 'act old' is to lock down some repair mechanisms. They believe that the body has mechanisms capable of repairing the damage, but doesn't use them. 
Gene expression can be locked down by modifications called 'methylation'. For example, in response to fasting, certain genes that control appetite become methylated and switch off. According to the methylation theory of aging, our body's repair mechanisms become methylated over time, leading to the breakdown and age-related diseases.
There is some good evidence backing the methylation theory. By measuring the methylation of DNA, scientists can tell the age of a tissue sample to within 5% accuracy. Factors known to accelerate aging -such as obesity and Down's syndrome-  also accelerate DNA methylation. Katcher presented the argument in a 2013 essay called 'Studies that Shed New Light on Aging', and also in a 2015 paper 'Towards an evidence based theory of aging'.
It would be good news if the methylation theory is true. Repairing cellular damage would be hard, but if cells can be old or young depending on what signals they receive, then we need only identify the signalling molecules and inject them. The race is on. Two years ago, with funding from Akshay Sanghavi, Katcher set up a lab in Mumbai and got busy turning the methylation theory of aging into a practical therapy.

The mysterious 'Elixir'
The current study used six young rats (aged 30 weeks), and 12 old rats (aged 109 weeks), half of whom got the treatment and half of whom did not. The old rats in the treatment group were injected with something derived from the blood plasma of the young rats. What exactly? The paper is thin on details, just calling it "plasma fraction". Until Katcher and his partner Akshay Sanghavi can get a patent, they are keeping the recipe a secret. Katcher has repeatedly stated that he expects the relevant molecules can be synthesised without the need to harvest blood from young people. 
The desire to protect their discovery is understandable, but one could argue that they should have held off on publishing the experiment until their patents were secured. Reproducibility is a key part of the scientific method, and it is impossible to reproduce their study as it stands. (As a side note, the instrument used in DNA methylation profiling also falls short of reproducibility. The paper describes it as a "custom array contains two thousand probes selected from human biomarker studies" without specifying what these probes are.)
The treatment described in the paper is agreeably non-invasive: "Plasma fraction treatment consists of two series of IV injections, four times on alternate days for 8 days. A 2nd series of injections were given 95 days later. In its entirety, the experiment lasted 155 days." Katcher has said that if this becomes a human therapy, it would require a series of injections every few years.
Katcher's initial plan had been to give old rats the whole blood plasma of young rats. But in the current paper, blood plasma per se was not used, but an unknown 'something' from the plasma. The paper says "Although transfusion technologies for humans are well-developed and safe, transfusion of small animals is still at the infancy stage of development, requiring state-of-the-art techniques and remains challenging. We used a unique plasma fraction "Elixir" developed by Nugenics Research." (Nugenics is Sanghavi and Katcher's company.)
David Sinclair comments, "What is in the plasma fraction that helps? Proteins, small chemicals, exosomes?" We don't know, but Katcher's statements that the substance can be synthesised makes exosomes unlikely.

Measuring rejuvenation

Whatever it is, it seems to have worked. The paper reports, "Crucially, plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]... According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age."
The study required a new clock to quantify the age of rats from their DNA methylation. The paper says, "To build the human-rat clock, we analyzed previously generated methylation data from n=850 human tissue samples". It seems unusual to use human tissue as a source of data for studying rat tissues. The paper does not explain why human tissue was used. What's even stranger is that the human tissue samples are from AIDS patients, from the Cape Town Adolescent Antiretroviral Cohort study, and the National NeuroAIDS Tissue Consortium which "collects and distributes well-characterized antemortem and postmortem tissue specimens with clinical and serological data from HIV-infected individuals". Why was methylation data from HIV-infected humans used to train a rat model? Did they only take data from the non-HIV-infected controls? The paper doesn't say. It is likely that using AIDS sufferers rather than healthy people could distort the DNA methylation data.
It wouldn't be that interesting if a fringe group developed a clock not generally thought to be important to aging, and then reset that clock. But that's not the only change measured in the rats. The paper also reports changes in senescence burden, biomarker levels, and behaviour.

Senescent cells
"Plasma fraction treatment reduced the level of senescent cells by a very considerable degree". David Sinclair comments, "senescent cells were reduced "by a very considerable degree". Presumably, the immune system cleared the senescent cells. This is what the field is looking for." Part of what makes this interesting is that senescent cell burden is separate from epigenetic aging; if a treatment directly addresses aging in the methylation paradigm, and somehow leads to senescent cells also being cleared up, that indicates a broad-spectrum rejuvenation. However, the quality of the data on senescent cells is low: the effect is shown by images, with the accompanying statistical analysis notably absent. It is unusual, even for a pre-print awaiting peer review, to be missing this data. Someone familiar with the technique of staining to detect senescence markers notes that there seems to be an unusual amount of blue staining in the brain tissue of the old rat, possibly indicating a methodological error. (Fig 7 of the paper, click for image

Outside of the group of scientists who believe that DNA methylation is key to aging, others believe that senescent cells and inflammation are to blame. Katcher's work shows promising results at addressing these problems. The paper says, "Plasma fraction treatment reduced the level of senescent cells by a very considerable degree", and Katcher has commented, "I can definitively say that chronic inflammation due to aging can be reversed with factors present in young blood". As senescent cells and inflammation markers weren't specifically removed by the intervention, it seems to work by flipping epigenetic switches, turning on the body's disposal mechanisms to clear out the trash.

Biomarker results
The paper claims that "accumulation of fat in old tissues was greatly reduced". However, no quantified measures of adipose tissue accompany this claim, as would be expected in the scientific community.
Biomarkers in the old rats "were altered towards the values of young rats, without exception". Biomarkers tested include total bilirubin, direct bilirubin, SPGT (serum  glutamic-pyruvic  transaminase), SGOT (serum glutamic-oxaloacetic transaminase), triglyceride, HDL (high-density lipoprotein), cholesterol, glucose, creatinine, BUN (blood  urea  nitrogen), total protein, IL-6 (a marker of inflammation), and oxidation markers glutathione (GSH) and superoxide dismutase (SOD). Again, the data here leaves something to be desired: it is presented as graphs without detailed numbers or statistical analysis.

Behavioural results
Performance in cognitive tests improved: "it was clear that treated rats remembered the maze much better than the untreated ones". Strength also increased. They write that "At 15 days post-treatment, the strength of plasma fraction-treated old rats was indistinguishable from that of young ones." However, it seems behaviour was not measured under conditions of blinding.

Regardless of what was in the plasma fraction, and regardless of whether this ever scales up to humans, the study is noteworthy for major rejuvenation in a mammal. (Tiny creatures like yeast and nematodes have been rejuvenated before.) It seems likely that the same results could be achieved by taking the blood plasma from a young animal and putting it into an old animal. Early rumours of Katcher's research suggested this. A study published in 'Nature' in 2014, and another in 2016 also lend weight to the rejuvenating powers of young blood.
It's not easy to transfuse plasma in small animals like rats. Blood loss becomes an issue. Mechanically it's easier in humans, but what about morally? The fear of Countess Bathory scenarios where the rich and old need the blood of the young and poor is at the forefront of much popular writing around this area, and dominated the Reddit comments on the research. If Katcher's team have identified and isolated molecules in young plasma that can have the same effect, that is a significant breakthrough that will shape the field in years to come.
Improved physical and cognitive performance are nice, but what would really convince the skeptics is data on how long these rats live. If treated mice lived two years longer than controls, the team will have a promising treatment on their hands. There's no way to get that data but to wait, and restrictions caused by the Covid-19 pandemic are delaying research.
Katcher and Sanghvi have not yet found a suitable partner to provide financing for human trials, and have not yet applied for patents, with Sanghvi commenting, "we plan to file patents worldwide sometime this year". Until the patents are filed, the nature of the treatment will remain a secret. Human trials may also take years to get approved and conducted. In the meantime, none of us are getting any younger.


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