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David Sinclair

David Sinclair

May 11, 2020
23 tweets

Finally had time to carefully read the new preprint that claims to reverse the age of rats by 54%. I spoke to the first author & in this thread ask whether the results are believable and what if it is true? 1/n

The result is so literally incredible that even the first author, Prof. Steve Horvath, didn't believe it at first. I suggested he check if the rats were mixed up, but he assured me he checked their genomes. The rats weren't mixed up and the data is the data. 2/n
Being from a commercial operation called Nugenics (sounds like eugenics?) and calling the blood plasma fraction "Elixir" doesn't inspire confidence. But let's dig in...3/n
Why would this be a big deal? Chemicals called methyls, which are added & subtracted from our DNA over time, control which genes remain on/off. This DNA methylation pattern can also serve as a BIOLOGICAL clock with <5% error. If you smoke or overeat, your clock ticks faster 4/n
The aging field is embracing the idea that changes to these methyl patterns and other gene regulators are a part of the aging process, and that it can be reversed. (Steve & Harold: thanks for citing Kane & Sinclair, 2019)... 5/n
Six years ago, a lifetime in the aging field, the mere suggestion that aging could be reversed was enough to have your colleagues & donors screw up their noses. Tom Rando @Stanford Medicine deserves a shout out for being brave enough back then to use the word "reversal" openly 6/n
Even a few years ago, the best we could do was delay aging. For example, we could reverse the age of the microvasculature (cf. #COVID) and muscle within 4 weeks just by letting them drink some NMN. Similarly, young mouse blood rejuvenated the hearts and muscles of old mice. 7/n
Last year, a study of Greg Fahey and Steve Horvath @UCLA (discoverer of the methylation clock) made headlines by rejuvenating the thymus and reversing the blood clock about 1-2 years. This was a big deal in 2019. 8/n
Now to this new paper by Nugenics Inc. & Horvath: 18 rats were divided into three groups. 6 young rats (30 weeks old), 6 old rats (109 weeks old) & 6 old rats (also 109 weeks old) treated with plasma fractions from the young rats. 9/n
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. 10/n
Blood was drawn at regular intervals for analyses to monitor the impact and cognitive functions were assessed 4 times. DNA methylation profiles of several organs were generated and age was calculated using six epigenetic clocks. 11/n
Using the final versions of their epigenetic clocks the reversal was: liver 75%, blood 66%, heart 57%, hypothalamus 19%. Average rejuvenation across four tissues was 54.2%. This is astounding. 12/n
What else did they see? Accumulation of fat in old tissues was greatly reduced. All health-related blood biomarkers they assessed (lipids, liver function, blood cells) "were altered towards the values of young rats, without exception." 13/n
Memory improvements anyone? By the third month, it was clear that treated rats remembered the test maze much better than the untreated ones. 14/n
The brain was an exception in terms of age-reversal, where the age reduction was significant using only some of the rat clocks (why is the brain so darn hard to fix? In this case, BBB barrier?) 15/n
Level of oxidative stress, and (wait for it) 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. 16/n
The work shows, for the first time, that plasma fraction treatment reduces the epigenetic age of multiple tissues, and not by a little. What is in the plasma fraction that helps? Proteins, small chemicals, exosomes? 17/n
This reminds me of Fleming and Florey, who found an extract of penicillium mold could treat infections. There will be a race to find all these factors. is already on the case. 18/n
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. Controls Sure, I'd like to see more controls, quantification of images, etc. 19/n
From what I can tell, the old control group didn't get injected with anything but saline. A better control would have been an injection of the old rats with old plasma fractions from rats of the same age, processed exactly the same way as the young plasma. 20/n
Expect a rush to India to get this treatment. I do hope Nugenics conduct careful human clinical trials first. In the US, young plasma treatments were stopped by the FDA until further notice citing a lack of proven safety. 21/n
If this finding holds up, rejuvenation of the body may become commonplace within our lifetimes, able to systemically reduce the risk of the onset of several diseases in the first place or provide resilence to a wide variety of infections. 22/n
It will be interesting to see if reprogramming factors, such as OSK, are induced in the tissues of treated animals. This might explain the ability to reset age. Maybe it's a different set of genes for each organ. We will see....! 23/n end.
David Sinclair

David Sinclair

Harvard professor working to extend healthy life for people & other animals. Sign up for Harvard lab news
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