More comments to take GDF-11
220601 – GRG:If you read enough stem cell biology, especially hematopoiesis, it’s pretty easy to deduce why GDF11 has to be a powerful senolytic. Hematopoietic stem cells (HSCs) upregulate their own telomerase and are technically immortal. However, the average HSC produces 90,000 progeny per day of either myeloid or lymphoid progenitors, which go on to divide/differentiate up to five levels to produce all of our blood cells. Due to this high replication rate, HSCs incur considerable DNA insult. When the DNA damage reaches a certain level, the HSC senesces, stops producing myeloid/lymphoid progenitors, eventually dies and is not replaced.
GDF11 repairs senescent stem cell DNA and brings the HSC back into production. Based on our immune, especially NKs and naïve T cell counts, and telomere lymphocyte lengths for GDF11ers (see “Actual Biomarkers” on site), we estimate that at age 60, GDF11 increases your HSC population by at least 10%. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation. If we have go with the low end of the daily blood cell production estimate, which is 100 billion, upping your HSC count by even 10%, creates 10 billion more blood cells/day. Common sense dictates that something has to “make room” for these new cells, so surely GDF11 has to initiate apoptosis of short telomere, DNA damaged cells.
And this is exactly what we see with GDF11ers: CD8+/CD28- (senescent T cells) go down by an average 25% after 3 months of GDF11 supplementation.
The attached paper further suggests GDF11’s senolytic capabilities. Key paragraph:
Notably, compared with mice in AMG1 and AMG2, SA-β-Gal contents in the cells of liver and kidney of aged mice in AMG3 were considerably decreased (liver: 9.16 ± 0.87% vs 16.89 ± 1.17% or 16.02 ± 1.51%; p < 0.05; kidney: 34.46 ± 2.03% vs 44.02 ± 1.95% or 44.52 ± 1.87%; p < 0.05) (Fig. 4c and d). These suggested that oral administration of rGDF11 reduced the accumulation of SA-β-Gal in aged male mice.
Note that AMG1 mice are fed a normal diet, AMG2 mice are fed a control diet, and AMG3 mice are fed a GDF11 diet. Knowing what the AMGs stand for, we can restate the above as:
In the liver, we see normal diet mice SA-β-Gal of 16.89 and GDF11 mice SA-β-Gal of 9.16, which is a 7.73 or 45.7% reduction in senescent liver cells.
In the kidneys, we see normal diet mice SA-β-Gal of 44.02 and GDF11 mice SA-β-Gal of 34.46, which is a 9.56 or 21.7% reduction in senescent kidney cells.
I am not an expert at senolytics, so I ask Dr. She (cced) is the above reduction in SA-β-Gal significant and how does GDF11 compare to other senolytics?
For those of you that believe eliminating free radicals are an important part of de-aging, you’ll be happy to see this the paper goes on discuss GDF11’s antioxidant capabilities:
Therefore, it is highly likely that the chain of reaction for GDF11 executing its rejuvenation activity is that GDF11 induces generation of antioxidant enzymes (CAT, SOD and GPX), which directly results in reduction of ROS levels, which then decelerates protein oxidation, lipid peroxidation and possibly LF and SA-β-Gal development, which in turn extends lifespan of aged mice.
Finally, for those who won’t take GDF11 due to the fact that it has to be injected, the paper’s authors have devised an oral method GDF11 administration which appears to work according to this paragraph:
GDF11 contents in the serum of mice in AMG1 and AMG2 showed little difference, but compared with young group mice, GDF11 contents in the serum of mice in AMG1 and AMG2 were markedly decreased, confirming that
blood GDF11 content declined with age (Zhou et al.2019a). Notably, GDF11 content in the serum of mice in AMG3 was significantly increased compared with that of mice in AMG1 and AMG2 (Fig. 2c). These together indicated that the displayed rGDF11 fed entered into the blood of aged male mice.
Personally, I have no problem with GDF11 injections – one of the benefits of injections is you know exactly how much GDF11 enters your bloodstream. GDF11 supplementation is complex enough as it is and we don’t need any more variables.
However, I do realize that oral GDF11 would reach a far larger audience, so I have a question for this learned group on “display yeast”: How does GDF11 displayed on yeast surfaces somehow make it into the bloodstream? Seems to me that this GDF11 yeast would be broken down / denatured in the digestive process and have zero absorption into the bloodstream. Remember that GDF11 is a large molecule, weighing in at 45,091 Daltons, which is more than 8x the size of insulin. And speaking of insulin, if this display yeast technique really works, then why not use it to make oral insulin and help out the 1.5 million type 1 diabetics that have to inject insulin every day?
211225 – HOW MUCH HUMANS SHOULD TAKE: “Growth differentiation factor 11 accelerates liver senescence through the inhibition of autophagy” paper in the same category as “Supraphysiological levels of GDF11 induce striated muscle atrophy”. Both papers just prove that excess GDF11 levels are detrimental. And what else is new with most peptides?
Also, this paper, which is on GDF11 Wikipedia, “GDF11 attenuates liver fibrosis via expansion of liver progenitor cells. The protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease. completely contradicts the above “GDF11 inhibition of liver autophagy” paper.
And now I will add my own proof of how flawed this paper is. I’ve been doing clinical work with GDF11 in hundreds of humans and dogs, and I know first hand that the window for proper dosing of GDF11 is extremely narrow. And the proper doses of GDF11 are infinitesimal – the average human down regulates with a mere 15,000 pg (1.5 ng) of GDF11. From a GRG member: I thought I would give a little update on any changes I have noticed since I started GDF11 injections in March, 2019. I have reduced my intake now to a miniscule 20pg/week. My total supplementation is just under 14,000 pg. So a tiny amount. I am 63 years old, 5 feet 11 (180cm) and weigh about 158 pounds (72 kg). When I started, my reaction time to a visual stimulus was about 375 milliseconds. Now it is about 220 milliseconds. Actually, I don’t record that anymore as it was rather stable at that level. My blood pressure has not changed much, but is typically about 115/65 to 120/70 in the morning. My heart rate has trended down slightly from 54 to 50. The most interesting finding for me was fasting glucose. In March 2019 a typical reading was 5.3 – 5.4. Now it is a full unit lower at 4.3-4.4 mMol/L. In American terms, that went from 95 mg/dL to 77 mg/dL. Given that my diet and other supplements have remained the same, I can only attribute the change to GDF11. Perhaps this can be explained by a paper showing in a mouse model that GDF11 is essential for production and maturation of islet progenitor cells in the pancreas. A link to the paper: https://dev.biologists.org/content/131/24/6163
211225 – Asking what the proper dose of GDF11 is like asking what the proper dose of insulin is. Like insulin, there is not set GDF11 dose – it is highly correlated with age, fitness level and weight. And like insulin, GDF11 is difficult to dose which is why you see some people have great success with it and others see detrimental effects. We start most of the 60+ crowd at 250 pg per day and then close watch key Emfit biomarkers. Emfit all night HRV is the most important biomarker to determine when one is down regulated. Once a person approaches down regulation (which means they have erased their GDF11 deficit), you’ll see the all night HRV graph (heart graph on Emfit) start to show signs of arrhythmia. Other Emfit biomarkers such as pulse, BPM, ANS balance, etc. may start to trend the wrong direction also.
