Minicircle skeptics?

[this isn’t the only one, though I feel it’s mistargeted b/c minicircle isn’t about stem cells]

there are previous threads of skepticism too [from SarahC, and from kanzure]

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And again, Bryan Johnson is spreading more bullshit talking about stem cell injections.

I’ve worked in stem cell research and coinvented an HSC therapy. The reason why stem cell injections into joints is largely a scam is because stem cells differentiate based on the signals they receive and require the contribution of stem cell niches which are complex structures that maintain stemness and progenitor cells and feed daughter cells to the right places. These microstructures can be as small as only five cells in a pyramid shape. It’s so tough to even get cells to differentiate correctly in vitro, and very complicated to get them to seed back into their niches unless it’s calcium-driven like HSCs.

An injection of stem cells usually just results in them losing their stemness and primarily becoming fibroblasts which solves nothing and frequently can even be harmful. Joints in particular tend to be poorly irrigated as well without the proper differentiation factors present, so they just don’t do anything and die or become the wrong cells. You aren’t going to get cartilage cells that repair the damage unless the injection is near the red zones closest to blood vessels, and even then you probably didn’t need them there- you need daughter cells in the white zone for the worst parts of aging.

The reason MSC stem cell therapy isn’t recommended in the US is because it simply doesn’t work and is an expensive nothingburger. Attempts have been made to use predifferentiated cells or adding differentiation factors mixed with the cells, but to my knowledge this remains an unsolved problem and all current companies offering it as a therapy are lying about their capabilities. If I recall, the MILES studies indicated that MSC joint therapies were no better than the temporary relief steroid injection for age-related conditions. You should probably bank your stem cells, but there are sparingly few use cases for them right now.

Not to mention the stem cells he used aren’t his own and I’m not even sure they’ve been made compatible with his self-recognition receptors. At the very least I’m familiar with the leading multiplex editing programs for that and his company isn’t doing that. This wouldn’t be the first time Karolinska alums have started a scam stem cell company despite the institute’s reputability.

It really saddens me to see his channel promoting scam therapies like minicircle and this is damaging to serious biohacking for antiaging. Honestly his medical advisors are bullshitting him or he’s just gotten a big head from fame.

I’d be interested to hear OP’s take on why Minicircle is a scam (the technology is in principle legitimate, but the implementation is perhaps ineffective or just unproven), but it seems this post is addressing stem cell therapies instead?


That the stem cells he used aren’t his own probably makes it pretty safe for him. Because they are quickly eliminated, there’s little chance of odd things growing where they shouldn’t. Placebo effect also works better if it’s expensive.


I had stem cells injected into my knees in the Grand Caymans (Regenexx) and they helped my pain and function substantially. I went from not being able to jog at all without being in weeks of pain, to being able to play basketball and pickleball. Before and after doing the stem cells I had a ton of other types of injections such as PRP etc. (which I spent unfortunately spent a ton of money on) and none of them helped at all so I’m pretty sure the stem cells weren’t a placebo and were the opposite of a nothing burger. I have no ties to the company.

Even though Regenexx is a US company, I had to go abroad because the FDA has inane prohibitions about culturing the cells to increase their number.


I’m not the original poster of this twitter thread but here are my thoughts after 20+ years in gene therapy research.

I’d be interested to hear OP’s take on why Minicircle is a scam (the technology is in principle legitimate, but the implementation is perhaps ineffective or just unproven), but it seems this post is addressing stem cell therapies instead?

I think Minicircles have potential if they can be delivered to the cells of a particular tissue efficiently. It turns out you can do that quite efficiently in a tissue culture dish in the lab. Delivery to tissues in living volunteers is another story where you either sacrifice precision or efficiency but getting efficient precise delivery seems to be a pipe dream.

One way around this is to deliver circles to ex vivo cultured stem cells from the volunteer and have the minicircle-modified stem cells repopulate a tissue. This too has been a dream that hasn’t been realized with minicircles but has been accomplished with viral vectors. Bone marrow stem cells are the best model system but getting minicircles into BMSC’s without destroying their ability to repopulate the hematopoietic system has eluded scientists and often one need to destroy existing stem cells to create a niche for repopulation by the modified cells leaving the patient without an immune or hematopoietic system if it fails. Luckily nature has solved this problem with viruses and viruses can be “vectorized” so that essentially they are a minigenome (not always circular) coated in protein or lipid that efficiently transduces HSC’s prior to their transplantation.

Alternatively one could deliver minicircles IV and hope they affect the target tissue but the consequences of off target gene expression are real, and can be dangerous. Some scientists claim that minicircles don’t integrate into the genome but in fact they do, and if they contain strong gene promoters then integration (albeit random) next to many genes in our genomes can result in unregulated gene expression and dysregulated cell growth (cancer) or other problems of inappropriate gene expression in specialized cells. BJ’s protocol where expression of folistatin from a strong promoter within a minicircle is dangerous, I definitely would not sign up for it. I also don’t think the benefit is all that great.

When these approaches fail (death cancer etc), they make big news. That will likely hurt the rest of us as it will result in a crackdown of off label drug use, more regulation of the medicine supply lines (India) and make the often thoughtful, careful approaches of the people on this forum difficult to continue. We will all be lumped in with BJ…


Thank you, this is very helpful!

I’ve been considering another issue for awhile, which is that for reprogramming to achieve true age reversal, it needs not only a high degree of selectivity, but probably also needs to be bespoke to each cell type. This becomes a massive engineering issue when you consider how many different cell types we have, so the obvious solution is to reprogram the stem cells of each tissue, and then (fingers crossed) you get age reversal trickling down to all their lineages.

Of course just being able to modify the stem cells in vivo is a difficult problem like you said. the ex vivo method really does seem like the best solution for this!

Also, is there any obvious reason why the modified cells have such a difficult time repopulating the tissue? Is it that the existing tissue resident stem cells are already being exposed to a much wider range of factors, that perhaps give them a competitive advantage? Or perhaps only one clone with a competitive advantage comes to dominate the entire population (a la clonal hematopoiesis), so your transfer won’t be successful unless said clone resides in your culture and not the tissue?

My hunch is the endogenous stem cells are physically occupying a unique niche so they must be removed for new cells to take root. Its a fact that myeloablation needs to occur for bone marrow transplants to be effective.

One other point I forgot to make re minicircles into stem cells is that this combination really doesn’t make sense. Because minicircles don’t have centromeres they are lost after a few cell divisions so once a stem cell begins to differentiate it loses the minicircle. This has all been shown using non-integrating viruses in liver cells. Once the liver cells are induced to divide (through partial hepatectomy) the non-integrated vector DNA is lost.

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