√ Can Stem Cells Really Fight Aging If So, How?

If you want to fight aging, should you turn to stem cells? Does the idea of stem cells to battle getting old even make any sense? The answer is, “it depends.” It’s a really interesting area conceptually and technically for stem cells. 

A theory. There is evidence that things that happen to our endogenous stem cells are linked to aging. In my book Stem Cells: An Insider’s Guide, which I’m hoping to get a new edition out for next year, I even proposed the idea that the number of stem cells in our body acts like a biological clock for aging. Less stem cells = older person (see cartoon from the book by my former student, Taylor Seamount). It’s probably not that simply for each individual, but there is a connection. Certainly reduced populations of our existing stem cells are not likely to be helpful to our tissues as we live over the years and decades.

Sketchy or long-shot stuff. The fact that our stem cell numbers tend to decrease with age does not necessarily mean that stem cell treatments for aging make any sense. In fact, there are a lot of problems with the idea of infusions of stem cells to fight aging. First, most clinics selling this idea simply infuse fat (or amniotic) stem cells into the bloodstream, collect their thousands of dollars from customers, and then wave a magic wand or something.

There’s good evidence that those fat stem cells injected into the bloodstream mostly are gone with hours or days, certainly within weeks. They are filtered out in the lungs (one reason for worrying about pulmonary emboli or blood clots in the lungs as a side effect) or elsewhere. Many probably die from the shock of entering the blood stream or are killed by immune cells. In short, there’s a very limited window of time that such cells could do anything helpful and the idea that during that window they could permanently help counteract aging seems like a snowball’s chance in hell. Maybe bone marrow cells would have a relatively better chance.

To really claim help for aging, you’d have to invoke the idea that whatever stem cells you use can permanently engraft in the body, which then raises the possibility of cancer as a side effect. Alternatively, and some clinics go this route, those pushing their own stem cell treatment for aging notion say that many repeated infusions of stem cells are necessary over years and years. That can add up to a lot of profits even if there’s no science backing it up and can empty out customers’ bank accounts.

Then there’s the young blood for aging idea, which has some connections to “stem cells for aging” mantras. There might be something in young blood that can fight aging, but nobody knows what that is and whether it would work in humans or if it’s just a phenomenon in mice. Still, you can pay thousands or even hundreds of thousands of dollars to be in a “trial” of young blood for old, but I think it’s a waste at this point.

Things with better odds. Okay, so you can see I’m skeptical, but in the longer run there may be ways that stem cell research can help battle aging. There may be molecules that can be anti-aging drugs by targeting stem cells. There might even be ways that stem cells themselves could be the basis for a treatment that counteracts aging. Hopefully someone will figure these things out in coming decades because right now there’s nothing real on the stem cell front for aging.

There is legit clinic trial work being planned and conducted related to the stem cell-aging connection including by AgeX and Longeveron, although as to the latter I don’t the data to date are particularly compelling as I blogged before, particularly pertaining to the flu connection. We’ll see. It’s really important to try to avoid hype related to stem cells for aging as well.

In another way of looking at it, stem cell treatments may increase lifespan not through systemically slowing aging, but rather by keeping us alive via maintaining or replacing the function of one key organ. Often us humans die not because of our body’s overall physiological age, but rather because one vital organ gives out on us. On that front there is real promise via stem cells.

I really hope that some real way of fighting aging is discovered and proven…and it’d be extra meaningful for me if it was via something related to stem cells, but in the meantime we should focus as individuals on concrete things proven to add quantity and quality to life. Small changes in behavior that tie in to heart disease, for instance, may be far more impactful as something to focus on than even some ultimately proven anti-aging drug in the future. Me, Dr. Skeptic, even blogged about 5 potential “stem cell boosts” that are focused on just changing every-day things to be healthier like sleeping a good amount.

If there ever is a focused, stem cell anti-aging treatment in the next 50 years, I’d bet that exercise will always beat it out anyway, but we’ll see. Hopefully I’ll live long enough to see if I’m right.

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√ Can We Grow New Brain Cells As 4Dukts? It Depends On Who You Ask

Can we humans grow healthy new brain cells as 4dukts?

The answer to this question is a big deal because it could have major impact on aging. Those hoped-for new brain cells could keep our brains functionally younger. Who doesn’t want to slow down the aging of their brain, right? Slowing down aging of the brain via new cell growth more broadly would have major impacts on society.

Cell Stem Cell Boldrini, et al., 2018, Part of Figure 1

Researchers have gone back and forth on this over years.

Fairly long ago, it was thought the answer was definitely “No, we humans can’t grow new brain cells”, but in the last few decades a loose consensus has emerged that in fact the answer is, “Yes, to some degree.”

A recent Nature paper, however, said “No” again. It challenged that “Yes” by directly arguing we don’t make new brain cells. Neuroscientists who study this stuff generally reacted skeptically. The paper’s title was, “Human hippocampal neurogenesis drops sharply in children to undetectable levels in 4dukts.”

Yet an even newer paper,this time in Cell Stem Cell that is Boldrini, et al. argues “Yes” and goes further to say, in fact, that we 4dukts and even older 4dukts can grow brain cells just about as well as the younger folks. This paper’s title pretty much directly contradicts the above one as it says, “Human Hippocampal Neurogenesis Persists throughout Aging.”

So who’s right and who’s wrong?

My gut feeling is that there is 4dukt human neurogenesis and there are stem cell populations in 4dukts and even fairly aged humans.

It’s really hard to conclusively prove a negative thing in science like the claim that there’s no neurogenesis in 4dukt brains. I bet the team recently arguing no detectable new neurogenesis used methods that simply didn’t detect it. It’s much harder to dismiss the findings in the newer paper (and in many past ones) showing 4dukt human hippocampal neurogenesis and the presence of stem/precursor cells. See part of Boldrini Figure 1 above showing evidence of neural progenitor/stem cells in the 4dukt brain. The data in that paper are clear.

Still, this new paper arguing for sizable levels of stem cell activity in the 4dukt human brain found some effects of aging on the brain and that neural precursor numbers in older 4dukts are somewhat lower than say teenagers.

People are more generally really wanting their brains to stay robust as they age. I’ve covered brain aging in the past on this blog and efforts to counteract it, mainly via stem cell-related efforts such as exosomes, which were the focus of a paper I was fairly skeptical about some months back. Some people also think that stem cell transplants or infusions of young blood might fight brain aging, but those are somewhat wilder ideas.

I’m hopeful that there are real ways eventually found to keep our brains healthy and even producing more new, healthy cells and stem cells as we add on the decades. The debate over 4dukt human brain stem cells might continue in years to come, but most people I know think there is some neurogenesis going on even as we age, which provides hope for the aging human brain.

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√ Stem Cell News Update: The Good, The Bad, The Weird

Blastocyst embryo model from legos, Copyright Nicolas Rivron, used with permission

With stem cells there’s always all kinds of developments and news every week or even every day.

Here is an assortment in no particular order of some of the latest news including some across the spectrum including weird and sometimes stuff. The linked phrases are often the actual headlines of the media pieces.

New CIRM Alpha Stem Cell Clinic offers HOPE for boys with deadly disease (article focused on our CIRM-funded Alpha Clinic here at UC Davis as part of our Stem Cell Program).

Note that I suggest you follow Jan Nolta (@jan_nolta ), Director of the Stem Cell Program and Editor-In-Chief of Stem Cells, on Twitter for a regular stream of great updates and links on stem cells in general including for instance recently the ISCT meeting that she has been Tweeting.

Tech workers are paying $7000 to freeze their stem cells in hope of extending life. Is this a good use of money and resources? It’s too soon to know.

Embryo-like structure synthesized in a lab could help decipher infertility. Synthetic embryos have been making news for a few years. Here’s a past post on one of the earlier developments last year. See cool images including the one of a blastocyst made of legos above from Dr. Nicolas Rivron on embryo modeling. Here’s the actual new Nature paper. And here are some other related papers in this line of research suggested by Dr. Rivron:

• https://onlinelibrary.wiley.com/doi/abs/10.1002/dvg.20473 


• https://onlinelibrary.wiley.com/doi/abs/10.1002/mrd.22585


• http://dev.biologists.org/content/141/22/4231

The big Washington Post piece on stem cell clinics is worth a look if you haven’t already read it: What you should know about stem cells, from promising research to dubious uses.

Virginia clinic patients who got ineffective stem cell treatments: They played on our pain. In addition to the recent story on issues in North Dakota on stem cells, now there’s news of unhappy patients in Virginia too. From this news story, “For the debilitating pain of neuropathy, the patients and their spouses turned to a new clinic in Woodbridge, Virginia called RegenPath.” Although, it’s not clear if the Virginia clinic had permission to use that name. Also from the news piece, “However, Liveyon, the California company which provides the stem cells, “does not promote its use for neuropathy … and discloses that our product is not FDA-approved,” its Chief Compliance Officer told 7 On Your Side.” It’s all very complicated so read the story if you are interested.

And finally, this is interesting but pretty weird in spots: Is the Secret to Significantly Longer Life Hidden in Our Cells?

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√ Anti-Aging And The Billionaires Young Blood Stem Cell Club

Parabiosis with older man getting young blood: Season 4 episode 5 of Silicon Valley, “The Blood Boy”.

What is the Billionaire’s blood & stem cell club and how does one get into that?

The focus of what I’m satirically calling this “billionaire’s club” is on anti-aging and prolonging life. If you have a lot of money and are willing to take risks on yourself toward some specific goal such as staying young or fixing some disease or injury via spending big bucks, the young blood & stem cell club might be right for you. Billionaires tend to be risk-takers any way, right?

There have been some whispers (and even a recent article or two), in the last couple years especially, of rich and often famous folks getting sketchy stem cell and other “out there” biological “treatments.” Of course, we all heard about Rick Perry’s stem cell shots (see here for example) and about the famous celebrities who’ve gotten stem cell offerings from clinics including in particular aging former sports stars, some near and dear to people’s hearts.

However, this new phenomenon, if it exists, is different in some ways.

There’s almost a club-like feel to what I’m hearing of rich folks, especially older and aging men but also some women, dropping large sums of money for all kinds of stem cells and other iffy stuff. Maybe there’s a “let’s all catch a game or grab a drink, and then go get injected with XYZ” stuff together kind of feel. The ‘stuff’ they’re getting injected with can range from their own stem cells to placental stem cells to some mystery product to animal stem cells.

And, of course, young blood.

Maybe a few pints a couple of times a year of some teenager’s “youthifying” blood for $50K or $100K? Far-fetched? See the image above from an episode of HBO’s Silicon Valley where an older guy (maybe the writers were thinking this was supposed to be Peter Thiel-like?) gets a younger one’s blood to try to fight aging. Silicon valley is apparently one real epicenter of expensive, unproven, alternative therapies like some of the kinds of stem cells out there.

What could go wrong, right?

There are some big names floating around that could constitute a club-like group, which may tend to encourage one another to try the latest thing. As the oldest president ever, I wonder if Donald Trump has considered stem cells or even gotten some? I’ve never heard that, but it wouldn’t shock me. They say stress ages one so the last month might have Trump looking for some fountain of youth.

I suppose if one has the money, is aging, and is into risk taking, what’s to stop them from giving it a go and maybe turning it into a clubby thing?

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√ Dissecting 4 Possible Roles For Stem Cell Therapy Besides Cell Replacement

An illustration of stem cell drug delivery by Taylor Seamount Stem Cells: An Insider’s Guide by Paul Knoepfler.

Historically, the main route of proposed healing via stem cells was cell replacement. In this way of thinking the transplanted cells engrafted (took up home) in the patient’s tissue and replaced dead or diseased cells. However, interest continues to grow in other possible modes of healing by stem cells that don’t rely on cell replacement. In today’s post I cover 4 other possible mechanisms.

Secreted factors

An alternative, not mutually exclusive model to cell replacement is that stem cell transplants have beneficial effects via the factors they directly secrete. These growth factors, cytokines, and other molecules (collectively sometimes called “the secretome”) could have a positive impact by a number of mechanisms. After stem cell transplantation, these factors might tell endogenous stem or precursor cells to start growing. They could tell some cells not to die, while encouraging others that are beyond hope and might actually be mediating toxic effects to go ahead and croak. (Incidentally, you might have seen the research (mentioned here) supporting the notion that senescent cells hanging around the body are actually actively harmful and removing them could fight aging. There’s even a germinal field of “senolytics”.) Secreted molecules might also stimulate angiogenesis, aiding in tissue healing. It’s a fact of life that secreted factors produced by transplanted stem cells would also pose risks such as sparking cancer or enhancing the growth of an already existing, undetected tumor.

Immunosuppression

Another popular, related idea is that infused stem cell specifically have immunosuppressive functions. In this way of thinking, although injected stem cells don’t stay around a long time, while present they tell the immune system to “cool it”. It’s an interesting concept, but not concretely proven. Let’s say for the moment that it sometimes happens. In that context, we have to be very aware of risks associated with this hypothetical stem cell-mediated immunosuppression. For instance, patients may get sick from an infection or developing a tumor as a consequence of reduced immune activity. The immunosuppressive route of function has been discussed the most for mesenchymal stem cells or whatever you prefer the MSC acronym to stand for these days.

Exosomes

An additional idea invokes a different kind of “secretion” by cells. In addition to making molecules that are dumped out directly into the interstitial space, the blood, or onto neighboring cells, stem cells (and really all cells) make what are called exosomes. These are little, budded-off membrane-bound packages full of many different molecules. Exosomes can then deliver their soup of factors to other cells. There is a lot of legitimate excitement about exosomes and their possible clinical potential. Unfortunately, there is abundant hype too. Also, some unproven “exosome therapy” is already being sold to patients. Of course, if exosomes can have potential benefits, their function as little packages of potent molecules will also pose some risks, which at this point are not well understood.

Drug delivery

This last notion is related to the first three ideas above, but involves more time in the lab. Stem cells can be engineered in the lab to produce (or be loaded with) drugs that they then can secrete or in theory deliver with exosomes or even by cell fusion. In this way designer stem cells, once transplanted, can potentially deliver medicines to a diseased tissue. This delivery could even be on a cell-to-cell basis (I could say one cell acts as doctor and the other as patient, but I won’t), rather than systemically as most pharmaceutical drugs are given. For example, imagine stem cells loaded with chemotherapy delivering it directly to a brain tumor like a glioma.

Risks here include that the stem cells give too much drug, that the drug is delivered to the wrong cells, that the drug given by stem cells is uniquely toxic, or that the designer stem cells themselves engraft and grow into an undesired tissue or have some other negative effects. That last possibility is perhaps avoidable via a built in cellular su1cide switch.

You can see an illustration of envisioned stem cell-based drug delivery to a diseased region of brain in an illustration by Taylor Seamount for my book, Stem Cells: An Insider’s Guide, above.

Overall, what other possible, helpful non-cell replacement-based roles for transplanted stem cells come to mind?

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√ The Niche Weekend Reads Include Herding Brains, Stem Cells, Crispr

Every so often here on The Niche I list science and news articles worth a look. Below is my list for this weekend. Enjoy! The first article doesn’t really fit into the other main categories, but the title “herding brains” caught my eye.

Stem Cells

Stem cells and regenerative capacity in aging brain, article in Cell. Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain. Does this kind of research have relevance to humans? See interesting, complex graphical abstract from the paper, Kalamakis, et. al.

Graphical abstract Kalamakis et al, Cell, 2019

William Wan and Laurie McGinley at WaPo do a deep dive into controversial umbilical cord “stem cell” supplier Liveyon including quotes from the company’s founder, John Kosolcharoen. Many patients are reporting serious adverse events. I’m hoping to have an interview with Kosolcharoen here on The Niche soon.

“Scientists at the University of Bath have identified how a mutant gene in fish is involved in controlling stem cells.” When I first saw a newsy note on this and it said something like “scientists in Bath…identify mutant gene in fish” I kind of imagined the scientists and the fish in a bath together.

When two brain organoids meet. hESC-Derived Thalamic Organoids Form Reciprocal Projections When Fused with Cortical Organoids

CRISPR

One type of the base editor system is very error prone so in many cases likely won’t be a viable alternative to CRISPR gene editing without some kind of major improvement (Science). Here’s the research article, also in Science.

Is CRISPR patent battle finally over?

Did the Chinese government fund He Jiankui’s “rogue” CRISPR of babies and then later try to make him a scapegoat?

Cancer

Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair

Hacking the Cancer Genome: Profiling Therapeutically Actionable Long Non-coding RNAs Using CRISPR-Cas9 Screening

 

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√ Stunning Video Of Diy Self-Injection Of Apparent Us Stem Cell Product Posted After Court Loss

A fitness guru named Ben Greenfield has now reported self-injecting non-FDA approved stem cells. He says the stem cells came from a clinic that lost a big federal court case 9 days ago. Greenfield posted a Facebook video of the actual injection, which he narrates. There’s some text along with the video. Together they raises many troubling questions.

Date of video vs. date of court ruling

Greenfield says in the text describing the video that the stem cells were sent to him at home. They are part of what seems most likely to me based on the text and the video itself to be a DIY self-injection kit. Greenfield indicates in the text that the cells came from the Florida stem cell clinic firm US Stem Cell via its affiliate US Stem Cell Clinic. Importantly, it seems to me as a non-attorney (I could be wrong) that the firms are now subject to effectively a temporary injunction. The Florida judge wrote this in response to an instant motion on June 4:

“ORDERED AND ADJUDGED that UNLESS AND UNTIL this Court enters a permanent injunction, pursuant to the terms of this Court’s Order on the Parties’ Motions for Summary Judgment, D.E. 73, Defendants SHALL NOT sell, provide or otherwise engage in any SVF therapy or any other activities to be regulated by the FDA as explained in the Court’s Order on the Parties’ Motions for Summary Judgment.D.E. 73.”

The original ruling came down on June 3.

It was some days later on June 8th when Greenfield posted the unusual video on Facebook in which he reports in the text of having recently received adipose “stem cells” from US Stem Cell Clinic, again a part of US Stem Cell, Inc.

The timing here could be really important.

What’s going on in the video exactly?

Ben Greenfield doing what he reports to be a US Stem Cell-related DIY stem cell administration. Screenshot of FB video.

In the video, Greenfield seems to give himself an IV push of the stem cells. It’s hard to see what’s going on at times and to see his face in the video but it seems to be him and it’s on his FB page. You can see a screenshot from the video I’ve included below.

Here’s the text associated with the video, emphasis mine:

“*WARNING* For anyone uncomfortable with needles, please skip this video. I’m not a doctor, and what you will see in the video below is not to be taken as medical advice. But – from getting full body stem cell makeovers (Learn more here: http://bit.ly/2I4EyXW) to getting stem cells injected into my junk (http://bit.ly/2I3wRBt) to doing crazy blood stem cells protocols like this (http://bit.ly/2I5kO6B) – I have done some interesting things with stem cells…

In the video below, you can see me demonstrating how I inject mesenchymal stem cells extracted from my own adipose tissue by the US Stem Cell Clinic (https://usstemcellclinic.com/greenfield/). This is a fringe way to keep my endogenous stem cell pool elevated as I age, but it certainly does the trick…”

Big questions arise

I’ve got a lot of questions. Back to the timing issue, did US Stem Cell, et al. send him the stem cells and other materials after they lost the federal court case? There seem to be 4-5 days in between the court events and the video posting, but it’s also possible that Greenfield posted a video taken some days or weeks earlier.

Another caveat here is that at times Greenfield might somehow not be describing entirely accurately what is going on in the video and in the text, but I don’t see any particular reason to doubt what is said and written. Why? Last year, Greenfield openly discussed injection of his p3enis with stem cells from the company too (what he mentions in the text above as “stem cells injected into my junk.”) In addition, US Stem Cell Clinic has a webpage on Greenfield (see link in the statement with the video above).

More broadly, setting aside for the moment the timing issue, is it legal at any time for US Stem Cell Clinic or any other firm to ship an unapproved biologic product to a customer and importantly also one apparently intended for self-administration?

Does Greenfield live in a state other than Florida? I couldn’t figure that out yet. If so, then the apparently unapproved stem cell drug product may have been shipped across state lines, which could be significant. Again, I’m not an attorney, but these things do seem notable.

Dead or living cells in injection, and what about cryo chemicals?

Some practical issues come up here too in my mind as a stem cell biologist. I wonder if these cells were shipped on dry ice and did Greenfield store them properly if he didn’t immediately inject them? Were they alive? Were they thawed carefully without contamination?

Furthermore, if you mix stem cells with pure water as seems to be indicated in the video, they will literally pop open due to osmotic differences. Then they’ll be beyond dead and just debris. Perhaps Greenfield meant isotonic saline instead of water?

Also, cells are typically frozen in a special solution often containing DMSO or other cryopreservatives. Those specific chemicals may not be (A) intended for in vivo use, and (B) be safe to inject into one’s blood stream.

Serious possible risks

My opinion is that this kind of practice is likely to be highly risky including a chance of infections (note that Greenfield doesn’t wear gloves for instance), immune reactions, or customers having other serious, acute adverse reactions with no medical personnel around to help.

Company leader Kristin Comella herself seemed to mention in a striking FB video last year that reactions such as fevers and passing out do happen at times after adipose stem cell injections.

What if no one is around to help or call 911 after a DIY stem cell self-administration causes major side effects?

I’ve heard some rumors more broadly for a half dozen or more years that some stem cell clinics including in Mexico sell purported stem cells expressly for the purpose of self-injection via shipments to customers, but evidence has been scant. Then there is or was the mobile stem cell clinic in Florida. Is it still scooting around?

How many people might be following Greenfield’s example using stem cell clinic cells shipped to them and what does the FDA think of this kind of thing?

It sure does feel like the “stem cell wild west” out there still.

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