Longeveron is a biotech studying clinical applications of mesenchymal stromal/stem cells or MSCs .
MSCs are interesting, usually heterogeneous cell preparations. They are probably most well known for modulating the behavior of other cells via their secretome. The clinical potential of MSCs is often overstated, typically based on small, uncontrolled trials.
So, when randomized, double-blinded, placebo-controlled trials on MSCs are published, it’s important to take a close look.
A new Cell Stem Cell paper on a controlled Longeveron clinical trial of MSCs for aging-related frailty (and a problematic Nature news piece on it) are worth discussing. The paper is interesting and upbeat, but I remain somewhat skeptical about the long-term potential here.
The report comes from a team led by Josh Hare of the University of Miami and Longeveron. They also have recently reported potentially upbeat trial results with the same MSC product for Alzheimer’s.
Let’s go through the new paper and some coverage of the trial.
What are MSCs?
As some brief background, most MSC preps are not pure stem cells. Most of the cells are more akin to stromal and other cells within the greater fibroblast family tree.
There often can be additional cell types present in MSC preps as well including blood vessel cells.
For these reasons, the acronym MSC by consensus has come to mean mesenchymal stromal/stem cells. This rightly represents the heterogeneity of almost all MSC preps.
So far, there are only very limited approved uses of MSC-type products clinically, primarily for GvHD, but many MSC clinical trials are ongoing.
The MSC frailty trial
Here’s the new paper: Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty. I’ve been following Longeveron’s work with their MSC product for at least eight years. Also, way back in 2018, I wrote about a Phase II Longeveron cell therapy study for frailty that led up to the new Phase IIb study.
One thing that I noted about this new paper is that it seems that part of the same data, including the laromestrocel preliminary walk test results, had been viewed not so enthusiastically back in 2021. Now, with more follow-up and data, things seemed to have turned around with much more favorable reported outcomes.
The key result is that the team reported in the new paper that infusions of Longeveron’s MSC product laromestrocel seem to have improved the ability of frail, older folks to walk versus placebo control and there was a dose response.
See an image of Figure 2a below of the dose response and response over time. On first glance, these results seem fairly convincing that there’s an effect, but there are a few things that should be discussed.
Thinking about the data
For example, I wonder what happened to the placebo group between three and nine months, and especially six and ninth months. Their ability to walk suddenly dropped, an unexpectedly steep decline. Is this walking test somehow inherently very noisy in terms of the data it produces?
I wonder if attrition bias could have had an impact here too. While the overall study was N=148, the division into four arms means each group is relatively small. If the ‘healthiest’ placebo patients dropped out or the ‘frailest’ treatment patients didn’t make it to the 9-month finish line, the resulting graph could tell more of a story of trial dynamics rather than MSC-related reduced frailty.
In addition, while there is some dose response, why did the 50M dose seem to perform better than the 100M dose?
Broader perspectives on MSCs and aging: why I’m still somewhat skeptical
What about potential mechanisms of MSC action here if the improvement holds up and is reproducible?
The new paper used TIE2 as an aging-related marker, with reported improvements with MSC infusions. The TIE2 marker suggests one possible mechanism of MSC-based improvement of frailty related to reducing vascular inflammation, but it’s not entirely clear.
To me, the lack of a concrete mechanism is particularly notable if you consider the actual intervention: a one-time, transient IV MSC infusion. IV-infused MSCs don’t engraft and likely don’t hang around long. In fact, most of the MSCs are probably gone in just a few days. But many months later there’s still a benefit in this trial? Plus, the effect seems to increase the more time has passed since the one infusion? That doesn’t seem intuitive to me. Even if transient MSC infusions lead to a long-term reset in something frailty-related, these are not the kind of curves I would have expected to see. For comparison, think about how something like an NSAID could help frailty by reducing pain and stiffness, but you must take those pills every day.
Overall, I’d like to see more data before this approach gets a nod from the FDA. Investors were surprisingly unmoved as Longeveron stock was actually modestly down for the week the paper came out. However, with today’s FDA, you never know how or when investigational cell and gene therapies might be approved or receive a negative reception from the agency.
Caution is needed in the bigger picture and with portrayal of studies
Shifting gears a bit, but also related, one bigger-picture concern is that the graphical abstract for this paper shows an elderly person supposedly being transformed into a healthy, apparently younger version of themselves after getting the investigational cell therapy (see graphical abstract I’ve included above, bottom left part).
I believe that depiction risks giving people the wrong idea about the effect here.
This also reminded me of an MSCs for heart disease paper graphical abstract that included actual happy and sad faces.
Let’s talk about Nature’s news coverage of this study.
Problematic Nature news item
It’s not particularly fun to criticize a powerhouse like Nature, but their news item on this study is frankly a real mess. Here it is: Stem cells provide a potent treatment for frailty.
Potent treatment?
Based on that, you’d think it just got FDA approval based on a Phase 3 study or something. This is not yet a proven treatment and this was a Phase 2b trial. Then who decided to go further by adding the word “potent” here to describe “treatment”? You can see a screenshot at the top of the top of this news item that appeared at the top of the Nature.com website for a time.
The actual text of the piece is also overly excited in my view and doesn’t provide enough context.
What makes this kind of coverage potentially more problematic is that unproven stem cell clinics often overstate the benefits of MSCs. These clinics also sometimes use legitimate research and news items to promote their unproven offerings.
The risks of getting ahead of data
I asked Tim Caulfield, a professor at the University of Alberta, who has written extensively about stem cell therapy development and marketing, for his thoughts on this situation:
“Given how much misinformation there is surrounding health right now, and given all the exploitive unproven ‘stem cell’ therapies, I think we need to be very careful how we talk about research on emerging therapies. We need to watch the hype. History tells us that these therapies often (very often) don’t pan out as promised. I worry that this study and the media surrounding it will be exploited by clinics pushing unproven products and therapies.”
This Nature news item is already in the running for the 2026 Screamers Science Hype Award and it’s only early March.
Overall, if there’s something truly therapeutic here, we need to see a robust, multi-center Phase III trial that meets its pre-specified primary endpoints at a biologically plausible time point. Until then, some caution is warranted.
One final note is that I realize that biotechs needs enthusiasm and investor support to keep going financially. I also believe that MSCs have promise for some specific conditions, but we should be careful not to get ahead of the data.