Look, you can give your cartilage a break by losing weight which can stave off further damage. But we don’t have any reports to date that anything can grow it back. Once you lose it that’s it. So this report is groundbreaking. I don’t understand what there is to fuss about. Yes we’re awaiting confirmation and more info but if it pans out it’s astounding. The only skepticism I can relate to is, let’s wait till there’s more data. But if the claims pan out, they’d have zilch to do with weight loss.
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Jesus Joseph and Mary!
If they can report even a single case of cartilage regeneration that’s earth shattering in itself. Cartilage is supposed to only deteriorate with time, a one way street. So if found an intervention that only resulted in pulling off time friggin travel in 17% of a 20 subject group, would you ask, “but what’s the p value” or holler, “holy shit time travel is possible!?”
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Thankfully no. Cartilage, like tendon, is a living tissue that adapts to the load. For instance long term runners have thicker cartilage areas. As usual it’s a U-shaped curve and extreme volume of running might be detrimental to cartilage though.
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Science is skeptical.
This is an MRI finding not a tissue biopsy. X-rays lie is surgical dogma. Yes, MRI is not x-ray but same idea. As a general surgeon, we always meant CTs lie. I can tell you that MRIs are significantly worse but cartilage is not my field. But MRIs are not nearly as good as the radiologists think.
What we don’t know -
- what scanners they used. How modern?
- did they change scanners half way through study? Which is why we need to compare to placebo.
- did the scanners get a software update?
- did they change any protocol?
- did they change radiologists?
- they injected the joints - did that change anything?
- does the injection or GLP1 change the radiologic appearance enough to change measurements? As we know creatine increases water content of muscles which effects measurements. Maybe the GLP1 changes the water content?
- does weight loss change the density of cartilage - ie making it appear larger with less compression?
There is no way a MRI finding proves to me there is cartilage regrowth on 20 people without strict controls and blinding and placebo comparison statistics.
I have a blind spot for MRI technology and with cartilage, even more of a blind spot. And I am skeptical. And I have a career of disagreement at times with radiologists - even a paper published that says CTs lie - on a specific diagnosis with pathologic confirmation.
None of this means that GLP1s aren’t great for joints. Does that mean every BMI 20 person who eats a good clean diet should start GLP1s? Probably not yet. It is well documented that people lose muscle with GLP1s so let’s not pretend they don’t have any downside. Does that mean a weight lifter who doesn’t change calories will lose muscle? Probably not but could be if the same thing grows cartilage, right?
Everything has a down side.
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I think I’ve found the paper that this video is referring to. Should make the discussion more concrete and shed more relevant details.
cell-oa-paper.pdf (4.3 MB)
AI Summary
The provided document detailing a 2026 study in Cell Metabolism describes how semaglutide (SG), a GLP-1 receptor agonist, effectively treats osteoarthritis (OA) through a mechanism that is independent of its well-known weight-loss effects.
Main Findings
- Chondroprotective Effects: Semaglutide treatment significantly reduced cartilage degeneration, osteophyte formation, and synovial lesions in obese mouse models of OA.
- Pain Alleviation: SG treatment substantially improved mechanical and thermal allodynia in mice. It also downregulated pain-related neurochemical markers such as CGRP, PGP9.5, and NGF.
- Weight-Loss Independence: By using a diet-controlled “pair-feeding” (PF) group that matched the weight loss of the SG group, researchers proved that weight loss alone was insufficient for cartilage protection; only the SG group showed significant improvement.
- Clinical Evidence: A pilot clinical study in humans with obesity and knee OA showed that SG (in combination with hyaluronic acid) increased cartilage thickness by approximately 17% and significantly improved joint function compared to controls.
Mechanism of Action
The study identifies the “GLP-1R-AMPK-PFKFB3” axis as the primary pathway for SG’s therapeutic effect:
- Metabolic Reprogramming: SG shifts chondrocyte (cartilage cell) metabolism from glycolysis (which is elevated and harmful under OA inflammatory conditions) to oxidative phosphorylation (OXPHOS).
- ATP Production: This metabolic shift restores intracellular energy balance and supplies ample ATP to support chondrocyte repair.
- Signaling Pathway: SG activates the GLP-1 receptor (GLP-1R), which triggers PKA and subsequently AMPK signaling. This leads to the activation of PFKFB3, a key regulator that manages the switch between glycolysis and OXPHOS.
The pilot clinical trial described in the study evaluated the efficacy of semaglutide (SG) in treating obesity-related knee osteoarthritis (OA) by comparing its effects against a standard treatment.
Pre-clinical trial details
The pre-clinical study utilized an obesity-related mouse model to investigate the effects of semaglutide (SG) on osteoarthritis (OA). This phase of the research was critical in demonstrating that SG’s benefits for joint health are independent of its well-known weight-loss effects.
Pre-Clinical Trial Design
- Model Establishment: Researchers first established obesity in C57BL/6J mice using a high-fat diet until they reached a body weight at least 20% higher than regular diet controls.
- OA Induction: Osteoarthritis was induced via Destabilization of Medial Meniscus (DMM) surgery performed four weeks before treatment began.
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Groups Analyzed:
- Obesity + DMM: The OA control group (obese mice with DMM surgery).
- Obesity + DMM + SG: The treatment group receiving weekly subcutaneous injections of semaglutide.
- Obesity + DMM + PF (Pair-Fed): A critical control group where food intake was restricted to match the appetite suppression and weight loss of the SG group exactly.
- Sham/Control Groups: Standard controls to establish baseline health.
Analysis of Cartilage Thickness and Area
The researchers assessed the health of the joint cartilage using histology (Safranin-O-fast green staining) and micro-CT imaging after 12 weeks of treatment.
| Group | Cartilage Condition & Change Analysis |
|---|---|
| Obesity + DMM (Control) | Showed severe OA-like changes, including significant cartilage degradation and a notable reduction in cartilage area. |
| Obesity + DMM + SG (Treatment) | Demonstrated a significant increase in cartilage area and reduced degradation compared to the DMM group. The OARSI scores (which measure OA severity) were markedly lower. |
| Obesity + DMM + PF (Weight Control) | Despite achieving a comparable weight loss to the SG group, these mice showed no significant cartilage protection. Their cartilage area remained reduced, and OA progression was similar to the DMM control. |
Because both groups lost the same amount of weight, but only the SG group showed preserved cartilage area and thickness, the authors concluded that semaglutide mitigates OA progression through mechanisms independent of its weight-lowering effect. Instead, the drug works by reprogramming chondrocyte metabolism from harmful glycolysis to beneficial oxidative phosphorylation.
Clinical Trial Details
- Design: A randomized, controlled, prospective pilot study (Registration: ChiCTR2200066291).
- Participants: 20 individuals (7 male, 13 female) aged 50–75 with both obesity and early-to-moderate knee OA.
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Intervention Groups:
- HA + SG Group: Received a combination of weekly semaglutide injections and sodium hyaluronate (HA).
- HA Group (Control): Received sodium hyaluronate (HA) injections alone.
- Duration: The treatment and observation period lasted for 24 weeks.
- Primary Endpoints: Changes in Body Mass Index (BMI) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score.
Analysis of Cartilage Thickness Changes
The study utilized Magnetic Resonance Imaging (MRI) to assess changes in cartilage degradation. The findings revealed a stark contrast between the two groups:
- HA + SG Group: This group showed significant improvement in cartilage health. Specifically, there was a ~17% increase in cartilage thickness compared to the control group.
- HA (Control) Group: While HA is effective for symptom management, it did not significantly alter cartilage thickness. The study noted that semaglutide provided a distinct chondroprotective effect that was not achieved by standard HA treatment alone.
Supporting Weight Loss Data
While the animal models proved the cartilage protection was weight-loss independent, the human trial recorded the following at week 24:
- HA + SG Group: Experienced a mean BMI reduction of -7.96%.
- HA (Control) Group: Experienced a negligible BMI change of 0.49%.
The researchers concluded that semaglutide acts as a disease-modifying drug by shifting chondrocyte metabolism from harmful glycolysis to beneficial oxidative phosphorylation, thereby directly restoring cartilage integrity.
The authors determined that the 17% increase in cartilage thickness in the semaglutide-treated group was statistically significant.
The key statistical findings regarding this increase include:
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Significant Improvement vs. Control: The semaglutide (SG) group (specifically the HA + SG group) showed a significant reduction in cartilage degradation compared to the control group.
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Statistical Threshold: The study consistently utilized a threshold of p<0.05 to define statistical significance for its primary and secondary endpoints, including MRI-based cartilage parameters.
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Comparative Result: While the HA + SG group experienced this ~17% increase in thickness, the control group receiving only sodium hyaluronate (HA) showed no significant change in cartilage thickness over the same period.
The authors noted that these clinical results were “encouraging” as they mirrored the strong chondroprotective effects observed in their weight-loss-independent mouse models. However, they also cautioned that because of the small sample size (n=20), these results should be validated in larger clinical trials
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My bad. My comment was more of a general comment on interventions that reduce calorie intake. It is indeed interesting that the GLP-1 drugs seem to be able to amplify some of the benefits of weight loss due to independent effects. I wonder if such effects are significant in people that don’t need to lose weight.
Also I am most curious to know if GLP-1 drugs cause benefits in people that do not need to lose weigh at all, and make sure to not eat less at all when on these drugs. For such people, if they have any benefits at all, they would likely be much smaller, since they don’t have the problems the GLP-1 drugs are mainly used to solve. I would only call them longevity drugs if they improve lifespan in animals that are already lean and calorie restricted by adding benefits beyond what you could achieve by merely reducing calorie intake.
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I’m not trying to nitpick, but this study does have some issues.
There were no statistically significant differences between the HA monotherapy group and the HA+SG combination group in terms of WOMAC pain scores or joint stiffness scores. The only area where the combination group showed a clear advantage was in physical function scores. So why did semaglutide win on this measure? At 24 weeks, the SG combination group saw a roughly 7.96% drop in BMI, compared to just 0.49% in the control group. If you look at the 17 assessed items in the paper—such as “going up and down stairs,” “rising from sitting,” “getting in and out of a car,” and “doing heavy housework”—these are all anti-gravity movements that heavily rely on lower limb loading. An 8% reduction in body weight means the mechanical load on the knee joint during these activities is greatly reduced.
Then the MRI data showed that cartilage thickness increased by about 17% in the HA+SG group, compared to less than 1% in the HA group. But here’s the catch: MRI resolution is sub-millimeter. With such a small sample size (only 14 participants completed the trial), manually segmented cartilage thickness measurements using 3D Slicer are highly susceptible to measurement error and individual variation.
Some might think I’m being biased, but the mouse study was flawless. In mice, the PF group had body weight and food intake curves identical to those of the SG treatment group, and SG treatment significantly raised pain thresholds in pain sensitivity tests. In humans, however, weight loss didn’t translate into a statistically significant difference in WOMAC pain scores. Moreover, the average cartilage thickness in the human knee is only about 2 to 3 mm. At sub-millimeter resolution, a cartilage layer may occupy just a handful of pixels in the image. Frankly, there are countless ways the authors could have made the results look significant. If cartilage truly had been repaired, the clinical outcomes in human patients would not look like this.
The mouse study used micro-CT (10 µm resolution), and that research does support the conclusion that cartilage repair in mice is achievable.
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A large body of research supports that GLP-1 drugs should absolutely not be used casually in people with normal weight. However, in the current climate of biohackers widely misusing these drugs, such research is highly unwelcome. So I’m curious to hear doctors’ perspectives. @KarlT @DrFraser
I don’t know if they’re longevity drugs in the sense you mean. Personally I take 2.5 mg of tirzapetide as I can use a bit of weight loss and because of all the positive signals I am seeing. In this particular case I am pretty amazed at the reported results. A couple years back I was binge watching orthopedists’ & podiatrists’ videos on YT due to a sprained ankle and I kept hearing how there’s all sorts of things you can do to prevent cartilage degeneration but that once under way, you can’t reverse damage … as of today … or two years ago. These were the words from the experts in the field. So the result is super impressive to me. But yeah if I were very lean I would think more than twice before dabbling with GLP1s. That’s neither here nor there for the purposes of cartilage regeneration.
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I find this very interesting. A possible game changer. Looking forward to intraarticular glp1 studies in humans.
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Please help me with this “large body of research that glp-1 drugs should absolutely not be used …”
I mean who has gone around and given it to normal weight people en masse and found deleterious issues? That outweigh the positive ones.
What I see is extrapolation of negative issues in obese people and saying you should not use them on normal weight people. Nothing wrong with that but it isn’t a large body of research.
I give GLP1s to normal weight people who were once obese as maintenance and that is standard of care. I generally wear them off but many are unable. So 5 years later, they have normal BMI and take a shot per week. This is not considered harmful of course. So you see, I would argue, what is the difference? Of course, the difference is the benefit of not regaining weight outweighs the risk but it can be splitting hairs a bit at some point.
I think the benefits of restricting calories is so dramatic that it probably over comes the risk for many people outside the trials that have been done. But I am open to influence so show me the studies.
Biohacking is pushing boundaries. It is working outside of established medical protocols. Tell me that post menopausal women should not take testosterone even though it is biohacking. Nearly every cholesterol hacker was validated last month when the AHA changed their guidelines. Ditto with blood pressure when guidelines were changed. Guidelines are slow and financially motivated based on populations.
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This is essentially common knowledge. There are almost no clinical studies on the long-term safety and benefits of these drugs in metabolically healthy individuals with a normal BMI. That means you’re essentially conducting a self-experiment with no scientific literature to back it up. If your blood pressure, blood sugar, and cardiovascular status are already healthy, you’d be taking on the same side-effect risks without gaining any meaningful health improvement. This is precisely the benefit-risk ratio issue I’ve always emphasized—and I’ve stressed these anti-aging concepts many times.
Take tirzepatide as an example. Patients first received tirzepatide for 36 weeks, then were randomly assigned to either a continued-treatment group or a placebo group for another 52 weeks. Both groups continued a low-calorie diet and exercise plan. Results showed that by the end of the 88-week period, about 82.5% of participants had regained at least 25% of the weight they had lost. The more weight they regained, the more the improvements in heart and metabolic health reversed. This clearly shows that the vast majority of tirzepatide’s benefits come from weight loss. As someone with a completely normal BMI and no metabolic disease, your benefit-risk ratio is quite low. Look, I don’t want to repeat this again. If you don’t care about the benefit-risk ratio, then go ahead and experiment on yourself. But I believe the consensus among all physicians regarding whether healthy people should take GLP-1 drugs is clear. I have always stood with the majority of anti-aging clinics.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2841273
BTW,Regarding negative studies on GLP-1, I don’t want to go into them further here — there are far too many, and they’re not exactly popular among biohackers. I’m not currently willing to provide that kind of consultation.
In reality, self-experimentation by biohackers holds little value, because this group already has access to a wide range of anti-aging interventions, leading to too many confounding factors. Even if any benefits were observed, they wouldn’t be meaningful. So I would not encourage them to try many things with unclear benefits. If they could organize themselves and provide scientists with research data—even just observational studies—then I would encourage them, even if the risks are high, because I would benefit from the data. But now I’ve come to terms with it; it’s better to just encourage them blindly. People always prefer a positive message. Some things are better kept to yourself—speaking them out only makes everyone unhappy."
Doctors are the last people I would ask about anything. Their incentives are to gatekeep access to everything behind their bureaucratic ceremonies so they can extract monopoly rents from the populace.
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BTW,Regarding negative studies on GLP-1, I don’t want to go into them further here — there are far too many, and they’re not exactly popular among biohackers. I’m not currently willing to provide that kind of consultation.
Please share the “far too many” studies or refrain from spreading fear, uncertainty and doubt.
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One thing I would say about doctors is that we are all patients also. So while we have financial incentives that would go against certain activities, we also have personal incentives that might go the other way.
That can actually give an appropriate balanced view although the financial part would dominate rules and guidelines that physicians have to live under. So I would argue that it isn’t necessarily the individual physician’s attitude so much as the system we live under.
That vast majority of relevant rent seeking is the pharmaceutical companies. And as physicians, we have no way around this even for ourselves. I have just as much struggles getting a script as the next person. Nearly everyone is employed now and could lose their job if they electronically (the only way) write a script for a friend without the required electronically recorded clinic visit with a bill. All subject to big brother monitoring.
Gone are the days of calling in a script of antibiotics for your sister or whatever. Some may practice still without oversight but our hospitals and medical board will sanction someone in a second for stepping out.
Now that being said, I still come down strongly on restricting medications to prescription when it comes up here for debate. I would argue it is because I have seen what can happen. Yes, it is paternalistic.
Back to GLP1s. So there is no “large body of research”. Why make such a claim if you can’t back it up? And, of course, the primary benefit of GLP1s in an obese population is weight loss and benefits go away when they stop the drug and gain weight. If that is your primary article saying that GLP1s should not be used by normal weight people, it will obviously fail to convince anyone.
I don’t take a GLP1 because I don’t want to lose weight. But people experiment on themselves everyday. Mostly people experiment in how eating too much of a horrible diet will reduce their QOL and lifespan. Because that horrible diet gives them a boost of dopamine to compensate for the stress or pain they want to get away from. And for the majority of say US citizens, GLP1s would be a smarter experiment. And I bet that is true for 90% rather than the 50% or so that guidelines would suggest are appropriate GLP1 patients. That is just rational extrapolation of very safe drugs.
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This is just the tip of the iceberg. Of course, I have a large number of papers that are not mentioned in this review — I only provided this review for convenience.
A good review and really not much.
Increased incidence of a few very rare things. Much if which don’t apply to the general population.
I’m honestly curious what is your beef or motivation here. Saying kind of inflammatory things like “tip of the iceberg” etc.
I’ll admit I own S&P index funds that hold Novo and Lilly but nothing directly. I am not currently prescibing GLP1s as I am semi retired. I essentially have no skin in the finances. As I said above, I don’t take one either.
The vast majority of people in Western developed economies consume too many calories for ideal health. IMO - this is costly and detremental to their health. It is also bad for the environment. Our brains weren’t built for this type of excess and GLP1s are a balance to that. A doubling of a .5 per 100,000 risk is relevant but overwhelmed by the benefits.
I don’t mean to be preachy and everyone is entitled to an opinion. I want to hear you full argument but this article isn’t changing my viewpoint.
An interesting perspective to bring to a biohacker forum 
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Another AI analysis the supports the other ones in this thread. Not enough of the right data yet to fully confirm or negate the hypothesis.
As someone who has arthritis and had fatty liver concerns and kidney disease risk, I’m not terribly concerned about the “but what about…”, when I can see, feel and have tested the positive results from my biohacking adventures.
With all the other benefits from GLP1 + GIP + GCGR I’ll keep taking it.
Similar to our fav topic of Rapamycin, which I will also keep taking
evaluate this paper and provide strengths and weak.pdf (335.7 KB)
Regarding conflicts of interest, if you think I hold any Eli Lilly stock and am attacking tirzepatide just to profit from it, emmmm, what can I say? Maybe I need to screenshot my positions to show a conflict of interest disclosure? Enough. Maybe I should go through every past statement you’ve made and ask you to provide all your conflict of interest declarations and published papers to back up your claims. I truly have nothing to say. Enough. I have already responded to the “far too many” description.
I strongly believe that if I treated your words the way you treat mine, you would only play the victim or refuse to respond. Yes, without a doubt.