No criticism towards you. That’s how it’s always written.
New drug combination shows massive fat loss and muscle gain without steroids - "The End Of Steroids?
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Agree.
That’s not what I said. I was quite careful with my wording. I said “anybody actually exercising and interested in fitness and nutrition doesn’t need the GLP-1RA aspect”, and I stand by that. Bodybuilders are very used to counting calories, tracking macronutrients, and don’t need the “help”. Obviously lay people just eating “ad libitum” are a totally different population.
In this context is massive fat loss and muscle gain, the GLP-1RA is there simply to reduce caloric intake. And it’s that reduction which is causing the muscle loss (in non-training populations). Looking at those who are “into” fitness and nutrition, they are exercising, thus providing stimulation for muscle preservation, and they can control their caloric intake. Thus, the major benefit comes from the muscle gaining drugs, not the fat loss drugs.
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I always wonder about effects in the mouth like saliva reduction… So many molecules and microorganisms depend on oral health… (even nitric oxide formation). Have you seen any investigation focused on the saliva under these drugs combination on the medium run?
I had never considered that. I used semaglutide for 6-12 months before swapping to tirzepatide 2-3 months ago and I have not noticed any reduction in salivation or oral health problems.
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Caloric deficit causing the loss of lean muscle is the current narrative but there is some emerging evidence and active studies going on showing GLP1’s can tip the myostatin/activin switch towards catabolism.
When you block myostatin/activin while holding the calorie deficit constant (via the identical semaglutide dose), muscle loss largely disappear , so the excess lean-mass loss can’t be pinned on calories alone; it’s drug-linked and ligand-mediated.
Anyway - Something to watch for. And ties back into the results that Mike was so excited about.
https://www.nature.com/articles/s41574-025-01140-w
https://www.nature.com/articles/s41467-025-59485-9
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We’ve seen the benefits of acarbose when combined with rapamycin, but I imagine rapamycin + tirzepatide would perform far better.
Summary of study you provided:
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Objective & Scope
Tested whether activating the glucagon-like peptide-1 receptor (GLP-1R) can reverse age-related decline, using comprehensive “multi-omic” profiling (transcriptome, DNA-methylome, plasma metabolome) plus functional read-outs in old mice. -
Intervention
A low dose of a GLP-1R agonist was given to aged but not young-adult mice. The dose was chosen specifically because it did not change food intake or body-weight, isolating direct drug effects from weight-loss side-effects. -
Whole-body functional rejuvenation
Treated old mice showed better physical performance and cognition (grip-strength, endurance, behavioural memory tasks), indicating that benefits extend beyond glycaemic control. - Multi-omic “youthful shift”
- Transcriptomes: Age-associated gene-expression signatures in multiple organs (brain, liver, kidney, muscle, WBCs) moved toward the young profile.
- DNA-methylomes: Epigenetic-age patterns in tissues and circulating leukocytes were partially reset.
- Plasma metabolome: Youth-like metabolite profile, including lowered inflammatory and lipid-dysregulation markers.
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Organ-specific patterns mediated by the hypothalamus
Rejuvenation magnitude varied by tissue but, mechanistically, most effects required an intact hypothalamic GLP-1R signal—highlighting a central neuro-endocrine axis. -
Specific to old age
Young-adult mice derived no additional benefit, suggesting the drug normalises age-linked damage rather than pushing physiology “beyond youthful”. -
Benchmark vs. rapamycin
Molecular signatures produced by GLP-1R agonism overlapped strongly with those seen under mTOR inhibition (rapamycin), a canonical anti-aging strategy—implying convergent downstream pathways. -
Clinical relevance
Because GLP-1R agonists are already FDA-approved for diabetes/obesity, the findings support rapid translation into human geroprotection trials and may explain their observed pleiotropic benefits (cardiovascular, renal, neuro-cognitive). [ouci.dntb.gov.ua] -
Limitations & next steps
Mouse study, preprint status, lifespan not measured, single agonist & dosing paradigm used—human trials must establish optimal compound, dose, duration, and long-term safety for anti-aging use.
Sorry, which study are you refering to?
The one that mjmj linked here.
GLP-1’s have quickly become very popular with the bodybuilding community. You can visit some of the forums and verify for yourself. So these folks do want the “help”.
You are incorrect about the muscle loss - at least in mice. Mice broken up into 2 groups, one on a GLP-1, the other was not. The mice on the GLP-1 got to eat what they wanted, whatever they ate was tracked. The other group of mice got to eat the exact same amount as the GLP-1 mice had eaten. So the calories were identical.
The mice on the GLP-1 lost more weight, lost more fat, and retained more lean mass (although they still lost some lean mass) than the other mice. The other mice even started to regain weight - all of it fat - past a certain point in the experiment.
Cleary the GLP-1s are doing something other than simply reducing caloric intake.
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Do you have a reference/link to this study?
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Yea I’d like to see it too.
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Please see this. It is a bit long. If you start by examining figure 3A you’ll be in the right part of the study if I recall correctly. It has been some time since I read it slowly and carefully, I just scanned it now. Please let me know your thoughts once you’ve had a chance to digest it. Thanks.
https://doi.org/10.1016/j.cmet.2022.07.013
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Well sure. But they also take whatever research chemicals off the Internet. That doesn’t mean much, haha. I was a pretty active member of those communities for a decade or more.
I was going to ask you to share, then saw that you just did a few moments ago, thanks. I would gladly stand corrected because I wasn’t aware of any new evidence. I know the whole “GLP-1RA = muscle loss” thing is predicated mostly on obese people who don’t exercise, and I had presumed the effect could be negated by exercise. But of course the pharma companies work on the Activin A stuff because it would be a huge money-maker to be co-prescribed alongside every GLP1R1 prescription. The study you shared seems to be talking about a new drug, and not any of the drugs people are currently using, so I’m not sure how to interpret it.
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LY3437943 is retatrutide. I’ve seen anecdotal reports that it is a bit more muscle sparing compared to tirzepatide and semaglutide.
Most muscle loss is just improper use.
I’m sure they’re looking at a lot more than just myostatin and activin A. I say bring it on!
We need something to help with motor units as well, they seem to heavily rely on extensive exercise to maintain. But heavy exercise isn’t good for longevity.
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I actually misread @Thorin’s original post. Yes he’s right, the newer drugs (at least the ones that agonize receptors beyond just GLP-1) do definitely have effects beyond decreased caloric intake, especially those with glucagon activity (retatrutide, mazdutide, survodutide and others in development).
The glucagon agonism causes increased caloric expenditure, which is indeed independent of caloric intake and results in weight loss over and above what you’d see with GLP-1 and/or GIP agonism alone. Tirzepatide also causes a small increase in energy expenditure, although much less than the others with GCG agonism.
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I’ve been using Retatrutide for over a year now. It is not FDA approved yet so anyone using it is in a study or buying it from overseas peptide providers (which is what I’ve been doing). Many, many people are using it.
From what I have been able to find, I am not sure if Reta is more muscle sparing than Tirzepatide. I would like to know which is best on that measure but I have not come across anything convincing on it. Like you, I think Reta might be the best on that, but I am just not sure.
I am not saying the answer to that is not known by anyone, I am merely admitting it is not known by me. I would like to know.
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We’ll get some retatrutide DEXA body comp data when the first of the phase 3 trial data is released later this year. Can’t wait!
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That is exciting! I did not know that. Thank you for sharing.
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I don’t know any lifters who can bench over 400 that are not taking PEDS.
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I have not found any research that investigates muscle preservation on reta. There is some speculation among users on Reddit that glucagon receptor activation might help preserve muscle mass by increasing energy expenditure and promoting fat breakdown. While this may not directly impact muscle, perhaps since reta achieves some of its fat loss via increased metabolism, the caloric deficit required for the same amount of fat loss is lower; therefore, muscle mass loss due to calorie restriction is also lower. Anyhow, I think the key is to have reasonable nutrition and protein intake and keep resistance training. I have not tried any GLP1s yet, but I’ve lost a few pounds of fat a week with calorie restriction while simultaneously gaining some muscle by following this formula.
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