This is a further dive into and expansion of a Journal Club video that I offered in September 2025 in response to a fascinating article related to the power of GLP-1 peptides to create positive epigenetic changes at the cellular level.
The study, Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial, is in preprint and has not yet been peer-reviewed, but offers substantive evidence of semaglutide’s versatile effects on cellular pathways related to metabolism, inflammation, and the immune system. In particular, the study examines the use of semaglutide (a GLP-1 receptor agonist) to control or slow the epigenetic aging of people with HIV (PWH) and associated lipohypertrophy, a common condition with this population of patients.
Through the lens of “the emerging geroscience paradigm” (Kennedy,et al, 2014), the study authors suggest that HIV-associated lipohypertrophy (a condition characterized by excessive accumulation of visceral and ectopic adipose tissue) offers an opportunity to examine the impact of semaglutide on a cohort who represent the “accelerated-aging phenotype” and look at possible implications for GLP-1 RAs as agents that improve biological age.
I was drawn to this article because of its focus on the pleiotropic power of GLP-1 RAs, a topic that I’ve discussed in several Masterminds, focused on in my soon-to-be released weight loss course, and devoted an entire book to – The Quantum Power of GLP-1 Peptides (SSRP, 2025). As we know from the plethora of existing research, GLP-1 peptides such as Semaglutide decrease inflammation, improve metabolism, and support the immune system. The two-part question that the article prompted for me was this: if GLP-1 RAs can positively affect cellular metabolism, immune function, and inflammation, thereby altering the cellular environment, wouldn’t it make sense that they also have the potential to increase the healthspan – or lifespan – of the cell? And I think the answer, intuitively, is – absolutely.
This study is first-of-its kind because it presents us with a model that enables us to make some valuable correlations, within the context of the established evidence that GLP-1 RAs can create mechanistic changes that go beyond weight loss. Again, since GLP-1 peptides improve metabolic flexibility and efficiency, mitochondrial signaling, and immune regulation – then all of these processes will more than likely have an eventual consequence on the cell and its healthspan. Again, I return to the basic premise of my approach to cellular medicine: if we work on inflammation, if we work on the immune system, if we work on metabolism, we have the potential to improve biological age. Peptides like GLP-1s change the cellular environment from one that is severely stressed and inflamed and functioning sub-optimally to one that is balanced, efficient, and flexible. And when these essential cellular processes are addressed and optimized, we improve the overall environment of the cell, allowing it to live longer.
A Caveat
Before diving into the methods and outcomes of the study, it’s important to acknowledge the significance of the control group being a population with significant metabolic and autoimmune issues. Therefore, any correlations that may be observed need to take into account the fact the study population is suffering from accelerated aging. HIV/AIDS is a disease process that has severe consequences on metabolism and on both the innate and adaptive arms of the immune system.
HIV patients demonstrate accelerated aging in terms of systemic inflammation, immune activation, and metabolic dysfunction. These areas also influence the mitochondria’s cell signaling and functioning, and hence create an effect on the immune system and inflammatory conditions. Another significant feature of this control group is its associated lipohypertrophy, which creates a further burden related to metabolic problems and an increase in production of inflammatory cytokines – both of which are linked to oxidative stress, disease states and accelerated aging.
What is Associated Lipohypertrophy?
Lipohypertrophy in AIDS patients, also known as HIV-associated lipohypertrophy (HIV-HL), is the abnormal accumulation of fat in specific areas like the abdomen, neck, and back, and is primarily caused by certain antiretroviral therapies (ART) for HIV. It is a component of HIV-associated lipodystrophy syndrome, which also includes lipoatrophy (fat loss) and metabolic disturbances.
The Study
The study authors examined the effects of semaglutide treatment on biological aging using 17 different DA methylation (DNAm)-based epigenetic clocks spanning first-, second-, and third-generation models. For example, in ANCOVA models adjusting for baseline covariates (sex, BMI, hsCRP, and sCD163), semaglutide was associated with significantly reduced epigenetic aging relative to placebo across multiple clocks. For DunedinPACE, semaglutide was associated with a 0.09 lower pace-of-aging (units per year) relative to placebo, translating to roughly a 9% slower pace of aging and a 3-year reduction in annual biological age increase in the semaglutide group compared to placebo. Semaglutide also significantly reduced biological age acceleration in SystemsAge, PhenoAge, PCPhenoAge, and OMICmAge, (Chen et al. 2023).
The researchers then investigated the effects of semaglutide on organ-specific biological aging and applied a panel of 11 DNA methylation–based “system clocks” derived from a single blood methylation assay across specific organ systems, including blood, brain, inflammation, heart, hormone, immune, kidney, liver, metabolic, lung, and musculoskeletal. Each system clock captures both all-cause mortality risk and organ-specific decline; for example, the Heart clock predicts cardiovascular events, while the Brain clock tracks cognitive function and neuroimaging correlates. In adjusted ANCOVA models controlling for age, sex, BMI, hsCRP, and sCD163, semaglutide treatment was associated with consistent reductions in epigenetic age across all 11 systems, with the largest effects observed in the Blood (–4.37 years, p = 0.011), Brain (–4.99 years, p = 239 0.0049), and Inflammation (–5.01 years, p = 0.0056) clocks.
Abstract from the article:
“Semaglutide is a once-weekly GLP-1 receptor agonist that has been proposed as a gerotherapeutic, yet no data exist on its effects on epigenetic aging. We therefore conducted a post-hoc epigenetic analysis of a 32-week, double-blind, placebo-controlled phase 2b trial in 46 adults with HIV-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). Paired peripheral-blood methylomes were profiled to evaluate semaglutide’s impact across multiple generations of DNA-methylation clocks. After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years, P = 0.007), GrimAge V1 (-1.4 years, P = 0.02), GrimAge V2 (-2.3 years, P = 0.009), PhenoAge (-4.9 years, P = 0.004), and DunedinPACE (-0.09 units, ≈9 % slower pace, P = 0.01). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years, P = 0.009) and the transposable element focused RetroAge clock (-2.2 years, P = 0.030). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged (P = 0.31). These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.”
Cited from: Corley, M.J, et al. (2025) Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial. medRxiv. https://doi.org/10.1101/2025.07.09.25331038
Reviewing the Cellular Power of GLP-1 Receptor Agonists
So let’s review what the evidence has shown about the effects of GLP-1 RAs on the major cellular pathways. GLP-1 RAs have been shown to directly or indirectly
- improve PI3K–Akt signaling, which boosts GLUT4 translocation in muscle and adipose tissue and improves glucose uptake.
- reduce ROS generation and improve redox balance, protecting cells from oxidative stress.
- enhance ATP production efficiency and reduce metabolic stress.
- downregulate NF-κB signaling, reducing inflammatory cytokine release.
- suppress JNK and IKK-β stress kinase activation, which normally interfere with insulin signaling.
- improve lipid metabolism by lowering hepatic de novo lipogenesis and enhancing fatty acid oxidation.
- shift cells toward greater metabolic flexibility (switching between glucose and fat as energy sources).
- have anti-apoptotic effects, improving β-cell survival and possibly supporting repair pathways in other tissues.
- enhance autophagy, helping clear damaged proteins and organelles.
Knowing these pathways and what’s been already done in the literature to validate the improvement of these pathways and improvement of cellular efficiencies, the results of the study only make sense. However, once again, we want to err on the side of caution and not make automatic translations or applications from this study, given its population (i.e., HIV related immune activation may have an independent influence on methylation). In other words, we cannot say that GLP-1 peptides improve chronological age.
Keep in mind, too, that these models are proxies for organ-aging risk. They are not proof of tissue regeneration or rejuvenation, so these results are indirect measures. But the results do prompt certain questions: what happens with the change in systemic signaling in this disease state in the blood? Are there specific DNA changes in the mononuclear cell? What are the methylation changes and other parameters that have been looked at in the blood and how are they specific to these potential system clocks?
Considering the accuracy of these organ specific clocks from the blood, the researchers show that the measurements of the validation correlations go from negative one to one – with negative one meaning there is absolutely no correlation, to one meaning it’s right on target. Looking at the brain clock, the heart clock, the kidney clock, and the inflammation clock, these numbers usually hover between as low as 0.35 to as high as 0.6, meaning that the inflammation clock is probably the strongest at 0.6, which is still a moderate, reliable marker. It’s not exact, but it’s not bad either. Are these clock values reliable for individuals as proof of tissue regeneration? Probably not, but I do think they are valuable as group-level trends and detection for systemic changes.
The data shows some significant reductions in biological aging. When they looked at the GrimAge, the PhenoAge, and some other measurements, the results varied between three years to two, two and a half years, showing a nine percent slower pace of aging. And the multisystem results showed the largest changes were based on the inflammatory markers, as well as changes in the brain and the heart. And, again, these results reflect statistical projections from blood methylation data, not from organ specific data. But we do know that there was dampening of pro-inflammatory signaling, which could be expected as a result of GLP-1 RA treatment.
Looking at the data points on a graph, where in a high correlation you see a fairly linear structure, it would make sense that there’s a high correlation between the actual organ measurement and the blood measurement, which makes them highly correlatable. That said, I consider most of the data emerging from this paper to show a moderate correlation, with inflammation probably being the strongest of the moderate correlations.
The authors created a good model in choosing to use a GLP-one because its positive impact on metabolism and inflammation are so well evidenced. In fact, I’d go as far as hypothesizing that if Tesamorelin were used that similar improvements in visceral adiposity, metabolism, cardiovascular, and neuroprotective effects would follow a similar process and suggest an improvement in biological age, especially given the data we have on Tesmorellin and its improved activation of SIRT 1 and SIRT 3, as well as on cytoplasmic and mitochondrial activity and DNA.
Of course, a lot goes into answering these related questions and they point to the importance of continued follow up research. However, I do think the model itself is very valuable, and I think the authors have made a valuable contribution.
In conclusion, I see that this study is a good beginning and its take home message is that this is the first randomized controlled study that shows that GLP-1s can modulate epigenetic clocks in HIV patients. And the strongest inferred system effects were in inflammation, then the brain, then the heart clocks. And again, bear in mind that these clocks are statistical models and should be interpreted as proxies – not as proof. They’re not organ specific.
Citations
Corley, M.J, Dwarka, V., Pang, A., Labbato, D., Smith, R., Ross Eckard, A., McComsey, G.A. (2025) Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial. medRxiv. https://doi.org/10.1101/2025.07.09.25331038
Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow 593 GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss-Coray T & 594 Sierra F (2014) Geroscience: linking aging to chronic disease. Cell 159, 709–713.
Seeds, W.A. (2025) The Quantum Power of GLP-1 Peptides: Unlocking the Science that Leads to Lasting Weight Loss and Optimal Healthspan. SSRP Institute.
Further Reading
Guzman N, Vijayan V. (2022) HIV-Associated Lipodystrophy. StatPearls, Treasure Island, FL. https://www.ncbi.nlm.nih.gov/books/NBK493183/
Zandman-Goddard, G., & Shoenfeld, Y. (2002). HIV and autoimmunity. Autoimmunityreviews, 1(6), 329–337. https://doi.org/10.1016/s1568-9972(02)00086-1