The Blog

Building a Future Free of Age-Related Disease

Rejuve.ai logo

Rejuve.AI Launches International Longevity Research Database

Roatán, Honduras — Rejuve.AI is activating the International Longevity Research Database (IRLDB) through its first real-world study cohort at the Longevity Biomarkers Competition and Summit, taking place February to March 2026 as part of the Infinite Games in Roatán, Honduras.

The IRLDB is being activated through its first registered, consented cohort. Participants enrolled in the Longevity Biomarkers Competition are pre-boarded into the database under a formally registered IRLDB protocol. They contribute standardized baseline and follow-up biomarker data alongside continuous, app-mediated real-world tracking using the Rejuve Longevity App,

This cohort represents an early deployment of Rejuve.AI’s research infrastructure, ahead of a broader public rollout planned as on-chain and scaling components are introduced to support larger study volumes.

In parallel, Infinita City will host the next installment of the JoyScore experiment in collaboration with Longevity Rave, following a pilot conducted at Frontier Tower in December 2025.

A Real-World, App-Enabled Longevity Study

The Longevity Biomarkers Competition functions as the first live application of the IRLDB protocol, demonstrating how longevity research can be conducted in real-world settings while maintaining scientific rigor.

Participants undergo standardized testing at defined timepoints while contributing longitudinal data via the Rejuve App between assessments. Measurements include blood-based biomarkers, epigenetic clocks, metabolomic profiles, wearable-derived physiological data, and structured questionnaires capturing function, behavior, and environment.

This approach enables consistent benchmarking while preserving ecological validity, capturing how individuals actually live, train, and adapt over time. It also provides a structured framework for self-experimentation that prioritizes data quality, participant safety, and informed consent.

Mapping the Signatures of Human Longevity Summit

The competition is preceded by an opening summit on February 7–8, bringing together leading figures in aging research, clinical longevity, and translational science, including Eric Verdin, Andrea Maier, and other international researchers and practitioners, with participation from organizations including XPRIZE, the Buck Institute for Research on Aging, and the Biomarkers of Aging Consortium.

A central focus of the summit is the ongoing debate in the longevity field around healthspan versus lifespan as the primary goal of intervention. Discussions explore the premise that meaningful lifespan extension necessarily implies preserved or improved healthspan, and that regenerative and damage-repair approaches should not extend periods of decline.

Additional themes include how emerging and partially unvalidated therapies are being used in practice, and how clinics, consumers, and researchers can approach such interventions in ways that maximize learning, data sharing, safety, and participant autonomy.

JoyScore Part II and the Exposome

The summit also incorporates the second installment of the JoyScore experiment, led by longevity researcher Tina Woods. JoyScore explores how psychological wellbeing, social connection, and environmental and lifestyle exposures interact with biological aging processes over time.

Attendees of the Infinita Games may opt in to participate, contributing JoyScore data through the Rejuve App. This enables psychosocial and exposomic signals to be analyzed alongside biomarker and functional data within the same research infrastructure.

About Rejuve.AI

Rejuve.AI is a decentralized longevity research network developing open, protocol-driven systems for studying aging, healthspan, and potential rejuvenation through real-world, longitudinal data.

About Infinita City

Infinita City is a longevity-focused innovation environment in Prospera, Roatán, supporting real-world experimentation in health, science, and emerging technologies.

About Longevity Rave

Longevity Rave is a global platform exploring longevity through science, culture, and participatory experiences, including the JoyScore experiment.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Heartbeat chart

Engineered Extracellular Vesicles Reduce Arrhythmia in Rats

In Nature Communications, researchers have described how small extracellular vesicles (sEVs) fused with plasma membrane proteins successfully treated heart arrhythmia in a rat model.

Why do people need pacemakers?

In a healthy heart, the sinoatrial node (SAN) serves as a natural regulator, commanding the heart to regularly contract. As it becomes dysfunctional and fibrotic with age, heart arrhythmia is the result [1]. Artificial pacemakers are the standard of care for this condition, but such devices come with their own complications [2].

Some work has focused on regenerating the SAN, including turning heart cells into pacemaker cells with gene therapy [3], directly injecting SAN cells created through induced pluripotency [4], and, in some cases, targeting specific ion channels through RNA editing [5]. However, there are inherent risks of cancer and cellular death, and making these interventions into safe, reliable, and broadly applicable therapies has proven to be difficult [6].

An effective delivery method

These researchers, therefore, turned to sEVs as their desired method for bringing protective RNA and proteins to the cells that need them. Ordinary sEVs, however, are quickly recycled in the body and do not naturally target specific cells [7]. Engineering these vesicles, therefore, has become a priority, with multiple techniques being explored [8]. Coating them in platelet membrane proteins serves two key functions: it hides them from the immune system, and it encourages delivery to injured areas [9].

The particular sEVs used in this experiment were derived from human induced pluripotent stem cells (hiPSCs), filtered by size. Rat platelets were then stripped of their contents and their membranes were attached to the sEVs, creating PM@i-sEVs. The researchers then subjected these modified sEVs to a barrage of tests, confirming that the plasma membrane was securely fastened to the sEV and that the membrane-enclosed sEVs do not congeal together the way that actual platelets do.

PM@i-sEVs

PM@i-sEVs were confirmed to be taken up into induced cardiomyocytes (iCMs). 24 hours after they were taken up, they released their contents into the cells’ cytosol. Further testing in rats found that they were found to be better taken up by SAN cells instead of being concentrated in the liver the way that unmodified sEVs are. Further in vitro testing found that they were significantly more attracted to collagen-coated cells than their unmodified counterparts.

Effective in rats

To test the effectiveness of PM@i-sEVs, the researchers created a rat model of heart arrhythmia. The rats’ SANs were injured with sodium hydroxide and ischemia-reperfusion, which was confirmed to induce arrhythmia.

24 andd 72 hours after this injury, some of these rats were injected with PM@i-sEVs, others were injected with i-SEVs, and others served as controls. After a month, the rats treated with PM@i-sEVs fared much better than the other two groups as measured by multiple metrics of heart rhythm function, and there was no damage to other organs as a result of this treatment.

A closer examination found that the treated rats had SANs that were visibly less diseased than those of the other two groups. There was less fibrosis, better collagen deposition, more organized tissue structure, and less congestion; further in vitro experiments found that PM@i-sEVs do indeed significantly reduce fibrosis in cells.

An examination of the specific microRNA molecules found in the sEV payloads suggested potential reasons why. Several of these molecules that were “previously linked to cardiac repair, arrhythmia suppression, and ischemic preconditioning” were found in these vesicles. While this was only an injured rat model and further work needs to be done to confirm these EVs’ effects in naturally aged organisms, including humans, this approach appears to be promising.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Duan, S., & Du, J. (2023). Sinus node dysfunction and atrial fibrillation—Relationships, clinical phenotypes, new mechanisms, and treatment approaches. Ageing Research Reviews, 86, 101890.

[2] Glikson, M., Nielsen, J. C., Kronborg, M. B., Michowitz, Y., Auricchio, A., Barbash, I. M., … & Witte, K. K. (2022). 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: Developed by the Task Force on cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology (ESC) With the special contribution of the European Heart Rhythm Association (EHRA). EP Europace, 24(1), 71-164.

[3] Kapoor, N., Liang, W., Marbán, E., & Cho, H. C. (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature biotechnology, 31(1), 54-62.

[4] Protze, S. I., Liu, J., Nussinovitch, U., Ohana, L., Backx, P. H., Gepstein, L., & Keller, G. M. (2017). Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. Nature biotechnology, 35(1), 56-68.

[5] D’Souza, A., Pearman, C. M., Wang, Y., Nakao, S., Logantha, S. J. R., Cox, C., … & Boyett, M. R. (2017). Targeting miR-423-5p reverses exercise training–induced HCN4 channel remodeling and sinus bradycardia. Circulation research, 121(9), 1058-1068.

[6] Vo, Q. D., Nakamura, K., Saito, Y., Iida, T., Yoshida, M., Amioka, N., … & Yuasa, S. (2024). IPSC-derived biological pacemaker—From bench to bedside. Cells, 13(24), 2045.

[7] Rai, A., Claridge, B., Lozano, J., & Greening, D. W. (2024). The discovery of extracellular vesicles and their emergence as a next-generation therapy. Circulation research, 135(1), 198-221.

[8] Fan, M., Zhang, X., Liu, H., Li, L., Wang, F., Luo, L., … & Li, Z. (2024). Reversing Immune Checkpoint Inhibitor–Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering–Driven Extracellular Vesicle Redirecting. Advanced Materials, 36(45), 2412340.

[9] Hu, C. M. J., Fang, R. H., Wang, K. C., Luk, B. T., Thamphiwatana, S., Dehaini, D., … & Zhang, L. (2015). Nanoparticle biointerfacing by platelet membrane cloaking. Nature, 526(7571), 118-121.

Vaccine

Shingles Vaccination Is Associated With Slower Aging

An analysis of over 3800 older adults found that shingles vaccination is associated with lower inflammation scores, slower epigenetic and transcriptomic aging, and a lower composite biological aging score [1].

Beneficial side effects

Vaccines are developed to prevent specific diseases, such as polio, measles, hepatitis, and many others. However, recent data suggest that some adult vaccines may have unintended yet beneficial effects. For example, vaccines against herpes zoster (shingles), influenza, and pneumococcus were linked to reductions in the risk of age-related diseases, such as dementia and cardiovascular diseases [2, 3, 4].

This initial data sparked the interest of other researchers, including the authors of this study, to investigate this topic further. The study’s authors specifically focused on the shingles vaccine, which protects against a viral infection caused by the reactivation of the chickenpox virus.

The researchers used data from the nationally representative U.S. Health and Retirement Study of 3,884 adults 70 years old and up in order to address the impact of shingles vaccination (specifically an earlier version called Zostavax) on seven biological aging domains: inflammation, innate and adaptive immunity, blood flow forces (cardiovascular hemodynamics), neurodegeneration, and epigenetic and transcriptomic aging that affect gene expression.

Vaccinating against aging

Analysis of the data, after adjusting for demographic, socioeconomic, and health-related factors, showed significant associations between shingles vaccination and three of the seven biological aging domains: lower inflammation scores and slower epigenetic and transcriptomic aging.

The lower observed inflammation scores suggest reduced chronic inflammation. In the elderly, chronic inflammation, often referred to as “inflammaging,” contributes to multiple age-related conditions such as heart disease, frailty, and cognitive decline.

“By helping to reduce this background inflammation — possibly by preventing reactivation of the virus that causes shingles, the vaccine may play a role in supporting healthier aging,” said Research Associate Professor of Gerontology Jung Ki Kim, the study’s first author. “While the exact biological mechanisms remain to be understood, the potential for vaccination to reduce inflammation makes it a promising addition to broader strategies aimed at promoting resilience and slowing age-related decline.”

Beyond inflammation, gene expression and epigenetic profiles were also positively affected by vaccination. Epigenetic age acceleration was assessed using DNA methylation-based aging clocks, which are used to measure biological age, assess the rate of aging, and evaluate the risk of various health outcomes, including mortality, frailty, and chronic diseases.

Since aging affects multiple systems in the body, the researchers created a composite biological aging score by integrating information across six domains into a single measurement; the adaptive immunity domain was excluded due to unexpected results, which could have obscured meaningful effects. Shingles vaccination was associated with a lower composite biological aging score, suggesting that this vaccine affects multiple bodily systems.

Overall, “This study adds to emerging evidence that vaccines could play a role in promoting healthy aging by modulating biological systems beyond infection prevention,” said Kim.

Unexpected results

However, not all measured components showed improvements. The authors reported that, contrary to their expectations, vaccination was associated with higher adaptive immunity scores, reflecting poorer adaptive immune function. This was difficult to interpret, and the lack of additional biomarkers prevented the researchers from testing some of their hypothesized explanations. They also suggest the possibility that vaccination might simultaneously have protective and potentially adverse effects.

The lack of effect of the shingles vaccine on neurodegeneration biomarkers was also rather surprising, given previous links between shingles vaccination and reduced dementia incidence. However, the researchers believe that the biomarkers they used, which reflect long-term damage, might not capture the direct effect of the vaccination on dementia; instead, the effect might be indirect, such as through reduced inflammation, which is more dynamic.

The long-term effects

While vaccination is a one-time intervention, it may have long-term effects. An analysis of the impact of vaccination over time shows that reduced epigenetic and transcriptomic aging, as well as composite biological aging scores, are present in peopple who had recently received the vaccine and in people who had received it 4 or more years earlier. While the persistence of epigenetic and gene expression effects suggests a potential for long-term effects, those effects may diminish over time, since both DNA methylation and gene expression changes were greater in people vaccinated more recently. However, this needs further investigation.

Regarding different domains of aging, the initial three years post-vaccination were not associated with changes in other measured domains. However, three or more years after vaccination, the researchers observed an association with lower inflammation and innate immunity scores, but poorer adaptive immune function. The researchers point out that these observations might suggest that the impact of the shingles vaccine on the immune system and inflammatory responses unfolds slowly over time, thereby impacting the immune system in the long term.

Beyond preventing illnesses

“These findings indicate that shingles vaccination influences key domains linked to the aging process,” said study coauthor Eileen Crimmins, USC University Professor and AARP Professor of Gerontology. “While further research is needed to replicate and extend these findings, especially using longitudinal and experimental designs, our study adds to a growing body of work suggesting that vaccines may play a role in healthy aging strategies beyond solely preventing acute illness.”

This is promising, especially since this intervention was effective even in the older population (people studied here were over 60 when they received the vaccine), who are usually less responsive to interventions. However, it remains to be determined whether stronger effects would be observed if a younger population (in their 50s) were to receive the vaccine or if participants received a newer formulation of the shingles vaccine (Shingrix).

This study also raises a very important question of whether interventions not designed to target aging have geroprotective effects. If so, some of them, such as the shingles vaccine, might be low-cost interventions with the potential to positively influence biological aging and extend healthspan.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kim, J. K., & Crimmins, E. M. (2026). Association between shingles vaccination and slower biological aging: Evidence from a U.S. population-based cohort study. The journals of gerontology. Series A, Biological sciences and medical sciences, glag008. Advance online publication.

[2] Shah, S., Dahal, K., Thapa, S., Subedi, P., Paudel, B. S., Chand, S., Salem, A., Lammle, M., Sah, R., & Krsak, M. (2024). Herpes zoster vaccination and the risk of dementia: A systematic review and meta-analysis. Brain and behavior, 14(2), e3415.

[3] Bukhbinder, A. S., Ling, Y., Hasan, O., Jiang, X., Kim, Y., Phelps, K. N., Schmandt, R. E., Amran, A., Coburn, R., Ramesh, S., Xiao, Q., & Schulz, P. E. (2022). Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. Journal of Alzheimer’s disease : JAD, 88(3), 1061–1074.

[4] Addario, A., Célarier, T., Bongue, B., Barth, N., Gavazzi, G., & Botelho-Nevers, E. (2023). Impact of influenza, herpes zoster, and pneumococcal vaccinations on the incidence of cardiovascular events in subjects aged over 65 years: a systematic review. GeroScience, 45(6), 3419–3447.

Rapamycin molecule

Rapamycin Protects Immune Cells by Reducing DNA Damage

A new study from the Universities of Oxford and Nottingham has uncovered a potential new mechanism by which rapamycin counters immunosenescence. Rather than increasing autophagy or reducing protein synthesis, the effect appears to involve directly reducing DNA damage burden in immune cells [1].

How can this work?

Rapamycin, a powerful inhibitor of the nutrient-sensing mTOR pathway and probably the small molecule most associated with geroscience, extends lifespan and healthspan in many species [2]. Despite having studied rapamycin for decades, scientists still do not know all the mechanisms behind its geroprotective effect.

It is thought that blocking mTOR shifts energy from growth to maintenance, increasing the process of intracellular junk removal (autophagy) [3]. A new study from the University of Oxford and the University of Nottingham, published in Aging Cell, tests a different hypothesis: that mTOR inhibition directly protects genomic stability in aging immune cells.

Rapamycin decreases DNA lesions

First, the researchers activated T cells from cultured human peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. The cells were then subjected to zeocin, a molecule that induces double-strand breaks in DNA.

Zeocin treatment led to a significant increase in T cells positive for γH2AX, a marker of DNA damage. These cells showed elevated DNA damage response signaling and cellular senescence markers. Cells with high γH2AX levels also exhibited signs of increased mTORC1 but not mTORC2, both of which are protein complexes that mTOR forms.

These surges in γH2AX and mTORC1 activity were greatly attenuated by rapamycin. Moreover, continuous treatment with low-dose rapamycin improved cell survival significantly after DNA damage. T cells treated with rapamycin showed over 60% viability 24 hours post-exposure to zeocin, compared to only 20% in controls.

To see whether treated cells indeed experienced less DNA damage rather than just weaker signaling, the researchers ruled out alternative explanations. The results were not explained by cell-cycle arrest, which could have reduced the readouts. Protein synthesis was also not consistently suppressed.

Autophagy inhibition by chloroquine increased γH2AX positivity, showing that autophagy does help limit damage in these T cells. However, even when autophagy was strongly inhibited, rapamycin still markedly reduced DNA damage markers, suggesting that its protective effect is autophagy-independent.

Finally, the team directly tested DNA damage levels. After zeocin, lesion burden rose, but it was markedly reduced with rapamycin. The authors note that the results may indicate reduced lesion formation, not just faster repair afterward, but this requires further investigation.

Professor Lynne Cox, one of the study’s authors, said, “The cells showed less DNA damage even after only four hours – it’s a very fast response. We don’t yet know whether rapamycin is blocking damage formation or helping cells to repair the damage more quickly and efficiently, so this research opens up a whole new area of study to identify the mechanism of protection.”

“Regardless of whether rapamycin is given before, during, or after DNA damage occurs, we observe a consistent protective response,” added Professor Ghada Alsaleh, a co-author. “These findings uncover a previously unrecognized role of mTOR inhibition in directly protecting the genome, offering new insight into the biological basis of rapamycin’s effects on aging. This suggests that rapamycin, or other mTOR inhibitors, may have broader relevance in contexts involving DNA damage, including healthy aging, clinical radiation exposure, and exposure to cosmic radiation during space travel.”

Confirmed in a small human study

Next, the researchers identified age-associated immune subsets (certain types of T cells, B cells, natural killer cells, and monocytes) in blood samples taken from healthy donors. These aged cells were enriched for markers of DNA damage and senescence, especially p21. There was also more mTORC1 activity broadly across immune cell types in older vs younger donors, suggesting that it is a general biomarker of immune aging, not restricted to one lineage.

Motivated by these findings, the team ran a small randomised placebo-controlled study in older male volunteers. Four people received 1 mg/day of rapamycin, while five received placebo. No significant differences in leukocyte counts were observed after 8 weeks, suggesting that at this dose, rapamycin was not immunosuppressive.

In both groups, mTORC1 activity was positively correlated with γH2AX levels and was lower in the rapamycin group, corresponding with lower γH2AX. The senescence marker p21 dropped robustly across most immune subsets with rapamycin vs placebo after 4 months. The treatment also reduced several T cell exhaustion markers, while p53 expression was elevated at 4 months.

“Our findings provide a new understanding of why rapamycin and other mTOR inhibitors have such promising anti-aging potential in the immune system and more widely across the body,” said Dr. Loren Kell, the lead author. “Since DNA damage is a central driver of immune system aging, our study supports future endeavors to identify more strategies that can improve DNA stability during aging.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kell, L., Jones, E. J., Gharahdaghi, N., Wilkinson, D. J., Smith, K., Atherton, P. J., … & Alsaleh, G. (2026). Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage. Aging Cell, 25(2), e70364.

[2] Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.

[3] Kim, Y. C., & Guan, K. L. (2015). mTOR: a pharmacologic target for autophagy regulation. The Journal of clinical investigation, 125(1), 25-32.

Placenta concept

Using Placental Cells to Test Anti-Aging Compounds

Researchers publishing in Aging Cell have discovered that cells derived from the human placenta may be useful in estimating the effects of potential anti-aging treatments.

A seemingly odd choice

Of all the organs in the body, the placenta may be the least concerning with regards to aging; it only exists for at most 10 months, after which it is discharged as part of the birthing process. The researchers openly admit that this lifespan difference may make placenta-related aging processes distinct from those in other tissues, which harms translation and generalizability.

However, it is this limited lifespan that makes placental tissue potentially desirable for study. Its lifespan is under half that of mice, and it is made of human cells rather than murine ones. Just like in other organs, senescence and other core aging processes happen in the placenta as well, and unsurprisingly, accelerated placental senescence is linked to preterm birth and other problems [1]. There is also some evidence that the placenta may affect the rest of the body’s aging [2], and placenta-specific genes have been found to be activated in unrelated cells during senescence [3].

These researchers focus on three core placental cell types: cytotrophoblasts (CTBs), which differentiate into multinucleated syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). Differentiating CTBs into STBs can be done within a week in vitro and has been done since 2018 [4]. These researchers focus on this process, determining how similar it is to natural placental aging and how it can be harnessed to study aging more broadly.

Differentiated placental cells age quickly

The researchers first did a thorough examination of STBs compared to CTBs. Tthe differentiated CTBs had significantly more signs of senescence and across-the-board decreases in gene expression related to DNA maintenance, and there were increases in telomere attrition and metabolic differences as well. EVTs were found to have similar differences. Tthe researchers also discovered that results derived from the CTB to STB transition matched well with the epigenetic clock results of stem cells derived from the same donors, leading them to conclude that “cellular aging features observed in other tissue contexts can, therefore, be effectively modeled by the CTB-STB system.”

In their next experiment, the authors used human trophoblast stem cells (hTSCs), which themselves came from human expanded potential stem cells (hEPSCs), in order to ultimately differentiate them into STBs. As expected, these cells were pushed towards senescence as well, exhibiting familiar signs of resistance towards death by apoptosis while becoming more susceptible to death by necroptosis. Other molecular hallmarks of cellular senescence, including p16, were more prevalent as well.

Highly relevant aging features

Very unsurprisingly, this increase in senescence coincided with an increase in the inflammatory senescence-associated secretory phenotype (SASP). Along with telomere maintenance failures, deregulated nutrient sensing, and mitochondrial dysfunction, STBs were far more likely than hTSCs to exhibit SASP upregulation. Interestingly, however, the results between mRNA expression and actual proteins did not match as expected, suggesting a possible age-related change in protein function.

The researchers then tested how well the cells resisted DNA damage. Undifferentiated hTSCs, which contained plenty of active DNA repair pathways as well as protective lamins, were strongly resistant to etoposide, a chemical that damages DNA. STBs, however, had fewer lamin protections and less repair capability; they were far more susceptible, exhibiting signs of double-strand breaks along with the DNA damage marker γH2AX.

This loss of protection also extended to the epigenome. Compared to hTSCs, STBs had significant alterations in histones and histone regulators, which are at the core of epigenetic alterations. H3K9me3 and H3K27me3 were downregulated, H3K4me3 was increased, and total histones and methylation were both decreased; all of these results are in line with those of other aging tissues.

Transposable elements normally found in the human genome, which come loose and become expressed during aging, lead to systemic inflammation [5]. They were far more expressed in STBs than in hTSCs. Knocking down some of these retrotransposons (HERVK) partially suppressed some features of senescence and inflammation in STBs.

Intended for practical use

The researchers then moved on to the possibly most critical portion of their experiment: testing anti-aging molecules against STBs. They began with a screen of the most well-known interventions, including rapamycin, fisetin, NMN, quercetin, resveratrol, and navitoclax. All of these compounds were found to have effects, to varying extents, on the aging of STBs.

While these results are entirely preliminary, this study is meant to, and does, serve as a proof of concept. These are cells that can be rapidly produced and tested to determine the effects of potential anti-aging treatments. While they may not apply to every potential treatment, these cells may be used to accelerate the verification, and thus development, of promising interventions.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kajdy, A., Sys, D., Modzelewski, J., Bogusławska, J., Cymbaluk-Płoska, A., Kwiatkowska, E., … & Kwiatkowski, S. (2023). Evidence of placental aging in late SGA, fetal growth restriction and stillbirth—a systematic review. Biomedicines, 11(7), 1785.

[2] Pham, H., Thompson-Felix, T., Czamara, D., Rasmussen, J. M., Lombroso, A., Entringer, S., … & O’Donnell, K. J. (2024). The effects of pregnancy, its progression, and its cessation on human (maternal) biological aging. Cell metabolism, 36(5), 877-878.

[3] Bi, S., Jiang, X., Ji, Q., Wang, Z., Ren, J., Wang, S., … & Qu, J. (2024). The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA. Developmental Cell, 59(8), 991-1009.

[4] Okae, H., Toh, H., Sato, T., Hiura, H., Takahashi, S., Shirane, K., … & Arima, T. (2018). Derivation of human trophoblast stem cells. Cell stem cell, 22(1), 50-63.

[5] Liu, X., Liu, Z., Wu, Z., Ren, J., Fan, Y., Sun, L., … & Liu, G. H. (2023). Resurrection of endogenous retroviruses during aging reinforces senescence. Cell, 186(2), 287-304.

Outdoor exercise

Exercise Variety Is Associated With Lower Mortality Risk

A new study links exercise variety, defined as regularly engaging in several types of physical activity, to significantly lower all-cause mortality. Exercise amount matters as well, but the effect plateaus quickly [1].

How exactly is it good for you?

“Exercise is good for you” is a stale truism, but researchers continue to uncover new information about how the amount and specific types of physical activity affect our health. A new study from the Harvard T.H. Chan School of Public Health, published in the journal BMJ Medicine, focuses on the relationship between mortality and the variety of physical activity in two large cohorts of health professionals.

The researchers analyzed data from over 100,000 participants across two major long-term studies (the Nurses’ Health Study and the Health Professionals Follow-Up Study) over a period of 30 years. The former study included only women, while the latter only men. Both cohorts were free at baseline of diabetes, cancer, and any cardiovascular, respiratory, or neurological disease. The levels of physical activity were self-reported every two years. In total, almost 2.5 million person-years were recorded.

Metabolic equivalent of task (MET) is the amount of energy expended during an activity compared to energy expenditure at rest, and in this study, activity doses were expressed as MET-hours/week. For example, brisk walking has a MET value of 3.5 to 4.5, meaning it is about four times more energy-demanding than chilling on a couch.

Lower mortality rates for most types of exercise

Habitual engagement in most measured activities was associated with significantly lower mortality rates. For example, compared to people with the lowest activity levels, the people in the highest categories saw risk reductions of 17% for walking, 15% for tennis and other racquet sports, 14% for rowing/calisthenics, 13% for running and weight/resistance training, and 11% for jogging.

Two activities showed surprisingly low effect sizes: bicycling (4% risk reduction) and swimming (1% risk increase, but statistically insignificant). However, this might simply reflect measurement problems, which is a well-known issue for both cycling and swimming [2].

These mortality benefits from single activities appear more modest than in some earlier studies [3]. One possible reason is that in this study, the comparison group was the lowest quintile of activity, which may not reflect true inactivity, especially since these were groups of of health professionals. The authors also used robust protections against reverse causation (when people lower their activity levels after they become unhealthy), which tends to shrink associations.

Total Activity Effects

Like many recent studies [4], this one shows that mortality risk plateaus at certain levels of activity rather than decreasing indefinitely. However, here, the benefits of exercise peter out rather quickly (at least for cardiovascular, cancer, and respiratory mortality), around 20 MET-hours per week, which may also be due to the reference group not being completely inactive.

Variety matters (usual caveats apply)

The researchers then compared participants with different levels of variety in physical activity, defined as the number of different types of activity that participants regularly performed. After adjusting for total physical activity, the highest-variety group had about a 19% lower all-cause mortality compared to the lowest, with comparable reductions across major causes.

When they combined people into groups by total activity and variety, the highest on both had about 21% lower mortality compared to the lowest-lowest reference group. The authors report no interaction here, signifying that variety helps across activity levels rather than only at high or low volume.

“People naturally choose different activities over time based on their preferences and health conditions. When deciding how to exercise, keep in mind that there may be extra health benefits to engaging in multiple types of physical activity, rather than relying on a single type alone,” said corresponding author Yang Hu, research scientist at the Department of Nutrition.

Anna Whittaker, Professor of Behavioral Medicine at the University of Stirling, who was not involved in this study, said: “This large-scale longitudinal study adds to what we know about the impact of physical activity on mortality by showing that engagement in a range of different types of physical activity is beneficial for longevity, independently of the total amount of physical activity engaged in. This is likely due to the different types of activity having different physiological effects and helping to meet all of the aspects currently outlined in physical activity guidelines (i.e. moderate intensity exercise, resistance exercise, vigorous intensity exercise, flexibility work, recovery activities).”

Like all populational studies, this one can only show correlation, but not causation, and the results depend on many design choices. While the authors did an admirable job controlling for possible confounders, which included age, race/ethnicity, family history of myocardial infarction and cancer, body mass index, smoking, alcohol intake, energy intake, diet quality, social integration, baseline hypertension and hypercholesterolemia, and (for women) postmenopausal hormone use, it is impossible to rule out residual confounding such as sleep, stress, or the built environment. For instance, it is possible that people who can find the time and energy for various types of activity have more free time, enjoy better sleep, and live in an environment better suited for exercise.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Han, H., Hu, J., Lee, D. H., Zhang, Y., Giovannucci, E., Stampfer, M. J., Hu, F. B., Hu, Y., & Sun, Q. (2026). Physical activity types, variety, and mortality: Results from two prospective cohort studies. BMJ Medicine, 5(1), e001513.

[2] Harrison, F., Atkin, A. J., van Sluijs, E. M., & Jones, A. P. (2017). Seasonality in swimming and cycling: Exploring a limitation of accelerometer based studies. Preventive medicine reports, 7, 16-19.

[3] Arem, H., Moore, S. C., Patel, A., Hartge, P., De Gonzalez, A. B., Visvanathan, K., … & Matthews, C. E. (2015). Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA internal medicine, 175(6), 959-967.

[4] Garcia, L., Pearce, M., Abbas, A., Mok, A., Strain, T., Ali, S., … & Brage, S. (2023). Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes: a dose–response meta-analysis of large prospective studies. British Journal of Sports Medicine, 57(15), 979-989.

Synapses

How Senescent Astrocytes Don’t Support Neurons

Resesarchers have found that thrombospondin-1 (TSP-1), a compound that is critical in growing brain synapses, is secreted by normal astrocytes but not senescent ones.

Senescence is harmful to the brain

It is well-known that cellular senescence causes brain damage and impairment. The SAMP8 mouse, which is used in this study, has accelerated senescence and quickly develops related brain problems [1]. For example, last year, we reported that senescent microglia are overly aggressive in pruning brain synapses.

This research, however, focuses on astrocytes, other resident brain cells that fulfill a wide variety of maintenance functions [2]. The authors of this paper note that the exact effects of astrocytic senescence on neural synapses have not been particularly well-studied. To remedy this, they closely examined SAMP8 mice to determine how their senescent astrocytes might be indirectly affecting their neurons.

Direct cellular contact is not required

In their first experiments, the researchers verified that hippocampal astrocytes derived the SAMP8 mice were indeed more senescent than those of a control group, including increased expression of the characteristic SA-β-gal. Then, they developed conditioned media (CM) from these astrocytes and discovered that unmodified neural stem cells derived from wild-type mouse embryos were much more able to grow synapses in the CM derived from control astrocytes than in CM from SAMP8 astrocytes. These results held whether the CM was derived from astrocytes differentiated from neural stem cells (NSCs) or from astrocytes directly derived from SAMP8 animals.

The researchers then investigated the molecules present in this CM. As previous work had found that TSP-1 decreases with aging [3] and that its function is critical in cognitive maintenance [4], they took a close look at this particular factor, finding decreases in both the TSP-1 protein and the expression of the Thbs1 gene that encodes it in mice. Once again, these results were verified in both NSC-derived astrocytes and directly taken astrocytes, and unsurprisingly, TSP-1 was also decreased in the hippocampi of SAMP8 mice compared to controls.

Focusing on TSP-1

The biological effects were confirmed through the use of gabapentin, a compound that blocks the receptor of TSP-1. Introducing gabapentin nullified the differences between SAMP8-derived CM and control-derived CM.

Encouraged, the researchers then did the opposite in two ways: they simply added TSP-1 into CM, and they engineered SAMP8 astrocytes to overexpress Thbs1 and then derived CM from those. Both of these approaches had the desired effect: neurons exposed to either one of these CMs were much more able to develop synapses.

It is clear that further work needs to be done to determine whether or not TSP-1 can be used as a functioning strategy in living organisms. The researchers did not attempt to use TSP-1 to treat mice, particularly naturally aged mice, nor did they create a SAMP8 or other model mouse that overexpresses Thbs1. Combined with cognitive tests, such experiments could inform the research world whether or not this might be a viable path to restoring neuroplasticity and cognitive function to older people.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Akiguchi, I., Pallàs, M., Budka, H., Akiyama, H., Ueno, M., Han, J., … & Hosokawa, M. (2017). SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology, 37(4), 293-305.

[2] Phatnani, H., & Maniatis, T. (2015). Astrocytes in neurodegenerative disease. Cold Spring Harbor perspectives in biology, 7(6), a020628.

[3] Clarke, L. E., Liddelow, S. A., Chakraborty, C., Münch, A. E., Heiman, M., & Barres, B. A. (2018). Normal aging induces A1-like astrocyte reactivity. Proceedings of the National Academy of Sciences, 115(8), E1896-E1905.

[4] Cheng, C., Lau, S. K., & Doering, L. C. (2016). Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. Molecular brain, 9(1), 74.

LWF

The Longevity World Forum Confirms Madrid for 2026

The Longevity World Forum announces its move to Madrid, reinforcing its international positioning with a new location aligned with its growth and leadership objectives in the field of longevity science and healthy ageing.

The Spanish capital beats the cities that were postulated as possible venues for the next edition and thus adds an important asset to its program of benchmark events related to science, research and technological innovations.

A new stage is beginning that will culminate with the celebration of the 4th edition of the Longevity World Forum from 18 to 20 February 2026. An edition that, in the words of Francisco Larrey, director of this project, “raises the profile of an event that aims to revolutionize knowledge and practices in the field of longevity. In this sense, bringing Longevity World Forum to Madrid will enrich the link between the region and science by bringing together international experts, scientists and technologists to learn about the latest research in this field”.

2024: A successful edition

In October 2024, Alicante hosted the third edition of the Longevity World Forum. A global event which, over two days, brought together nearly 1,000 people around a program with top international experts. A program that addressed issues on preventive medicine, epigenetics and lifestyle and their impact on longevity and healthy ageing.

The Longevity World Forum announces its move to Madrid, reinforcing its international positioning with a new location aligned with its growth and leadership objectives in the field of longevity science and healthy ageing.

The event confirmed its global relevance by presenting itself as an international meeting place for the exchange of ideas and the creation of synergies between different actors in the sector.

2026: An opportunity for international projection

From 18 to 20 February 2026, Longevity World Forum will hold its fourth edition at the La Nave innovation center, the first in the key international city of Madrid.

Within this framework, the congress will reinforce its role as the epicenter of the scientific community, the innovative ecosystem and the industry linked to the sector. To this end, it is already working on a hybrid format that will allow both in-person and virtual attendance.

It is also announcing new features, such as the inclusion of a conference aimed at start-ups to generate a new pole of attraction for emerging companies related to the longevity industry.

The conference is aimed at anyone with scientific, business, social and economic interests related to longevity. This includes healthcare professionals and researchers, companies in the sector, E-Health startups, students and anyone curious about this topic. The global accessibility of the event will allow the participation of interested people from all over the world, breaking geographical barriers and promoting a global community of knowledge and collaboration.

More information: www.longevityworldforum.com

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Pregnancy

The Impact of Childbearing Trajectories on Aging

The authors of a recent study investigated the relationship between reproduction (number and timing of children), aging, and survival. An analysis of seven distinct reproductive trajectories suggested that two groups, women with the most live births and childless women, showed accelerated aging and increased mortality risk [1].

To maintain the body or to reproduce?

“From an evolutionary biology perspective, organisms have limited resources such as time and energy. When a large amount of energy is invested in reproduction, it is taken away from bodily maintenance and repair mechanisms, which could reduce lifespan.” This idea from evolutionary biology, explained by the doctoral researcher Mikaela Hukkanen, who conducted the study, has been under investigation for many years.

Previous studies investigating this theory often focused on a single variable in female reproduction: the number of children. However, childbearing is much more complex than that. Some women have their first child as teenagers, while others wait until their late 30s or even 40s. Some do not have children at all, while others might have ten or more. This study recognized these facts and investigated childbearing’s impact on aging in a more complex way.

The researchers used data on the timing and number of childbearing events from almost 15,000 women born between the 1880’s and the mid-20th century. This data comes from the Finnish Twin Cohort, a population-based study that also included data on socioeconomic background and lifestyle-related factors. The researchers used advanced modeling techniques to group women based on their childbearing history, and these models suggested seven distinct trajectories (including childlessness).

Classes of Childbearing Women  

The biggest risks are at the extremes

After adjusting for different living standards in different time periods, the researchers found distinctions between each class’s survival rate. They observed the greatest increases in risk of death for women with many (6.8 on average) live births throughout life (Class 6) and childless women (Class 0), and these findings were consistent between different models. There was also a somewhat higher risk for women who only had a few live births early in life (Classes 1 and, to a lesser extent, 2) when compared to Class 3, which was used as a reference. The strength of this association weakened but remained significant after adjustment for known risk factors, including BMI, tobacco and alcohol use, and education.

These different childbearing trajectories were also associated with distinct epigenetic aging profiles, which better reflect the impact of childbearing on age acceleration before old age.

First, the authors used GrimAge, an epigenetic clock known for its strong predictive ability for time-to-death and its association with many age-related conditions. According to this clock and DNA methylation data from over 1,000 women, women in class 1 have the most accelerated aging compared to Classes 3, 4, and 5, which include women who gave birth in their late 20s and early 30s.

When the data was adjusted for known risk factors, childless women had more accelerated aging by 1 year compared to class 5, which consisted of females with some of the lowest numbers of children (2 children on average) but had those children rather late in life. However, the largest difference in epigenetic age acceleration (1.35 higher epigenetic aging rate) was between class 6, which consisted of females with the highest number of children, and Class 5. The latter group was epigenetically younger. Class 6 also had the highest rate of aging compared to Class 0 and Classes 2-5 when the same analysis was performed using two different epigenetic clocks.

“A person who is biologically older than their calendar age is at a higher risk of death. Our results show that life history choices leave a lasting biological imprint that can be measured long before old age,” says the study lead, Dr. Miina Ollikainen.

“In some of our analyses, having a child at a young age was also associated with biological aging. This too may relate to evolutionary theory, as natural selection may favor earlier reproduction that entails shorter overall generation times, even if it entails health-related costs associated with aging.”

The connection between early motherhood, the pace of aging, and survival can also be driven by limited access to healthcare and resources and a generally worse socioeconomic situation, all of which lead to higher physical, emotional, and economic stress loads in young mothers; however, this study didn’t directly investigate this.

U-shaped pattern

The researchers summarized that the patterns they observed, especially increased mortality risk and accelerated aging among childless women and those with a high number of children, are in line with previous studies that reported a U-shaped relationship between the number of children and health [2-5].

The findings regarding the high number of children might not be surprising, since childbearing requires significant resources, tilting the balance away from body maintenance towards reproduction. However, the opposite might be expected of childless women, whose resources should be devoted entirely to body maintenance, thus suggesting a longer lifespan, but the results suggest a higher mortality risk and accelerated aging in this group.

Such an observation was previously explained by pre-existing risk factors that negatively affected reproduction. Those same factors might accelerate aging and increase mortality risk in those women. However, in this study, the association between increased mortality risk and accelerated aging among childless women is significant even after adjusting for risk factors, suggesting that such pre-existing risk factors cannot fully explain the effect on lifespan and healthspan and “that childbearing history itself may have a direct effect on survival and age acceleration.” The authors suggest that childless women might suffer those higher risks and accelerated aging due to a lack of pregnancy and lactation’s protective effects on certain diseases as well as a lack of social support from children.

On average, the women who aged the slowest gave birth to 2-2.4 children and had their children when they were around 27 years old, with 24 and a half years and almost 30 years for first and last childbirth. However, differences in survival and aging profiles between different classes are rather modest, which suggests “reproductive timing and number of offspring may have a smaller impact on aging and survival than we initially expected.”

The researchers underscore that those results are based on this specific sample and are not only driven by biological parameters but also by socioeconomic and cultural effects. While they support the idea of balancing resources between offspring and body maintenance, this study can only indicate associations, not causal effects. Additionally, the researchers caution that they do not suggest any reproductive choices on the individual level, as this study focuses on population-level observations. “An individual woman should therefore not consider changing her own plans or wishes regarding children based on these findings,” said the study lead, Dr. Miina Ollikainen.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Hukkanen, M., Kankaanpää, A., Heikkinen, A., Kaprio, J., Cristofari, R., & Ollikainen, M. (2026). Epigenetic aging and lifespan reflect reproductive history in the Finnish Twin Cohort. Nature communications, 17(1), 44.

[2] Long, E., & Zhang, J. (2023). Evidence for the role of selection for reproductively advantageous alleles in human aging. Science advances, 9(49), eadh4990.

[3] Wang, X., Byars, S. G., & Stearns, S. C. (2013). Genetic links between post-reproductive lifespan and family size in Framingham. Evolution, medicine, and public health, 2013(1), 241–253.

[4] Grundy, E., & Tomassini, C. (2005). Fertility history and health in later life: a record linkage study in England and Wales. Social science & medicine (1982), 61(1), 217–228.

[5] Keenan, K., & Grundy, E. (2018). Fertility History and Physical and Mental Health Changes in European Older Adults. European journal of population = Revue europeenne de demographie, 35(3), 459–485.

Fat on liver

Study Uncovers How Obesity Drives Chronic Inflammation

Scientists have discovered that obesity causes macrophages to ramp up mitochondrial DNA production, leading to more inflammation [1].

Obesity and inflammation

Obesity is associated with multiple acute and chronic conditions, including cardiovascular disease and various metabolic disorders [2]. Increased sterile (not pathogen-induced) chronic inflammation is a major mechanism behind this wide impact [3]. A new study from the University of Texas Southwestern Medical Center, published in Science, sheds light on one peculiar inflammatory pathway triggered by obesity.

Obesity-associated sterile inflammation is largely driven by the activation of a protein complex called the NLRP3 inflammasome, primarily in macrophages. Activation of NLRP3 leads to the production of pro-inflammatory cytokines, especially IL-1β, which disrupts insulin signaling and promotes inflammation in the liver, contributing to conditions such as fatty liver (steatohepatitis), cirrhosis, and even cancer.

Why does NLRP3 get activated in the absence of pathogens? One mechanism involves mitochondrial DNA (mtDNA) sensing: when mitochondrial DNA leaks into the cytosol – especially in an oxidized form – it can act as a danger signal that strongly promotes NLRP3 activation.

mtDNA is subject to oxidative damage from reactive oxygen species (ROS). Oxidized mtDNA is a particularly strong NLRP3 trigger. More mtDNA also means more substrate that can become oxidized under mitochondrial stress.

Increased dNTP influx

The researchers wanted to know how obesity contributes to this dynamic. First, they took peripheral blood mononuclear cells (PBMCs) from lean and obese people and isolated monocytes, which were then differentiated into macrophages. Macrophages from obese individuals showed NLRP3 inflammasome hyperactivation and higher levels of mature IL-1β. Similar effects were observed in macrophages taken from mice on a high-fat diet.

Importantly, the levels of tumor necrosis factor (TNF), a central modulator of inflammation, were not elevated in cells derived from obese subjects, showing that the difference is in the specific NLRP3/IL-1β pathway rather than a broader inflammatory issue.

This hyperactivation correlated with elevated mtDNA levels in macrophages from obese subjects. These cells also produced more oxidized mtDNA following stimulation. Impeding mtDNA production or oxidized mtDNA binding to NLRP3 inhibited the obesity-linked NLRP3 hyperactivation.

Increased dNTP influx

MtDNA is produced from deoxyribonucleoside triphosphates (dNTPs). Mitochondria can obtain them via two main routes: the intramitochondrial salvage pathway and dNTPs from the cytosol. The researchers found that overproduction of mtDNA in obese subjects occurs mostly via the latter.

Since the enzyme SAMHD1 degrades excess dNTPs, preventing mitochondria from overproducing mtDNA, the researchers measured its expression and functional state. Apparently, cells from obese subjects have more phosphorylated SAMHD1, indicating inhibition of function. The researchers then prove that it’s specifically the loss of SAMHD1’s dNTP-degrading ability that causes the inflammation-related problems.

SAMHD1-deficient mice and zebrafish, as well as human macrophages, showed much higher IL-1β with NLRP3 triggers. The study reports that myeloid-specific SAMHD1 knockout mice on a high-fat diet developed insulin resistance and glucose intolerance compared with controls, despite similar body weight and composition. The animals also progressed towards steatohepatitis and fibrosis.

In their final mechanistic test, the authors asked whether excess dNTPs in the cytosol are actually feeding the inflammasome loop by being imported into mitochondria. They demonstrated that all four dNTPs accumulate when SAMHD1 is absent, consistent with the idea that mitochondria are being over-supplied. Pharmacologically blocking mitochondrial dNTP transport prevented the NLRP3 hyperactivation phenotype in SAMHD1-deficient mouse cells and in macrophages from obese human donors, supporting the idea that abnormal nucleotide influx helps drive mtDNA and oxidized mtDNA production that sensitizes NLRP3.

More energy – at a cost

In obesity, macrophages need lots of energy for jobs like phagocytosis and lysosomal cleanup. The authors suggest that SAMHD1 may be blunted to keep up with higher metabolic demands by increasing mitochondrial DNA synthesis. Instead of relying mainly on the slower, more energy-costly salvage pathway, macrophages may start importing ready-made dNTPs from the cytosol as a quicker alternative. The tradeoff is that this could also fuel NLRP3 hyperactivation, inflammation, and metabolic damage.

“It’s been known for a long time that obesity causes uncontrolled inflammation, but no one knew the mechanism behind it. Our study provides novel insights about why this inflammation occurs and how we might be able to stop it,” said Zhenyu Zhong, Ph.D., Assistant Professor of Immunology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, who co-led the study with Danhui Liu, Ph.D.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Liu, D., Zhou, C., Wang, X., Luo, Z., Xu, R., Huo, S., … & Zhong, Z. (2026). Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity. Science, 391(6782), eadq9006.

[2] Powell-Wiley, T. M., Poirier, P., Burke, L. E., Després, J. P., Gordon-Larsen, P., Lavie, C. J., … & American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. (2021). Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 143(21), e984-e1010.

[3] Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022). Inflammation in obesity, diabetes, and related disorders. Immunity, 55(1), 31-55.

Blood cells

A New Look at How Blood Stem Cells Age

In Aging Cell, four Japanese researchers have recently described the aging of the hematopoietic system, which is responsible for the creation of blood.

A system that affects all the others

Aging and age-related diseases are often discussed in terms of hallmarks, such as senescence and genomic instability. However, the bodies of complex organisms, such as humans, have systems that are all affected differently by these hallmarks, and many of them have downstream consequences for the rest of the body.

These researchers note that hematopoietic aging appears to be driven by metabolic issues, epigenetic alterations, genomic instability, and inflammaging, although they contend that inflammaging may have more roots in environmental factors than intrinsic ones [1].

Being responsible for the creation of blood, this particular aging leads to severe consequences. One major aspect of this system’s aging is clonal hematopoiesis, which generates a steady population of mutant cells that have evolved more towards parasitism than fulfilling the body’s needs; this is directly linked to multiple age-related diseases, such as atherosclerosis [2], and as can be expected, aging of the blood system is linked to the aging of many other organs.

Bone marrow aging consequences

This review, therefore, aims to summarize the current state of knowledge about hematopoietic aging an what might be done about it.

Fundamental causes

DNA aging caused by oxidative stress has been found to be a key part of hematopoietic aging; fortunately, this appears to be potentially mitigated through antioxidants [3]. Mitochondrial dysfunction, another hallmark of aging, spurs this oxidative stress [4], and this is exacerbated by a reduction in the cellular maintenance process known as autophagy, which destroys defective mitochondria and other unwanted organelles [5].

This DNA damage is key to the beginnings of clonal hematopoiesis. Three epigenetic regulator genes, DNMT3A, TET2, and ASXL1, have been identified as conferring advantages to these mutants over more functional cells. Broader changes such as mosaic mutations can also occur, and in men, the Y chromosomes of these cells may be entirely absent with advanced age, making them more susceptible to age-related diseases [6].

The mutant cells are better adapted to survive in an inflammatory environment than regular cells are. They have less mitochondrial maintenance, but their mitochondria are more active, and they have abandoned function in favor of proliferation. While they are still technically stem cells, they behave somewhat more like cancer. Metformin has been reported to mitigate the advantages that these clones have, preventing them from excessively proliferating [7]. Other cells upregulate mitochondrial activity while still maintaining their function, and those cells have been suggested as being useful for therapies [8].

Clonal hematopoiesis survival

When the marrow promotes aging

Among the characteristics of aged bone marrow, the reviewers found that three stand out in particular: a reduction in the number of blood vessels [9], an increase in fat [10], and the depletion of osteoblasts [11], which are responsible for building bone. Not all bones suffer the same amount of this dysregulation; the femur ages rapidly, but the skull is less vulnerable, and its bone marrow remains robust throughout life [12].

Physical stresses have been reported to be a key part of these negative effects. As the extracellular matrix stiffens, the bone marrow stem cell niche is degraded [13]. Likewise, an increase in fat might be both a cause and consequence of altered hematopoiesis [14]. The contributions of inflammation in the microenvironment are unsurprising, with even short bursts of inflammation leading to long-lasting consequences [15]. This inflammation can come from multiple sources, including the gut flora [16]; while gut-related therapies have been found to work in mice [17], it is uncertain if they can work in people.

Potential therapies

Other than the potential interventions already discussed, the reviewers suggest other strategies for abating this problem. Cellular senescence is one obvious target, as senescent cells leak factors that promote systemic inflammation; however, while senolytics and senomorphics that target these cells have been found to have broad benefits, the researchers note that their effects in this particular context are unclear.

Youthful plasma transfusion appears to be effective in some contexts, such as for bone marrow stromal cells [18], although it may or may not directly affect hematopoietic decline. The reviewers suggest that therapies directly targeted at the hematopoietic niche, such as directly targeting clones, may be more effective. Future work will need to be done to determine the approaches that can halt or reverse clonal hematopoiesis and related problems.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Franck, M., Tanner, K. T., Tennyson, R. L., Daunizeau, C., Ferrucci, L., Bandinelli, S., … & Cohen, A. A. (2025). Nonuniversality of inflammaging across human populations. Nature aging, 1-10.

[2] Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., … & Ebert, B. L. (2017). Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New England Journal of Medicine, 377(2), 111-121.

[3] Yahata, T., Takanashi, T., Muguruma, Y., Ibrahim, A. A., Matsuzawa, H., Uno, T., … & Ando, K. (2011). Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood, The Journal of the American Society of Hematology, 118(11), 2941-2950.

[4] Bratic, A., & Larsson, N. G. (2013). The role of mitochondria in aging. The Journal of clinical investigation, 123(3), 951-957.

[5] Warr, M. R., Binnewies, M., Flach, J., Reynaud, D., Garg, T., Malhotra, R., … & Passegué, E. (2013). FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature, 494(7437), 323-327.

[6] Bruhn-Olszewska, B., Markljung, E., Rychlicka-Buniowska, E., Sarkisyan, D., Filipowicz, N., & Dumanski, J. P. (2025). The effects of loss of Y chromosome on male health. Nature Reviews Genetics, 26(5), 320-335.

[7] Hosseini, M., Voisin, V., Chegini, A., Varesi, A., Cathelin, S., Ayyathan, D. M., … & Chan, S. M. (2025). Metformin reduces the competitive advantage of Dnmt3a R878H HSPCs. Nature, 1-10.

[8] Totani, H., Matsumura, T., Yokomori, R., Umemoto, T., Takihara, Y., Yang, C., … & Suda, T. (2025). Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow. Nature Aging, 1-17.

[9] Stucker, S., Chen, J., Watt, F. E., & Kusumbe, A. P. (2020). Bone angiogenesis and vascular niche remodeling in stress, aging, and diseases. Frontiers in cell and developmental biology, 8, 602269.

[10] Ambrosi, T. H., Scialdone, A., Graja, A., Gohlke, S., Jank, A. M., Bocian, C., … & Schulz, T. J. (2017). Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell stem cell, 20(6), 771-784.

[11] Morrison, S. J., & Scadden, D. T. (2014). The bone marrow niche for haematopoietic stem cells. Nature, 505(7483), 327-334.

[12] Koh, B. I., Mohanakrishnan, V., Jeong, H. W., Park, H., Kruse, K., Choi, Y. J., … & Adams, R. H. (2024). Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature, 636(8041), 172-181.

[13] Zhang, X., Cao, D., Xu, L., Xu, Y., Gao, Z., Pan, Y., … & Yue, R. (2023). Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation. Cell stem cell, 30(4), 378-395.

[14] Tuljapurkar, S. R., McGuire, T. R., Brusnahan, S. K., Jackson, J. D., Garvin, K. L., Kessinger, M. A., … & Sharp, J. G. (2011). Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging. Journal of anatomy, 219(5), 574-581.

[15] Bogeska, R., Mikecin, A. M., Kaschutnig, P., Fawaz, M., Büchler-Schäff, M., Le, D., … & Milsom, M. D. (2022). Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell stem cell, 29(8), 1273-1284.

[16] Agarwal, P., Sampson, A., Hueneman, K., Choi, K., Jakobsen, N. A., Uible, E., … & Starczynowski, D. T. (2025). Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1. Nature, 1-11.

[17] Zeng, X., Li, X., Li, X., Wei, C., Shi, C., Hu, K., … & Qian, P. (2023). Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood, 141(14), 1691-1707.

[18] Baht, G. S., Silkstone, D., Vi, L., Nadesan, P., Amani, Y., Whetstone, H., … & Alman, B. A. (2015). Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature communications, 6(1), 7131.

Single gene

Vast Majority of Alzheimer’s Cases Attributable to One Gene

According to a new study, as many as 90% of Alzheimer’s cases can be attributed to “suboptimal” variants of the APOE gene. These results highlight the gene’s importance for Alzheimer’s prevention [1].

Three alleles of APOE

A growing amount of research links Alzheimer’s disease to the gene APOE, which codes for apolipoprotein E [2]. This protein helps move cholesterol and other fats around the body and brain, facilitating, among other things, membrane repair and post-injury cleanup.

APOE has three common alleles: ε2, ε3, and ε4 (often written APOE2/3/4). APOE3 is the most widespread and is usually considered the “normal” one – that is, neither protective nor risk-associated. Having APOE4 substantially increases the risk of eventually getting Alzheimer’s, especially in homozygous (ε4/ε4) individuals. Conversely, APOE2 confers significant protection, but it’s also the rarest of the three. A new study from University College London, published in the journal npj Dementia, purports to show how much of Alzheimer’s burden can be directly attributed to APOE genetics.

Genetics explain the majority of cases

The study analyzes data from approximately 470,000 participants across four large cohorts: UK Biobank (UKB), FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC). It included participants aged 60 and older, focusing on those with genetic data and confirmed diagnoses.

Outcomes were assessed through clinical diagnoses, neuropathology, and amyloid-β positivity, with population attributable fractions (PAFs) calculated to quantify the burden of Alzheimer’s and dementia linked to APOE genotypes. PAF is the proportion of cases that would not occur in a population if the causal effect of the exposure were removed, assuming everything else stayed the same.

The PAF for Alzheimer’s cases attributable to APOE3 and APOE4 ranged from 71.5% in FinnGen to 92.7% in ADGC, linking a vast majority of Alzheimer’s cases to these alleles. For all-cause dementia, PAFs were 44.4% in UKB and 45.6% in FinnGen. In the A4 Study, where the outcome was amyloid-β positivity on PET scans at baseline, 85.4% of cerebral amyloidosis cases were attributable to APOE3 and APOE4.

These striking results were mostly due to choosing the most protective ε2/ε2 variant as baseline, despite it also being the rarest (0.3% to 0.6% in the study’s cohorts). This constitutes a significant departure from most previous studies, which treated APOE3 as the baseline “neutral” allele and only considered the additional risk from APOE4.

Lead author Dr. Dylan Williams said: “We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The ε4 variant of APOE is well recognized as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ε3 allele, which has been typically misperceived as neutral in terms of Alzheimer’s risk.”

Some experts push back

Not all Alzheimer’s researchers appreciated this approach. “The claim that ‘most cases’ are linked to a single gene is simply an artefact of the authors’ choice to use the rare, protective ε2/ ε2 genotype as their baseline, effectively labelling approximately 95% of the population (who have ε3 or ε4 alleles) as being ‘at genetic risk’,” said Anneke Lucassen, Professor of Genomic Medicine at the University of Oxford.

Some scientists also highlighted the fact that Alzheimer’s is a multifactorial disease, where “nothing is guaranteed” and where risk can be substantially reduced by lifestyle interventions such as diet, exercise, and sleep [3].

“While these findings offer a better understanding of the role of genetics, it is important to remember that having a high-risk form of the gene is not a certain diagnosis,” said Dr. Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society: “Alzheimer’s remains a complex condition influenced by a mix of people’s backgrounds, genetics, and lifestyle. As we continue to further our understanding of risks and causes, we must not lose sight of the risk factors that remain within our control.”

A paradigm shift

The authors’ choice to treat the most protective genetic variant as baseline is a sign of a paradigm shift worth dwelling on. Conventional medicine tends to equate “normal” with “good enough” – something that does not warrant investigation or intervention. This study, on the other hand, considers the entire range of effects of various APOE genotypes on Alzheimer’s risk, demonstrating an approach that can be described as “suboptimal is pathological” as opposed to “abnormal is pathological.”

This echoes the geroscience postulate that aging is a pathological process in its entirety. Armed with the latest tech, including rapidly advancing gene editing techniques, medicine should aim at the biggest possible prize rather than confine itself to treating deviations from the norm.

“There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly,” said Williams, “Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs. Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.”

That said, the study had several noteworthy limitations. The PAF estimates may be imprecise due to the rarity of ε2 homozygotes, which served as the reference group, potentially affecting confidence intervals. Additionally, most participants were of European ancestry, limiting the generalizability of findings to other ethnic groups.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Williams, D. M., Heikkinen, S., Hiltunen, M., FinnGen, Davies, N. M., & Anderson, E. L. (2026). The proportion of Alzheimer’s disease attributable to apolipoprotein E. npj Dementia, 2(1), 1.

[2] Troutwine, B. R., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. M. (2022). Apolipoprotein E and Alzheimer’s disease. Acta Pharmaceutica Sinica B, 12(2), 496-510.

[3] Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., … & Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The lancet, 404(10452), 572-628.

Megaphone

Longevity Advocacy in 2025: The Expert Roundup

The last installment in our end-of-year series of expert roundups might be the least flashy, but it is arguably no less important than the previous ones dedicated to longevity biotech and geroscience.

Public advocacy is a powerful lever. To quote Abraham Lincoln: “Public sentiment is everything. With it, nothing can fail; against it, nothing can succeed.”

Wide public support could turn longevity into the next global moonshot project, with governments dedicating immense resources and creating a favorable regulatory climate, while the public pushes for faster change. Currently, we are far from this point, but the tide might be turning.

We asked six prominent figures in longevity advocacy to share their thoughts on the movement’s ups and downs in 2025 and its prospects going into 2026.

What successes and failures did longevity advocacy have in 2025, and how did they change your long-term outlook on its prospects?

Andrew Steele, author of Ageless, longevity scientist and advocate

I think 2025 continues a trend we’ve seen over the last few years which is both good and bad: the word ‘longevity’ has become increasingly visible, and concepts like biological age are being discussed more both on social media and in traditional newspapers, magazines, and so on. The good news is that the idea of measuring and even slowing biological aging is catching on. The bad news for longevity science is that it’s mostly a repackaging of well-worn lifestyle advice – sleep well, get some exercise, eat whatever diet the newly pivoted ‘longevity’ influencer was promoting before, and so on – and doesn’t touch on the idea of medical interventions to slow aging, which is where the real prize is.

Melissa King and Bernard Siegel, co-founders of the Healthspan Action Coalition (HSAC)

2025 marked longevity’s shift from marginal science to mainstream policy concern. States tested the boundaries of access and regulation. Montana expanded “Right to Try” beyond terminal illness, and Florida legislation increased access to unapproved stem cell therapies, but both demand scrutiny for patient safety and efficacy.

The THRIVE Act (Therapeutic Healthspan Research, Innovation, and Validation Enhancement Act), proposed U.S. legislation, was spearheaded by the Kitalys Institute and HSAC to create a new FDA regulatory pathway for healthspan-extending products, incentivizing treatments that improve the years lived in good health rather than just extending lifespan. This act aims to overcome current barriers by offering incentives like market exclusivity for therapies targeting aging-related diseases, making healthy longevity a national health priority.

Washington has, in Lifespan.io’s words, “arguably the most pro-longevity administration in history,” through key appointments, while pharma committed billions to longevity programs. However, proposed budget cuts for NIH and NSF budget cuts threaten critical basic research. Broad institutional and patient advocacy coalitions likely will prevail keeping the budgets close to being fully funded. More problematic is a loss of expertise and experience in Institute leadership.

Commercialization setbacks, including Unity Biotechnology’s shutdown and Calico partnership dissolution, exposed the field’s uncertainty. Meanwhile, premature clinic proliferation, inconsistent biomarker validation, and high-cost interventions risked eroding public trust and deepening equity gaps.

Our outlook is optimistic. Political recognition creates unprecedented regulatory opportunities, but funding crises and credibility risks could close this window quickly. The field must prioritize rigorous evidence, standardized protocols, and equitable access, or risk squandering a historic moment. The infrastructure we build now determines whether longevity becomes a transformative public health policy or boutique medicine for elites.

Dylan Livingston, founder and CEO of the Alliance for Longevity Initiatives (A4LI)

2025 felt like a turning point. The biggest signal to me was getting someone like Jim O’Neill [O’Neill is a former CEO of SENS Research Foundation] into the Deputy Secretary of HHS role; that’s a level of institutional leverage the field hasn’t had before.

Some people expected overnight change, and that was the main “failure” of our industry in 2025: unrealistic timelines and impatience. Biotech and policy compound slowly, then quickly. My long-term outlook is more bullish, not because everything changed instantly, but because the right levers are now closer to being pulled – and once one major barrier moves, a lot of other things can move behind it. I also think Jim’s appointment set a precedent by making it easier for future administrations to bring longevity-literate leaders into senior roles and treat this as a serious policy priority.

Adam Gries, co-founder of the Vitalism Society

2025 marked a shift from aspiration to law. States led the charge: New Hampshire’s HB 701 substantially expands right-to-try for terminal patients; Montana’s SB 535 created a licensed framework for experimental treatment centers using post-Phase I therapies, positioning the state as a potential hub for innovation. Florida’s stem cell carve-out (effective July 1) allowed physicians to administer certain non-FDA-approved therapies under rigorous manufacturing and consent rules – controversial, but a clear signal of demand for faster translation.

Federally, Dylan Livingston and A4LI grew the bipartisan Longevity Science Caucus significantly, with Dr. Mehmet Oz headlining their fly-in and lending real political momentum.

Some gaps remain. We still lack a pathway for prevention-focused biologics, and the community hasn’t encouraged enough great scientists and innovators into government roles.

My outlook is unchanged and bullish. Advocacy is still the cheapest, highest-ROI lever for change, especially with overall longevity-positive tailwinds.

Anastasia Egorova, CEO of Open Longevity

If we measure success by public recognition, then yet again, no one outperformed Bryan Johnson. However, that is a very niche type of fame, and the jury is still out on whether it actually benefits longevity R&D – you know, the science that will actually extend our lifespans.

I know of several projects initiated in 2025 that went barely noticed, even by the longevity community itself (a couple of new books, a new documentary in the making, and so on). Let’s count them as seeds planted for the future; they have potential, even if they’re quiet.

As for advocacy’s influence on policy and funding? It’s too early to call. The year felt like one long transition period; this world moves slowly.

In summary: there were no obvious wins for advocacy in 2025, but R&D itself isn’t looking too bad. I’d say the probability of success within our lifetimes (specifically for those currently 35-55) shifted from 0.1% to… let’s say, 0.1-something-percent. It’s movement.

Which event from 2025 – in politics, policy, public opinion, media, or popular culture – do you consider the most influential for longevity advocacy, and why? You’re welcome to name a runner-up.

Andrew Steele

I think, frustratingly, that the biggest longevity story of 2025 was the exchange between Chinese and Russian presidents Xi Jinping and Vladimir Putin in September, where they were caught on mic discussing living to 150 through repeat organ transplantation. This was heavily covered by global media and played into multiple negative stereotypes about longevity science: that it will mean dictators can hold onto power for longer, that the medicines will only be available to the rich, and so on. This is another reason longevity science needs a stronger voice in popular culture; none of the coverage I saw pushed back on these stereotypes, and it would be great if the positive sides of longevity got an airing too after an event like this.

Melissa King and Bernard Siegel

For HSAC, the core takeaway is not technological acceleration but governance. 2025 is the year that longevity entered the public policy arena but before it earned durable public legitimacy. Longevity is no longer just a scientific or commercial conversation. It is now a question of public responsibility. Who gets access, under what standards of evidence, and with what protections against harm and inequity are all questions that must be answered.

Our role is to help ensure that this transition strengthens public trust and does not undermine or seek to abuse it. The field advanced, and continues to advance, faster than its regulatory, ethical, and equity frameworks. Without coordinated action, early policy wins risk being interpreted, and even implemented, as deregulation rather than public health progress.

Dylan Livingston

Since I already mentioned Jim, I’ll be a shameless self-promoter and say A4LI’s Montana Right-to-Try bill. It put longevity on the map in a really meaningful way. We’ve never had longevity legislation written about in the Wall Street Journal and other major outlets, and that matters because it shows two things at once: first, the industry is making real progress, and second, the mainstream is starting to take longevity seriously.

Runner-up: the continued acceleration of the science and the companies behind it – more trials moving forward, more funding, and more real momentum.

Adam Gries

Hands down, the most influential was the appointment of key longevity-friendly leaders: Jim O’Neill as Deputy HHS (a longtime advocate who ran SENS Research Foundation), Dr. Oz at CMS, Marty Makary at FDA, and Alicia Jackson at ARPA-H.

All have publicly framed aging as malleable and are positive towards longevity science. This makes the current administration the most pro-longevity in U.S. history. The respective roles oversee NIH funding, FDA approvals, Medicare/Medicaid policy, and high-risk research, directly impacting translation of aging biology into therapies.

Collectively, these shifts move longevity to the mainstream of public priority.

Anastasia Egorova

Like most other causes, longevity advocacy is at the mercy of macro-politics. We have a new administration in the country responsible for the bulk of longevity R&D, and we have wars burning through resources and distracting the public. Worse, these conflicts harden the collective psyche, making people even more prone to justifying death. The value of human life, economic stability, global optimism – all of these affect our field. The problem is we still don’t have good metrics for this influence and public attitudes towards longevity in general.

On the media front, MIT Technology Review ran two bold ethics-related articles on a topic that was tabooed until recently: “Spare” living human bodies might provide us with organs for transplantation” and “Ethically sourced “spare” human bodies could revolutionize medicine.” Then we had that viral clip of Putin and Xi discussing immortality and organ transplantation. That is certainly publicity, but did it actually help the science of organ replacement? Again, we don’t have a way to measure it.

AI might help with both the activism and measuring its effects. We just need more actual human talent in longevity advocacy.

Thinking back to what you believed about the state of longevity advocacy on January 1, 2025: did anything in 2025 genuinely surprise you or make you update your priors?

Andrew Steele

I think the most surprising thing was when my dentist asked me about my appearance in Don’t Die, the Bryan Johnson documentary that came out on January 1, 2025! I live in Berlin, so that means I’m a step further removed from English-language longevity content, but apparently the message is getting through. To me, it was another sign of how fast the concept of longevity has moved in the last year and another example of the public receiving the message in a form that doesn’t always do longevity science favors.

Melissa King and Bernard Siegel

HSAC anticipated that longevity advocacy would advance through scientific validation first, then cultural acceptance, followed by policy change. We expected public institutions to wait for consensus on biomarkers, endpoints, and interventions before committing resources or political capital.

It surprised us how quickly policy moved, often ahead of scientific consensus. State-level Right-to-Try expansions and early federal proposals revealed political appetite for action, but not always for the guardrails needed to ensure safety, efficacy, and equity.

This updated our prior belief that policy would be guided by science. Instead, we saw policy move first, shaping the field for better or worse. Advocacy therefore cannot wait for scientific closure. Without early engagement, longevity risks being defined through deregulation rather than responsible governance.

We were struck by the fragility of public support for research. Proposed cuts to NIH, including the NIA, exposed a disconnect between growing interest in longevity and sustained investment in the science required to legitimize it, even as ARPA-H directed a significant share of its smaller budget toward longevity.

Most unexpectedly, credibility emerged as the field’s most immediate risk. Premature commercialization, inconsistent biomarker claims, and rapid clinic proliferation threatened public trust, while high-cost interventions increased, rather than decreasing, equity concerns.

Dylan Livingston

Not really. If you’ve tracked the field for years, you know the trajectory has been building. Biotech takes time, and a lot of the organizations and companies launched in the late 2010s and early 2020s are now reaching stages where tangible things start happening.

To a non-insider, the pace of clinical updates, funding, and legislation can look surprising, but I expected the tempo to increase around now. If you zoom out (Kurzweil-style timelines and all), this is roughly the window that many people have pointed to as the start of more visible acceleration toward longevity.

Adam Gries

The diversity and speed of state-level regulatory strategies. Bills like Montana’s SB 535, New Hampshire’s HB 701, and Florida’s stem cell expansions showed states willing to innovate, creating platforms for accelerated innovation and delivery of potential longevity therapies.

The key goal, which affects longevity therapies alongside all therapies is: how can we get therapies to humans faster and more cheaply without sacrificing safety.

While longevity advocacy remains highly underfunded, these outcomes prove targeted effort can yield outsized results. It updated my priors upward on how quickly regulatory momentum can build bottom-up when the science is compelling, and public interest in healthier aging grows.

Anastasia Egorova

[After some deliberation, Anastasia decided not to respond to this question.]

What are your expectations for 2026 in terms of opportunities and risks for longevity advocacy?

Andrew Steele

As a field, we need to work harder to own the narrative and reclaim the word ‘longevity’ for real longevity science. That’s why in 2025 I co-founded The Longevity Initiative with lawyer and longevity advocate Kamen Shoylev. We want to bring real longevity research to policymakers, scientists, doctors and the public, and be a part of recapturing ‘longevity’ for real lifespan- and healthspan-extending research. We’re starting out in the UK and Europe, not least because there are already excellent organizations like the Lifespan Research Institute with more of a US focus, and we look forward to working together to spread this vitally important message in 2026.

Melissa King and Bernard Siegel

We believe that healthspan should be declared a fundamental human right. In 2026, this global advocacy campaign will begin in earnest. Promotion of this lofty goal will unify stakeholders, galvanize public discourse, and bring healthy longevity, and the benefits of converging technologies, to all populations.

2026 will be a year of institutionalization. Longevity advocacy has an opening to move from pilot policies and exploratory legislation into more durable structures, including regulatory pathways, public-sector research commitments, and early reimbursement conversations.

The federal interest in healthspan, combined with continued pharmaceutical and biotech investment, creates a rare chance to align innovation with public health goals. For advocates, this is the moment to shape standards for evidentiary thresholds, biomarker validation, post-market surveillance, and equity safeguards. 2026 can be the year we start anchoring longevity within mainstream health policy rather than exceptional access frameworks.

The primary risk is overreach. If access expands faster than evidence, or if credibility erodes through premature commercialization and uneven clinical practices, public trust could collapse. Funding instability, especially at the US federal level, remains a structural threat. Equity risks will also intensify as high-cost interventions reach the market without clear pathways for broad access.

2026 will reward disciplined advocacy. Progress will depend less on breakthrough science than on whether the field proves it can govern itself responsibly in the public interest. If all goes well, the world will be changed for the better.

Dylan Livingston

More of the same, in the best way: more readouts, more new companies, more funding, and more foundational science translating into programs people can actually point to. The risk is PR and narrative warfare. As we get closer to real-world access and real-world policy, opposition gets louder and more creative. Our polling showed that when you explain longevity in plain language, people are broadly supportive. But the SB 535 testimony showed the other side of the coin: if you don’t control the framing, a loud minority can hijack the narrative, strip out the context, and replace it with misinformation.

In 2026, that means advocates need to fight on messaging as hard as we fight on policy – tight talking points, fast response, and repeatable, values-based framing that ties longevity to what people already want: more healthy years, more independence, less disease, and more dignity as we age.

Adam Gries

We need to encourage great talent to join the public sector, especially at NIH, FDA, CMS, and ARPA-H. States will keep innovating on regulation. We’ll see more proof-of-concept in accelerated translation, real-world data collection, and treatments. Also, growing the Longevity Caucus and securing more legislative support will build lasting momentum.

Risks include failing to attract top talent or pushing poorly scoped initiatives without considering the full set of stakeholder incentives. Progress could also be slowed if longevity gets politicized instead of staying bipartisan. With the right thoughtfulness and focus, we have a rare window to see rapid acceleration of meaningful aging science.

Anastasia Egorova

The biggest risk for longevity advocacy is irrelevance. In fact, this is, sadly, our starting point: we ARE currently mostly irrelevant. Compared to mainstream politics or entertainment, we barely register.

But therein lies some good news, too. If you have ideas and an appetite for longevity advocacy, the bar is low. Think about it: your biggest competition is a guy swapping plasma with his son. I have the utmost respect for Bryan and his team; it just shows that the field is wide open. So, be bold. Do whatever you want. Connect with others. Launch projects. Break boundaries.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Women discussing options

The Geroprotective Potential of Hormone Replacement Therapy

A recent review of literature investigated the risks and benefits of hormone replacement therapy. The authors point out that this approach could be used as a geroprotector to extend the healthspan of women. However, the risk-benefit ratio should be individually evaluated. [1]

Sex-specific aging trajectories

Female and male aging trajectories differ, and one contributor is sex-specific hormones and reproductive organ aging. We have discussed this in detail in two pieces dedicated to female reproductive aging and menopause, but in brief, the decline in female reproduction, specifically the decrease in estrogen and progesterone production, occurs relatively early in life, accelerating many aging processes.

The roles of estrogens and progesterone are not limited to reproductive organs; they affect the whole body’s health. Therefore, their withdrawal leads to numerous disturbances and negative consequences, such as a higher risk of osteoporosis, sarcopenia, cardiovascular disease, metabolic syndrome, and cognitive impairment along with many unpleasant everyday symptoms such as hot flashes and sleep disturbances [2].

More than managing symptoms

To remedy the loss of hormones associated with menopausal transition and address associated symptoms, women might be prescribed hormone replacement therapy. Currently, clinical practice uses this treatment for symptomatic menopausal patients. However, the authors of this review present evidence that it could be used as a “continued proactive geroprotective strategy in healthy, mid-life women, independent of ongoing symptom status.” In this light, hormone replacement therapy can be used as an intervention to slow or reverse biological aging processes.

This is supported by the molecular roles of estrogen and progesterone, which affect different “hallmarks of aging,” suggesting that hormone replacement can help mitigate the negative impact of estrogen and progesterone withdrawal on those hallmarks.

Estrogen has been described to have geroprotective effects across the 12 hallmarks of aging. Broadly speaking, estrogen was shown to “enhance genomic stability, support telomere maintenance, modulate epigenetic patterns, and promote mitochondrial efficiency, preserve proteostasis, suppress chronic inflammation, and maintain intercellular communication and extracellular matrix integrity.” Progesterone also has ben shown to have many positive effects on cellular processes, including “modulating autophagy, maintaining general hormonal and immune balance, and supporting tissue regeneration and stem cell homeostasis.” Therefore, they can work in concert to preserve health.

Ovarian aging effects

Weighing risks and benefits

Going beyond first-order molecular interactions, hormone replacement therapy has also been shown to have geroprotective effects on many systems, including improving cardiovascular health by reducing progression of atherosclerosis and coronary events [3]; reducing postmenopausal osteoporosis by reducing vertebral and hip fractures by around 34% [4]; improving sleep quality; improving different metrics of memory and visuospatial skills [5]; and improving metabolic health by counteracting various aging-related metabolic changes, such as increased adiposity and insulin resistance [6]. It was also reported to improve sexual function and improve overall quality of life [7].

Those reported beneficial effects suggest that there is a need to change current clinical guidance and include women who do not experience menopause-related symptoms as potential candidates for hormone replacement therapy.

That said, the authors recognize that this approach has been associated with some adverse effects. For example, it was shown to increase the risk of venous thromboembolism (VTE), especially when taken as oral estrogen preparations. The risk of stroke and coronary events can also increase if hormone replacement is initiated more than 10 years after menopause [8].

Timing appears to be a crucial factor here, and its importance is underscored by a recent subgroup analysis of the Women’s Health Initiative (WHI) data and findings from the ELITE trial, which suggest that initiating hormone replacement therapy within 10 years of menopause or before age 60 decreases its risks and may lead to greater cardiovascular benefits [9].

The route of administration is also essential. Studies have found that transdermal estrogen formulations and micronized progesterone are safer when it comes to VTE, stroke, breast cancer, and metabolic effects [10, 11].

There are also other factors that are important in personalizing such a therapy, including whether the patient had a hysterectomy or still has a uterus; in the former case, estrogen-only therapy is better, and in the latter, combined estrogen/progesterone is recommended [12], with micronized progesterone appearing to be a safer option in general.

Personalizing the approach

The authors propose dividing women into three groups based on risk-benefit ratio:

  • The low-risk group consists of women who can be considered for early hormone replacement therapy. Women in this group are below the age of 60, have experienced less than 10 years since menopause, have a BMI lower than 30, no cardiovascular diseases, and do not smoke.
  • The intermediate-risk group consists of women who may be considered for a personalized approach and should be monitored during use. They might have mild metabolic syndrome, a family history of cardiovascular diseases, or a history of smoking.
  • The high-risk group should avoid hormone replacement therapy. Those are patients with prior VTE, stroke, active malignancies, or uncontrolled cardiovascular diseases.

However, this general framework could be further personalized by evaluating aging-related biomarkers. The authors propose including epigenetic clocks, inflammatory biomarkers since chronic low-grade inflammation frequently increases during the menopausal transition, metabolic markers, cardiovascular aging metrics, bone turnover biomarkers, neurocognitive and sleep biomarkers, and ovarian aging markers. While those biomarkers can provide a lot of information, they also have limitations. It is also recommended to integrate information from multiple biomarkers rather than relying on a single one.

The authors also suggest conducting larger future trials to continue evaluating different trajectories and personalized approaches, as well as the possibility of combining hormone replacement with other geroprotective therapies.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Rabinovici, J., Oonk, H. P., Huang, Z., Mirando, T., Zhou, M., Strauss, T., Olari, L. R., Wilczok, D., Maier, A. B., & Bischof, E. (2025). Perimenopausal Hormone Replacement Treatments as a Geroprotective Approach – Adapting Clinical Guidance. Aging and disease, 10.14336/AD.2025.1391. Advance online publication.

[2] Dong, L., Teh, D. B. L., Kennedy, B. K., & Huang, Z. (2023). Unraveling female reproductive senescence to enhance healthy longevity. Cell research, 33(1), 11–29.

[3] Hodis, H. N., & Mack, W. J. (2014). Hormone replacement therapy and the association with coronary heart disease and overall mortality: clinical application of the timing hypothesis. The Journal of steroid biochemistry and molecular biology, 142, 68–75.

[4] Mosekilde, L., Beck-Nielsen, H., Sørensen, O. H., Nielsen, S. P., Charles, P., Vestergaard, P., Hermann, A. P., Gram, J., Hansen, T. B., Abrahamsen, B., Ebbesen, E. N., Stilgren, L., Jensen, L. B., Brot, C., Hansen, B., Tofteng, C. L., Eiken, P., & Kolthoff, N. (2000). Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women – results of the Danish Osteoporosis Prevention Study. Maturitas, 36(3), 181–193.

[5] Santoro N. (2025). Understanding the menopause journey. Climacteric : the journal of the International Menopause Society, 28(4), 384–388.

[6] Nejat, E. J., Polotsky, A. J., & Pal, L. (2010). Predictors of chronic disease at midlife and beyond–the health risks of obesity. Maturitas, 65(2), 106–111.

[7] Portman, D. J., Gass, M. L., & Vulvovaginal Atrophy Terminology Consensus Conference Panel (2014). Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause (New York, N.Y.), 21(10), 1063–1068.

[8] Canonico, M., Plu-Bureau, G., Lowe, G. D., & Scarabin, P. Y. (2008). Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ (Clinical research ed.), 336(7655), 1227–1231.

[9] Hodis, H. N., Mack, W. J., Henderson, V. W., Shoupe, D., Budoff, M. J., Hwang-Levine, J., Li, Y., Feng, M., Dustin, L., Kono, N., Stanczyk, F. Z., Selzer, R. H., Azen, S. P., & ELITE Research Group (2016). Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. The New England journal of medicine, 374(13), 1221–1231.

[10] Scarabin, P. Y., Oger, E., Plu-Bureau, G., & EStrogen and THromboEmbolism Risk Study Group (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet (London, England), 362(9382), 428–432.

[11] Fournier, A., Berrino, F., Riboli, E., Avenel, V., & Clavel-Chapelon, F. (2005). Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. International journal of cancer, 114(3), 448–454.

[12] Academic Committee of the Korean Society of Menopause, Lee, S. R., Cho, M. K., Cho, Y. J., Chun, S., Hong, S. H., Hwang, K. R., Jeon, G. H., Joo, J. K., Kim, S. K., Lee, D. O., Lee, D. Y., Lee, E. S., Song, J. Y., Yi, K. W., Yun, B. H., Shin, J. H., Chae, H. D., & Kim, T. (2020). The 2020 Menopausal Hormone Therapy Guidelines. Journal of menopausal medicine, 26(2), 69–98.

Biological research

Geroscience in 2025: The Expert Roundup

2025 was a good year for geroscience, marked by rapid strides and critical milestones. Yet, the path wasn’t always smooth: progress in some areas lagged, research hit dead ends, and familiar bottlenecks persisted.

Against this backdrop, we asked five prominent geroscientists to share their perspectives on the highs and lows of 2025, along with their outlook for 2026. We are proud to have covered many of the breakthrough papers they highlight, and we remain committed to keeping you at the forefront of science’s most important field in the year ahead.

Where did geroscience exceed your expectations in 2025, and where did it underperform or stall? Has this changed your long-term outlook for the field’s progress?

Steve Horvath, Principal Investigator at Altos Labs

Geroscience exceeded my expectations through the rapid integration of AI and foundation-model thinking into aging biology. Large language-style models are now being adapted to molecular data, enabling representations that generalize across cohorts, species, tissues, and platforms. A striking example is CpGPT: A Foundation Model for DNA Methylation by Lucas Paulo de Lima Camillo.

CpGPT illustrates how such models can already generate improved versions of established epigenetic clocks, e.g. new versions of GrimAge that appear to outperform existing epigenetic clocks. This represents a qualitative shift: from handcrafted biomarkers to self-improving aging models. In this context, I also want to mention the paper on BioLearn by Albert Ying and Vadim Gladyshev in Nature Aging: “A unified framework for systematic curation and evaluation of aging biomarkers.”

Where the geoscience field disappointed me was in human rejuvenation trials. In particular, plasmapheresis, despite compelling animal data and strong narratives. A couple of published studies largely failed to produce convincing improvements in epigenetic clocks or other molecular aging markers in humans. For example, the negative or null findings reported by Borsky et al. underscore how difficult it remains to translate systemic interventions into durable molecular rejuvenation.

George Church, Professor at Harvard Medical School & MIT

Previously neglected categories of aging-reversal targets exceeded expectations as they matured from 2024. For example, the ATPIF1 gene product (mitochondrial ATPase inhibitory protein) has renewed interest in reactive oxygen species (ROS) and led to the use of a repurposed ischemia drug. We also saw progress in engineered enzymes designed to break extracellular crosslinks, such as the glycoxidation end-product N-epsilon-(Carboxymethyl)lysine (CML).

Clinical trials for dietary supplements underperformed and were underfunded. Similarly, overfunded multi-billion-dollar startups seemed to lag behind, lapped by nimble, creative NewCos. The long-term outlook is bright as more research teams commit seriously to the multiple targets and tissues of aging (polypharmacy).

Andrea Maier, Professor in Medicine at the National University of Singapore

In 2025, geroscience exceeded expectations in the precision and scalability of biological age measurement. We finally moved from “promising biomarkers” to clinically deployable, interoperable aging phenotypes combining multi-omic clocks, digital mobility signatures, and organ-specific functional reserves. The integration of cardiovascular, immune, and musculoskeletal risk trajectories into actionable platforms is a milestone I did not think we would reach this soon; this enables precision geromedicine.

Where the field clearly underperformed was in late-stage interventional trials. The pipeline is rich, but translation slowed due to inconsistent phenotyping and regulatory uncertainty around composite aging endpoints. Several highly anticipated therapies showed safety but only modest clinical effect sizes, an expected but still sobering reminder that human aging biology is multi-dimensional.

These dynamics have not dampened my long-term optimism. If anything, 2025 reinforced that precision multimodal interventions, not single gerotherapeutics, are the path forward. We are entering the era in which geroscience becomes truly medical: measurable, monitorable, and modifiable.

Matt Kaeberlein, CEO of Optispan

One thing that impressed me in 2025 was how much traction geroscience gained outside the usual scientific circles. There’s been a clear shift in awareness among industry leaders and policymakers.

At the A4Li Summit in April, for example, Dr. Mehmet Oz, now Administrator of the Centers for Medicare & Medicaid Services, explicitly referenced geroscience and the Hallmarks of Aging in his remarks. That would have been unthinkable not long ago.

We now have a Longevity Science Caucus in the U.S. House, and similar initiatives are emerging internationally. Geroscience is increasingly part of a broader conversation about healthcare sustainability, prevention, and long-term outcomes, and that momentum is encouraging.

On the flip side, 2025 was another year where no intervention convincingly outperformed rapamycin, let alone caloric restriction, in terms of effect size on aging biology. While there has been meaningful progress translating geroscience principles into clinical practice, particularly around lifestyle-based interventions, and while a few promising candidates are moving through regulatory pipelines, I don’t see strong evidence that we’re close to large-effect interventions that can substantially slow or partially reverse aging. There’s no shortage of hype, but the data simply haven’t caught up yet. That hasn’t dampened my long-term optimism, but it has reinforced the need for rigor and innovative discovery science.

Oliver Medvedik, Chief Science Officer at Lifespan Research Institute

There wasn’t really one critical moment in 2025 in this field for me; rather, it has been the culmination of progress that I have witnessed over the years. There has been an explosion of interest in this field from students, along with biotech companies that are specifically focusing on aging that just wasn’t there 20 years ago.

This has been driven by both new discoveries, such as the identification of the role of epigenetic alterations in aging, along with new technologies such as CRISPR and cellular reprogramming factors. However, despite these advances, it is sobering to realize that we don’t have any therapeutic interventions available that significantly outperform calorie restriction when it comes to extending lifespan.

Which paper, experiment, or trial from 2025 do you consider the most influential, and why? You’re welcome to name a runner-up.

Steve Horvath

Based on both scientific impact and personal correspondence, the most influential paper of 2025 appears to be: Lei, J., et al. Senescence-resistant human mesenchymal progenitor cells counter aging in primates. Cell, 2025. This study crossed a critical boundary by demonstrating that engineered, senescence-resistant human cells can improve aging-related phenotypes in non-human primates.

The paper that most altered my personal thinking was Jayne, L. et al. A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan. Nature Aging, 2025. By showing that reduced body temperature and torpor-like physiology slow epigenetic aging, this work clarified that epigenetic clocks are deeply responsive to thermometabolic states. It taught me something fundamental about what the methylome is sensing. Overall, 2025 was a landmark year for understanding the mechanisms underlying epigenetic aging, with multiple breakthrough studies substantially advancing the field.

George Church

The grand challenge of highly specific therapeutic delivery – required for lower doses and lower toxicity – saw numerous advances. For example, intravenous injection of a new AI-designed AAV vector showed 280-fold higher brain transduction and 50-fold lower liver transduction compared to the previous best in this category (AAV9).

This underlines how AI applications for protein engineering and target discovery are arguably the most impressive and rapidly improving areas of the field. Their influence is beginning to impact powerful de-aging and anti-cognitive decline strategies. The use of multiplex libraries with molecular barcodes enables an immediate path from millions of AI designs into primate testing for the cost of a single animal, skipping often-misleading in vitro and rodent phases or under-powered ‘single-design-at-a-time’ approaches.

Andrea Maier

The single most influential contribution in 2025 was ‘From geroscience to precision geromedicine’ led by Guido Kroemer. This was not just a review or a position piece; it represented a collective, cross-disciplinary manifesto from leaders across molecular biology to translational medicine. The unusually broad authorship functions as a de facto consensus about how we should now conceptualize aging: as a systemic, network-mediated process driven by “gerogenes” (aging-promoting pathways) and modulated by “gerosuppressors,” interacting dynamically with environment and behavior.

We describe a shared framework that has the power to unify previously fragmented subfields – proteostasis, immunosenescence, metabolic dysregulation, and organ cross-talk – under a clinically relevant, mechanistic paradigm. It does so not by rehashing old “hallmarks,” but by advocating for a precision geromedicine approach: identifying actionable pathways, matching interventions to individual molecular “aging signatures,” and integrating multi-omic, functional, and clinical data to inform real-world treatments. It means geroscience is no longer just a promising theory but feeds into the translational, precision-medicine discipline.

A close runner-up was Tony Wyss-Coray’s organ-specific proteomic clock study, which offered the most granular evidence to date that biological age is fundamentally organ-resolved. By quantifying distinct proteomic trajectories for brain, liver, kidney, muscle, and vasculature, the study showed that individuals do not age uniformly and that interventions will need organ-specific endpoints and timing. Clinical data were already available; now we also have biological evidence. This has immediate implications for trial design, risk stratification, and clinical implementation.

Matt Kaeberlein

It’s hard to single out one “most influential” result in a field as broad as geroscience. From a pragmatic, real-world perspective, I was particularly impressed by the LinAge2 paper from Jan Gruber’s group. It represents one of the first aging clocks that is both easy to implement and grounded in actionable, clinically validated measures, with a clear link to future mortality risk. That combination of being practical, interpretable, validated, and clinically relevant is exactly what the field needs right now.

As a runner-up, I’d point to the FDA approval of rapamycin for veterinary use under the brand name Felycin-CA1. Although the indication – heart disease in cats – is not a pure geroscience endpoint, the scientific rationale for using rapamycin in age-related cardiac decline comes directly from geroscience research in mice and dogs. This approval represents a critical regulatory milestone and may provide a template for how existing gerotherapeutics can be responsibly repurposed, particularly in companion animals.

Oliver Medvedik

Not a paper or trial necessarily, but rather the progress of organizations such as the Biomarkers of Aging Consortium in promoting the research and adoption of a variety of biomarkers of aging in determining biological age. As a runner-up, I know this is biased, but I’ll add the recent paper from the Sharma Lab, “Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis.” I thought it to be a well-crafted paper that identifies a potentially very useful target for senescent cells.

Thinking back to what you believed about aging biology on January 1, 2025: did any results this year genuinely surprise you or make you update your priors?

Steve Horvath

I was genuinely surprised by evidence showing that acute, high-intensity exercise can transiently reduce epigenetic age measured in saliva within 90 minutes. In professional soccer players, 90 minutes of intense match play produced measurable reductions in epigenetic age estimates, which rebounded within a day.

This finding was surprising not because exercise is beneficial but because it revealed how rapidly and reversibly the DNA methylome can respond to extreme physiological stress. It forced me to update my assumptions about temporal stability and reinforced the importance of sampling timing, tissue choice, and acute exposures when interpreting epigenetic clock data. This has consequences for geroscience clinical trial design and biomarker deployment. Arkadi Mazin wrote a very nice article about this study.

George Church

Since aging impacts most or all body tissues, the tendency to target the liver would seem to leave many holes. However, in addition to the intravenous targeting mentioned above, another ray of hope is that seemingly non-secreted (ergo cell-autonomous) therapies – like transcription factors (OSK) and RNA splicing factors (SRSF1) – can nevertheless (surprisingly) impact total body function. This is reflected in preclinical (animal) survival curves even if administered very late in life.

Such survival curves are not required (or even welcome) for FDA approval, but they are good signs that the field is getting closer to general and core aging mechanisms, not just biomarkers or one-off symptoms.

Andrea Maier

The study by Li et al “Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia” builds the first senescence atlas of human skeletal muscle by applying single-nucleus multi-omics (RNA + chromatin accessibility) to over 50,000 muscle-derived nuclei from young and older donors. Aging muscle harbors widespread and highly heterogeneous senescent cells across multiple cell types (muscle stem cells, fibro-adipogenic progenitors, endothelial and smooth muscle cells), with considerable variation in transcriptomic and epigenomic senescence signatures.

They also map the senescence-associated secretory phenotype (SASP) of these cells, revealing both shared and cell type-specific SASP factors. Importantly, the study identifies drugable SASP components and demonstrates in mice that the HIV drug Maraviroc can mitigate age-associated muscle mass decline (sarcopenia), suggesting a senomorphic (SASP-modulating) therapeutic strategy. That moves senescence from a theoretical hallmark into an actionable therapeutic target in humans. Trials are needed!

Matt Kaeberlein

My thinking about aging biology has shifted based on several talks and conversations from the Global Conference on Gerophysics held at NUS this year. There seems to be a growing consensus that species’ maximum lifespan may be harder to overcome in humans than we’ve previously anticipated.

The work of Peter Fedichev and others in this area is compelling and suggests that the mechanisms underlying the maximum-lifespan barrier in humans may be fundamentally different than the mechanisms the field has been focused on for several decades, which may be more able to impact healthspan and population median lifespan in humans. It’s a reframing that doesn’t diminish the importance of geroscience, but it does sharpen our expectations and suggests, once again, the importance of a return to discovery science for this field.

Oliver Medvedik

Nothing has really surprised me, nor have any results from this year have had me update any major priors, as of yet. I still view aging as a consequence of the inability of various intrinsic cellular repair systems to keep up with the pace of damage accumulation/cellular entropy of varying sorts until homeostasis has collapsed. Species and populations of cells have evolved mechanisms that effectively solve this problem, whereas individual cells and somatic cells in tissues, for example, have not. Therein lies the rub.

What do you expect from 2026 in terms of scientific breakthroughs, clinical progress, and the regulatory or business climate for geroscience?

Steve Horvath

I expect the unexpected. We have entered a phase of accelerating convergence, where biological insight, data scale, and computational power are reinforcing one another. Datasets are becoming unprecedented in both size and depth, enabling questions that were simply inaccessible a few years ago. At the same time, AI models are becoming reusable and transferable.

Clinically, a new generation of well-powered, biomarker-informed trials is coming into view. Scientifically, this convergence is reshaping how we think about aging as a modifiable process. It has truly never been a more exciting time to work in geroscience.

George Church

I expect 2026 to see more cases of dramatic shortening in the FDA approval process, representing a general sea change. Examples include the first iPSC-derived therapy to receive FDA clearance for a Phase 3 trial (the Fertilo product from Gameto), and the sprint from disease diagnosis to FDA-approved cure in just 7 months for ‘Baby KJ’ (using kayjayguran abengcemeran, an intravenous LNP-delivered CRISPR base editor) [4].

Systems medicine and AI, along with the multiplex primate testing mentioned above, should help catalyze this trend via better initial designs for safety and efficacy. We expect better antibodies and other categories of binders to create improved agonists, antagonists, targeting mechanisms, and delivery systems.

2026 could also be a turning point for life-extending cell and organ therapies, as 2025 marked by far the longest xenotransplant (pig-to-human) survival, keeping a patient free of kidney dialysis for 271 days. The ARPA-H FRONT program (Functional Repair of Neocortical Tissue) recognizes this and seeks to catalyze progress in the most challenging and inspiring area of aging-relevant repair: specifically, the brain regions impacted by stroke and other late-onset maladies.

Andrea Maier

In 2026, I expect the field to pivot decisively from generalized gerotherapeutics to stratified, mechanism-matched, and gerodiagnostic-matched therapeutics. We will see the first trials powered on organ-specific biological age reversal – specifically muscle, immune, and vascular – and regulators will increasingly accept multi-dimensional aging outcomes when linked to validated risk reduction.

Scientifically, I anticipate breakthroughs in the safety of human in vivo cellular reprogramming, particularly regarding transient, tissue-restricted epigenetic reset strategies.

Clinically, we will see the expansion of healthy longevity medicine (academically termed precision geromedicine) into mainstream healthcare systems, as insurers recognize the value of quantifying and modifying risk for age-related diseases and functional decline decades earlier. The business environment will reward companies that integrate gerodiagnostics, gerointerventions, and longitudinal monitoring, rather than those chasing single-product silver bullets based on no evidence.

Matt Kaeberlein

I think there’s a very high likelihood that we’ll see the first FDA approval for a pure geroscience indication in companion animals. Loyal, for example, appears to be on track for conditional approval for lifespan extension in dogs, and that would be a watershed moment for the field. Success there would lower regulatory barriers and create a clearer pathway for others to follow.

Clinically, I expect continued acceleration in the integration of AI into healthspan medicine. We’ll certainly see advances in imaging analysis and predictive biomarker algorithms. What I’m most excited about, though, is the emergence of personalized healthspan agents: AI systems capable of integrating medical records, diagnostics, and wearable data to provide continuous, individualized feedback. If done well, these tools have the potential to make geroscience actionable at scale while keeping the focus on evidence rather than hype.

Oliver Medvedik

I find it impossible to have expectations when it comes to scientific breakthroughs or clinical progress. That said, I do have some rather modest expectations for the regulatory landscape in 2026 that should be attainable and, if enacted, quite possibly would lead to the largest boost in the field of geroscience to date.

Simply put, if we can identify biomarkers of aging that reliably predict biological age, and thus reliably couple that with increased risk of morbidity, then we can identify a sub-population that can be characterized as having “accelerated aging.” This would enable us to then recognize this particular group as having a true disease, as medically defined, rather than considering all of aging as a disease state, which the medical establishment is averse to do.

Having “accelerated aging” thus defined would, in my opinion, open the floodgates towards more streamlined clinical trials that encourage the development and adoption of novel classes of drugs that target the root causes of aging. Initially prescribed for people who fit the category of “accelerated aging,” i.e. having a biological age that is maybe 5-10 years older than their predicted chronological age, these classes of drugs would in turn be predicted to have efficacy in people who exhibit “normal aging” as well. This, to me, is the best way to get through the present bottleneck of translating the findings of geroscience into the clinic.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.