[Mountain View, September 17, 2025] — Lifespan Research Institute (LRI) today announced the launch of the Public Longevity Group (PLG), a new initiative focused on bridging the cultural gap between scientific breakthroughs in aging and their public acceptance. To kickstart its work, PLG has opened a crowdfunding campaign to develop tools that measure and strengthen public trust in longevity science.
While the science of longevity biotechnology continues to advance, skepticism and cultural resistance limit progress, with some studies showing that more than half of Americans would reject a safe, proven therapy to extend life. This hesitation poses risks of raising costs, delaying health-promoting regulation, and slowing the delivery of treatments that could combat age-related diseases and extend healthy lifespan.
“The breakthrough that unlocks all other breakthroughs is public trust,” said Sho Joseph Ozaki Tan, Founder of PLG. “Without it, even the most promising therapies may never reach the people they’re meant to help. PLG exists to change that.”
“Persuasion is a science too,” said Keith Comito, CEO of Lifespan Research Institute. “To bring health-extending technologies to the public as quickly as possible, we must approach advocacy with the same rigor as our research. With PLG, we’ll be able to systematically measure and increase social receptivity, making the public’s appetite for credible longevity therapies unmistakable to policymakers, investors, and the public itself.”
PLG is developing the first data-driven cultural intelligence system for longevity—a platform designed to track real-time sentiment, test narratives, and identify which messages resonate and which backfire. Early tools include:
The Longevity Cultural Clock: a cultural barometer mapping readiness and resistance across demographics and regions.
Sentiment Dashboards: real-time monitoring of public, investor, and policymaker perceptions.
Narrative Testing Tools: data-driven analysis that will enable robust pathways to public support.
The crowdfunding campaign will provide the initial $100,000 needed to launch these tools, creating the cultural foundation required for healthier, longer lives.
With a lean, data-driven team, the group aims to provide open-access cultural insights for advocates and policymakers while offering advanced analytics to mission-aligned partners.
The PLG campaign is sponsored by the members of LRI’s Lifespan Alliance, a consortium of mission-aligned organizations that believe in the promise of extending healthy human lifespan. Newly-joined members include OpenCures, AgelessRx, and Lento Bio.
About Lifespan Research Institute
Lifespan Research Institute accelerates the science and systems needed for longer, healthier lives by uniting researchers, investors, and the public to drive lasting impact. LRI advances breakthrough science, builds high-impact ecosystems, and connects the global longevity community.
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.
It has been long known that, somewhat counterintuitively, exercise transiently suppresses appetite. Scientists suspect that this contributes to exercise-related weight loss. However, the exact mechanisms behind this effect, which can possibly be used to help treat obesity and metabolic disorders, were not well understood. In this new study published in Nature Metabolism, researchers from Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, Stanford University School of Medicine, and collaborating institutions, reveal one such mechanism that works through the brain.
“Regular exercise is considered a powerful way to lose weight and to protect from obesity-associated diseases, such as diabetes or heart conditions,” said co-corresponding author Dr. Yang He, assistant professor of pediatrics – neurology at Baylor and investigator at the Duncan NRI. “Exercise helps lose weight by increasing the amount of energy the body uses; however, it is likely that other mechanisms are also involved.”
The two-stage neuronal pathway
Prior work demonstrated that intense exercise raises blood levels of N-lactoyl-phenylalanine (Lac-Phe, a small molecule made from lactate and the amino acid phenylalanine) and that dosing mice with Lac-Phe suppresses appetite without obvious side effects [2]. Another study found that Lac-Phe gets elevated by the anti-diabetes drug metformin [3]. The researchers of this new study set out to answer which brain cells Lac-Phe acts on to curb feeding.
First, they reconfirmed its basic effect by injecting Lac-Phe into the abdomen and brain ventricles of mice. This resulted in reduced food intake in both normal-diet and high-fat-diet mice, suggesting a brain-based mechanism of action rather than something related to gut distress. They also ran behavioral tests to show that the compound wasn’t just making mice feel sick.
The team then stained brains for c-Fos, a protein used as a marker of recently activated neurons, after Lac-Phe administration. Two regions showed increased activity: the nucleus tractus solitarius (NTS) and the paraventricular nucleus of the hypothalamus (PVH). This marked both as potential relay points.
The researchers then selectively silenced the exact NTS neurons or PVH neurons that Lac-Phe had activated. Silencing the NTS neurons did not change appetite suppression by Lac-Phe, while silencing the PVH neurons blunted it. This suggested that PVH activation is required for feeding suppression, while NTS activation is incidental.
However, PVH neurons turned out to be the downstream part of the pathway. Experiments showed that a large fraction of their input comes from Agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARH). These neurons are classic “hunger” cells, well known for their role in appetite regulation through AgRP, neuropeptide-Y (NPY), and the neurotransmitter GABA. Indeed, applying AgRP or NPY directly inhibited PVH neurons.
Direct application of Lac-Phe to AgRP neurons dose-dependently reduced their firing, and a set of further experiments confirmed their role. This suggested that when Lac-Phe inhibits AgRP neurons, PVH neurons become disinhibited, causing animals to eat less. The researchers then showed that the post-exercise dip in feeding depended on the inhibition of AgRP neurons.
“Understanding how Lac-Phe works is important for developing it or similar compounds into treatments that may help people lose weight,” He said. “We looked into the brain as it regulates appetite and feeding behaviors.”
Fight or flight, but don’t eat
The researchers were also able to show that Lac-Phe directly quiets AgRG hunger neurons by opening KATP: energy-sensing potassium channels on cell membranes that inhibit neuronal activity when energy is plentiful.
“We found that Lac-Phe acts on a protein on AgRP neurons called the KATP channel, which helps regulate cell activity. When Lac-Phe activates these channels in AgRP neurons, the cells become less active,” Dr. He said. “When we blocked the KATP channels using drugs or genetic tools, Lac-Phe no longer suppressed appetite. This confirmed that the KATP channel is essential for Lac-Phe’s effects.”
These results suggest a specific ion-channel mechanism that can be targeted by future therapies to recapitulate the weight loss associated with exercise. “This finding is important because it helps explain how a naturally produced molecule can influence appetite by interacting with a key brain region that regulates hunger and body weight,” said co-corresponding author Dr. Jonathan Long at Stanford University School of Medicine.
Interestingly, according to the researchers, previous studies have shown that Lac-Phe is most elevated by sprinting, followed by resistance training and then endurance training. There might be a deep evolutionary reason here: if you have to run, it is possible that this is not an isolated event but rather a sign that you are in a dangerous environment that might require more running. Keeping appetite down for a while should make future sprinting easier.
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.
[1] Liu, H., Li, V. L., Liu, Q., Liu, Y., Su, C., Wong, H., … & Xu, Y. (2025). Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice. Nature Metabolism, 1-14.
[2] Li, V. L., He, Y., Contrepois, K., Liu, H., Kim, J. T., Wiggenhorn, A. L., … & Long, J. Z. (2022). An exercise-inducible metabolite that suppresses feeding and obesity. Nature, 606(7915), 785-790.
[3] Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., … & Long, J. Z. (2024). Lac-Phe mediates the effects of metformin on food intake and body weight. Nature metabolism, 6(4), 659-669.
Date Posted: September 22, 2025
Comments Off on AI Model Accurately Predicts Multiple Disease Risks
For millennia, people have wanted to know what health events await them in the future. Models have been created that can forecast the onset of a single disease reasonably well. However, predicting several health outcomes simultaneously has been proven tricky. According to a new study published in Nature by an international group of researchers the immense power of AI can be harnessed to solve this problem.
The researchers created a model based on the GPT architecture, which powers chatbots such as ChatGPT. The model was fed data from UK Biobank, a huge repository of longitudinal health data on some half of a million British citizens.
The team notes that health events, biomarkers, and risk factors create an interconnected network that somewhat resembles language. Just like a large language model, such as GPT, predicts the next word, a model trained on health data can predict the next outcome. Age, sex, BMI, and risk factors such as tobacco use were also included in the model.
“Here we demonstrate,” the paper says, “that attention-based transformer models, similar to LLMs, can be extended to learn lifetime health trajectories and accurately predict future disease rates for more than 1,000 diseases simultaneously on the basis of previous health diagnoses, lifestyle factors and further informative data.”
Big results from big data
The model accepts the patient’s previous health history as a prompt. It then predicts the probability of the next health event in their life (for example, “pneumonia 18%, heart failure 9%, death 3%”, and so on) and the time to that event, with accuracy comparable to that of single-disease tools. Consequently, it can “generate entire future health trajectories,” study co-author Moritz Gerstung, a data scientist at the German Cancer Research Center in Heidelberg, said to Nature. “A health care professional would have to run dozens of them to deliver a comprehensive answer,” he added.
The model, called Delphi-2M (after the two million parameters it uses), also generally outperformed a multi-disease predictor trained on 67 UK Biobank biomarkers. However, its predictive power trailed some strong lab markers, such as HbA1c for diabetes, underscoring the value of biomarkers for some endpoints.
The model was validated and tested on UK Biobank data that was not used for training. Then, it was also tested on a separate Danish dataset of about 1.9 million health trajectories, where it showed only slightly reduced accuracy.
Delphi-2M can be used not only for flagging potential health concerns in individuals but also for populational modeling. For instance, it can model thousands of health trajectories for a given region and demographic mix, producing forward-looking estimates of incidence, hospitalizations, deaths, and years lived with disease. Because it preserves competing risks, it also enables ‘what-if’ analysis; for instance, it can estimate the gain in average life expectancy from eliminating cancer.
Delphi-2M, named after the legendary Greek oracle, cannot actually predict death with complete certainty. It can, by simulating many futures, draw a survival curve, showing how your risk of death changes with age. This is simply risk stratification and planning, with uncertainty bands and competing risks baked in, rather than fortune telling.
The data bottleneck
The researchers acknowledge several potential problems with their design. One is related to the data they used: UK Biobank recruits people aged 40-70. By this age, some people have already died, and the absence of their health trajectories from the data creates bias. The follow-up is limited in time, and hence, it misses people older than 80, meaning that very old-age dynamics are not represented.
Scarcity of data is a major bottleneck for most large AI models in biology. Health systems in various countries sit on mountains of health data spanning from birth to death. Figuring out ways to free this data, while addressing safety concerns and maintaining anonymity, can help accelerate progress in this area. Data from wearables, which are becoming increasingly popular, is another promising source.
Yet another way to augment data for large models is by using synthetic data: that is, data simulated by the model itself. Delphi-2M was asked to generate fake patient histories, and then a new model was trained only on those synthetic records without any real people’s data. Surprisingly, the model trained exclusively on synthetic data was almost as accurate in its predictions as the original model that used UK Biobank data. This approach can help solve the anonymity problem by minimizing the use of real patients’ data.
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.
[1] Shmatko, A., Jung, A. W., Gaurav, K., Brunak, S., Mortensen, L. H., Birney, E., … & Gerstung, M. (2025). Learning the natural history of human disease with generative transformers. Nature, 1-9.
Date Posted: September 19, 2025
Comments Off on Lipid Metabolism Is Causal in Some Alzheimer’s Cases
The key characteristics of Alzheimer’s disease, such as cognitive decline and brain deterioration, are very well-known [1]. However, other symptoms, such as pain sensitivity, may precede these key manifestations, providing an early warning of its development [2].
Previous research has pinpointed lipid metabolism as a key aspect of the relationship between pain and Alzheimer’s [3]. Changes in these lipids have been found to be among the first signs of Alzheimer’s, and they contribute to damage and inflammation [4]. In particular, lysophosphatidylcholine (LPC) is strongly associated with pain [5] along with both neuroinflammation and the removal of protective myelin from axons (demyelination) [6].
However, there are confounding factors in this relationship. Previous work has found that the allele APOE4, which greatly increases sensitivity to Alzheimer’s, plays a role [7]. Alzheimer’s presentation and pain sensitivity also vary by sex [8].
The biological chain of causality between these facts, however, had not been examined. These researchers aimed to rectify that by taking a close look at LPC acyltransferase 2 (LPCAT2), a core part of lipid metabolism and brain inflammation.
Large databases help find a limited group
Because of the number of involved variables, the researchers needed to use multiple large databases: the Alzheimer’s Disease Neuroimaging Initiative, the ROSMAP database on memory and aging, a Mayo Clinic database on gene expression in the brain, and the Taiwan Biobank were all used as data sources along with human brain samples from the NIH.
The researchers discovered that pain sensitivity is increased with mild cognitive impairment in men that do not have APOE4. Women, and men with APOE4, did not have results that reached the level of statistical significance. In fact, women without APOE4 trended towards suffering less pain with cognitive decline as measured by the MMSE, a commonly used metric of cognitive ability.
A gene expression analysis found that this increase in pain sensitivity in non-APOE4 men was indeed related to LPCAT2, which was associated with both increased pain and with the onset of Alzheimer’s disease. Men who did not express increased levels of LPCAT2 were unlikely to experience dementia; men who did had a much greater risk.
These findings were corroborated with an analysis of brain tissue. Nearly every sample that was derived from a non-APOE4 man with Alzheimer’s disease contained elevated LPCAT2. This was even found to be true in mice; male mice that were modified to be susceptible to Alzheimer’s disease were considerably more likely to have elevated LPCAT2 in the hippocampus, although this finding did not extend to the cerebral cortex.
Genetic susceptibility
The researchers found that there is a genetic component. Eleven single-nucleotide polymorphisms (SNPs) were found to be associated with increased LPCAT2, pain sensitivity, and the risk of Alzheimer’s disease. Mendelian randomization, a statistical technique, was used to confirm that this relationship is causal; these mutations do indeed raise the risk of increased pain sensitivity and Alzheimer’s disease in non-APOE4 men.
The researchers offer some hypotheses as to why this might be the case. They note that APOE is directly related to circulating LPC levels [9] and microglial behavior [10] and that estrogen has been found to play a role in this area as well [11]. However, this study is observational and does not suggest any methods of modulating LPCAT2. Determining whether or not this is a druggable target will be the domain of future work.
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.
[1] Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011). Alzheimer’s disease. the Lancet, 377(9770), 1019-1031.
[2] Zhao, W., Zhao, L., Chang, X., Lu, X., & Tu, Y. (2023). Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain. Proceedings of the National Academy of Sciences, 120(9), e2215192120.
[3] Yin, F. (2023). Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. The FEBS journal, 290(6), 1420-1453.
[4] Bazan, N. G., Colangelo, V., & Lukiw, W. J. (2002). Prostaglandins and other lipid mediators in Alzheimer’s disease. Prostaglandins & other lipid mediators, 68, 197-210.
[5] Ren, J., Lin, J., Yu, L., & Yan, M. (2022). Lysophosphatidylcholine: Potential target for the treatment of chronic pain. International Journal of Molecular Sciences, 23(15), 8274.
[6] Freeman, L., Guo, H., David, C. N., Brickey, W. J., Jha, S., & Ting, J. P. Y. (2017). NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. Journal of Experimental Medicine, 214(5), 1351-1370.
[7] Romano, R. R., Carter, M. A., Dietrich, M. S., Cowan, R. L., Bruehl, S. P., & Monroe, T. B. (2021). Could altered evoked pain responsiveness be a phenotypic biomarker for Alzheimer’s disease risk? A cross-sectional analysis of cognitively healthy individuals. Journal of Alzheimer’s Disease, 79(3), 1227-1233.
[8] Aggarwal, N. T., & Mielke, M. M. (2023). Sex differences in Alzheimer’s disease. Neurologic clinics, 41(2), 343.
[9] Law, S. H., Chan, H. C., Ke, G. M., Kamatam, S., Marathe, G. K., Ponnusamy, V. K., & Ke, L. Y. (2023). Untargeted lipidomic profiling reveals lysophosphatidylcholine and ceramide as atherosclerotic risk factors in apolipoprotein E knockout mice. International Journal of Molecular Sciences, 24(8), 6956.
[10] Yamamoto, S., Hashidate-Yoshida, T., Yoshinari, Y., Shimizu, T., & Shindou, H. (2024). Macrophage/microglia-producing transient increase of platelet-activating factor is involved in neuropathic pain. Iscience, 27(4).
[11] Karpuzoglu-Sahin, E., Zhi-Jun, Y., Lengi, A., Sriranganathan, N., & Ahmed, S. A. (2001). Effects of long-term estrogen treatment on IFN-γ, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine, 14(4), 208-217.
Date Posted: September 18, 2025
Comments Off on Looking Back at Summer, Looking Forward to Growth
For those of us in the Northern Hemisphere, autumn is underway. The fall is a time when the leaves that are green turn to brown, so let us see what the Lifespan team has been working on to help our field keep our own metaphorical leaves green and healthy.
Top longevity news stories of Summer 2025
As always, we have been bringing you the best longevity and aging research news this summer; let’s take a look at some of the top stories.
Tragedy at RAADFest
Two people nearly died, and several more sought treatment, after receiving peptide injections at the last RAADfest in Las Vegas. This highlighted some well-known problems and contradictions in the longevity field.
On one hand, there is a sense of urgency that pushes some people to offer and others to try therapies that have not been rigorously tested for safety and/or efficacy. Many people rightfully lament the increasingly lengthy and expensive regulatory process, which is not properly suited for rejuvenating therapies. There is a growing push to extend the “right to try” to all patients and all reasonably safe therapies, and to accelerate clinical trials by relaxing certain regulations and transitioning towards cost-effective methods, such as human organoids and in silico models.
On the other hand, a legitimate concern exists that the longevity movement might be overshadowed, compromised, and ultimately impeded by the murky wave of overblown claims, unfounded promises, unproven therapies, and flat-out “snake oil” cures. To make some sense of all this in the context of the RAADfest incident, we asked several prominent figures in the field about this incident and what led up to it.
A vertical longevity village in San Francisco
In the heart of San Francisco, a tower in the downtown area is transforming into a center for longevity, artificial intelligence, cryptocurrency, and robotics.
In March, three young German business owners, Jakob Drzazga, Christian Nagel, and Christian Peters, acquired a 16-story building located in San Francisco’s Mid-Market district. They plan to convert the tower into a premier collaborative workspace for various innovative fields, including cryptocurrency, artificial intelligence, robotics, and longevity research.
Lifespan journalist Arkadi Mazin attended their inaugural longevity conference in June to cover these developments. Join us to find out what he learned at Viva Frontier Tower.
Rejuve.AI: A new app focused on longevity
Rejuve.AI is a company founded by Jasmine Smith and well known AI researcher Ben Goertzel. Recently, they have launched a new longevity app, and Arkadi caught up with them to find out more.
Apparently, it is much more than simply yet another health and lifestyle app. The founders say it focuses on using real human data to study lifespan and potentially the efficacy of inventions that target aging.
In this interview we also discuss Ben and Jasmine’s predictions on the future for artificial intelligence, aging research, and how to create a world where medical data is controlled by patients.
The Longevity Summit Dublin has become quite the go-to event in the longevity community. The event first launched in 2022 and has grown in popularity since then.
Dublin is most famous for its Guinness brewery along with the pubs and restaurants of Temple Bar and its long history, but there is a significant buzz about longevity there too.
Hosted at Trinity College in the centre of Dublin, the event is very much in the heart of this vibrant city. The event saw a range of great speakers and workshops focused on aging research and advocacy. It really is great to see the popularity of this event growing and including a free public open day.
Lifespan Editor-in-Chief Steve Hill was at the Summit to bring you the highlights from the 2025 Longevity Summit Dublin. Join us as he shares his thoughts on some of the most interesting news from the conference.
Announcing the Lifespan Alliance
We have also launched the Lifespan Alliance, our corporate sponsorship program that brings together purpose-driven businesses and innovative organizations focused on promoting a longer, healthier human lifespan.
Sponsorship from Alliance members allows us to conduct innovative research, reach millions via news and other media, and link prominent figures in science, policy, and technology to speed up advancements.
If you are interested in supporting us as a company, including the benefits of doing so, please consider becoming a member of the Lifespan Alliance.
We would like to thank all of the organizations that have stepped up to join us so far. Your support means the world to us and allows us to continue our important research, advocacy, journalism, and educational activities.
Organizational leadership changes
There have been some changes to leadership at LRI. Keith Comito and Dr. Oliver Medvedik have become the Chief Executive Officer and Chief Scientific Officer, respectively. They will spearhead LRI leadership and enhance the Institute’s outreach and scientific efforts.
These new roles demonstrate LRI’s dedication to merging innovative leadership with scientific precision and utilizing years of experience in ecosystem development to establish a network that can effectively identify and address key challenges in aging research.
A new lease on life for the Rejuvenation Roadmap
The Rejuvenation Roadmap is a database tracking the many interventions against aging currently being developed and tested. It holds information about each therapy’s progress, from initial drug discovery through to clinical trials. It is a one-stop shop for finding out where the field is in bringing aging under medical control.
With that in mind, we are delighted to announce that Michael Rae is now curating the Rejuvenation Roadmap. Michael is the co-author of the well known rejuvenation biotechnology book Ending Aging, was a science writer for SENS Research Foundation, and is an active member of the longevity community.
We have also added two new aging damage types to the Roadmap: extracellular matrix damage and extracellular aggregates. We have added them to the Roadmap as they are important to our research and more accurately encompass our work.
Extracellular matrix damage involves the degradation and restructuring of its structural and functional elements that make up the extracellular matrix. This is the non-cellular part of tissues that offers structural support and a framework for cells.
Extracellular aggregates refer to a type of defective proteins that have lost their functionality. Instead, they have transformed into adhesive, misshapen forms that adhere to the surfaces of our cells and tissues, disrupting their proper functioning.
Michael has already been busy updating the Roadmap with new drugs and interventions. Keep your eyes out for more in the coming months as the database continues to grow.
A new look for our website
You may have noticed our website has changed a bit recently. Our regulars will recall that LEAF and SRF merged in October 2024 to create the Lifespan Research Foundation (LRI). It has taken a while, but we have now merged both org websites into one.
We like to think of our new site as a longevity switchboard, a place to connect with all of our initiatives. You can find the latest news about the field, learn about our exciting research projects at our Mountain View research centre, check out our educational programs, join the Longevity Investor Network, and much more!
Our goal is simple. Everything you need to know about rejuvenation biotechnology in one place. For those of you who visit us for the latest longevity news, please bookmark the news landing page.
Talking cellular senescence at Longevity Summit Dublin
At the 2025 Longevity Summit Dublin in June, Dr. Amit Sharma gave a talk about some of the work happening at our research center. Our Sharma Lab in Mountain View, California is conducting important research on senescent cells and therapeutic approaches to removing them.
Normally, cells becoming senescent is a helpful safety mechanism that helps us to avoid cancer. Damaged and worn-out cells pose a risk and need to be destroyed via a self-destruct process known as apoptosis.
The problem is that as we age, this safety system breaks down and cells that should be removed no longer are. They instead resist apoptosis and remain at large in the body, causing chronic inflammation. The accumulation of excessive numbers of senescent cells is one of the hallmarks of aging.
It has also been determined to affect the other reasons we age. This diagram shows how it affects other age-related damages. Senescent cells appear twice in the image because they can also encourage other nearby healthy cells to become senescent as well. This is caused by the inflammatory secretions known as the senescence-associated secretory phenotype (SASP).
Senescent cell accumulation is linked to a wide variety of age-related diseases:
Cognitive decline
Frailty
Type 2 Diabetes
Obesity-induced dysfunction
Atherosclerosis
Non-alcoholic fatty liver disease (NAFLD)
Alzheimer’s disease
Parkinson’s disease
Idiopathic Pulmonary Fibrosis (IPF)
Chronic obstructive pulmonary disease (COPD)
Liver fibrosis
Osteoarthritis
Osteoporosis
Age-related muscle loss (sarcopenia)
Heart failure
Hypertension
Therapy-induced senescence (TIS)
Rheumatoid arthritis
Kidney disease (Glomerulosclerosis)
Macular degeneration
Chemotherapy-induced fatigue
The research we are doing at the Sharma Lab aims to tackle such diseases by targeting senescent cells. Potentially, this means that therapies based on our research might address many diseases of aging by attacking a core reason that they develop in the first place. Here’s some of the research we are doing at our Mountain View research center.
Iron dyshomeostasis and ferroptosis-based senolytics
Most studies on senescent cells have focused on primary senescent cells. These are the classic senescent cells that become this way due to DNA damage, replicative exhaustion, or mitochondrial dysfunction.
However, more recently, researchers have discovered what are known as paracrine senescent cells, which become senescent due to prolonged exposure to the SASP. This creates a vicious cycle where more and more cells become senescent due to SASP exposure.
Paracrine senescent cells play a key role in the buildup of senescent cells as we age. Previous attempts to define paracrine senescence have been inconsistent because they relied on analyzing mixed groups of both senescent and non-senescent cells.
Senescent cells are not destroyed by accumulated iron like healthy cells are. They survive by repairing the plasma membrane and reducing the lipid peroxides induced by iron accumulation. These lipid peroxides create reactive oxygen species (ROS), which the senescent cells actively remove in order to survive.
With this in mind, the team used dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from regular cells. Our researchers found that ferroptosis dysregulation and ferrous iron accumulation are a common phenomenon in both primary and paracrine senescent cells.
Finally, our researchers identified drugs capable of inducing ferroptosis in target senescent cells. Essentially, the cells were already primed for ferroptosis cell death but were resisting it, and these drugs effectively tipped them over the edge. The approach works in primary and paracrine senescent cells.
These results have given us important insights into the nature of senescent cell populations and how we might approach their identification and clearance in a new way.
LAMP1 is a universal surface marker of senescence
Researchers at LRI have identified a cell surface marker of senescence that could make identifying senescent cell populations more reliable.
There have been many attempts to create accurate biomarkers in order to identify senescent cell populations. While there are some methods to do so, these have limitations and are less than adequate. It is therefore very important for reliable senescent cell biomarkers to be identified, otherwise it is impossible to confirm if an intervention is effective.
Senescent cells have increased lysosomal function. Lysosomes are bubble-shaped organelles that engulfs cellular waste and removes it from the cell. It does this by merging with the outer membrane to eject the waste through a process known as lysosomal exocytosis.
Researchers at LRI have used a database of membrane proteins to identify a protein called LAMP1. This protein is only present in healthy cells for a short time during lysosomal exocytosis, but in senescent cells, it persists.
Dr. Sharma and his team found a correlation between the expression of LAMP1 and senescence associated genes, including p21 and p16. They tested this association in human fibroblasts in a number of ways and found that LAMP1 expression increased significantly in senescent cells.
Untreated cells only expressed LAMP1 around 1% of the time, while cells that had induced senescence saw expression 20-60% of the time. How much depended on how senescence was induced in the cells.
We then investigated the possibility of utilizing LAMP1 as a therapeutic target. The team used an antibody-drug conjugate (ADC), which is comprised of an antibody aimed at a particular cell surface protein. The ADC was used to target LAMP1, which caused the senescent cells to die but didn’t affect healthy cells.
Ultimately, this opens up the possibility that LAMP1 could be a target for senolytic therapies that help clear harmful senescent cells. These are just two examples of how LRI is making important advances and driving progress in the aging research field.
Rejuvenation biotechnology has an advocacy problem
Advocacy is one of the most important things in our field, yet it is often the most overlooked thing. Often, the focus is understandably on the research side of things, but this comes at the cost of effectively engaging with policymakers, the medical world, and the public. While doing the actual research and achieving breakthroughs is critical, we also need to combine this with effective advocacy and communication strategies.
For years, we have watched the field develop, and one thing that has always struck us is how different groups in our community are often at odds with each other when it comes to advocacy. This has often led to completely opposing strategies, a disorganized community, and an unclear message. This is obviously not ideal.
Some groups suggest that public engagement isn’t important at all and that the focus should be on the science until there is something to show. Other groups believe that we should be engaging the public to pave the way for the emerging technologies that are to arrive. At face value, both of these seem like reasonable positions to take.
There may be a middle ground between both approaches, but how would we know, and how can we better understand public sentiment?
Developing a cultural intelligence platform for advocacy
This is why we are supporting the development of a cultural intelligence platform by the Public Longevity Group (PLG). Its goal is to create tools to gauge public sentiment, measure the impact of media coverage, study social media activity relating to the field, and develop optimal communication strategies to reach as-yet-untapped audiences.
In this video, Sho, the founder of PLG, highlights the importance of public trust in promoting rejuvenation biotechnology. He emphasizes that mere scientific advancements are insufficient; cultural acceptance and comprehension are vital. PLG employs data-driven techniques to assess public opinion, monitor discussions, and craft engaging narratives that appeal to various demographic groups.
By refining communication strategies and building partnerships with organizations like the Lifespan Research Institute, PLG aims to bridge the gap between science and society, ensuring that advancements are not only scientifically possible but are socially accepted.
Scientific narratives focusing on rejuvenation and longevity are gaining traction, while lifestyle-based messaging is plateauing, suggesting a shift in public interest towards more advanced interventions. Now is the perfect time to develop the tools to optimize our advocacy efforts.
Key points of the project:
The research is advancing, but for it to have a meaningful impact, gaining public trust, cultural acceptance, and legitimacy are essential. Without these, scientific breakthroughs may fail to reach the public or gain momentum.
Framing longevity in terms of long-term health and independence can significantly increase public support, shifting attitudes from opposition to acceptance.
The cultural intelligence platform will use strategic methods like tracking online discourse, conducting high-resolution surveys, and analyzing consumer behavior to understand public sentiment around longevity.
The cultural intelligence platform will also identify underserved regions and demographics, revealing new opportunities for targeted outreach.
Data-driven experiments will be used to test which narratives and communication strategies resonate across different demographics and political identities.
Finding new ways to communicate about the science using fresh metaphors, entry points, and language that engages the public without diluting the mission.
Recognizing the need for data-driven cultural insights to foster public engagement and collaboration within the rejuvenation and longevity field. This is a group effort, and we need to work together to make things happen.
PLG is already collaborating with key organizations like the Alliance for Longevity Initiatives and the University of Texas Medical Branch to turn cultural insights into actionable strategies for advancing longevity science.
The cultural intelligence platform campaign is live on the LRI website now; please help us to build the tools our movement needs to succeed! Thank you to everyone who has already stepped up to support this important initiative.
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.
Aging-related epigenetic changes result in decreased capacity to maintain cellular identity [2], and some studies suggest aging-related changes in cellular states [3].
Such changes to the cell state can be a target for rejuvenation strategies. Probably the most famous rejuvenation strategy is the use of the Yamanaka factors, OCT4, SOX2, KLF4, and c-MYC (OSKM), which can rejuvenate fully differentiated aged cells into pluripotent stem cells; however, there is much to be understood regarding the mechanisms driving this rejuvenation.
The authors of this study focus specifically on the process of mesenchymal-epithelial transition (MET), which initiates the rejuvenation of fibroblasts into a pluripotent state by OSKM.
Drifting into old age
The authors analyzed gene expression in human tissue biopsies to identify aging-related trends. They noted some trends that are common among tissues and already known to be associated with aging, such as the aging-related increase in inflammation.
One specific observation, common across the tissues, captured the researchers’ attention: upregulation of pathways related to epithelial-mesenchymal transition (EMT). Given the common nature of this process across aging tissues, they named it ‘‘mesenchymal drift’’ (MD). They defined this as a process during which “cells undergo a partial or complete transition, leading to a compromised original cellular identity while acquiring new or intensifying existing mesenchymal traits, including altered extracellular matrix (ECM) production, cellular junction, tissue mechanical stiffening, and cytokine production.” They suggest that mesenchymal drift contributes to age-related organ dysfunction and might contribute to age-related diseases.
To investigate the latter, they analyzed available data from human biopsies obtained in various studies. They observed an increased expression, to a varying degree, of mesenchymal drift-associated genes in the disease-affected tissues taken from patients with lung diseases, liver diseases, chronic kidney diseases, cardiomyopathies, Alzheimer’s disease, osteoarthritis, and inflammatory bowel diseases as well as aged skin and endothelial cells from calcified atherosclerotic cores.
Prognostic marker
Because of the observed associations between multiple aging-associated diseases and mesenchymal drift, the researchers investigated its role as a predictor of clinical outcomes. They focused on idiopathic pulmonary fibrosis (IPF) in order to establish a proof of concept.
They divided IPF patients into low, middle, and high mesenchymal drift gene expression groups. The median survival of those groups was inversely correlated with the magnitude of mesenchymal drift. This suggests that mesenchymal drift genes can be used as prognostic markers and therapeutic targets.
Rejuvenating potential
Since the data obtained so far only establishes associations between the two observations, the researchers investigated the causality between mesenchymal drift and aging. They asked if biological age, as measured by epigenetic clocks, would be changed if they modulate the regulator of mesenchymal drift.
They re-analyzed publicly available data from breast cancer cell experiments that repressed ZEB1, a key EMT transcription factor that suppresses epithelial markers. Two epigenetic clocks (Horvath’s and PhenoAge) showed that repressing ZEB1 resulted in reduced biological age, suggesting that targeting mesenchymal drift has rejuvenating potential.
With this in mind, the researchers analyzed plasma proteins for potential drivers of mesenchymal drift across organs. They used UK Biobank data to identify mortality-associated plasma proteins. that have a stronger association with mortality were enriched in EMT pathways. They suggest that these findings show a significant association between mesenchymal drift regulators, aging, and increased mortality and that these plasma proteins are possible factors in driving mesenchymal drift across organs.
Rejuvenating without pluripotency
These researchers also aimed to mitigate mesenchymal drift using the Yamanaka factors, which are famous for their rejuvenating effects. Previous research has found that differentiated cells dedifferentiate by going through MET during the Yamanaka factor-driven rejuvenation process. [4] To learn more about the transition between the mesenchymal and epithelial states in aged cells, the researchers measured gene expression in human fibroblasts from a 96-year-old donor at different time points following OSKM induction.
Among different paths taken by cells, they identified a “partially reprogrammed” trajectory that shows some rejuvenation features. This trajectory was characterized by downregulation of mesenchymal genes in the first days following OSKM induction, while reprogramming-associated epithelial genes “were only beginning to be upregulated toward the pluripotency state.” Such a response suggests a critical window during early partial reprogramming that plays an essential role in the dampening of mesenchymal drift through partial MET.
Experiments in cell cultures with a non-functional OCT4 ene, which are unable to be reprogrammed to pluripotent stem cells, showed that those cells are still able to suppress the mesenchymal drift gene program following the expression of the three other Yamanaka factors. Those results suggest that mitigating mesenchymal drift is a potential mechanism behind rejuvenation, independent of inducting pluripotency.
Partial reprogramming’s impact on tissues and cells
Promising results obtained in the cell cultures led to further research in mice. First, in naturally aged mice, long-term (over 7 months) OSKM induction led to significantly decreased mesenchymal drift gene expression in the kidney and liver, and the trend toward decrease was also observed in most other organs. Short-term (around 1 month) OSKM induction at an advanced age significantly reduced mesenchymal drift in the spleen and showed a trend towards a decrease in the liver. Similar results (downregulation of mesenchymal drift in the bone marrow compartment and a similar trend in the skin and spleen) were seen in progeroid mice treated with a virus expressing OSK for two and a half months.
A cellular analysis followed the tissue-level analysis. The researchers used the available data from different studies regarding the mouse intestine and pancreas gene expression following a few days of OSKM induction. In the intestine, most cell types showed mesenchymal drift gene expression reduction, which the researchers linked to improved intestinal regenerative capacity. However, in the pancreas, they observed increased mesenchymal drift gene expression in most cell types; however, some subpopulations showed a decrease, suggesting cell-type-specific responses to OSKM induction that call for optimization of the Yamanaka factors induction duration and cell-type-specific targeting for optimal effects in further therapies.
The researchers concluded that their results show “that the partially reprogrammed state exhibited a notable decrease in the expression of mesenchymal drift genes through partial MET.” While those results are promising, this research was conducted on cell cultures and animal models and needs further validation in human trials.
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.
[1] Lu, J. Y., Tu, W. B., Li, R., Weng, M., Sanketi, B. D., Yuan, B., Reddy, P., Rodriguez Esteban, C., & Izpisua Belmonte, J. C. (2025). Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming. Cell, S0092-8674(25)00853-0. Advance online publication.
[2] Hernando-Herraez, I., Evano, B., Stubbs, T., Commere, P. H., Jan Bonder, M., Clark, S., Andrews, S., Tajbakhsh, S., & Reik, W. (2019). Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nature communications, 10(1), 4361.
[3] Izgi, H., Han, D., Isildak, U., Huang, S., Kocabiyik, E., Khaitovich, P., Somel, M., & Dönertaş, H. M. (2022). Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity. eLife, 11, e68048.
[4] Waryah, C., Cursons, J., Foroutan, M., Pflueger, C., Wang, E., Molania, R., Woodward, E., Sorolla, A., Wallis, C., Moses, C., Glas, I., Magalhães, L., Thompson, E. W., Fearnley, L. G., Chaffer, C. L., Davis, M., Papenfuss, A. T., Redfern, A., Lister, R., Esteller, M., … Blancafort, P. (2023). Synthetic Epigenetic Reprogramming of Mesenchymal to Epithelial States Using the CRISPR/dCas9 Platform in Triple Negative Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10(22), e2301802.
Date Posted: September 16, 2025
Comments Off on A Short-Term High-Fat Diet Harms Memory in Mice
Scientists have demonstrated that even two days on a Western-like high-fat diet reduce hippocampal glucose availability, which activates a subset of inhibitory neurons and causes memory problems in mice [1].
Is it OK to eat junk occasionally?
Metabolic disease and obesity are known to harm cognitive function and have been linked to neurodegenerative diseases such as Alzheimer’s [2], among numerous other health problems. However, many people tend to think that they can get away with temporarily switching to an unhealthy diet or even with constantly eating such a diet while maintaining a healthy weight.
Recent research shows that it’s not that simple: even short periods of a high-fat diet can cause issues, including a decline in cognitive function [3]. A new study from the University of North Carolina, published in Neuron, delves deeper into this phenomenon, yielding intriguing insights.
Memory impairments after just two days
The researchers set out to investigate the impact on healthy adult mice of a very short-term high-fat diet (stHFD) consisting of 58% fat, 25% carbohydrates, and 17% protein. According to the paper, this diet resembles Western diets rich in saturated fat.
Two days into the experiment, the researchers put the mice through a battery of cognitive tests and found that mice on this stHFD did noticeably worse on some of them, particularly on novel place recognition (NPR) and contextual fear conditioning (CFC), indicating “significant impairments in hippocampus-dependent spatial and contextual memory.” Importantly, body weight and blood glucose levels remained unchanged due to the short duration of the intervention.
The stHFD mice, however, were more physically active in the arena, traveling farther (and/or at higher speed) during the open-field session. This suggests that the poorer scores on the two cognitive tests were not due to the mice being lethargic or motor-impaired.
The neurons that didn’t get enough glucose
NPR is thought to depend on the function of the hippocampal region called the dentate gyrus, and the hippocampus is especially vulnerable to brief HFD. The team detected greatly increased activity of a subset of neurons called cholecystokinin-expressing interneurons (CCK-INs) in the dentate gyrus. Interneurons are local inhibitory neurons. Stimulating CCK-INs impaired memory in controls, while dampening their signals rescued memory deficits in stHFD mice.
Prior research has found that just three days of HFD downregulates GLUT1, the main endothelial glucose transporter, across the brain, including the hippocampus. With less GLUT1 at the blood-brain barrier, less glucose gets from capillaries into brain tissue, as if a faucet is turned down, so neuronal glucose availability drops even if blood glucose is normal.
The researchers confirmed that CCK-INs in the dentate gyrus sit farther from capillaries than granule neurons and hence have worse access to the reduced amount of glucose. CCK-INs are glucose-inhibited, which means that when glucose is low, their activity increases, inhibiting that of other local neurons. Giving stHFD mice extra glucose or putting them on a one-night fasting-refeeding protocol restored the activity of CCK-INs. Crucially, if the researchers forced CCK-INs to stay active by chemogenetic activation, the glucose/refeeding no longer improved memory.
PKM2 inhibition rescues memory
Investigating what intracellular switch links low glucose to CCK-IN hyperactivity, the team focused on a glycolytic enzyme, PKM2. stHFD elevated PKM2 signaling markers in CCK-INs, while knocking down PKM2 in these cells reduced their baseline activity and rescued NPR without changing intake/weight. Shikonin, a PKM2 inhibitor, also rescued NPR.
“We knew that diet and metabolism could affect brain health, but we didn’t expect to find such a specific and vulnerable group of brain cells, CCK interneurons in the hippocampus, that were directly disrupted by short-term high-fat diet exposure,” said Juan Song, PhD, principal investigator, professor of pharmacology at the UNC School of Medicine, and a senior author of the study. “What surprised us most was how quickly these cells changed their activity in response to reduced glucose availability and how this shift alone was enough to impair memory.”
Having discovered this pathway for diet-related memory deficiency, the team asked whether this can be applied beyond stHFD. In a “classic” scenario of obesity induced by 10 weeks of HFD, mice showed spatial-memory deficits, but chronic CCK-IN inhibition for the duration of HFD or long-term PKM2 knockdown reversed these effects.
“This work highlights how what we eat can rapidly affect brain health and how early interventions, whether through fasting or medicine, could protect memory and lower the risk of long-term cognitive problems linked to obesity and metabolic disorders,” said Song. “In the long run, such strategies could help reduce the growing burden of dementia and Alzheimer’s linked to metabolic disorders, offering more holistic care that addresses both body and brain.”
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.
[1] Landry, T., Perrault, L., Melville, D., Chen, Z., Li, Y. D., Dong, P., … & Song, J. (2025). Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity. Neuron.
[2] Patel, V., & Edison, P. (2024). Cardiometabolic risk factors and neurodegeneration: a review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer’s disease. Journal of Neurology, Neurosurgery & Psychiatry, 95(6), 581-589.
[3] McLean, F. H., Grant, C., Morris, A. C., Horgan, G. W., Polanski, A. J., Allan, K., … & Williams, L. M. (2018). Rapid and reversible impairment of episodic memory by a high-fat diet in mice. Scientific reports, 8(1), 11976.
Date Posted: September 15, 2025
Comments Off on How Macrophages Manage Obesity and Change With Age
Macrophages declining with age is a well-known problem, and many proposed solutions involve changing their polarity from M1, which favors inflammation, to M2, which favors regeneration. However, this does not apply to adipose tissue macrophages (ATMs), which do not polarize themselves in this way [1]. These tissue-macrophages have subsets, including lipid-associated macrophages (LAMs) [2] and vasculature-associated macrophages (VAMs) [3]. These researchers note that little work has been done on relating these various subtypes of ATMs to aging.
This paper addresses several of these subtypes, including nerve-associated macrophages (NAMs), which not only police the nerves themselves [4] but are linked to the functions of the tissues where the nerves are located, such as the gut [5]. In the fat tissue, NAM behavior has been linked to obesity [6].
Macrophage subtypes can be clustered
The experiments began by deriving visceral white adipose tissue (VAT) from mice and isolating immune cells that were positive for both F4/80 and CD11b+. The mice were either 2 months or 22 months of age, and both male and female mice were used in this experiment.
About three-quarters of these cells were found to be tissue resident, with the other quarter flowing in the vasculature. Principal component analysis found that there were substantial differences between circulating and resident cells, and there were also found to be differences between the cells found in brown fat and white fat.
The researchers then clustered these cells based on single-cell RNA sequencing. This method allowed them to find and discard contaminating cells as well as identify cellular commonalities and differentiation into subtypes. Interestingly, the most numerous cluster was sharply different between sexes; a cluster that was very common in male mice, Cluster 0, was sharply reduced in females, and an exceptionally common female cluster, Cluster 5, was much less common in males.
Cluster 5 was found to be highly enriched for Maoa, which breaks down catecholamines such as neurotransmitters. This and other evidence led the researchers to conclude that these are NAMs. A similar gene expression analysis revealed that Cluster 0 is composed of VAMs.
Age changes the landscape
These clusters were significantly changed with aging, according to a flow cytometry analysis focusing on surface markers, and how they did so was largely dependent on sex. Between the 2-month-old and 22-month-old mice, Cluster 0 decreased with aging in males but not females, Cluster 5 decreased in females but not males, and cluster 13 increased in females but not males. Clusters 4 and 10 increased in both sexes, and Cluster 4 was recognized solely as being associated with aging rather than tissue function; the researchers called these aging-associated macrophages (AAMs), which express pro-inflammatory compounds and are characterized by the age-related marker CD38.
Interestingly, these flow cytometry results did not entirely agree with the RNA sequencing analysis, which suggested that the number of Cluster 5 NAMs remained unchanged in female mice. It is plausible that cell surface marker expression changed with aging.
NAMs were found to be almost uniquely associated with aging. While the AAMs in Cluster 4 were also found to have senescent-like features, these features were common in Cluster 5 NAMs. This was based on gene expression analysis and was relative to the behavior of aged cells rather than directly related to the known cellular markers of senescence.
A link to obesity
However, as the researchers discovered, these cells perform critical tasks. Specifically, adipose-derived NAMs were found to help maintain myelin, the cellular sheaths that protect neuronal axons. Depleting the adipose-derived NAMs of 3-month-old mice led to dysregulation of catecholamines as well as obesity; freely fed mice that had adipose-derived NAMs depleted were considerably more likely to gain weight. Further experimentation with older mice found that NAM depletion led to significant increases in inflammation.
This research highlights a small part of the heterogeneity found in biology, details its changes with aging, and suggests that it may be possible to specifically handle macrophage subtypes; for example, future experiments may find that it is beneficial to reduce the population of aging-associated macrophages as identified here. This focus on macrophages may also be valuable in examining the fundamental causes of obesity and analyzing the effects of existing anti-obesity drugs.
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.
[1] Camell, C. D., Sander, J., Spadaro, O., Lee, A., Nguyen, K. Y., Wing, A., … & Dixit, V. D. (2017). Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature, 550(7674), 119-123.
[2] Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., … & Amit, I. (2019). Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell, 178(3), 686-698.
[3] Silva, H. M., Báfica, A., Rodrigues-Luiz, G. F., Chi, J., Santos, P. D. E. A., Reis, B. S., … & Lafaille, J. J. (2019). Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges. Journal of Experimental Medicine, 216(4), 786-806.
[4] Kolter, J., Feuerstein, R., Zeis, P., Hagemeyer, N., Paterson, N., d’Errico, P., … & Henneke, P. (2019). A subset of skin macrophages contributes to the surveillance and regeneration of local nerves. Immunity, 50(6), 1482-1497.
[5] Muller, P. A., Koscsó, B., Rajani, G. M., Stevanovic, K., Berres, M. L., Hashimoto, D., … & Bogunovic, M. (2014). Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell, 158(2), 300-313.
[6] Pirzgalska, R. M., Seixas, E., Seidman, J. S., Link, V. M., Sánchez, N. M., Mahú, I., … & Domingos, A. I. (2017). Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nature medicine, 23(11), 1309-1318.
Date Posted: September 12, 2025
Comments Off on Microplastics Cause Cognitive Deficits in APOE4 Mice
Exposure to tiny particles that plastic products shed (microplastics) has been linked to increased mortality and diseases [2]. Microplastics are ubiquitous and enter organs, including the brain, triggering inflammation. A recent study showed alarming levels of microplastic accumulation in human brains [3]. However, rigorous studies of the exact effects of microplastics on the brain have been scarce.
A new study by researchers at the University of Rhode Island College of Pharmacy asked a question whether microplastics exposure can promote Alzheimer’s disease in mice genetically predisposed to it. The team created genetically modified mice that were homozygous for either the human APOE ε3 or APOE ε4 allele. The latter is strongly associated with an increased risk of Alzheimer’s, while the former is considered “normal,” neither increasing risk nor providing protection. Both sexes were included to avoid missing sex-specific effects.
At 3-6 months of age, before developing pathologies, mice were randomized into control or exposure groups, with 8 animals per each combination of sex, genotype, and condition. Then, for three weeks, the treatment groups drank water containing a mix of fluorescent polystyrene particles at two sizes: 0.1 μm (nanoplastic) and 2 μm (microplastic), at 0.125 mg/mL. The chosen dose was intentionally high relative to what the average human receives from the environment. This was done to compensate for the short duration of exposure.
“In these mice, like in people, it’s not a guarantee that you’re going to see any changes in cognition. You could have identical twins both carrying APOE4, one totally cognitively healthy, and the other could develop Alzheimer’s disease,” said URI pharmacy assistant professor Jaime Ross, the lead author of the study.
Males more apathetic, females more forgetful
The team then ran a battery of cognitive tests. In the open field test, cognitively normal mice are expected to spend little time in the open, which is these rodents’ natural behavior helping them to avoid predators. Male APOE ε4 mice who were exposed to microplastics, however, spent much more time in the center of the arena, a pattern that the authors interpret as apathy-like cognitive disruption.
Females did not show this pattern. However, in a different test, novel object recognition (NOR), it was the female APOE ε4 mice who showed poorer recognition memory. Several other tests produced null results, but the authors suggest it actually shows that, just like in human Alzheimer’s, the effect was less “broad anxiety” and more cognition-focused.
Ross tied the findings to known sex-related differences in Alzheimer’s symptoms in humans. “In human Alzheimer’s patients,” she said, “men tend to experience more changes in apathy; they care less. Women experience more changes in memory. So, the memory and the apathy connection are pretty clear: when you expose animals that are carrying the largest known risk factor in humans for developing Alzheimer’s disease to micro- and nanoplastics, lo and behold, their behavior changes in a sex-dependent manner similar to the sex-dependent differences we see with Alzheimer’s patients.”
“Similar to what we’re seeing in the real world”
The plastic particles were confirmed to reach the brain, at least the larger ones (0.1 μm particles are below histology detection limits), and the researchers attempted to analyze possible mechanisms behind the impact on cognition. The team examined GFAP, a marker of astrocyte activation/health, and IBA1, a microglial marker, but the results were inconclusive. The researchers suggest that microplastics exert their effect on cognition not via classical microglial inflammation and call for further research.
Two important caveats apply. First, the high dose and short exposure limits the study’s generalizability. Second, real-world plastics are weathered, chemically varied, and often carry adsorbed pollutants. This study used pristine polystyrene spheres, which do not mirror these conditions.
“So, that tells us there’s something about lifestyle, something about the environment going on,” Ross said. “There are modifiable factors we’re studying related to Alzheimer’s – diet, exercise, vitamins, and especially environmental toxins like microplastics. If you carry the APOE4, and you happen to consume a lot of microplastics, will this contribute to Alzheimer’s disease?”
“There has not been a lot of money spent on the human health impacts of microplastics,” she added. “It’s interesting that what we’re seeing in mice is similar to what we’re seeing in the real world. We want to encourage further research into the scourge of micro- and nanoplastics.”
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.
[1] Gaspar, L., Bartman, S., Tobias-Wallingford, H., Coppotelli, G., & Ross, J. M. (2025). Short-term exposure to polystyrene microplastics alters cognition, immune, and metabolic markers in an apolipoprotein E (APOE) genotype and sex-dependent manner. Environmental Research Communications, 7(8), 085012.
[2] Marfella, R., Prattichizzo, F., Sardu, C., Fulgenzi, G., Graciotti, L., Spadoni, T., … & Paolisso, G. (2024). Microplastics and nanoplastics in atheromas and cardiovascular events. New England Journal of Medicine, 390(10), 900-910.
[3] Nihart, A. J., Garcia, M. A., El Hayek, E., Liu, R., Olewine, M., Kingston, J. D., … & Campen, M. J. (2025). Bioaccumulation of microplastics in decedent human brains. Nature medicine, 31(4), 1114-1119.
Date Posted: September 12, 2025
Comments Off on LongX Hosts the Youth in Longevity Biotech Showcase
On September 18, 2025, Longevity Xplorer (LongX) will be hosting the first-ever “Youth in Longevity Biotech Showcase”, a virtual event featuring lightning talks from young professionals in longevity fellowships around the world. The event will cover fellow contributions and highlight the importance in supporting the next generation of leaders in aging biology. LongX welcomes the entire longevity community to attend.
A remote fellowship designed to help early career professionals apply themselves in the longevity biotech sector through courses, mentorship, and industry placements.
A program for undergraduate students and recent graduates to conduct biomedical research on age-related diseases under the guidance of a scientific mentor, with an emphasis on developing both laboratory and communication skills.
A 1-2 year program for recent college graduates to gain intensive research experience in aging and age-related diseases at the Buck Institute before pursuing an advanced degree or a career in the biotech industry.
An aging biology fellowship that serves as a talent accelerator, supporting ambitious future leaders with knowledge, community, mentorship, and project support.
This event serves to:
Promote cross-pollination between aging biology-focused fellowships
Improve transparency in program developments and outcomes
Increase support for aging biology training programs
Foster a networking space for those interested in talent and education in longevity
About LongX
LongX was launched in 2023 as a platform for youth interested in longevity. We prioritize fostering innovation and interdisciplinary collaboration, aiming for both short-term impact and long-term progress. We encourage exploration beyond traditional roles and aim to equip future experts with the skills to drive progress. Our Substack provides regular articles on our thoughts, experiences, and interviews.
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.
These researchers begin by discussing epigenetic clocks and how much the measured alterations in gene expression cause other aspects of aging, the details of which remain unclear [1]. Accelerated aging, as measured by these clocks, is associated with cardiometabolic diseases [2]; if altering the expression of clock-related genes is demonstrated to have benefits in this area, it could pave the way for interventions; if this method is demonstrated not to be beneficial, then they may remain useful simply as clocks. There is also the question of generalizability: whether or not clocks are equally valuable across populations.
Limited connections between clocks and metabolites
Here, the researchers focused on obese people by using data from the MACRO trial, which was conducted to test the effects of weight loss interventions between 2008 and 2011 [3].
This trial utilized 148 participants between 22 and 75 years of age who had high BMI indices (between 30 and 45) but did not have such metabolic diseases as cardiovascular disease or type 2 diabetes. They were divided into low-carbohydrate and low-fat groups; the low-carb group was reported to have more weight loss than the low-fat group. Adherence to these diets was high.
These researchers used three samples from each person: at baseline, 3 months, and 12 months. To minimize noise, two principal component-based clocks, PCPhenoAge and PCGrimAge, were used along with the DunedinPACE clock that natively measures age acceleration. Age, sex, ethnicity, body weight, education, smoking, and alcohol use were all factored in as covariates.
Interestingly, lower total cholesterol was found to be associated with more rapid aging, according to both PCPhenoAge and DunedinPACE. Other metabolic factors were found to be associated with accelerated aging, including reduced levels of ghrelin and adiponectin along with higher levels of insulin, the insulin resistance marker HOMA-IR, and C-reactive protein (CRP). PCGrimAge did not have any statistically significant association between metabolic factors and epigenetic aging.
After dietary interventions, however, most of these correlations disappeared; the only ones that remained were the low adiponectin and the high CRP according to the DunedinPACE clock.
The interventions themselves had noticeable effects. Only three months of dieting did not yield any statistically significant effect on epigenetic aging. However, after 12 months, despite the dets being more effective for weight loss, PCPhenoAge and PCGrimAge reported increased epigenetic aging in the low-carb group compared to the low-fat group. DunedinPACE, however, reported that epigenetic age acceleration was decreased in both groups.
As expected, the dietary interventions had significant benefits for metabolic issues. However, critical to this study, the reseachers found that none of these benefits were mediated by epigenetic alterations as measured by these clocks: “Specifically, all indirect effects and proportions mediated were non-significant (FDR > 0.05), suggesting that the observed associations were not driven through changes in epigenetic aging.”
A clock may not always reflect health
These results, or lack thereof, led the researchers to suggest that the health benefits of moderately rapid weight loss are not well-captured in epigenetic clocks designed to measure aging. Specifically, they note that there is an “uncoupling” between the metabolic benefits observed in these studies and clock measurements. They further suggest that this may be due to the time periods involved; DunedinPACE “may be more indicative of cumulative biological burden that changes gradually over time” and less sensitive to relatively short-term effects.
The researchers highlight that their study is in line with previous work on this topic; the CALERIE trial found that caloric restriction, a well-known longevity intervention, had some effects on DunedinPACE but fewer effects on PCPhenoAge and PCGrimAge [4]. In total, their findings led the researchers to specifically warn against the use of epigenetic clocks as surrogate endpoints in metabolism-related interventions, suggesting instead that they “should remain exploratory and be interpreted with more established physiological markers.”
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.
[1] Ferrucci, L., Barzilai, N., Belsky, D. W., & Gladyshev, V. N. (2025). How to measure biological aging in humans. Nature Medicine, 1-1.
[2] Lo, Y. H., & Lin, W. Y. (2022). Cardiovascular health and four epigenetic clocks. Clinical Epigenetics, 14(1), 73.
[3] Bazzano, L. A., Hu, T., Reynolds, K., Yao, L., Bunol, C., Liu, Y., … & He, J. (2014). Effects of low-carbohydrate and low-fat diets: a randomized trial. Annals of internal medicine, 161(5), 309-318.
[4] Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., … & Belsky, D. W. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging, 3(3), 248-257.
Date Posted: September 10, 2025
Comments Off on Regular Glucosamine Use Linked to Fewer Chronic Diseases
Glucosamine, a sugar molecule with an amine group (amino sugar), is a supplement used by almost 20% of middle-aged adults in the U.S., U.K., and Australia [2]. It is recommended for osteoarthritis patients to reduce knee pain [3].
Glucosamine has also shown some broader beneficial effects, including on inflammatory responses [4], and it has been linked to reduced risks of cardiovascular disease, type 2 diabetes, lung cancer risks, and all-cause mortality [2,5-7]. However, comprehensive studies on the impact of glucosamine supplementation on non-communicable chronic diseases are lacking.
Given that non-communicable chronic diseases cause around three-quarters of all deaths worldwide and are responsible for a considerable economic burden, and taking into account the preliminary data on glucosamine’s biological mechanisms and positive effects, the researchers examined the impact of regular glucosamine supplementation and its association with the risk of developing major non-communicable chronic diseases.
Large cohort
The authors used a large dataset from the population-based UK Biobank. They only included participants who were free from non-communicable chronic diseases at the beginning of the study and had completed information on medicine use. They obtained the data of 269,033 participants. 52,556 (19.5%) were regular glucosamine users, making it the currently largest cohort with which to analyze this research question.
The participants provided the information regarding glucosamine use through self-reported questionnaires, which weren’t validated in any way. Since the questionnaire was constructed to give simple answers (‘yes’ or ‘no’), the researchers were unable to analyze more detailed information, such as dose-response, impact of duration, or frequency of treatment, or the impact of supplement forms, such as glucosamine sulfate, glucosamine hydrochloride, and N-acetyl-glucosamine.
When glucosamine users were compared to non-users, the researchers noted that “glucosamine users were older, more likely to be female, and had a lower level of socioeconomic deprivation.” They were also more likely to be current or former smokers, “tended to engage in excessive alcohol consumption, exhibit unhealthy dietary patterns, and participate in irregular physical activity.” To remove those differences between the glucosamine and control groups and make those two groups comparable, the researchers employed propensity score matching (PSM). Using this method, they compared 52,525 glucosamine users and 52,525 controls that had comparable characteristics. The data regarding those study populations included a median of almost 14 years of follow-up.
Lower risk of non-communicable chronic diseases
Data analysis, which included false discovery rate correction, showed an association between regular glucosamine use and significantly lower risks of seven non-communicable chronic diseases: esophageal cancer, gout, chronic obstructive pulmonary disease, colorectal cancer, chronic liver disease, heart failure, and coronary heart disease. These associations were robust and persisted when different statistical tools were applied to test their strength. There were also associations between the combination of glucosamine and chondroitin, another supplement often combined with glucosamine, to the risk of non-communicable chronic diseases.
Most of the associations were independent of age and gender. The exceptions involved heart failure, as regular glucosamine use was associated with a 22% lower risk of heart failure in men but not women; and irregular and rapid heart rhythms (atrial fibrillation), in which “regular glucosamine use was related to a 51% higher risk” in people younger than 65.
The authors cautioned that while they observed associations between glucosamine use and the risk of non-communicable chronic diseases, this study is observational and does not prove causal relationships.
However, they also derived a number called the population attributable fraction, which allowed them to quantify, at the population level, what proportion of disease risk may have been prevented by glucosamine use if the relationship is indeed causal. These numbers came out to 12.84% for esophageal cancer, 11.14% for gout, 6.53% for colorectal cancer, 5.67% for chronic obstructive pulmonary disease, 6.54% for chronic liver disease, 6.09% for heart failure, and 4.16% for coronary heart disease.
Many possible mechanisms
While the researchers didn’t experimentally investigate the mechanisms behind he observed association, they speculated on the possible biological processes behind it and discuss it in the light of published studies. For example, they discussed how the connection between glucosamine and reduced risk of cardiovascular diseases can be driven by its ability to help mitigate atherosclerotic lesion formation and its anti-inflammatory effects. The reduced risk of non-communicable chronic diseases can also be linked to glucosamine’s ability to mimic the metabolic effects of a low-carbohydrate diet, its antioxidant properties, or modulation of many cellular processes.
Like every study, this one also has some limitations. While the UK Biobank is a large dataset with many participants, and a plethora of information about each person, some information is not included, such as their reasons for taking glucosamine. If some of the participants took it because of joint discomfort or undiagnosed osteoarthritis, this would change their disease risk and impact the analysis, as participants who had non-communicable chronic diseases at the beginning of he study were excluded.
The results might also have limited generalizability, as the population in the UK Biobank is primarily of European ethnicity and has healthier habits than the general population. Additionally, the authors suspect that glucosamine users might be more conscious about health, introducing another bias. However, they tried to minimize the impact of potential confounding factors by adjusting their analysis.
All in all, the researchers believe that glucosamine is a promising, low-cost, accessible candidate to prevent chronic diseases. Their research suggests that glucosamine benefits might extend beyond joint health, where it is currently employed. However, given that this study cannot establish a causal effect, future research should more directly address causality and establish a better understanding of the molecular processes behind the observed associations.
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.
[1] He, J., Ma, Y., Jiang, Y., Ji, J., & Song, F. (2025). Regular glucosamine supplementation and risk of age-related chronic diseases: evidence from a propensity score-matched cohort study. Aging clinical and experimental research, 37(1), 259.
[2] Ma, H., Li, X., Zhou, T., Sun, D., Liang, Z., Li, Y., Heianza, Y., & Qi, L. (2020). Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank. Diabetes care, 43(4), 719–725.
[3] Vo, N. X., Le, N. N. H., Chu, T. D. P., Pham, H. L., Dinh, K. X. A., Che, U. T. T., Ngo, T. T. T., & Bui, T. T. (2023). Effectiveness and Safety of Glucosamine in Osteoarthritis: A Systematic Review. Pharmacy (Basel, Switzerland), 11(4), 117.
[4] Dalirfardouei, R., Karimi, G., & Jamialahmadi, K. (2016). Molecular mechanisms and biomedical applications of glucosamine as a potential multifunctional therapeutic agent. Life sciences, 152, 21–29.
[5] Ma, H., Li, X., Sun, D., Zhou, T., Ley, S. H., Gustat, J., Heianza, Y., & Qi, L. (2019). Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. BMJ (Clinical research ed.), 365, l1628.
[6] Li, G., Zhang, X., Liu, Y., Zhang, J., Li, L., Huang, X., Thabane, L., & Lip, G. Y. H. (2022). Relationship between glucosamine use and the risk of lung cancer: data from a nationwide prospective cohort study. The European respiratory journal, 59(3), 2101399.
[7] Li, Z. H., Gao, X., Chung, V. C., Zhong, W. F., Fu, Q., Lv, Y. B., Wang, Z. H., Shen, D., Zhang, X. R., Zhang, P. D., Li, F. R., Huang, Q. M., Chen, Q., Song, W. Q., Wu, X. B., Shi, X. M., Kraus, V. B., Yang, X., & Mao, C. (2020). Associations of regular glucosamine use with all-cause and cause-specific mortality: a large prospective cohort study. Annals of the rheumatic diseases, 79(6), 829–836.
Date Posted: September 9, 2025
Comments Off on Microglial Aging Is Determined by Their Environment
A new preprint study from Calico has found that the local brain environment is the primary driver of microglial aging. After being transplanted into old brains, young cells adopted aged characteristics, but their susceptibility to these signals could be turned off [1].
Microglia grow old and irritable
Brain aging holds a special place in the longevity field as a strong limiting factor: even if we can rejuvenate the body by replacing its various parts and organs, the brain is what contains our memories and personality, hence it cannot be simply replaced. This makes rejuvenating the brain a crucial step in achieving meaningful lifespan extension.
Studies have consistently found that the support cells known as glia age faster than neurons. Of these glial cells, the brain’s specialized immune cells (microglia) are among the most profoundly affected by aging [2]. Aged microglia often develop a more aggressive, pro-inflammatory phenotype that is suspected to drive neurodegeneration [3].
One crucial question about microglial aging is about whether these cells age because of a pre-programmed internal clock (a cell-intrinsic process) or are pushed into an aged state by signals from their deteriorating neighborhood (a cell-extrinsic process). This study from Calico, the Alphabet-owned longevity company, was designed to test cell-intrinsic versus environmental effects by replacing microglia with donor myeloid cells across young and old brains.
Young cells for aged brains
The researchers developed a method to replace the native microglia in mice with new myeloid cells derived from the bone marrow of donor mice. They first produced a pool of donor hematopoietic stem cells (HSCs) taken from young female mice. The cells were genetically engineered to produce two extra proteins: an enhanced version of the green fluorescent protein (EGFP), which allows the tracking of cells that express it in vivo, and Cas9, an element of the CRISPR gene editing platform. This created “ready-to-edit” cells: to knock out a gene later in the study, the team simply needed to introduce a small piece of guide RNA to direct the pre-existing Cas9 to its target.
The bone marrow niche of the old recipient mice was then depleted to make room for donor stem cells. However, the researchers also needed to rid the brain of old microglia. This was done by adding a drug that inhibits CSF1R, a protein crucial for microglial survival. With the original microglia gone, the donor-derived myeloid cells circulating in the blood could now enter the brain. There, they settled down and became microglia-like cells.
With their system established, the researchers set out to investigate what happens when young, healthy ‘reconstituted cells’ are placed in an aged brain. Apparently, the environment is the dominant force. Young cells in old brains rapidly began to look and act old, especially in the cerebellum, adopting aged gene expression patterns. The researchers defined a “Cerebellar Accelerated Aging Signature” (CAAS), a molecular fingerprint of 403 genes, and watched the young cells in the old brain acquire this signature.
“What did the old brain tell the young cells? To get old, fast,” said Oliver Hahn, Ph.D., a principal investigator at Calico and the paper’s senior author, in an X thread. “The aged brain environment overrode the intrinsic youth of donor cells! These young ‘reconstituted cells’ acquired the molecular aging signatures we see in old microglia, an effect strongest in the cerebellum.”
To confirm that the brain environment could not only make young cells old but also make old cells young, the researchers performed the reverse transplantation. When transplanted into young brains, cells from old mice showed transcriptional and morphological rejuvenation.
Aging signals blocked
When the researchers compared the gene expression profiles of microglia from young and old brains, one of the strongest molecular patterns they found was a heightened pro-inflammatory interferon response signature. To see if dampening interferon response would rescue microglia aging, the team decided to knock out Stat1, a well-known master regulator of this signaling pathway.
Using their Cas9 “edit-ready” platform, the researchers produced Stat1-deficient young cells and repeated their repopulation protocol. Unlike in the previous experiment, these cells were largely protected from the rapid aging that the researchers had previously observed: they resisted the aging signals from the environment and did not activate the CAAS signature.
The researchers wanted to know which type of cells produced these aging signals. As it turned out, at least for the interferon response, the culprit was natural killer (NK) cells rather than T cells, which initially were the researchers’ primary suspect. Depleting NK cells in aged mice blunted the age-related interferon response in microglia.
“Our findings are clear,” Hahn said. “The local brain environment drives microglia aging, with NK cells acting as an unexpected upstream trigger. Crucially, this is blockable, as Stat1-KO shields young cells from pro-aging cues. This challenges simple ‘rejuvenation-by-replacement’ ideas. This is just the beginning. We’re now using this platform to map out other pro-aging signaling axes. We hope our new, scalable eHSC system will be a powerful resource for the field, enabling future in vivo screens to find new targets for neuroinflammation.”
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.
[1] Gizowski, C., Popova, G., Shin, H., Mader, M. M., Craft, W., Kong, W., Shibuya, Y., Wranik, B. J., Fu, Y. C., Depp, C., Lin, T. D., Martin-McNulty, B., Yoo, Y., Tai, P.-H., Hingerl, M., Leung, K., Atkins, M., Fong, N., Jogran, D., … Hahn, O. (2025, September 7). Heterochronic myeloid cell replacement reveals the local brain environment as key driver of microglia aging [Preprint]. bioRxiv.
[2] Costa, J., Martins, S., Ferreira, P. A., Cardoso, A. M., Guedes, J. R., Peça, J., & Cardoso, A. L. (2021). The old guard: Age-related changes in microglia and their consequences. Mechanisms of ageing and development, 197, 111512.[3] Adamu, A., Li, S., Gao, F., & Xue, G. (2024). The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets. Frontiers in aging neuroscience, 16, 1347987.
[3] Adamu, A., Li, S., Gao, F., & Xue, G. (2024). The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets. Frontiers in aging neuroscience, 16, 1347987.
Date Posted: September 8, 2025
Comments Off on Study Boosts Brain Mitochondria, Rescues Memory in Mice
Many neurodegenerative diseases, such as Alzheimer’s disease, are associated with mitochondrial dysfunction [2], which might lead to cells not working properly or dying off. However, it’s been difficult to determine whether mitochondrial problems are a root cause or a symptom of these diseases.
This uncertainty exists mainly due to the lack of reliable ways to specifically and quickly boost mitochondrial function in the brain. In a new study published in Nature Neuroscience, researchers from Inserm and the Université de Bordeaux, in collaboration with researchers from the Université de Moncton in Canada, inched closer to answering the question and maybe developing therapies for mitochondrial disorders.
In previous studies, the researchers worked on the role of guanine nucleotide-binding proteins (G proteins). Their main role is signal transduction: they typically sit inside the cell’s main outer membrane, linked to G protein-coupled receptors (GPCRs). When a signaling molecule, such as a hormone or a neurotransmitter, binds to a GPCR on the cell surface, the receptor activates its associated G protein, which initiates a downstream cascade of biochemical reactions within the cell, leading to a specific physiological change.
However, recent studies have found that G proteins exist also in mitochondrial membranes and regulate energy production [3]. The researchers reasoned that activating G proteins directly inside the mitochondria could rapidly ramp up the organelles’ activity and improve cognitive function.
The tool they built to influence mitochondrial Gs protein (“s” for the stimulatory subtype) is based on Designer Receptor Exclusively Activated by Designer Drugs (DREADD) technology. A DREADD is a receptor protein that has been altered so that it no longer responds to its natural activators but can be switched on by a specific and otherwise inert “designer drug,” such as clozapine-N-oxide (CNO).
The researchers also attached a sequence to the construct that would guide it directly to mitochondria, ensuring that it does not end up in other membranes. Using high-resolution microscopy and protein analysis, they confirmed that the new tool was successfully delivered and embedded into the outer membrane of mitochondria in various cell types and in the hippocampi of mice.
A phosphorylation cascade triggers energy production
The experiments showed that activating mitoDREADD-Gs with CNO had a direct and rapid effect on mitochondrial function. In cells and hippocampal tissue expressing the tool, CNO treatment significantly increased mitochondrial membrane potential, which is an indicator of energy-producing activity, and oxygen consumption rate (OCR), which directly measures mitochondrial respiration. The team also used a control DREADD that wasn’t targeted to the mitochondria, and it had no such effect.
“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration,” said Giovanni Marsicano, Inserm research director and co-senior author of the study.
The researchers also confirmed that mitoDREADD-Gs works by activating the naturally present (endogenous) Gs protein. When cells genetically engineered to lack Gs were used, the tool failed to boost mitochondrial activity.
Investigating the entire mechanism, the team found that the mitochondrial Gs protein triggered a cascade of phosphorylation, starting with the enzyme protein kinase A (PKA). The ultimate target turned out to be NDUFS4, a component of Complex I of the electron transport chain, the machinery in the heart of mitochondrial energy production, promoting its assembly and activity.
Memory rescued in mice
The researchers then turned to two mouse models: one of of frontotemporal dementia (FTD) and another Alzheimer’s disease. They first confirmed that these mice had lower mitochondrial respiration and reduced PKA activity in the hippocampus, a brain region critical for memory.
In both models, when mitoDREADD-Gs was expressed in the hippocampi of these mice and activated with CNO, the animals’ performance in novel object recognition (NOR), a common memory test in rodent studies, was fully restored to the level of healthy mice. The control (non-mitochondrial) DREADD had no effect.
“These results will need to be extended, but they allow us to better understand the important role of mitochondria in the proper functioning of our brain. Ultimately, the tool we developed could help us identify the molecular and cellular mechanisms responsible for dementia and facilitate the development of effective therapeutic targets,” said Étienne Hébert Chatelain, professor at the Université de Moncton and co-senior author of the study.
“Our work now consists of trying to measure the effects of continuous stimulation of mitochondrial activity to see whether it impacts the symptoms of neurodegenerative diseases and, ultimately, delays neuronal loss or even prevents it if mitochondrial activity is restored,” added Luigi Bellocchio, Inserm researcher and co-senior author of the study.
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.
[1] Pagano Zottola, A. C., Martín-Jiménez, R., Lavanco, G., Hamel-Côté, G., Ramon-Duaso, C., Rodrigues, R. S., … & Hebert-Chatelain, E. (2025). Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice. Nature Neuroscience, 1-14.
[2] Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Molecular neurodegeneration, 15(1), 30.
[3] Suofu, Y., Li, W., Jean-Alphonse, F. G., Jia, J., Khattar, N. K., Li, J., … & Friedlander, R. M. (2017). Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proceedings of the National Academy of Sciences, 114(38), E7997-E8006.
Date Posted: September 5, 2025
Comments Off on A Mechanism Behind Protein Aggregation Discovered
Most neurodegenerative diseases are age-related, and many of them are similar in other ways. For instance, amyotrophic lateral sclerosis (ALS), Huntington’s disease, and Alzheimer’s disease have all been linked to abnormal protein aggregation [1], albeit with different proteins involved. This is unsurprising, since one of the key hallmarks of aging is the decline of proteostasis.
While the protein culprits are different between these diseases, this similarity hints at possible common mechanisms that scientists have been looking for. In a new study from the University of Cologne, published in Nature Aging, the researchers might have made a big leap towards understanding these common causes.
One protein causes several others to aggregate
The team worked with models based on C. elegans, a nematode worm and a workhorse of longevity research. Researchers focused on a signaling pathway involving two proteins, EPS-8 and RAC. Previous work had found that as C. elegans ages, EPS-8 accumulates, which upregulates RAC signaling. This hyperactivation shortens the worm’s lifespan [2].
The key question was whether this known aging pathway could also be the trigger for disease-related protein aggregation. To find out, the team used genetically engineered worms that express the toxic human proteins responsible for Huntington’s (polyglutamine, or polyQ) and ALS (mutant FUS and TDP-43).
Using RNA interference (RNAi) to knock down the eps-8 gene and its partner rac genes, the researchers observed a significant decrease in the aggregation of all the disease-related proteins. This effect occurred without simply reducing the total amount of the protein, suggesting that it specifically prevented the clumping process.
This reduction in protein clumps had a direct functional benefit. The worms’ neuronal health was preserved, as evidenced by their improved performance on behavioral tests like avoidance response and the ability to sense and move towards chemicals (chemotaxis).
Digging for the mechanisms
To confirm that high levels of EPS-8 were the direct cause, the team used a mutant worm producing a reinforced form of EPS-8. This mutation increases the protein’s levels from a young age. The worms showed accelerated protein aggregation and earlier onset of neuronal deficits, directly linking EPS-8 accumulation to the disease pathology.
The researchers found that the overactivated EPS-8/RAC pathway drives aggregation through at least two downstream mechanisms. The first one is excessive actin polymerization, which leads to the overproduction and destabilization of the cell’s actin cytoskeleton. While the exact link isn’t definitive, the authors hypothesize that a destabilized actin cytoskeleton could promote protein aggregation by causing actin to form aggregates, which then act as “seeds” for other toxic proteins to clump onto.
The second mechanism is hyperactivation of another signaling protein called JNK. Knocking down the worm’s JNK homolog, kgb-1, also effectively prevented protein aggregation. The authors suggest that the chronic upregulation of the JNK stress pathway during aging may lead to broader cellular changes that hurt the cell’s ability to maintain healthy proteostasis.
Moving further upstream, the team investigated why EPS-8 accumulates with age. They discovered that the culprit is a deubiquitinating enzyme (DUB), USP-4. Proteins in a cell are often tagged with a ubiquitin molecule to mark them for recycling. DUBs remove these tags, which prevents protein degradation.
The study showed that as worms age, levels of usp-4 increase. This leads to more EPS-8 being deubiquitinated and saved from destruction, which causes its accumulation. Importantly, knocking down usp-4 in aging worms reduced protein aggregation and extended their lifespan.
Confirmed in human cells
To confirm that these findings are relevant to humans, the researchers replicated their experiments in human cell models, including motor neurons derived from induced pluripotent stem cells (iPSCs) taken from an ALS patient. Remarkably, the results were similar. Knocking down human EPS-8 or USP-4 significantly reduced the aggregation of mutant HTT, FUS, and TDP-43 proteins. In the ALS patient-derived motor neurons, this intervention also reduced apoptosis and necroptosis, two forms of cell death.
“We are delighted to uncover a molecular mechanism that could shed light on how aging contributes to diseases like ALS and Huntington’s,” said first author Dr. Seda Koyuncu. “For years, we’ve known that age is the major common risk factor for different neurodegenerative diseases. However, how exactly age-related changes contribute to these diseases remains largely unknown. This study may contribute to filling in a part of that puzzle.”
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.
[1] Hommen, F., Bilican, S., & Vilchez, D. (2022). Protein clearance strategies for disease intervention. Journal of Neural Transmission, 129(2), 141-172.
[2] Koyuncu, S., Loureiro, R., Lee, H. J., Wagle, P., Krueger, M., & Vilchez, D. (2021). Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature, 596(7871), 285-290.
Two people nearly died, and several more sought treatment, after receiving peptide injections at the last RAADfest in Las Vegas. This highlighted some well-known problems and contradictions in the longevity field.
In the heart of San Francisco, a tower in the downtown area is transforming into a center for longevity, artificial intelligence, cryptocurrency, and robotics.
Rejuve.AI is a company founded by Jasmine Smith and well known AI researcher Ben Goertzel. Recently, they have launched a new longevity app, and Arkadi caught up with them to find out more.
The Longevity Summit Dublin has become quite the go-to event in the longevity community. The event first launched in 2022 and has grown in popularity since then.
