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Microgravity Exposure as a Model for Aging
https://www.fightaging.org/archives/2025/07/microgravity-exposure-as-a-model-for-aging/
Life on earth evolved in an environment of gravity; ubiquitous, always there. Take it away, and cellular biochemistry can run awry. Microgravity exposure in higher animals, studied in astronauts who have spent prolonged periods of time in orbit, is a harmful exercise. The longer the exposure, the worse the harms. Many of the changes that microgravity exposure causes to cell and tissue function can be viewed as analogous to those produced by aging. That said, it is important to recognize that microgravity exposure is not aging, just as progeroid conditions resulting from DNA repair deficiency are not aging, the unpleasant dysfunction of type 2 diabetes is not aging, and obesity is not aging. These line items involve the accumulation of forms of damage and dysfunction, but each is a different mix, and the details matter when it comes to trying to draw conclusions about process A when studying process B.
Still, researchers work in an environment that is very sensitive to expenditure of funds and time. Models of degeneration that are at least somewhat similar to aging, and that can be established rapidly, are favored over the old fashioned approach of waiting for animals and people to get old, even though the relevance of the results might be questionable. While one might not think of putting materials into orbit to experience microgravity as a cost-effective approach, it can be when someone else is paying for the necessary facilities in orbit and lift capacity to get there.
An interesting point is made by the authors of today’s open access paper about the principle way in which microgravity exposure differs from other models that might resemble aging enough to be interesting, which is that people recover from microgravity exposure, and that exposure can be turned on and off quickly. This is an easier alternation of circumstances for scientists to engineer in human subjects than, say, removal of type 2 diabetes or obesity. One could argue that there may well be interesting biochemistry to be found somewhere in this reversal of dysfunction. Will it be in any way applicable to the production of therapies to treat aging? Without looking, that is impossible to say.
Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity
Given the growing aging population, understanding the mechanisms driving the decline in bodily functions with age has become increasingly essential. Identifying strategies to slow down or even prevent these changes could enhance public health and extend longevity, while yielding significant economic benefits for society. This task is complicated by the long follow-up timeframes needed for such studies, even short-lived rodent models take about three years to observe lifespan changes, and studies in primates can last anywhere from 15 to 30 years. The need for a short-duration human aging model is challenging, and decades of research have not generated one. Recently, we proposed a model that may overcome these challenges.
Gravity plays a crucial role in shaping human physiology, and prolonged exposure to microgravity during space missions can lead to various pathologies that mirror age-related changes. Astronauts frequently experience significant bone density loss, muscle atrophy, cardiovascular deconditioning, immunological, cerebrovascular, cognitive alterations, and metabolic problems. These changes, observed in both aging populations and astronauts in microgravity, reveal striking similarities that highlight the potential of utilizing space as a model for accelerated aging research. In microgravity, aging-like processes are accelerated by up to ten times, occurring over days or weeks rather than years. This makes the space environment a unique model for studying aging in an accelerated format, offering insights that are otherwise unattainable on Earth.
Transcriptomic analyses of human cell lines exposed to both real and simulated microgravity have identified a panel of eleven candidate genes exhibiting consistent differential expression. Upregulated genes include CSGALNACT2, CSNK2A2, HIPK1, MBNL2, PHF21A, and RAP1A, which are involved in pathways such as glycosaminoglycan biosynthesis, chromatin remodeling, RNA splicing, and cytoskeletal organization. In contrast, down-regulated genes such as DNPH1, EXOSC5, L3MBTL2, LGALS3BP, and SPRYD4 reflect impairments in nucleotide metabolism, RNA degradation, chromatin compaction, and intercellular communication, processes that are frequently disrupted during aging. Similar transcriptional signatures have also been observed in human iPSC-derived cardiac progenitor cells cultured aboard the International Space Station, including upregulation of cell cycle regulators (CCND1, CCND2), the proliferation-associated growth factor (IGF2), and the cardiac differentiation marker (TBX3), accompanied by downregulation of extracellular matrix genes. These changes suggest a shift toward increased proliferation and structural remodeling.
Engineered human heart tissues exposed to long-term microgravity similarly displayed downregulation of contractile and calcium signaling genes, alongside increased expression of genes related to oxidative stress, mitochondrial dysfunction, and inflammation, consistent with aging-associated cardiac decline. Additional evidence from single-cell RNA sequencing of immune cells revealed altered expression of genes involved in cytoskeletal organization, IL-6 signaling, and sirtuin-regulated metabolic control, suggesting disruption of immune homeostasis and activation of inflammaging-related pathways. Collectively, these findings define a core set of microgravity-regulated genes in human cells whose altered expression mirrors aging-related molecular deterioration. Their functional roles in key cellular pathways highlight their potential as biomarkers of microgravity adaptation and as therapeutic targets for promoting resilience in aging tissues
Aged Hunter-Gatherers Exhibit Low Arterial Stiffness
https://www.fightaging.org/archives/2025/07/aged-hunter-gatherers-exhibit-low-arterial-stiffness/
In recent years, researchers have turned their attention to the long-term health and aging of the few remaining populations of hunter-gatherers, such as the Tsimane that are the subject of today’s open access paper. The lifestyle led by these individuals is characterized by high levels of exercise and a diet low in all of the usual line items that we know are not that good for us, such as processed sugars. Hunter-gatherer populations exhibit dramatically lower levels of cardiovascular disease and dysfunction than is the case for people in wealthier parts of the world. Their existence is a mirror, held up to show the rest of us just how much harm can be done by a sedentary life and a bad diet.
The Tsimane have been the subject of a range of studies of late. They exhibit slower onset of neurodegeneration, minimal degrees of atrial fibrillation, little hypertension and obesity, superior metabolic health, little to no increase in systemic inflammation with age, and so forth. We should all be so lucky – but there is no luck involved here, this is all the outcome of a particular lifestyle. Today’s open access paper produces the expected data on arterial stiffness to accompany other published work on the cardiovascular health of the Tsimane; there are a few eye-opening numbers in that data set. The few metabolically unhealthy Tsimane are outperforming the healthy US populations in the metric of arterial stiffness, for example. We might take that as a measure of the degree to which a sedentary lifestyle is actively harmful to long-term health.
Arterial Stiffness in Heart-Healthy Indigenous Tsimane Forager-Horticulturalists
We conducted a cross-sectional study comparing 3 arterial stiffness metrics among Tsimane forager-horticulturalists with 2 representative US cohorts. Tsimane participants exhibited superior arterial health compared with US cohorts, with higher elasticity and lower stiffness. Stiffness measures were 47.3% and 35.7% better than US cohort participants by age 40 years, respectively, and differences remained sustained throughout adulthood. The carotid-femoral pulse wave velocity in Tsimane participants was 33.9% lower and showed a minimal age-related increase, with carotid-femoral pulse wave velocity only higher by age 70+. Tsimane participants with ≥2 comorbidities (hypertension, obesity, and diabetes) had ≈25% higher arterial elasticity than healthy Americans with no comorbidities.
The disparities in arterial stiffness between Tsimane and urbanized cohorts can be attributed to their subsistence-oriented lifestyle and environmental context, which align with key metrics in cardiovascular health promotion, such as a lean diet, high physical activity, and consistently low blood glucose and blood pressure. The combined effect of the aforementioned factors might promote optimal vascular health from early life and contribute to sustained cardiovascular well-being. In fact, Tsimane individuals lifestyle exemplifies many of the core principles outlined in the American Heart Association’s Life’s Essential 8 metrics, a framework that emphasizes proactive cardiovascular health improvement and preservation across the life course. Based on that framework, the primary distinctions between Tsimane and their urbanized peers are diet and physical activity, the 2 criteria in which US adults scored the lowest among all 8 cardiovascular health metrics between 2013 and 2020.
Tsimane individuals typically engage in high levels of low- and moderate-intensity activities year-round, despite seasonality of production tasks. Men and women typically engage in physical activity for 6 to 7 hours/day and 4 to 6 hours/day, respectively, averaging ≈17,000 steps daily. Activity levels remain relatively high throughout adulthood, though decline at late ages. Studies have reported an attenuated age-related arterial stiffness increase in physically active populations. A recent meta-analysis found that sustained aerobic exercise interventions reduce arterial stiffness, particularly measures of pulse wave velocity. The underlying mechanism involves improved vessel wall homeostasis through a combination of pathways, including decreased vascular oxidative stress, increased endothelial nitric oxide bioavailability, and upregulation of vascular growth factors. Moreover, the diet of Tsimane individuals is best characterized as high-carbohydrate, fiber-rich, and low-fat, with a high intake of micronutrients, such as potassium and magnesium. This dietary pattern, centered on cultigens, freshwater fish, and wild game, closely resembles the recommended heart-healthy diet, with an emphasis on healthy fats, dietary fiber, whole grains, healthy-sourced proteins, and limited refined sugars and processed foods.
Gut Microbiome Metabolite Imidazole Propionate Contributes to Atherosclerosis
https://www.fightaging.org/archives/2025/07/gut-microbiome-metabolite-imidazole-propionate-contributes-to-atherosclerosis/
Most people who arrive an a hospital in the wake of a first heart attack or stroke due to rupture of an unstable atherosclerotic plaque in the arteries do not have elevated LDL cholesterol. This is cholesterol attached to LDL particles, coming from the liver for delivery to the rest of the body. While high LDL cholesterol is recognized as, on balance across a population, contributing to the pace at which plaque grows, it is not the whole story. It is probably not the most important part of the story either, given than the well-established therapies to lower LDL cholesterol do not reliably regress plaque, and only slow its growth somewhat.
Researchers have in recent years searched for and uncovered a broad range of other mechanisms that contribute to plaque growth in animal models of atherosclerosis. This has led to various markers, such as circulating Lp(a), that correlate with atherosclerotic plaque and consequent cardiovascular disease in human study populations. A number of biotech and pharmaceutical companies are working on the development of therapies to target these mechanisms, near all of which only produce a slowing of plaque growth when tested in animal models.
In today’s open access paper, researchers propose a novel way in which the gut microbiome can contribute to the creation and growth of atherosclerotic plaque in blood vessel walls. They point to a metabolite generated by microbes in the gut, imidazole propionate, and demonstrate that it can be used to promote plaque growth in animal models of atherosclerosis. Like all mechanisms promoting plaque growth, this appears to negatively affect the macrophage cells that are drawn to a plaque and attempt to repair the damage, ensuring that more of these cells are incapacitated and killed by the toxic plaque environment.
Imidazole propionate is a driver and therapeutic target in atherosclerosis
Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors. However, individuals at risk for early vascular disease often remain unidentified. Recent research has identified new molecules in the pathophysiology of atherosclerosis, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy.
Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation.
Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP-I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP-I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.
Stem Cell Exosomes Improve Mitophagy in Photoaged Skin
https://www.fightaging.org/archives/2025/07/stem-cell-exosomes-improve-mitophagy-in-photoaged-skin/
Aging is an accumulation of specific forms of cell and tissue damage, coupled with the dysfunctions produced by that damage. While the damage of aging would occur regardless of the surrounding environment, many environmental exposures also produce cell and tissue damage. This additional burden of damage can result in what appears to be accelerated aging, even if the damage is somewhat dissimilar in character to that produced during aging by the body itself. Sometimes the damage is in fact similar. Photoaging of skin resulting from ultraviolet light exposure is a good example; like any radiation exposure, this causes a greater burden of some of the forms of damage and dysfunction known to occur with age, such as DNA damage and an increased burden of senescent cells.
One way to reduce the impact of aging is to increase the activity of cellular maintenance processes. Many of the interventions show to slow aging in animal studies involve upregulation of autophagy, for example, a way for cells to remove damaged components in order to better resist damage-induced dysfunction. When most of the cells in the body are more aggressively maintained, age-related declines in tissue function are slowed. In today’s open access paper, researchers show that this sort of approach also reduces the impact of photoaging. One of the targets of autophagy is damaged mitochondria in the cell, and this specific form of autophagy is called mitophagy. Since there are hundreds of mitochondria in every cell, and only some of them are at any given time rendered damaged and dysfunctional by radiation exposure, more aggressive clearance of those damaged mitochondria via mitophagy helps to reduce consequent impairment of tissue function.
Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging
Various factors contribute to skin aging, which can be categorized into internal and external factors. External factors include air pollution, ultraviolet (UV) radiation, lack of sleep, and smoking. UV radiation, in particular, causes photoaging. Repeated exposure to UV, especially UVB radiation, generates reactive oxygen species (ROS), which accelerate the breakdown of collagen and elastin by upregulating matrix metalloproteinases (MMPs), leading to photoaging symptoms such as wrinkles, dryness, loss of elasticity, and pigmentation.
Current treatments for skin photoaging include photodynamic therapy, oral and topical drugs, and stem cell therapies. Human adipose-derived stem cells (hADSCs) are a type of mesenchymal stem cell with self-renewal and multidifferentiation abilities, as well as immunomodulatory effects. Exosomes are extracellular vesicles, ranging from 30 to 200 nm, formed through endocytosis, fusion, and exocytosis. These vesicles are rich in nucleic acids, proteins, cytokines, and other bioactive compounds. As a promising alternative to stem cells, exosomes eliminate the risk of immune rejection associated with stem cell transplants, offering an effective, non-invasive option for anti-aging therapies. This has led to increasing interest in their potential for skin rejuvenation.
Research has shown that photoaged skin exhibits a tenfold increase in mitochondrial DNA (mtDNA) common deletion compared to sun-protected skin in the same individual. Preserving mtDNA integrity is critical for mitochondrial function. Accumulation of mutations can impair mitochondrial subunits, increasing ROS production and perpetuating oxidative damage within mitochondria. However, mtDNA has limited repair capacity, making the clearance of damaged mtDNA via mitophagy essential for reducing oxidative stress in cells. Mitophagy is a crucial process that regulates mitochondrial quality and quantity in eukaryotic cells, selectively eliminating damaged or dysfunctional mitochondria. The PINK1/Parkin pathway is a well-established mediator of mitophagy.
This study aimed to explore the role and mechanism of hADSC-derived exosomes (hADSC-Exos) in addressing skin photoaging. hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to UVB irradiation, and treated with hADSC-Exos. Oxidative stress, senescent cell burden, and photoaging were assessed. In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels. In conclusion, hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.
The Aged Stem Cell Niche Obstructs Hematopoietic Stem Cell Rejuvenation via Transplantation
https://www.fightaging.org/archives/2025/07/the-aged-stem-cell-niche-obstructs-hematopoietic-stem-cell-rejuvenation-via-transplantation/
One of the reasons why the immune system declines with age is that hematopoietic stem cell populations that are resident in the bone marrow and responsible for creating immune cells become progressively more damaged and dysfunctional over time. It isn’t just the stem cells, however. Stem cells reside within structures of supporting cells known as niches. The niche itself becomes damaged and dysfunction, contributing to the problems exhibited by stem cell populations.
One of the most direct approaches to stem cell aging is to introduce into the body a replacement population of undamaged, rejuvenated stem cells, such as those that can be generated via the creation of induced pluripotent stem cells from a patient tissue sample. Some preparation and finessing is needed for hematopoietic stem cell transplants to ensure the transplanted cells survive, but this is already accomplished as a form of treatment for severe disease. The preparation is stressful on the patient at the present time, but it should be possible to develop less stressful approaches if the potential for a much broader use of hematopoietic stem cell transplantation emerges.
Unfortunately, and as noted in today’s open access paper, the age-damaged state of the stem cell niche ensures that one cannot just transplant youthful hematopoietic stem cells and expect it to reliably improve function. Young cells are impeded by the damaged niche, and coerced into adopting a state that is closer to that of old cells. This is a universal issue across stem cell populations, and a solution is much needed.
Differential effects of young and old hematopoietic stem cell niches on bone marrow-derived dendritic cells
Aging is linked to various dysfunctions of the immune system, including the decline of its primary developmental source: the hematopoietic stem cell (HSC) niche. This decline leads to chronic inflammation, increased vulnerability to infections, cancer, autoimmune diseases, and reduced vaccine efficacy. As individuals age, the HSC niche undergoes significant changes, including greater adipocyte accumulation and alterations in the molecular microenvironment, which may influence the development and function of immune cells. Among these cells, the impact of the aging HSC niche on dendritic cell (DC) function is less understood.
Heterochronic autologous HSC transplantation is a promising intervention to prevent age-related disorders, contributing to the extension of healthspan and longevity, however, several murine experiments failed to produce the expected results, which led us to presume that the problem lies within the old HSC niche. Therefore, we created in vitro models of young and old HSC niches and examined how these microenvironments affect the differentiation and maturation and functionality of BM-derived DCs (BMDCs).
An analysis of the conditioned media from young and aged HSC niches revealed that the environment of aged niches exhibited an increased presence of adiponectin. This media was subsequently utilized in BMDC differentiation and maturation protocols, with their effects closely monitored. Our results indicate that the old HSC niche microenvironment promotes premature BMDC activation, characterized by elevated MHC class II expression and enhanced allostimulatory capacity of BMDCs at their immature stage.
Additionally, lipopolysaccharide stimulation of BMDCs, used to induce DC maturation, significantly increased CD86 expression on BMDCs from the aged niche. However, these cells did not show superior allostimulatory capacity compared to their counterparts from the young niche environment. By analyzing the BMDC cytokine profile, we observed that when cultured in aged niche-conditioned media, the BMDCs secreted significantly higher levels of IL-6, indicating a heightened proinflammatory activation state. Collectively, our findings suggest that aging-related changes within the HSC niche can considerably alter DC functionality by disrupting their normal development from BM precursors.
ARPA-H Launches Program to Develop Replacement Brain Tissue
https://www.fightaging.org/archives/2025/07/arpa-h-launches-program-to-develop-replacement-brain-tissue/
Studies of forms of brain cancer and other slow, progressive damage to specific regions of the brain have demonstrated that the information stored in at least some parts of the brain can move around. Undamaged parts of the brain can be repurposed in response to damage. This means that it is in principle possible to place new, functional tissue into some portions of the living brain and expect that tissue to become used and useful over time, a replacement for damaged tissue. Researchers are initially focused on the neocortex, one of the most plastic areas of the brain. The biggest challenge is to be able to engineer suitable neocortical tissue for transplantation, growing it from a patient’s own cells.
The Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services (HHS), today unveiled its groundbreaking Functional Repair of Neocortical Tissue (FRONT) program, a transformative initiative to restore brain function. The neocortex, the largest part of the brain, is critical for sensory perception, motor control, and decision-making. Damage to this area – due to conditions like stroke, traumatic injury, or neurodegeneration, such as Alzheimer’s disease – has long led to irreversible damage, leaving individuals dependent on costly therapies or caregivers. The FRONT program aims to change that, using cutting-edge neurodevelopmental principles and stem cell technology to regenerate brain tissue and restore lost functions.
FRONT will work to develop a curative therapy for over 20 million U.S. adults suffering from chronic neocortical brain damage caused by stroke, neurodegeneration, and trauma, providing life-changing treatments for these individuals. The FRONT program spans five years, with strict performance metrics and a focus on preparing for human clinical trials. ARPA-H will solicit proposals under its Innovative Solutions Opening (ISO) in two key areas: graft tissue generation and engraftment procedures for functional brain recovery. ARPA-H encourages collaboration among experts across disciplines to meet the program’s ambitious goals.
Further Exploration of the Biochemistry of Zebrafish Heart Regeneration
https://www.fightaging.org/archives/2025/07/further-exploration-of-the-biochemistry-of-zebrafish-heart-regeneration/
Some species, such as salamanders and zebrafish, are capable of reactivating programs of embryonic development following injury in order to regrow limbs and even major portions of vital internal organs. Since mammals share the same ability to conduct embryonic development, it is hoped that all of the necessary biochemical machinery to also conduct complete regeneration of organs still exists in adult mammals, merely suppressed in some way. Researchers investigate the exceptional regeneration of species like zebrafish in search of controlling mechanisms that might be manipulated to turn on the same exceptional regeneration in humans and other mammals. It remains to be seen as to how long this will take, and whether the options will be as straightforward as hoped for.
Humans can’t regenerate heart muscle damaged by disease, but scientists have long known that some animals, such as zebrafish, can. The heart is made up of many kinds of cells that comprise muscle, nerve, and blood vessel tissue. A portion of these heart cells – in zebrafish, around 12 to 15% – originate from a specific population of stem cells called neural crest cells. Humans have analogous neural crest cells that give rise to varied cell types in almost every organ of the body, ranging from the facial skeleton to the nervous system. For some reason, zebrafish and a few other animals retain the ability as adults to rebuild tissues derived from the neural crest – the jaw, skull and heart, for example – while humans have lost that ability. These animals are not merely repairing damaged tissue, however. In the heart, cells around an injury revert to an undifferentiated state and then go through development again to make new heart muscle, or cardiomyocytes.
In the newly reported research, the scientists used single-cell genomics to profile all the genes expressed by developing neural crest cells in zebrafish that will differentiate into heart muscle cells. They then pieced together the genes expressed after they snipped away about 20% of the fish’s heart ventricle. This procedure seemed not to affect the fish, and after about 30 days their hearts were whole again. By knocking out specific genes with CRISPR, they identified a handful of genes that were essential to reactivation after injury, all of which are utilized during embryonic development to build the heart. One in particular, called egr1, seems to activate the circuit first and perhaps triggers the others, suggesting a potential role in regeneration. The researchers also identified the enhancers that turn on these genes. Enhancers are promising targets for CRISPR-based therapies, since they can be manipulated to dial up or down the expression of the gene.
An Aging Clock Integrating Epigenetic and Inflammatory Measures
https://www.fightaging.org/archives/2025/07/an-aging-clock-integrating-epigenetic-and-inflammatory-measures/
Researchers here present an interesting approach to epigenetic clock development. Based on a large set of training data, the researchers used epigenetic data to predict clinical biomarkers, in this case circulating proteins measured in a blood sample that are relevant to the chronic inflammation of aging, an assessment of the inflammatory state of the immune system. Then the researchers used the predicted biomarkers of inflammation as a basis for predicting age. This approach to clock development has the advantage of producing results that are more explicable than a direct prediction of age from epigenetic data, as one can theorize more readily about the role of specific inflammatory markers than is the case for specific epigenetic changes. We will likely see more of these two-stage clocks developed in the future.
We introduce EpInflammAge, a novel deep learning framework that bridges the epigenetic and inflammatory aspects of aging. Our results demonstrate three key advances: (1) successful prediction of inflammatory markers from DNA methylation data, (2) accurate age estimation using synthetic inflammatory profiles, and (3) robust disease sensitivity across multiple pathological conditions
One of the primary objectives of this research was to integrate the two hallmarks of aging – namely, epigenetic modifications and immunosenescence. To this end, we conducted a simultaneous examination of DNA methylation data and levels of cytokines and chemokines. We developed models for estimating inflammatory marker levels from epigenetic profiles and subsequently evaluated their performance on a large cohort of healthy and diseased samples. As measuring inflammation is clinically significant, the developed model enables the acquisition of epigenetic data and the prediction of inflammatory biomarkers based on methylation. This development presents an opportunity to progress in the direction of evaluating inflammaging, which is characterized by low-grade inflammation associated with age and age-related diseases.
EpInflammAge achieves competitive performance metrics against 34 epigenetic clock models, including an overall mean absolute error of 7 years and a Pearson correlation coefficient of 0.85 in healthy controls, while demonstrating robust sensitivity across multiple disease categories. Explainable AI revealed the contribution of each feature to the age prediction. The sensitivity to multiple diseases due to combining inflammatory and epigenetic profiles is promising for both research and clinical applications. EpInflammAge is released as an easy-to-use web tool that generates the age estimates and levels of inflammatory parameters for methylation data, with the detailed report on the contribution of input variables to the model output for each sample.
Early Life Exercise Improves Healthspan But Not Lifespan in Mice
https://www.fightaging.org/archives/2025/07/early-life-exercise-improves-healthspan-but-not-lifespan-in-mice/
Exercise is demonstrably beneficial, but does little to lengthen maximum life span in mice. It does compress morbidity, in the sense of extending the period of healthy life and increasing median life span without increasing maximum life span. The study noted here is an example of this sort of outcome. Mice were put through a program of exercise in early life, roughly equivalent of teenage human years through to mid-20s, and were shown to have a longer healthspan but not a longer lifespan. This might suggest that exercise affects many of the forms of damage and dysfunction that cause aging, but that there are some processes it has little effect on. It is the consequences of the unaffected processes that eventually produce mortality, regardless of a slowing of other aspects of aging.
It is well-known that physical activity exerts health benefits, yet the potential impacts of early-life regular exercise on later-life health and lifespan remains poorly understood. Here, we demonstrate that 3 months of early-life exercise in mice results in lasting health benefits, extending healthspan, but not lifespan. C57BL/6J mice underwent swimming exercise from 1 to 4 months of age, followed by detraining for the remainder of their lives.
While early-life exercise did not extend the overall lifespan, it significantly improved healthspan in both male and female mice, as evidenced by enhanced systemic metabolism, cardiovascular function, and muscle strength, as well as reduced systemic inflammation and frailty in aged mice. Multiple-organ transcriptome analyses identified enhanced fatty acid metabolism in skeletal muscles as a major feature in aged mice that underwent early-life exercise. These findings reveal the enduring long-term health benefits of early-life exercise, highlighting its pivotal role in improving healthspan.
CAR-T Cells Generated Inside the Body via Messenger RNA Therapy
https://www.fightaging.org/archives/2025/07/car-t-cells-generated-inside-the-body-via-messenger-rna-therapy/
Chimeric antigen receptors are artificial structures added to immune cells such as T cells in order to direct the cells to aggressively attack a cancer. Such CAR-T therapies have proven effective against leukemia, and researchers are working on making them effective for solid tumors as well. At present delivering such a therapy is a slow and onerous process, requiring cells to be harvested from a patient, engineered, expanded in culture, and then injected. This is very expensive. A potentially cheaper approach is to use gene therapy tools to engineer some fraction of circulating T cells in situ in the patient. Researchers have been working on this for a while now, and here find a proof of principle demonstration carried out in mice.
CAR-T cells are made in the laboratory by tinkering with the genetic instructions in immune cells called T cells that are removed from a patient. In particular, the T cells are tweaked to recognize and bind to a protein called CD19 that is abundant on other immune cells called B cells. Many blood cell cancers, including some types of lymphomas and leukemias, develop due to uncontrolled B cell growth.
In this study, researchers used tiny, fat-soluble bubbles called lipid nanoparticles to package messenger RNA (mRNA) molecules encoding a receptor protein that binds to CD19 as well as a modified version of another protein that is highly expressed in prostate cancer cells but is rare in other tissue. This second protein allows the researchers to trace the generation and movement of the recipient cells noninvasively using a common medical imaging technique called positron emission tomography. Finally, they designed the surface of the nanoparticles to include an antibody that binds to a protein called CD5 that is primarily found on T cells. Once the nanoparticle latches onto the T cell, it is engulfed, the lipid bubble disintegrates and the mRNA molecules are released into the interior of the cell to be made into proteins.
When researchers injected the nanoparticles into mice with a type of B cell lymphoma, they were able to track the generation of the CAR-T cells in the animals – or “in situ” – and see that they traveled to the location of the animals’ tumors. The in situ method generated about 3 million CAR-T cells per animal, which is similar to the cell numbers infused into patients undergoing conventional CAR-T therapy. Importantly, the newly generated CAR-T cells were efficient cancer killers; six out of eight mice with lymphoma were tumor-free 60 days after treatment began, and tumor growth in the remaining two was controlled.
The Transcriptomics of Slowed Brain Aging in Mice Produced by Calorie Restriction
https://www.fightaging.org/archives/2025/07/the-transcriptomics-of-slowed-brain-aging-in-mice-produced-by-calorie-restriction/
The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining sufficient micronutrients, is well demonstrated to slow aging in many species, though to a greater degree in short-lived species than in long-lived species. Human studies have demonstrated improved long-term health and measures of aging to result from even mild calorie restriction, closer to 10% fewer calories consumed. Calorie restriction alters near everything in cellular biochemistry throughout the body, making it an unending project for researchers to map and catalog its effects. The consensus is that calorie restriction largely produces its benefits via improved operation of autophagy, but there is so much biochemistry to wade through that it is reasonable to think that more of significance is waiting there to be discovered.
Aging induces functional declines in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among various interventions to slow the aging process, caloric restriction (CR) has consistently demonstrated the ability to extend lifespan and enhance brain function across different species. Yet the precise molecular and cellular mechanisms by which CR benefits the aging brain remain elusive, especially at region-specific and cell type-specific resolution.
In this study, we performed spatiotemporal profiling of mouse brains to elucidate the detailed mechanisms driving the anti-aging effects of CR. Utilizing highly scalable single-nucleus genomics and spatial transcriptomics platforms, we profiled over 500,000 cells from 36 mouse brains across three age groups and conducted spatial transcriptomic analysis on twelve brain sections from aged mice under CR and control conditions. This comprehensive approach allowed us to explore the impact of CR on over 300 cellular states and assess region-specific molecular alterations.
Our findings reveal that CR effectively modulates key aging-associated changes, notably by delaying the expansion of inflammatory cell populations and preserving cells critical to the neurovascular system and myelination pathways. Moreover, CR significantly reduced the expression of aging-associated genes involved in oxidative stress, unfolded protein stress, and DNA damage stress across various cell types and regions. A notable reduction in senescence-associated genes and restoration of circadian rhythm genes were observed, particularly in ventricles and white matter. Furthermore, CR exhibited region-specific restoration in genes linked to cognitive function and myelin maintenance, underscoring its targeted effects on brain aging.
In summary, the integration of single-nucleus and spatial genomics provides a novel framework for understanding the complex effects of anti-aging interventions at the cellular and molecular levels, offering potential therapeutic targets for aging and neurodegenerative diseases.
Generating Sensory Hair Cells via Lineage Reprogramming
https://www.fightaging.org/archives/2025/07/generating-sensory-hair-cells-via-lineage-reprogramming/
Age-related deafness is the consequence of some mix of (a) a loss of sensory hair cells of the inner ear, and (b) a loss of connections between these cells and the brain. One approach to treating this problem is to introduce new cells, either via transplantation or via inducing the generation of replacement cells in situ. Both approaches have their challenges, and both would benefit from a greater detail-level understanding of how exactly hair cells develop and become dysfunction. Thus researchers are working towards the production of hair cells on demand. While the initial application of this capability will involve running in vitro studies in research facilities, ultimately it may lead to cell therapies in which patient-matched hair cells are introduced into the inner ear to replace those that are damaged or lost.
Hearing loss affects hundreds of millions of people worldwide and often results from the loss of sensory hair cells in the inner ear – specialised cells that convert sound vibrations into electrical signals for the brain. These hair cells can be damaged by exposure to loud noise, certain medications or infections, and aging. In humans, once these hair cells die, they do not regenerate, meaning hearing loss is often irreversible. Research into how this could be countered has been limited by the inaccessibility of real human hair cells and the inefficiency of lab-based models.
In earlier work, the authors showed that mouse cells can be reprogrammed into those that are more like hair cells using four transcription factors: Six1, Atoh1, Pou4f3, and Gfi1, collectively referred to as SAPG. However, this method relies on viral delivery, which poses challenges for consistency and scalability. Instead, researchers engineered a stable human stem-cell line carrying a doxycycline-inducible version of the SAPG transcription factors. By adding the antibiotic doxycycline to the culture, this method allowed precise control of the reprogramming process. To track when the cells began to take on hair cell characteristics, they included a fluorescent reporter gene that switched on as reprogramming progressed.
When doxycycline was added, the team observed the first signs of reprogramming within three days. By day seven, around 35-40% of the cells expressed key hair cell gene markers such as MYO7A, MYO6, and POU4F3. This represented a more than 19-fold increase in efficiency compared to their previous virus-based approach, in half the time.
A Novel Muscle Age Acceleration Clock
https://www.fightaging.org/archives/2025/07/a-novel-muscle-age-acceleration-clock/
Sarcopenia is the name given to the later, more severe stages of the age-related loss of muscle mass and strength that afflicts all older individuals. Over the past few decades, researchers have increasingly focused on establishing clinical definitions of sarcopenia and and exploring the mechanisms of sarcopenia. Here, researchers take the present standards for diagnosis and use them to build an aging clock for muscle loss, an attempt to provide a more definite measure of risk and progression of sarcopenia, particularly in its earlier stages.
Sarcopenia is a progressive, generalised skeletal muscle disease linked to negative health changes that accumulate across the lifespan. From a pathophysiological standpoint, endocrine and metabolic abnormalities interact with the low-grade chronic inflammation (i.e., “inflammageing”), that is observed in advanced agers, leading to a reduction of protein-synthesis and regeneration, and a parallel pattern of muscle wasting due to increased apoptosis and protein-lysis.
Among the number of initiatives launched to advance knowledge on sarcopenia and prompt preventive/therapeutic approaches, the European Working Group on Sarcopenia in Older People (EWGSOP) has emerged as the most influential in raising awareness and moving the field forward. EWGSOP consensus firstly introduced a broad clinical definition for sarcopenia not limited to muscle loss. This was eventually developed more recently (EWGSOP2) to move muscle weakness and reduced performance to the forefront as primary indicators of sarcopenia. EWGSOP2’s recommendations also developed an algorithm for case-finding, diagnosis, and severity determination for a consistent identification of people with sarcopenia or its risk, and simple, specific cut-off points for measures that identify and characterise sarcopenia.
While EWSGOP2’s algorithm for sarcopenia screening has undeniably increased awareness of this condition, its categorical nature does not allow to automatically obtain an outcome that quantifies the degree of sarcopenia. Conversely, a scalar, quantitative measure would help identify individuals who do not qualify as sarcopenic despite displaying subclinical alterations that potentially deserve preventive strategies. Such marker would also allow to determine whether interventions aimed at mitigating sarcopenia are truly effective.
This cross-sectional study was planned to develop, in healthy middle-aged and older adults, a novel predictor of sarcopenia based on the motor-functional and anthropometric tests derived from EWGSOP2, which were the primary outcome measures. Participants were tested for body composition, physical performance, blood biomarkers, and risk scores for major healthy issues. Muscle Age Acceleration (MAA) was modelled with Elastic Net regression to extract EWGSOP test mostly contributing to the musculoskeletal ageing trajectory. According to MAA, three trajectories were identified: accelerated agers displayed higher risk for sarcopenia (19%), as compared to normal (9%) and decelerated (2%), paralleled by significant subclinical alterations of blood chemistry markers in accelerated agers.
Advocating for Aging to be Declared a Disease is the Wrong Point of Focus
https://www.fightaging.org/archives/2025/07/advocating-for-aging-to-be-declared-a-disease-is-the-wrong-point-of-focus/
The debate over whether aging should be formally declared a disease is entirely driven by the structure of medical regulation. The flow of funding through the medical system is shaped by lists of defined and allowed medical conditions derived from the International Statistical Classification of Diseases and Related Health Problems, and everything not explicitly allowed by regulators is either outright forbidden or a great deal more challenging to bring to the clinic than would otherwise be the case. The people who want aging to be defined as a disease are demanding a less costly, more rapid path of development for therapies to treat aging. It is as simple as that. Here, it is argued that perhaps advocating more directly for that goal of a faster, cheaper development process would be a better idea than focusing on definitions of aging.
Is aging a disease? Debate continues, with both good and flawed arguments, but progress is needed, so here are three ways to move discussions forward. First, this is the wrong question. The right question is what regulatory framework optimizes long term health. Second, aging isn’t one thing, but multiple distinct pathological processes. Third, there were analogous debates on obesity – it wasn’t a disease but now is. A new proposal to distinguish clinical obesity could be copied.
Advocates rightly see disease status as a path towards clinical trials for aging interventions using aging itself as primary endpoint instead of an individual chronic disease. Opponents rightly worry that labeling everyone past a certain age as ‘diseased’ loses a meaningful distinction versus current clinical illness thresholds. The real question is whether aging should be a clinical indication for trials. All aged adults are meaningfully biologically less robust when compared with young adults; age is by far the top risk factor for all age-related diseases, and intervening to mitigate this difference is a valid medical goal.
Obesity went through analogous debates for years. Like aging, obesity is a risk factor for and plays a direct causal role in many diseases. Over many years, more and more important organizations classified obesity as a disease – but this remains controversial. The history of arguments on both sides are worth reading and mirror much of the aging-as-disease debate. Recently, the Lancet Commission published a consensus proposal to distinguish more severely pathological obesity, labeled clinical obesity, from less significant pre-clinical obesity. They propose that clinical obesity is a disease, and while they admit obesity and its consequent increased disease risk exist on a continuum, they consider illness to be a meaningful binary state.
Aging is analogous, both overall and its subpathologies. There’s a clear continuum with a severe region that even without clinically diagnosable chronic diseases is clinically significant enough based on dysfunction of organs or tissues or functional decline to warrant treatment, before progression to outright age-related diseases. An analogous esteemed commission of aging experts should define criteria for this.
Small Increases in Physical Activity Produce Meaningful Benefits in Older Adults
https://www.fightaging.org/archives/2025/07/small-increases-in-physical-activity-produce-meaningful-benefits-in-older-adults/
Studies of physical activity in older people have long demonstrated that, at the lower end of the dose-response curve, even small increases in the amount of activity produce meaningful benefits. While human studies can only show correlations between exercise and health, animal studies fill in the gap to show causation. Being sedentary is bad for your health, but being even a little less than sedentary is meaningfully less bad for your health. Small increases in physical activity are not irrelevant when the overall level of physical activity is low. The study noted here reinforces this point.
Walking cadence has been suggested as a measure of activity intensity; however, it remains uncertain if prefrail and frail older adults can increase their walking cadence and if doing so leads to improvements in functional capacity. We aimed to determine if cadence can be increased and if this leads to improvement in functional capacity in prefrail and frail older adults. We performed a secondary data analysis of a walking intervention in prefrail and frail older adults living in retirement communities. Patients were randomized to Casual Speed Walking (CSW) and High-Intensity Walking (HIW) groups. Our primary outcome was improvement in 6-minute walk test distance above the minimally clinical important difference.
102 participants were included in the final analysis with 56 in the CSW group and 46 in the HIW group. Participants in the HIW group increased their walking cadence as compared to the CSW group during the intervention (HIW averaged 100 steps/min vs. CSW averaged 77 steps/min). Participants that increased their walking cadence demonstrated an increased odds of improvement in their 6-minute walk test minimum clinically important difference (odds ratio: 0.11). Older adults can increase their walking cadence and walking cadence can serve as a surrogate measure of activity intensity during walking interventions. An increase of 14 steps/minute from their comfortable walking cadence increased the odds of improvement in 6-minute walk test.
