Fight Aging!

One of the ways in which transplanted stem cells aid native cells in the short period of time before they die is by transferring mitochondria. This happens in much the same way as the cells also transfer signals via extracellular vesicles. A mitochondrion and a vesicle are both membrane-wrapped packages of molecules, albeit that the former is much more complex and functional. Mitochondria are important to cell function, as they generate the chemical energy store molecule adenosine triphosphate (ATP) required to power the cell.

Unfortunately, loss of mitochondrial function occurs with age, and is thought to be an important component of degenerative aging. The roots of age-related mitochondrial dysfunction are complex, involving damage to mitochondrial DNA, epigenetic changes that alter the expression of important mitochondrial genes, failure of the quality control mechanisms of mitophagy, and so forth. Transferring in new, youthful mitochondria harvested from cell cultures has been shown to help, and a few companies are working on the manufacturing techniques needed to make this form of therapy a reality. What if existing stem cell therapies could be made more effective as a vector for the provision of new mitochondria, however? That question is explored in today's open access paper, a followup to work published last year.

Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency

Intercellular mitochondrial transfer has emerged as a fundamental biological process whereby cells exchange mitochondria to mitigate stress and promote tissue repair, an extension of mitochondrial movement and cellular communication. Occurring in a wide variety of cells, this innate mechanism has the potential to be co-opted to support local energy demands where existing mitochondrial networks struggle. Mesenchymal stem cells (MSCs) display a particular propensity for initiating mitochondrial transfer to nearby cells; their mitochondria enhance cellular respiration, induce cell reprogramming, and repair metabolic function in recipient cells. Due to their lower energy demands, MSCs are favored for mitochondrial transfer to diseased cells with high bioenergetic needs. Their immune privilege, availability from various sources, and ease of use render MSCs ideal donor cells for delivering healthy mitochondria.

However, despite growing recognition of the therapeutic potential of mitochondrial transfer, its widespread adoption is hindered by limited rates of mitochondrial translocation. Existing methods to enhance transfer rates-such as overexpressing mechanistic proteins like the motor protein Miro1 and gap junction Cx43, or engineered techniques like MitoCeption and MitoPunch, are cumbersome and labor-intensive. Consequently, despite advances in understanding intercellular mitochondrial transfer, current therapeutic strategies often fall short due to limited efficacy and challenges in delivery, underscoring the need for new approaches.

To address these limitations, we have developed a biomaterial-based therapeutic strategy employing molybdenum disulfide (MoS2) nanoflowers with atomic-scale modifications to transform human mesenchymal stem cells (hMSCs) into mitochondrial biofactories. The increased mitochondrial content within MSCs enhances their capacity for intercellular mitochondrial transfer via tunneling nanotubes (TNTs). Utilizing nanomaterial platforms allows us to bypass limitations in transfer rates and eliminates the need for complex genetic interventions or extensive use of systemically administered drugs targeting mitochondrial function. This method capitalizes on the natural propensity of MSCs to transfer mitochondria, amplifying this capability through available mitochondrial mass. Our findings underscore the potential of nanomaterial-enhanced intercellular mitochondrial transfer as a viable therapeutic option for treating a wide range of mitochondrial dysfunctions.

In studies in mice, it is much easier to show a slowing of atherosclerotic plaque growth over time than it is to show regression of existing plaque. Only a tiny number of approaches have shown any robust ability to regress obstructive plaque in the arteries once it has formed. Thus one should suspect that any new approach presented with data to show a slowing of plaque growth may not actually have the capacity to regress plaque - otherwise the researchers would have presented that much more desirable outcome instead.

Here, researchers turn the well established approach of engineering T cells to have chimeric antigen receptors to the problem of oxidized LDL particles. LDL particles carry cholesterol from the liver out into the body, and when they become oxidized they cause additional stress to cells and accelerate the development of plaque by worsening an already toxic plaque environment in blood vessel walls. Engineering T cells to target and clear oxidized LDL particles is clearly beneficial, producing a sizable slowing of plaque growth. This reinforces other lines of research indicating that oxidized LDL is an important mechanism in these mouse models.

CAR T cell therapy has revolutionized treatment for blood cancers. It works by engineering a patient's own T cells in the lab and training them to recognize a marker found on cancer cells, creating an immune response that destroys the cancer. Scientists have been exploring the potential of this powerful technology to treat other diseases. Researchers have now engineered a CAR regulatory T cell (Treg) that targets oxidized LDL (OxLDL), the main inflammation-stoking form of LDL cholesterol that drives plaque buildup in atherosclerosis.

Initial lab-dish tests with human cells confirmed that the anti-OxLDL CAR Tregs suppress inflammation in response to OxLDL, greatly reducing the buildup of the cells that are a central feature of atherosclerotic plaques. The team then engineered a mouse version of the anti-OxLDL CAR-Treg and tested it in mice that were genetically predisposed to high cholesterol and atherosclerosis. After about twelve weeks of treatment, the treated mice's hearts and aortas showed a roughly 70 percent lower atherosclerotic plaque burden compared to control mice - indicating a clear preventive effect of the CAR-Tregs. Despite this effect, there was no disruption of general immune function in the treated mice.

Link: https://www.eurekalert.org/news-releases/1106906

The amino acid arginine has been shown to act as a chaperone, or improve the ability of existing chaperone molecules to reduce aggregation of misfolded proteins such as the amyloid-β associated with the development of Alzheimer's disease. Researchers here supplement the diets of mice with sizable doses of arginine in order to produce effects on amyloid-β aggregation; the equivalent dose in humans would be something like 1 gram per kilogram of body weight, daily. One caveat is that the mouse model of Alzheimer's used here is relevant to familial early onset Alzheimer's rather than the much more common sporadic late onset form of the condition. Nonetheless, it is an interesting study.

Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain.

In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an AppNL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated AppNL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes.

These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

Link: https://doi.org/10.1016/j.neuint.2025.106082

A large body of evidence indicates that forms of air pollution harm long-term health. This is largely epidemiological data, observing correlations with incidence of mortality and age-related disease in populations exposed to different levels of pollutants. A number of regions of the world exhibit, through happenstance, very similar populations that are exposed to significantly different levels of particulate and chemical pollutants. Consider studies covering the Puget Sound in the US or parts of China. These natural experiments provide an increased confidence that the observed correlations are a matter of air pollution causing harm to health.

The primary mechanism by which air pollution is thought to accelerate the onset and progression of age-related disease is via induction of chronic inflammation. Airway exposure to pollutants stresses cells, changes their behavior, and contributes to the burden of continual, unresolved inflammation that is characteristic of aging. This exposure exists on a spectrum, with smoking and indoor wood smoke at one end and the less severe degrees of industrial pollution in wealthier parts of the world at the other. Since effects are driven by inflammation, we should expect near all age-related conditions to be aggravated over time by exposure to air pollution, scaling by the severity of the exposure.

Air Pollution Exposure and Muscle Mass and Strength Decline in Older Adults: Results From a Swedish Population-Based Study

Emerging evidence suggests that air quality may impact muscle health. However, most studies are limited by cross-sectional designs or short follow-ups. We assessed the association of long-term exposure to ambient air pollutants with changes in muscle mass and strength in older adults. We included 3,249 participants from the SNAC-K longitudinal study (mean age 74.3 years; 35.8% males). Muscle strength (measured through handgrip and chair stand tests), muscle mass (derived from calf circumference) and physical performance (assessed through walking speed at a usual pace) were assessed over a 12-year period. Probable sarcopenia was defined as reduced muscle strength as per the EWGSOP2 criteria. Residential exposure to PM2.5, PM10, and nitrogen oxide (NOx) was estimated for the 5 years preceding baseline. Cox regressions and linear mixed models examined the association of air pollutant exposure with, respectively, probable sarcopenia and longitudinal changes in muscle parameters.

Over 12 years, the cumulative incidence of probable sarcopenia increased with higher exposure (above vs. below the median values) to NOx (36% vs. 28%), PM2.5 (35% vs. 28%) and PM10 (35% vs. 28%). The association between air pollutant levels and the risk of probable sarcopenia was nonlinear, with an increased risk showing a plateau at very high levels. Higher exposures were associated with an increased risk of developing probable sarcopenia, by 25% for NOx and PM2.5 to 33% for PM10. Elevated pollutant exposure was associated with significantly greater annual declines in lower-limb strength (chair stand test: 0.40-0.48 s) and walking speed (0.004 m/s).

Thus long-term exposure to moderate levels of ambient air pollutants may increase the risk of probable sarcopenia and accelerate declines in lower-limb strength and physical performance in older adults.

Metabolism is exceedingly complex, and incompletely understood. This is true of individual cells, let alone organisms made up of very large numbers of those cells. Most of the work done on interventions intended to slow aging takes the form of attempts to alter metabolism into a more favorable state in which aging progresses at a modestly slower pace, usually via the use of small molecules. This approach is doomed to failure at this stage of technological progress. We do not know enough of metabolism, we cannot control enough of metabolism. Studies show that combining any two marginally aging-slowing small molecules is as likely as not to produce an interaction that results in a marginal acceleration of aging. Similarly, researchers here demonstrate that a sizable fraction of marginally aging-slowing interventions only work at certain ages, and become marginally aging-accelerating at other ages. And at the end of the day, why is so much of the focus placed on interventions that cannot achieve more than a small benefit?

A growing number of compounds are reported to extend lifespan, but it remains unclear whether they reduce mortality across the entire life course or only at specific ages. This uncertainty persists because the commonly used log-rank test cannot detect age-specific effects. Here, we introduce a new analytical method that addresses this limitation by revealing when, how long, and to what extent interventions alter mortality risk.

Applied to survival data from 42 compounds tested in mice by the National Institute on Aging Interventions Testing Program, our method identified 22 that reduced mortality at certain ages, more than detected by the log-rank test, while 15 increased mortality at certain ages. Most compounds were effective only within restricted age ranges; just 8 reduced mortality late in life, when burdens of aging are greatest. Compared to conventional methods, this approach uncovers more beneficial and harmful effects, offers deeper insight into timing and mechanism, and can guide development of future anti-aging therapies.

Link: https://doi.org/10.1038/s41467-025-65158-4

Muscle tissue is metabolically active, particularly following exercise, in ways that improve function in other tissues. As a class, molecules secreted by muscle cells that affect other tissues are called myokines, and are not presently fully mapped and understood. The research community is actively engaged in identifying myokines and myokine interactions that could be targets for novel therapies that mimic some of the benefits of exercise. Here, researchers show that increased levels of the myokine cathepsin B can reduce the loss of function in the brain that occurs in a mouse model of Alzheimer's disease. Interestingly, this same treatment impairs cognitive function in normal mice, indicating that (a) there can be too much of this myokine in circulation, and (b) the relationship between cathepsin B signaling and cognitive function is likely complex.

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter.

Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wild-type (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes.

In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

Link: https://doi.org/10.1111/acel.70242

Every cell contains hundreds of mitochondria, a population of complex organelles that evolved from an ancient lineage of symbiotic bacteria that merged with early forms of cell to form the first eukaryotic cells. Mitochondria still act like bacteria in many ways, retaining a fragment of their original circular DNA, replicating by division, fusing together and passing around component parts, but are nonetheless now tightly integrated into cellular metabolism. Most mitochondrial genes have migrated into the cell nucleus, and a complex process of quality control known as mitophagy operates to recycle worn and damaged mitochondria.

The primary function of mitochondria is the manufacture of adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. The core of the protein machinery inside a mitochondrion that carries out this manufacture is the electron transport chain, also known as the respiratory chain. Collectively the structures of the chain are capable of building up the necessary energy to form ATP by, as one might guess from the name, reductive and oxidative chemical reactions that transport electrons along the chain. The electron transport chain consists of many distinct proteins that join together to form four protein complexes. These complexes themselves can also assemble in a number of ways to form supercomplexes. Indeed, researchers have shown that supercomplex formation is necessary for normal levels of ATP production.

Sadly, mitochondrial function (as measured by ATP production) declines with age, a consequence of damage to mitochondrial DNA and changes in gene expression that negatively impact mitochondrial structure, dynamics, and quality control. There is interest in the research community in finding ways to improve mitochondrial function. Many of the approaches demonstrated to date are essentially compensatory, in that they tend to work at any age to increase ATP production. Unfortunately near all compare poorly to the increase in mitochondrial function produced by exercise, and while we all know that exercise is a good thing, it is impossible to exercise an escape from aging. Better approaches are needed.

Today's open access paper covers a novel approach to improve mitochondrial function. Supercomplex formation in the electron transport chain is not a matter of chance, it is guided into happening by the activities of other proteins. This is usually the case for any critical function in a cell. Researchers discovered that supercomplex formation is in part steered by COX7RP, via the usual approach of disabling the expression of the COX7RP gene and observing the results. Interestingly, increasing the expression of COX7RP in genetically engineered mice in order to increase supercomplex formation in mitochondria both improves normal mitochondrial function and slows the onset of aspects of aging.

Mitochondrial Respiratory Supercomplex Assembly Factor Contributes to Lifespan Extension in Mice

Accumulating evidence from experimental animal models and human clinical studies suggests that mitochondrial function is closely associated with both lifespan extension and age-related decline. It is well established that aging is generally accompanied by a decline in mitochondrial function, which is attributed to mitochondrial DNA damage, increased oxidative stress, and deterioration of mitochondrial quality control mechanisms. These changes are characterized by reduced respiratory activity, altered mitochondrial dynamics, and increased production of reactive oxygen species (ROS). The age-related decline in mitochondrial function has been implicated in the pathogenesis of various aging-associated diseases.

We previously demonstrated that cytochrome c oxidase subunit 7a related polypeptide (COX7RP), or COX7A2L, is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive.

We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes.

This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.

Researchers here report a novel mechanisms by which aging impairs the immune system. The spleen is an immune organ, an important location where immune cells congregate to communicate with one another and coordinate the immune response to pathogens. The spleen is also responsible for filtering damaged and worn red blood cells from the circulation. Unfortunately the aged spleen accumulates too much iron and metabolic waste as a result of reduced efficiency in clearing out those unwanted red blood cells. Exposure to this aged spleen environment is here shown to degrade the efficacy of T cells of the adaptive immune system.

Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging.

Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice.

This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.

Link: https://doi.org/10.1038/s43587-025-00981-4

Parkinson's disease is a considered to be caused by misfolding and aggregation of α-synuclein, a particularly pernicious malfunction of protein structure that can spread from cell to cell like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Mitochondria are prominently involved in Parkinson's disease because forms of impairment to mitochondrial function, whether by aging or inherited mutation, make the motor neurons in the brain that are already most vulnerable to death due to α-synuclein pathology even more vulnerable to that fate. Here, however, researchers turn this around, and provide evidence for a specific dysfunction in mitochondria to accelerate α-synuclein pathology. Biology is complex: both arrows of causation could be true, and both could be significant.

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD.

We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein.

In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

Link: https://doi.org/10.1126/sciadv.adu0726

Therapeutic use of extracellular vesicles seems likely to replace much of the present use of stem cell therapy, as these first generation stem cell transplantation therapies achieve benefits near entirely via the signaling generated by the transplanted cells in the short period of time in which they survive. Much of that signaling takes the form of extracellular vesicles, membrane-wrapped packages of molecules. Vesicles can be harvested from cell cultures, and are much easier to store and transport than is the case for cells, allowing centralization of the harder part of the manufacturing process that is managing stem cell cultures.

In recent years researchers have moved on from simply harvesting vesicles to finding ways to induce cells to create a lot more vesicles than is normally the case. The mechanical process of membrane extrusion is one approach to the generation of vesicles that compare favorably with naturally generated vesicles, but which are more readily produced in large amounts. In today's open access paper, researchers combine membrane extrusion with engineered cells to produce a more favorable mix of molecules in the manufactured extracellular vesicles. The intent is to generate a therapy that can improve the environment following damage to the heart, and thereby reduce further harms and encourage greater regeneration.

Artificial cell derived vesicles from Ginsenoside Rg1-primed mesenchymal stromal cells mitigate oxidative stress and DNA damage in myocardial ischemic/reperfusion injury

Myocardial ischemia/reperfusion injury (MI/RI) remains a major challenge in the treatment of acute myocardial infarction due to the lack of effective therapeutic options. While mesenchymal stromal cells (MSCs) and their derivates show promising potential for MI/RI therapy, their clinical application is hindered by low transplantation efficiency and insufficient yield. In this study, we engineered nanoscale artificial cell-derived vesicles (ACDVs) by extruding Ginsenoside Rg1-primed MSCs (Rg1-MSCs), resulting in Rg1-ACDVs.

Rg1-ACDVs displayed superior therapeutic efficacy compared to non-primed ACDVs and extracellular vesicles derived from Rg1-MSCs (Rg1-EVs). Multi-omics analysis revealed that Rg1-ACDVs possess distinct molecular signatures associated with promoting cell cycle progression and reducing DNA damage. These findings were further validated experimentally, demonstrating that Rg1-ACDVs effectively reduce reactive oxygen species (ROS) accumulation and mitigate DNA damage both in vitro and in vivo.

This study highlights the synergistic benefits of combining Ginsenoside Rg1 priming with nanoscale engineering and introduces Rg1-ACDVs as a scalable and innovative strategy, offering a promising approach for improving clinical outcomes in MI/RI therapy.

Why does the inflammatory gum disease periodontitis tend to be worse in men versus women? As a possible answer to that question, researchers here demonstrate a sex difference in mammals in the inflammatory processes that drive the pathology of periodontitis. The condition progresses from chronic inflammation to bone loss and tooth loss, one example amongst many of the way in which unresolved inflammatory signaling changes the behavior of cells for the worse to cause disruption to tissue structure and function.

The inflammasome initiates inflammation via the maturation of interleukin-1 beta (IL-1β). Periodontitis is a prevalent, male-biased disease characterized by inflammation-driven bone loss, yet the mechanisms of this sex bias is unknown. This study explored whether enhanced inflammasome activity represents a causal mechanism for this bias. Analyses of three separate human studies (more than 6,200 samples) show that males have significantly higher IL-1β in the gingival crevicular fluid than females during health and periodontitis. This pattern is experimentally reproduced with different versions of the ligature-induced periodontitis mouse model where males show greater IL-1β secretion than females.

The inflammasome drives bone resorption in males but not females as revealed by analyses of inflammasome gene-deletion mice. Pharmacologic treatment with a caspase-1/4 inhibitor reduces inflammatory cell infiltration, dampens osteoclastogenesis signaling (via the receptor activator of nuclear factor-kappa B (RANKL) pathway), and prevents bone resorption in males but not females during experimental periodontitis. While ovariectomized females show no change in their nonresponsiveness to caspase-1/4 inhibition, orchiectomized males no longer respond to the inhibition, suggesting the importance of an intact male reproductive system in the mediation of this inhibition.

Thus, our study identifies inflammasome activation as causal for male-biased experimental periodontitis and supports sex-stratified studies to foster future advancement of inflammasome therapeutics in periodontics.

Link: https://doi.org/10.1073/pnas.2507092122

Much of the focus on the gut microbiome in aging revolves around its composition, the relative size of various populations of different microbial species, and how that composition changes over time. There is another dimension to consider, however, which is the activity and behavior of specific microbial species and how that is affected by the environment they find themselves in. This second dimension is relatively underexplored at the present time. As researchers here note, there may well be opportunities to improve health by adjusting the behavior of gut microbes in deterministic ways, rather than by changing the size of their populations.

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored.

Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induced transcription of the capsular polysaccharide synthesis (cps) operon responsible for CA biosynthesis in commensal E. coli at 37 °C, and attenuated age-related metabolic changes. We also found that low-dose cephaloridine overcomes the temperature-dependent inhibition of CA biosynthesis and promotes its induction through a mechanism mediated by the membrane-bound histidine kinase ZraS, independently of cephaloridine's known antibiotic properties.

Our work lays a foundation for microbiota-based therapeutics through chemical modulation of bacterial metabolism and highlights the promising potential of leveraging bacteria-targeting drugs in promoting host longevity.

Link: https://doi.org/10.1371/journal.pbio.3002749

Hypertension is the name given to a state of high blood pressure. The onset of this condition typically progresses over time, as aging or lifestyle choices cause slowly increasing dysfunction in the systems of regulation and feedback that control blood pressure. A number of mechanisms are involved in determination of blood pressure, such as the kidney's regulation of the volume of fluid in blood, the ability of blood vessels to contract and dilate to change the overall volume of the vascular system, and the pace at which the heart beats. The important processes of regulation are known as the renin-angiotensin-aldosterone system, in which signals pass back and forth from kidney to vasculature and other involved organs, including liver and brain.

One of the ways in which animal models of hypertension are created is to break the normal regulation of blood pressure by introducing excess angiotensin II, as increased angiotension II is seen in many cases of human hypertension. In today's open access paper, researchers note that inducing hypertension in this way produces dysfunction in cells in the vasculature and brain before blood pressure increases. This suggests that even the early stages of hypertension cause harm that contributes to the well-established correlation between hypertension and cognitive decline, and in a different way than this relationship is commonly considered, not via increased structural damage to the brain resulting from a greater pace of rupture of microvessels.

Hypertension Affects the Brain Much Earlier than Expected

Hypertension impairs blood vessels, neurons, and white matter in the brain well before the condition causes a measurable rise in blood pressure, according to a new preclinical study. Patients with hypertension have a 1.2 to 1.5-fold higher risk of developing cognitive disorders than people without the condition, but exactly why is not understood. While many current hypertension medications successfully lower high blood pressure, they often show little or no effect on brain function. This suggests blood vessel changes could cause damage independently of the elevated pressure associated with hypertension.

To induce hypertension in mice, the researchers administered the hormone angiotensin, which raises blood pressure, mimicking what happens in humans. Then, they looked at how different types of brain cells were impacted three days later (before blood pressure increased) and after 42 days (when blood pressure was high, and cognition was affected). At day three, gene expression dramatically changed in three cell types: endothelial cells, interneurons, and oligodendrocytes. Endothelial cells, which line the internal surface of blood vessels, aged prematurely with lower energy metabolism and senescence, indicating they stopped dividing. The researchers also observed early signs of a weakened blood-brain barrier, which regulates the influx of nutrients into the brain and keeps out harmful molecules.

Hypertension-induced neurovascular and cognitive dysfunction at single-cell resolution

Hypertension is a leading cause of cognitive impairment, attributed to cerebrovascular insufficiency, blood-brain barrier disruption, and white matter damage. However, how hypertension affects brain cells remains unclear. Using single-cell RNA sequencing (scRNA-seq) in a mouse model of hypertension induced by angiotensin II, a peptide involved in human hypertension, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, and interneuronal hypofunction and network imbalance emerged after 3 days, attributable to angiotensin II signaling. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction, developed.

These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and they provide the molecular bases for subsequent neurovascular dysfunction and cognitive impairment in hypertension. These data constitute a valuable resource for future mechanistic studies and therapeutic target validation.

This is a very readable review, for all that the authors have stapled together two quite distinct topics into the one binder. Firstly, cellular senescence in various cell types in the cardiovascular system and its role in driving the onset and progression of cardiovascular disease. Secondly, efforts to develop cell therapies to treat cardiovascular disease, including the present generation of stem cell therapies that largely reduce inflammation without achieving any other goals, and further the attempts to induce regeneration and restoration of lost function by delivering replacement cells that are intended to survive, integrate, and support the age-damaged local cell populations.

The issue of population aging presents a significant challenge for many countries, and the related physical health implications have been receiving increasing attention. Senescence impacts several aspects of the cardiovascular system, contributing to diseases such as atherosclerosis, myocardial infarction (MI), pulmonary hypertension, and heart failure (HF). In recent decades, scientists have significantly advanced in understanding the molecular and cellular processes involved in cardiovascular aging, including telomere shortening and damage, oxidative stress, mitochondrial dysfunction, and DNA damage. Molecules such as p53, p21, and p16Ink4a, along with enhanced signals for SA-β-gal, are commonly used to detect senescent cells.

Researchers have identified pathways and factors that could be potential targets for treating or alleviating cardiovascular aging. Furthermore, the rapid advancement of regenerative medicine, including mesenchymal stem cell (MSC) and induced pluripotent stem cell (iPSC) transplantation, has positioned heart regeneration as a promising strategy for addressing age-related cardiovascular diseases. This review summarizes the current understanding of senescent cells, such as cardiomyocytes, endothelial cells, fibroblasts/myofibroblasts, and vascular smooth muscle cells, and their roles in associated cardiovascular diseases. We will also discuss recent factors contributing to cardiovascular aging, including but not limited to Akt and AMPK, and emphasize the potential of heart regeneration research and insights into future regenerative therapies for cardiovascular aging.

Link: https://doi.org/10.1186/s13287-025-04731-6

Sirtuins are a family of proteins that largely undertake specific modification of other proteins, removing certain decorations that have been attached to those proteins. A great deal of the exceedingly complex regulation of cellular metabolism involves changing the function of molecules by adding or removing decorations such as acetyl groups, methyl groups, and so forth. Several sirtuins have been investigated in the context of aging, showing some ability to alter the operation of cellular metabolism to modestly slow aspects of aging in animal models. Sirtuin 1 was excessively overhyped and is probably not in actual fact very relevant to aging, but sirtuin 6 has the appearance of being more reliable in its effects, albeit still not large effects in the grand scheme of things.

Aging is a major risk factor for multiple diseases, facing humanity with the challenge of how to prolong healthspan. Here, we explore a molecular mechanism underlying the prolongevity activity of the Sirt6 enzyme in supporting healthy aging. We show that Sirt6 maintains youthful hepatic levels of hydrogen sulfide (H2S), a gasotransmitter linked to the benefits of caloric restriction, by regulating cystine uptake and methionine metabolism. Sirt6 also prevents age-related increase in S-adenosylmethionine (SAM).

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H2S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H2S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM).

Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing cystathionine gamma lyase (Cgl) H2S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 deacetylation reduces its SAM production activity and cystathionine beta synthase (Cbs) binding, thereby reducing its activation of Cbs-dependent H2S production. The net outcome is H2S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.

Link: https://doi.org/10.1073/pnas.2514084122

A protein is a sequence of amino acids joined together to form a single molecule, and consequently amino acids are everywhere in our biochemistry. Their presence influences many processes, and the complexity of cellular biochemistry continues to ensure that relatively little of this is anywhere near completely mapped. Circulating amino acid levels, as measured in blood samples, have received more attention in the context of aging and longevity in recent years. There are a few hundred different amino acids beyond the twenty used to manufacture proteins, some of which must be obtained via diet as they are not synthesized by our biochemistry. Researchers have found a number of associations between specific amino acid levels and aging, as well as demonstrating that supplementation or restriction of specific dietary amino acids can modestly influence the pace of aging in animal studies.

In today's open access paper, researchers demonstrate a small effect on male lifespan emerging from epidemiological data on tyrosine levels. The underlying mechanisms remain to be discovered, but this sort of study is intended as a prompt for others to dig into what might be happening under the hood. The authors of this paper speculate on mechanisms, but it is just speculation at this point. Tyrosine is not an essential amino acid, but is synthesized from the essential amino acid phenylalanine and so its availability in the body is still effectively constrained by diet. Phenylalanine restriction has not been shown to produce benefits in the way that restriction of some other essential amino acids does, and in fact severe restriction causes neurological issues if intake is sustained at very low levels.

The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study

Protein restriction increases lifespan, however, the specific amino acids affecting lifespan are unclear. Tyrosine and its precursor, phenylalanine, may influence lifespan through their response to low-protein diet, with possible sex disparity. We applied cohort study design and Mendelian randomization (MR) analysis. Specifically, we examined the overall and sex-specific relationships between circulating phenylalanine and tyrosine and all-cause mortality in the UK Biobank using Cox regression. To test causality, in two-sample MR analysis, we used genetic variants associated with phenylalanine and tyrosine in UK Biobank with genome-wide significance and uncorrelated with each other, and applied them to large genome-wide association studies of lifespan, including parental, paternal, and maternal attained ages in the UK Biobank.

Tyrosine was associated with shorter lifespan in both observational and MR study, with potential sex disparity. After controlling for phenylalanine using multivariable MR, tyrosine remained related to a shorter lifespan in men (-0.91 years of life) but not in women. Phenylalanine showed no association with lifespan in either men or women after controlling for tyrosine.

Based on our results, targeting tyrosine may be a potential strategy for improving lifespan. Partly consistent with our findings, animal experiment suggests that restricting dietary protein in rats extends lifespan while lowering tyrosine concentrations in liver and muscle. The biological processes linking tyrosine to lifespan have not been thoroughly determined. Tyrosine was associated with insulin resistance. According to evolutionary biology, more investment in growth and reproduction often comes at the expense of lifespan, while insulin acts as one of the key regulators of growth and reproduction. Consistently, insulin resistance has been shown to be related to multiple diseases and decreased lifespan. Insulin resistance may also have sex-specific effects.

Frailty is a state of inflammation, physical weakness, degraded immune responses, and in general a loss of resilience to stresses such as infection and injury. The state of frailty is well known to correlate with mortality risk. Clinicians assess the degree of frailty in a patient via the use of a standardized frailty index. This is a simple and rapidly conducted assessment focused on the capacity to undertake everyday tasks, quality of life, and health issues. As shown here, the risk of mortality is greatly increased in frail individuals.

The frailty index (FI), a proxy measure of accelerated biological aging, predicts adverse outcomes in older adults. We investigated whether the FI predicts mortality in a community-based Korean older adult population and its association with subjective health status over 2 years. This prospective cohort study included 936 community-dwelling individuals aged ≥60 years. The primary outcome was 2-year all-cause mortality. Quality of life was assessed using the European Quality of Life Five-Dimension Three-Level (EQ-5D-3L).

Of the 936 participants, 111 (12%) were non-frail, 230 (25%) were mildly frail, and 595 (63%) were moderately to severely frail. The prevalence of moderate to severe frailty increased with age. The moderate-severe frailty group had a ≥5-fold increased risk of mortality compared to the non-frail group (adjusted relative risk, 5.79). Among those completing follow-up, the moderate-severe frailty group reported more problems across all EQ-5D-3L domains at 2 years. To conclude, frail older adults are at increased risk of mortality, but this risk was significant only for those in the moderate-to-severe frailty category at 2-year follow-up.

Link: https://doi.org/10.3961/jpmph.25.210

Loss of function mutations in insulin signaling have been shown to slow aging and extend life, but at the cost of slow growth and insulin resistance. Researchers recently discovered in flies a mutation that slows aging while retaining insulin signaling function. Flies have a single receptor for their versions of insulin and insulin-like growth factor (IGF-1), while mammals have two receptors, the insulin receptor and IGF-1 receptor. Thus here researchers introduce the same mutation into one or other of the mouse receptors and conduct a relatively short study in order to assess whether it is worth conducting a much longer life span study in these engineered mice.

Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. Yet, long-lived loss-of-function mutants often produce insulin-resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin sensitivity, growth, and reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R).

We produced two knock-in mouse strains that carry the homologous KID Arginine/Cysteine substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce phospho-ERK but ERK was less phosphorylated in cells with IGF-1R heterodimers.

Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At four months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin, FGF21, and reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.

Link: https://doi.org/10.1172/jci.insight.189683

Circulating oxytocin levels are known to decline with age, and a number of research groups have focused on upregulation of oxytocin as an approach to treating aging. A couple of papers published a few months ago are indicative of the animal studies presently taking place, the first focused on increased longevity in mice achieved via the combined reduction of TGF-β and increase in oxytocin, and the second evaluating intranasal delivery of oxytoxin as a route to improve function in the aging brain.

Today's paper reports on another example of oxytocin delivery in aged mice. These researchers are also focused on the brain, but in this case the oxytocin is delivered via intraperitoneal injection. As with most peptide or protein therapies, the effects are limited in scope as the delivered molecules have a short half-life. Repeated treatments are required, often daily, as is the case here. Given further progress towards the clinic, however, we might expect that the community of developers presently assessing gene therapies to safely transform a small number of cells into long-lasting factories that produce a desired circulating molecule (such as klotho or follistatin) will add oxytocin to their list.

Oxytocin enhances neurogenesis and synaptic plasticity to attenuate age-related cognitive decline in aged mice

Brain aging is characterized by progressive structural and functional deterioration, leading to cognitive decline and impaired social functioning. A key factor in this process is the age-related decline in adult neurogenesis, particularly in the hippocampal dentate gyrus, which is linked to deficits in learning, memory, and increased social anxiety. Oxytocin, a neuropeptide synthesized in the hypothalamus, regulates social behavior, cognition, and emotion by acting on brain regions including the hippocampus. Importantly, oxytocin levels decrease with age, potentially contributing to cognitive impairment.

Here, we examined whether chronic intraperitoneal oxytocin administration could attenuate cognitive decline in aged mice. Twelve-month-old mice received oxytocin injections (0.5 mg/kg) five times weekly for 13 weeks. Behavioral testing at 12 weeks of treatment using the object-place recognition task showed enhanced spatial learning and recognition memory in oxytocin-treated mice compared with saline controls. Immunohistochemistry revealed significantly increased doublecortin (DCX)-positive cells in the hippocampus, indicating enhanced neurogenesis. Furthermore, oxytocin treatment upregulated the expression of glutamate receptor 1 (GluR1) and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B), which are markers of synaptic plasticity.

These findings suggest that chronic oxytocin treatment is associated with enhanced neurogenesis and synaptic plasticity, which may contribute to improved cognition in aged mice. Our results support oxytocin as a potential therapeutic agent for age-related cognitive decline.

Epigenetic clocks have existed for long enough for numerous large study databases to include data on their use. Thus meta-analysis papers are emerging to assess this body of data as a whole. This is a necessary part of the process of gaining confidence in the ability of epigenetic clocks, and indeed aging clocks in general, to rapidly assess the potential of any novel form of intervention intended to slow or reverse aspects of aging. This is a much needed capability. In many ways, efforts to treat aging as a medical condition proceed blindly, given just how much time and funding is required in order to understand whether one approach is better or worse than another. If there was a way to quickly assess the quality of an anti-aging therapy immediately after its application, then the field could adjust quickly to pursue the best paths forward. The hope is that aging clocks can be that tool - but we are clearly not there yet.

Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.

24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28,325 participants (14,757 female; median of mean age 65.2 years). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11,162; standardised β coefficient 0.06), PhenoAge EAA (eight studies; n=10,371; standardised β coefficient 0.07), GrimAge EAA (eight studies; n=10,371; standardised β coefficient 0.11), and pace of ageing (five studies; n=7,895; standardised β coefficient 0.10) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6,143; standardised β coefficient 0.02) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.

In conclusion, higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.

Link: https://doi.org/10.1016/j.lanhl.2025.100773

TDP-43 is one of a small number of proteins in the brain that can misfold or otherwise become altered in ways that allow toxic aggregates to form, or even encourage other molecules of the same protein to become dysfunctional in the same way. TDP-43 aggregation in later life is a relatively recent discovery, and has a neurodegenerative condition newly named for it, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has also been found that TDP-43 is likely important in amyotrophic lateral sclerosis (ALS), and thus progress on that front seems likely to help with other forms of TDP-43 pathology. Here, researchers report a promising discovery in the biochemistry of TDP-43 aggregation in the context of ALS.

Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset motor neuron disease, characterized by disruption of neuromuscular junctions (NMJs), axonal degeneration and neuronal death. Most ALS cases are linked to TDP-43 pathology, characterized by its mislocalization from the nucleus to the cytoplasm and the formation of phosphorylated aggregates. TDP-43 is a multifunctional DNA-binding/RNA-binding protein with roles in transcriptional and splicing regulation, RNA processing and RNA transport/subcellular localization.

Recently, we showed that TDP-43 co-localizes with the core stress granule component G3BP1 in axonal condensates of patients with ALS and mice. These TDP-43-G3BP1 condensates sequester RNA and inhibit local protein synthesis, resulting in mitochondrial malfunction and NMJ disruption with subsequent axonal degeneration. Furthermore, recent studies revealed aggregation of TDP-43 in peripheral motor axons of patients with ALS during initial diagnosis. Thus, axonal TDP-43 condensates exert pathological regulation over essential local synthesis events.

Here, we studied the localized accumulation of TDP-43 in axons and NMJs. Our findings highlight the presence of distal TDP-43 pathology in patients with SOD1 ALS and mouse models. We found that TDP-43 accumulates at NMJs due to aberrant local synthesis triggered by a reduction in miR-126a-5p within muscle extracellular vesicles. This chain of events ultimately initiates neurodegeneration. Notably, delivery of miR-126 is neuroprotective in neuromuscular co-cultures, delays TDP-43 accumulation at NMJs, and postpones the onset of motor symptoms in the SOD1G93A mouse model of ALS.

Link: https://doi.org/10.1038/s41593-025-02062-6

The human gut microbiome is made up of a few thousand distinct microbial species. The relative sizes of these populations shift in response to day to day circumstances, such as variations in diet, but one would expect consistency from one year to the next. Over longer spans of time, the gut microbiome ages. Populations producing beneficial metabolites are reduced in number, while populations that provoke the immune system into chronic inflammatory behavior grow in number. This data is derived from both animal and human studies. One can control what happens to a mouse over the course of its life, but for human data the detailed history of any particular individual is largely a mystery.

Antibiotics and a range of other pharmaceuticals produce dramatic short-term effects on the composition of the gut microbiome. To a large degree, the gut microbiome restores itself once the pharmaceutical is no longer present. That said, we might well ask how much of the observed human data on gut microbiome aging is produced by, say, antibiotic use. Researchers have observed gut microbiome changes in population studies taking place as early as the mid-30s, and it is hard to envisage any form of meaningful degeneration taking place at that age. But exposure to antibiotics and other pharmaceuticals? That is very prevalent. In later life, given the presence of chronic diseases of aging, there is a great deal more chronic pharmaceutical use, as well as the employment of pharmaceuticals with meaningful side effects. We might again ask how much of the observed aging of the human gut microbiome at the population level results from the use of these treatments versus mechanisms of aging.

Drug-mediated disruption of the aging gut microbiota and mucosal immune system

The dynamic relationship of gut microbiota, mucosal immunity, aging, and pharmaceutics interventions has a significant impact on overall physiological functions and disease susceptibility. Aging is associated with changes in the gut microbiome including decreased microbial diversity, reduced short-chain fatty acid (SCFA) production, and elevated pathobiont proportions. These changes are associated with impaired mucosal immunity, increased intestinal permeability, and heightened systemic inflammation in the host, which can exacerbate age-related disorders.

Medications such as proton pump inhibitors (PPIs), metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antibacterials also influence gut microbiota function. PPIs may alter microbial colonies and induce overgrowth of pathogenic bacteria, which compromises the mucosal defenses and in severe cases, the resulting infections may cause ulcers. Metformin, through its metabolic benefits, causes Akkermansia muciniphila to increase in relative abundance, which is associated with improved gut barrier composition. NSAIDs, because of their strong anti-inflammatory properties, disturb gut homeostasis by increasing intestinal permeability, reducing prostaglandin synthesis, and inducing dysbiosis in the host. Corticosteroids, through their immunosuppressive mechanisms, reduce microbial diversity and secretory immunoglobulin A levels, impairing mucosal immunity and enhancing the host's susceptibility to infections. Antibacterials are a major disruptor of the gut microbiota, causing a decline in beneficial bacteria and an increased risk for opportunistic infections such as Clostridium difficile.

To address drug-induced dysbiosis, probiotics and prebiotics products may be helpful to restore microbial balance, enhance SCFA production, and reinforce mucosal defenses. Individualized gut microbiota profiling may enable safer medication usage by identifying patients that are at an increased risk for dysbiosis-related complications. Additionally, development of microbiota-sparing medications and targeted therapies may help to enhance gut health outcomes in aging populations. Future research should address the long-term effects of pharmacological agents on gut microbiota and mucosal immunity in aging populations, as well as identification of connections between microbiota, immune function, and the effects of medications. Integrating microbiome-conscious approaches into clinical practice could allow healthcare providers to optimize patient care

Muscle mass and strength decline with age, a long-term consequence of accumulating molecular damage and its effects on muscle stem cell populations and neuromuscular junctions, among other mechanisms. Once past an arbitrary line in the sand, this loss is defined as an age-related disease and called sarcopenia, a part of age-related frailty. Here, researchers show that the state of sarcopenia correlates with the presence of age-related cardiovascular and respiratory conditions. This is not surprising: all of these conditions arise from the same underlying forms of damage to cells and tissues that accumulate with age.

Sarcopenia, the progressive loss of muscle mass and function, is a common condition in older adults and has been linked to both cardiovascular disease (CVD) and chronic respiratory diseases (CRD). However, the association between long-term changes of sarcopenia and cardiorespiratory multimorbidity remains underexplored. This study aims to investigate how changes in sarcopenia burden over time relate to cardiorespiratory multimorbidity. Data from the China Health and Retirement Longitudinal Study (CHARLS) were used, including 5,186 participants with mean age of 58.2 ± 8.4 years. Sarcopenia was assessed using criteria for muscle mass, strength, and physical performance.

A total of 301 (5.8%) participants experienced cardiorespiratory multimorbidity. Four distinct sarcopenia trajectory groups were identified: persistently low, moderate-to-low, low-to-high, and persistently high burden. Compared to the reference (persistently low group), the low-to-high trajectory of sarcopenia burden had the strongest association with cardiorespiratory multimorbidity (odds ratio, OR: 2.64), followed by the persistently high group (OR: 2.05) and moderate-to-low group (OR: 1.90). Thus Changes in sarcopenia burden are significantly associated with cardiorespiratory multimorbidity, with a rapid increase in sarcopenia burden (low-to-high trajectory) being particularly detrimental.

Link: https://doi.org/10.1016/j.jnha.2025.100670

The composition of the gut microbiome changes with age. Microbial populations that produce beneficial metabolites needed for optimal tissue function decline in number, while microbial populations that provoke the immune system into chronic inflammatory signaling increase in number. In recent years, researchers have demonstrated a range of specific consequences of gut microbiome aging, relationships with age-related loss of function and disease. This body of literature adds weight to the development of more precise means to produce lasting rejuvenation of the composition of the gut microbiome, an outcome that can be achieved via fecal microbiota transplantation or flagellin immunization, but with relatively little control over the exact outcome.

The gut microbiota is essential for immune function, nutrient absorption, digestion, and pathophysiological processes. However, aging influences alterations in the composition and diversity of gut microbiota. This age-related imbalance in the gut microbial community, characterized by reduced microbial diversity, loss of beneficial bacteria such as butyrate producers, and an increase in pathogenic species, results in gut dysbiosis. Dysbiosis is associated with impaired intestinal barrier integrity, weakened immune function, and elevated systemic inflammation, creating a vicious cycle that accelerates cellular senescence, tissue aging, and age-related kidney diseases.

Renal dysfunction further exacerbates this process by reducing toxin clearance and promoting the accumulation of uremic metabolites, which disrupt gut microbial balance. In turn, gut dysbiosis impairs kidney function, creating a self-perpetuating cycle of microbial imbalance and renal damage. Hence, breaking this vicious cycle of dysbiosis and kidney damage is important. This review sheds light on the bidirectional relationship between gut microbiota and kidney aging. It also highlights the potential of microbiota-targeted interventions to restore microbial balance and delay the onset of age-related issues.

Link: https://doi.org/10.1186/s12986-025-01032-w

The distinctive biochemistry of senescent cells has enabled researchers to produce proof of concept demonstrations for a range of ways to destroy senescent cells while having relatively little effect on non-senescent cells. The most established approach to date is to target well explored mechanisms that function to hold back senescent cells from programmed cell death. Senescent cells are primed to undertake programmed cell death, unlike normal cells. Thus sabotaging those mechanisms in normal cells has little effect, and delivering a sabotaging small molecule to a mix of normal and senescent cells will only kill large numbers of the senescent cells.

A more recent approach that is now progressing towards the clinic involves the use of prodrugs. A cytotoxic molecule, such as a chemotherapeutic drug, is modified to become a prodrug molecule with some added structure that interferes in its normal cell-killing function, making it safe. The trick lies in ensuring that this modification can be reversed only in the target cells that the prodrug is intended to affect. For example, senescent cells express high levels of β-galactosidase, which removes galactose where that decoration is added to another molecule. When the β-galactosidase inside a senescent cells interacts with a prodrug created by conjugating a chemotherapeutic with galactose, the toxic chemotherapeutic is unmasked. In normal cells, the prodrug remains intact and produces no harm.

Selective clearance of senescent cells has shown promise for the treatment of the degenerative joint disease of osteoarthritis, in which inflammation drives loss of cartilage and joint dysfunction. Senescent cells are responsible for generating much of that inflammation, in addition to disrupting tissue structure and maintenance in other ways. Unfortunately, early trials by UNITY Biotechnologies employed a local administration strategy and class of senolytic drug that were likely suboptimal. The results in human patients were poor in comparison to the results in animal models, and will probably discourage further clinical work on osteoarthritis until such time as senolytic drugs are approved by regulators for other uses.

β-galactosidase-targeted senolytic prodrug ameliorates preclinical models of post-traumatic osteoarthritis

Cellular senescence plays an important role in the pathogenesis of osteoarthritis (OA). Elimination of senescent chondrocytes by senolytic small molecule compounds show therapeutic effects in OA mice. However, results from a recent phase II clinical trial in the treatment of patients with painful knee OA were not optimistic. Hence, the development of new senolytics with different mechanisms for OA anti-ageing therapy is appealing. SSK1, a prodrug that consists of gemcitabine modified with an acetyl galactose moiety, could target senescence-associated β-galactosidase and eliminate senescent fibroblasts. SSK1 improves physical function and lifespan in aged mice and demonstrates good anti-inflammatory effect in non-human primates. The therapeutic action of SSK1 in OA disease deserves comprehensive investigation.

An oxidative stress-induced cellular senescence model was established to evaluate cell viability, replication, and genotoxicity after SSK1 treatment. Human OA chondrocytes and explants were collected to evaluate the therapeutic effect of prodrug SSK1 in vitro. In vivo evaluation was performed in young and aged male murine models. SSK1 (intra-articular injection every 3 days) was administrated 2 weeks after anterior cruciate ligament transection (ACLT) surgery. Animals were sacrificed 8 weeks after surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology, and pain-related behaviour tests.

SSK1 showed precise, efficient, and broad-spectrum elimination of senescent chondrocytes. When co-cultured with human osteoarthritic chondrocytes and cartilage explants, the senolytic SSK1 prevented the generation of senescence-associated secretory phenotype factors, enhanced production of extracellular matrix (ECM) molecules, and promoted a regenerative chondral environment. Intra-articular administration of SSK1 showed improved pain response, enhanced retention of ECM, and remodelled subchondral bone homeostasis in both young and aged ACLT-induced OA murine model. Thus SSK1 is an effective candidate for senolytics in alleviating OA. The anti-ageing therapeutic effect of SSK1 lies in restoring a regenerative phenotype by improving the proliferation microenvironment, and reducing the accumulation of apoptotic signals in the joint microenvironment.

Researchers here assess the effects of supplementation with the L-BAIBA metabolite combined with exercise in older mice. It modestly improves both muscle and bone, adding it to the long list of approaches that can help in some small way to resist the age-related declines in muscle mass, muscle strength, and bone mineral density. As often noted here, something better than this is required if we want to control aging rather than merely gently slow it down. Tinkering with metabolism can and does have small positive effects, which unfortunately combine in unpredictable ways, but if we want bigger and better outcomes, then we have to focus instead on repair of the cell and tissue damage that causes aging. You can't fix a malfunctioning engine by changing the oil mix, and you can't meaningfully rejuvenate a human (or a mouse) by altering metabolite intake.

Contracting skeletal muscles secrete the metabolite L-β-aminoisobutyric acid (L-BAIBA), which when supplemented in the diet can mitigate disuse-induced musculoskeletal dysfunction. However, the effects of L-BAIBA supplementation alone and combined with exercise on cardiac and musculoskeletal properties are currently unknown. We hypothesized that exercise with L-BAIBA supplementation would promote greater cardiac and musculoskeletal benefits than exercise alone. To investigate this hypothesis, we subjected 12-month-old (as a model of middle-age) male C57BL6 mice to voluntary wheel running (VWR) with L-BAIBA (100mg/kg/day) (VWR+L-BAIBA), VWR alone, L-BAIBA alone, or none (CTRL) for three months.

Soleus muscles from VWR+L-BAIBA, but not VWR, were larger, contracted more forcefully, and contained more slow-oxidative type I myofibers compared to CTRL. In extensor digitorum longus (EDL) muscle, VWR but not VWR+L-BAIBA improved fatigue resistance and caffeine-induced recovery. In bone, VWR+L-BAIBA but not VWR showed lower bone marrow adiposity, higher trabecular thickness, and connectivity, smaller bone diameter and Moment of Inertia, but higher Modulus of Elasticity than CTRL, suggesting L-BAIBA delays aging-induced periosteal expansion due to better bone material qualities.

These findings suggest a physiological interaction between exercise and L-BAIBA supplementation to improve soleus muscle and bone properties and reduce bone marrow adiposity.

Link: https://doi.org/10.18632/aging.206325

The well understood pathways by which cerebrospinal fluid drains from the brain are the glymphatic system and cribriform plate. These paths become less functional with age, for different reasons, and the consequently reduced drainage of cerebrospinal fluid allows metabolic waste to build up in the brain. This includes the misfolded and normally folded but excess amyloid-β that is associated with the development of Alzheimer's disease. Researchers here show that clearing amyloid-β from the brain via immunotherapy does not improve glymphatic fluid flow over the course of the first few months following treatment, reinforcing a view of Alzheimer's and other neurodegenerative conditions in which glymphatic dysfunction is a contributing factor to the development of the disease rather than a consequence of the disease.

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β peptides in the brain parenchyma, and impairment of interstitial waste clearance via the glymphatic system is suggested as one contributing factor. Recently approved disease-modifying monoclonal antibodies, such as lecanemab, are expected to slow cognitive decline by improving amyloid-β clearance. Diffusion tensor imaging along the perivascular space (DTIALPS) index has emerged as a noninvasive surrogate marker suggested to be associated with glymphatic activity. This index declines with normal aging and is significantly lower in patients with AD than in cognitively normal individuals.

The 13 participants included in this study were: (i) diagnosed with AD by neurologists; (ii) underwent brain magnetic resonance imaging (MRI) and subsequently initiated lecanemab therapy. Only participants who provided written informed consent were included. Mean DTI-ALPS index was 1.515 ± 0.152 at baseline and 1.513 ± 0.161 at 3 months, no significant difference.

The absence of early DTI-ALPS index improvement suggests that even though lecanemab treatment reduces plaque burden, the diffusion properties of perivascular spaces measured by DTI-ALPS do not change in the short term. DMT can reduce plaque burden and slow further cognitive worsening but does not restore lost function, likely reflecting the fact that neuronal damage and clearance system deficits have already been well established. Such observations, therefore, may reflect a multifactorial disease process that is not rapidly reversible during symptomatic stages, resulting in an unchanged early DTI-ALPS index.

Link: https://doi.org/10.1002/jmri.70118

Gene expression is the complex process of producing proteins from a specific gene sequence encoded in DNA. The DNA in the nucleus of a cell is constantly surrounded by the machinery of gene expression. That machinery will attempt to start the process of transcription, the first step of gene expression, for any sequence it bumps into. Recall that every part of a cell is a chemical soup of molecules moving at incredible speeds, interacting with everything that they can possibly interact with, as fast as possible, countless times every second. Control over which genes are expressed at any given time is a matter of the structure of DNA, which sequences are exposed and which are spooled around histone molecules so that they are hidden from transcriptional machinery. DNA structure is shaped by epigenetic processes, which include the addition and removal of decorations such as methyl groups to specific locations on DNA that alter its shape, modifications to the histone molecules that DNA wraps itself around, and so forth.

DNA becomes damaged constantly - again, the cell nucleus is a soup of fast-moving molecules with countless collisions and reactions taking place in every moment. DNA is protected by highly efficient repair machinery, and near every incident is fixed, even dramatic damage such as complete breakage of both strands of the double helix of DNA. A new and potentially important area of research is focused on the potential for DNA double strand break repair to produce lasting changes to DNA structure and epigenetic regulation of gene expression. This may allow researchers to explain why similar detrimental epigenetic changes occur across all cells with advancing age, driven by stochastic DNA damage that is different in every cell and largely fails to harm any sequence that is actually used by a damaged cell. Importantly, given a sufficient understanding of exactly why long-term effects result from DNA double strand break repair, researchers can focus on developing therapies to prevent this outcome.

One obvious form of therapy already known to fix these issues is partial reprogramming, exposing cells to Yamanaka factors for a period of time. But perhaps there are other approaches that do not present the same challenges that partial reprogramming presents when it comes to fixing an entire body's worth of cells. Delivery is hard, and different cell types need different degrees of Yamanaka factor exposure. If it turns out that depletion of just a few factors involved in DNA repair is the cause of epigenetic change resulting from DNA double strand break repair, perhaps restoring those targets to youthful levels will be an easier goal to achieve. But these are early days yet, and a great deal more time and funding is needed for a deeper investigation of DNA double strand breaks and their potential contribution to degenerative aging.

Repair of DNA double-strand breaks leaves heritable impairment to genome function

Eukaryotic genomes are subjected to hierarchical folding that is required to accommodate DNA wrapped around the histone scaffold (collectively called chromatin) within the three-dimensional (3D) nuclear space. Evolution harnessed the 3D arrangement of nuclear chromatin to facilitate interactions among genomic segments such as promoters and enhancers, whose proximity influences gene expression and who thus have an important role in cell fate decisions such as orderly execution of developmental programs, adaptation to a new environment, or transmission of cell identity across successive generations of dividing cells. Although beneficial in these and other physiological contexts, the 3D arrangement of the nuclear genome also enables a distinct vulnerability to environmental or metabolic assaults that can modify chromatin folding and thus derail cellular functions.

A prominent example of such stress assaults is the DNA double-strand break (DSB). Besides disrupting DNA integrity, DSBs are intrinsically coupled to massive chromatin alterations that include changes in 3D arrangement and gene silencing across megabase distances from the primary DNA lesions. Although the DSB-induced chromatin response is initially beneficial to attract genome caretakers and generate structural scaffolds for timely and efficient DNA repair, its fate after restoring the integrity of DNA sequence is unknown. This seems to be a formidable gap in understanding genome maintenance that poses important questions: Do cells restore DSB-induced chromatin folding and the associated gene expression after completion of DNA repair? If yes, is the restoration of postrepair chromatin complete and back to the predamage level? If not, do the lingering chromatin alterations cause physiological impairments that can be inherited by successive cell generations?

To answer these questions, we directed Cas9-induced DSBs to genomic loci harboring topologically sensitive protein-coding genes, as well as regulatory RNA species, to interrogate long-term consequences of DNA breakage on chromatin topology and gene activity. By combining quantitative imaging of large cell populations, DNA and RNA fluorescence in situ hybridization (FISH), and Region Capture Micro-C as readouts, we found that DSB-induced chromatin alterations do not recover to predamage level but persist as lasting changes in 3D arrangement and impaired gene expression throughout large chromatin neighborhoods that encounter, and subsequently repair, a single DSB. We show that such impairments persist through several rounds of successive cell divisions and can trigger concrete pathophysiological consequences. We term this phenomenon as chromatin fatigue and propose that it represents a hitherto unknown dimension of heritable responses to DNA breakage, with a potential to permanently alter physiology of cells that encounter DSBs through environmental or metabolic stress - but also lineages engineered for various experimental or therapeutic purposes by nuclease-based genome editing.

Finding molecules or nanoparticles that selectively target mitochondria and induce improved function is the most developed of the various strategies that might be employed to at least partially reverse the age-related loss of mitochondrial capacity thought to be important in age-related disease and dysfunction. Most of the small molecules developed to date appear to work by improving mitophagy, the processes of quality control that recycle worn and dysfunctional mitochondria, but the precise details of the mechanisms involved are incompletely understood. Mitophagy itself is incompletely understood. Continuing this trend, researchers here present a nanoparticle that is observed to improve mitochondrial function and thus cell function via improved mitophagy.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo.

Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

Link: https://doi.org/10.1038/s41467-025-64813-0

Researchers here present a list of open problems in aging research, mined from the literature and outreach to the scientific community. This is certainly a topic on which opinions differ as to which of these areas of research are more or less important than others. An assessment of literature and community will tend to capture these differences of opinion, and ongoing debates over the best course ahead. In large part the diversity of opinions reflects the lack of a consensus measure of aging that can accurately assess the outcome of a potentially age-slowing or rejuvenating intervention. If such a measure existed, there will likely be little debate over the best path forward.

Despite advancements, the field of longevity science is at a crucial point as it continues to face numerous open problems that hinder further progress. Recent works have highlighted fundamental knowledge gaps and strong disagreements amongst scientist studying ageing. Addressing these challenges is critical for unlocking new insights and developing effective interventions to extend both lifespan and healthspan.

We now present a new list of 100 open problems in ageing science, identified and curated through a combination of community engagement and text-mining approaches. These problems span a wide range of topics, from molecular biology and comparative approaches to translational efforts and clinical applications. By outlining these 100 problems, we aim to guide and provide goals for future research and map the key areas where knowledge gaps exist.

These open problems are presented on our website (https://longevityknowledge.app), where users can interact with and find more information on each selected problem.

Link: https://doi.org/10.1007/s11357-025-01964-4

A number of approaches to inducing muscle growth or improving muscle strength have been demonstrated in laboratory animals, in early human clinical trials, and in recent years employed in medical tourism clinics. These approaches are compensatory in the context of aging, they do not address any of the underlying issues that lead to loss of muscle mass and strength per se. An adjustment of the regulation of muscle growth to favor more growth will produce larger, stronger muscles at any age, which may help to generate greater attention and use of such therapies as they are developed.

These varied approaches directly interfere in cell signaling in some way, as it is easier to adjust the levels of circulating proteins and other molecules, or their ability to interact with cell surface receptors, then it is to adjust mechanisms that operate inside cells. Inhibition of myostatin signaling and upregulation of follistatin signaling are the presently dominant approaches. The use of antibodies targeting myostatin has been assessed, but more effort is now put toward upregulation of circulating follistatin via forms of gene therapy.

In today's open access paper, researchers discuss upregulation of a different signaling protein, FGF19. This does appear to have the effect of reducing myostatin levels, but that it only increases muscle strength rather than muscle mass suggests that other mechanisms are driving the outcome. Some indication has been given in recent years that these various strategies to grow muscle or improve muscle strength may also have a positive impact on bone mineral density. Unfortunately that doesn't seem to the be the case for FGF19.

Therapeutic potential of FGF19 in combatting osteosarcopenia: effects on muscle strength and bone health in aged male mice

Osteosarcopenia, characterized by the coexistence of osteopenia/osteoporosis and sarcopenia, represents a significant health concern in geriatrics, with an increased risk of falls and fractures. The enterokine fibroblast growth factor 19 (FGF19) was recently shown to prevent muscle weakness in preclinical models. This study investigated the therapeutic potential of FGF19 in mitigating bone and muscle deterioration in aged male mice. Twenty-one-month-old C57BL/6 male mice received daily injections of human recombinant FGF19 (0.1 mg/kg) for 21 days.

Histological and functional analyses revealed a shift toward larger muscle fibers in FGF19-treated mice as well as an increased muscle strength, without affecting muscle mass. In parallel, X-ray microtomography showed that FGF19 had no overt negative impact on bone, with a range of modest, site-specific, and opposing effects. In the distal femur metaphysis FGF19, it reduced cortical thickness, but significantly increased bone cross-sectional area, with an overall increased polar moment of inertia, a geometrical parameter linked to favorable mechanical properties. It also elevated cortical bone porosity in the same region. There were no significant effects on trabecular bone or cortical bone parameters in the proximal femur side. In the L2 vertebra, cortical porosity decreased. Histomorphometry of trabecular bone and analysis of transcriptional output of selected genes in femurs revealed only minor changes in bone cellular activities and gene expression after three weeks of treatment.

In conclusion, FGF19 treatment increased muscle strength in aged male mice, without negatively impacting aging bone.

The raised blood pressure of hypertension is damaging to sensitive tissues throughout the body, but particularly the brain. Alongside many other issues in the health and function of the vascular system, hypertension increases the pace of rupture of tiny blood vessels in the brain, each such event destroying a small volume of brain tissue. Over time this adds up to degrade cognitive function and contribute to the development of outright dementia. Thus high blood pressure is harmful, and the longer the period of time in which blood pressure is elevated, the more harm is done. Here, researchers assess cumulative blood pressure over time and find a correlation between high, sustained blood pressure and a large increase in the risk of dementia.

Cumulative blood pressure (BP), which takes into account both the magnitude and duration of BP exposure, is linked to cognitive impairment. The Chinese Longitudinal Healthy Longevity Survey (CLHLS) over 16 years was divided into two consecutive sub-cohorts, namely the 2002 sub-cohort from 2002 to 2011 and the 2008 sub-cohort from 2008 to 2018. Cumulative BP exposures were calculated as the area under the curve derived from two consequence BP measurements and their corresponding time intervals.

A total of 2,142 and 1,920 cognitively healthy older adults participants from the two sub-cohorts were included in the analysis, respectively. Over a median follow-up of 6.2 years and 7.0 years, 542 and 347 older adults experienced cognitive impairment in the two sub-cohorts, respectively. Higher cumulative systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were significantly associated with a higher risk of cognitive impairment. Compared to the lowest quartile in the two sub-cohorts, the hazard ratios for cognitive impairment risk in the highest quartile were 1.85 and 2.64 for cumulative SBP, 2.00 and 2.20 for cumulative DBP, and 1.59 and 2.10 for cumulative PP, respectively.

Link: https://doi.org/10.1186/s12877-025-06465-9

Provoking regrowth of tooth enamel by mimicking some of its structure appears to be a going concern in dental research, if judging from this paper and another similar approach using keratin. At the high level, the idea is to coat damaged enamel with material that encourages the chemical mineralization process that takes place during enamel formation. Interestingly, the specific molecular structures demonstrated here allow this process to take place even when applied to exposed dentin. We can hope that cavities and fillings will soon enough be a thing of the past.

Tooth enamel is characterised by an intricate hierarchical organization of apatite nanocrystals that bestows high stiffness, hardness, and fracture toughness. However, enamel does not possess the ability to regenerate, and achieving the artificial restoration of its microstructure and mechanical properties in clinical settings has proven challenging.

To tackle this issue, we engineer a tuneable and resilient supramolecular matrix based on elastin-like recombinamers (ELRs) that imitates the structure and function of the enamel-developing matrix. When applied as a coating on the surface of teeth exhibiting different levels of erosion, the matrix is stable and can trigger epitaxial growth of apatite nanocrystals, recreating the microarchitecture of the different anatomical regions of enamel and restoring the mechanical properties.

The study demonstrates the translational potential of our mineralising technology for treating loss of enamel in clinical settings such as the treatment of enamel erosion and dental hypersensitivity.

Link: https://doi.org/10.1038/s41467-025-64982-y

The aging of the blood vessels supplying the brain into a state of dysfunction provides an important contribution to the onset and progression of neurodegenerative conditions. There are many aspects to this vascular aging, including: loss of capillary density over time that reduces the ability of the vasculature to deliver sufficient nutrients to cells in brain tissue; the atherosclerosis that narrows and weakens major vessels with fatty deposits; the disruption of normal function of the endothelium, the inner layer of blood vessels; disruption of the normal function of the smooth muscle that controls contraction and dilation of vessels; leakage of the blood-brain barrier, the specialized cells that line blood vessels in the brain and control which molecules are allowed to pass; and so forth. Aging is a disruption of all normal functions, in one way or another.

In today's open access review, researchers take at look at the phenomenon of endothelial-to-mesenchymal transition, a feature of aging in which endothelial cells change their state and behavior to take on the characteristics of mesenchymal cells. This is detrimental to the function of surrounding tissue, which depends on cells of a specific type continuing to act as that type. As the authors note, while the causes of endothelial-to-mesenchymal transition are only partially understood, there is evidence to link its occurrence to mechanisms of aging, and particularly to the chronic inflammatory signaling that is a feature of aged tissues. There are many ways in which continual, unresolved inflammation changes cell behavior for the worse, making it an important target for future medical control over aging.

Endothelial-to-mesenchymal transition in the central nervous system: A potential therapeutic target to combat age-related vascular fragility

Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms.

During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. Too little is understood regarding the interplay between triggers associated with physiological aging and the process of EndMT in both non-disease and disease-related contexts in the central nervous system. This highlights a field ripe for exploration, as many age-related processes have also been shown to be triggers of EndMT. For example, many of the inflammatory factors found in the senescence-associated secretory phenotype generated by senescent cells are triggers of EndMT.

Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT.

Nicotinamide adenine dinucleotide phosphate (NADP) has a different portfolio of functions in the cell to the better known nicotinamide adenine dinucleotide (NAD) that has been a focus for parts of the research community in recent years. NADP is thought to be primarily important as a defense against oxidative stress. Here, researchers discuss the role played by insufficient levels of NADP in vascular aging, finding that it encourages greater cellular senescence in the vascular endothelium, thus promoting endothelial dysfunction as a contribution to cardiovascular disease. Thus strategies to increase NADP levels may act to usefully improve the state of the aged vasculature, better protecting it from dysfunction.

Age-related cardiovascular diseases are featured by changes in arterial function or phenotype. Moreover, microcirculation possesses a unique ability to influence the microenvironment of majority of the organs. Thus, understanding the molecular mechanisms of vascular aging is central to tackle age-related cardiovascular disease. The vascular endothelium is a single layer of cells covering the lumen of vascular vessels and plays an important role in maintaining vascular homeostasis. Numerous studies suggest that senescence of vascular endothelial cells leads to initiation and progression of cardiovascular diseases.

Nicotinamide adenine dinucleotide phosphate (NADP, oxidized form: NADP+, reduced form: NADPH) has long been recognized as a key cofactor for redox defense and reductive biosynthesis. Intracellular NADPH consumption and production in different compartments of the cell are independently regulated. While traditional enzymatic cycling assays, mass spectrometry, and chromatography have been used to monitor whole-cell NADPH pool, they require cell homogenization and cannot differentiate compartmental NADPH pools, where it regulates distinct functions. Here, we employed a highly responsive and genetically encoded NADPH sensor and revealed that cytosolic NADPH was elevated during endothelial cell senescence.

Decreased nitric oxide concentration promoted G6PD activity leading to elevated NADPH levels. G6PD overexpression significantly elevated NADPH level, inhibited glutathione oxidation and HDAC3 activity, and suppressed endothelial cell senescence and vascular aging. These results suggest that G6PD/NADPH pathway is upregulated by stimulators of vascular aging, and it plays a casual role in limiting endothelial cell aging. Furthermore, high-throughput metabolic screening of 1419 drugs approved by the Food and Drug Administration found that folic acid significantly elevated NADPH content via MTHFD1 and augmented vascular activity in naturally aged mice. These findings highlight a beneficial role of endothelial NADPH metabolism in vascular aging.

Link: https://doi.org/10.1038/s41467-025-64652-z

Thin sheets of engineered artificial tissue can be readily manufactured because they do not require a vasculature, perfusion of fluids is sufficient to support the cells. For some years now, researchers have developed the capability to manufacture thin heart tissue patches. A number of preclinical studies in various animal models have demonstrated that applying these patches to an injured heart promotes greater regeneration and restoration of function than normally takes place. Here, the technique is combined with a minimally invasive form of surgery as a proof of concept, and used in rats following heart attack to promote greater regeneration.

For years, scientists have been working on ways to replace damaged tissue with healthy heart cells derived from stem cells. Early efforts showed promise, but most required open-heart surgery - a procedure too risky for many patients already struggling with severe heart failure. Scientists have long hoped that stem cells could provide a way to rebuild what the body cannot. By reprogramming ordinary adult cells such as skin or blood cells into induced pluripotent stem cells (iPSCs), researchers can coax them into becoming replacement heart cells. But safely and effectively delivering engineered heart tissues made from these cells has remained a major challenge.

With this in mind, researchers developed a flexible, paper-thin patch made of nano- and microfibers coated with gelatin. This hybrid scaffold supports a blend of human heart muscle cells, blood vessel cells, and fibroblasts - cells that form the tissue's structural framework - to create a living, beating piece of heart tissue. Before transplantation, the tissue is infused with bioactive factors such as fibroblast growth factor 1 and CHIR99021 that encourage the growth of new blood vessels and help the cells survive once they are in place.

"The beauty of this design is that it can be folded like a piece of paper, loaded into a slender tube, and delivered precisely where it's needed through a small incision in the chest. Once in place, it unfolds and adheres naturally to the heart's surface." Testing in preclinical rat models showed that the minimally invasive method improved heart function, reduced scarring, enhanced vascular growth, and lessened inflammation compared with conventional approaches.

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-identify-a-new-stem-cell-patch-to-gently-heal-damaged-hearts/

Microglia are innate immune cells resident in the brain. They are broadly similar in behavior to the macrophages found elsewhere in the body, with an added portfolio of duties relating to maintenance of the synaptic connections that link neurons to form neural networks. Researchers have provided evidence for microglia to both harm and help the aging brain, with various subpopulations of microglia either acting to cause damage and dysfunction or attempting to resist that damage and dysfunction. One of the most studied aspects of microglial aging is the increase in inflammatory signaling, as microglia react to the age-damaged environment and their own internal age-related dysfunctions with maladaptive patterns of behavior. Chronic inflammation in aged brain tissue contributes to neurodegeneration, and is driven in part by microglia.

In today's open access paper, the authors expand on recent research that points to PU.1 as a gene of interest in the regulation of microglial inflammation. A few research groups have set their sights on selective PU.1 inhibition in microglia as a potential basis for therapy, as it appears to reduce inflammation in animal studies. In this new paper, the authors report that this feature of PU.1 inhibition is actually driven by a small subpopulation of microglia that are in some way acting to regulate the behavior of other microglia. This sort of behavior is well described in the adaptive immune system - consider regulatory T cells, for example. It is interesting to see innate immune cells specializing into the regulators and the regulated in response to circumstances.

Lymphoid gene expression supports neuroprotective microglia function

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD). The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with amyloid plaques.

Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated low PU.1 expression microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load.

Our findings indicate that low-PU.1 CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

Epidemiological research has consistently demonstrated a sizable difference in outcomes between those who are sedentary and those who conduct even a modest, low level of physical activity. More exercise is better, of course, but some researchers have have nonetheless focused on the degree to which small amounts of activity can be beneficial in older individuals. Here, for example, researchers show that relatively low levels of physical activity slow the progression towards outright Alzheimer's disease in patients with high levels of amyloid-β aggregation. The amyloid-β in and of itself causes only minor loss of cognitive function, but sets the stage for a later environment of inflammation and tau aggregation that causes much more severe damage to the brain and its function.

Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid.

Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals.

Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.

Link: https://doi.org/10.1038/s41591-025-03955-6

Researchers here demonstrate a novel way of delivering stem cells as a therapy for bone fractures that occur in the context of osteoporosis, by forming spheroids of stem cells combined with a bone mineral scaffolding material. The approach appears to encourage the survival of a larger fraction of transplanted cells, producing a greater regeneration of bone tissue. More usually near all of the transplanted cells die shortly after a transplantation procedure, and whatever benefits are obtained are derived from the signaling generated by the stem cells prior to that point.

Osteoporotic vertebral fractures substantially contribute to disability and often require surgical intervention. However, some challenges, such as implant failure and suboptimal bone regeneration, limit current treatments. Adipose-derived stem cells are promising for regenerative therapy because they are easily obtained, highly proliferative, and resistant to osteoporosis-related symptoms. This study aimed to evaluate the combined effects of osteogenic adipose-derived stem cell spheroids and β-tricalcium phosphate on vertebral bone regeneration in a rat osteoporotic vertebral fracture model.

Osteoporosis was induced in 33 rats (11 per group) by ovariectomy, and defects were created in the L4 and L5 vertebrae. Adipose-derived stem cells were spheroidized and mixed with β-tricalcium phosphate scaffolds. Groups included osteogenic spheroids, undifferentiated spheroids, and β-tricalcium phosphate alone. Bone regeneration was assessed using micro-CT, histology, and biomechanical testing at four and eight weeks. Further in vitro analyses were conducted.

The osteogenic spheroid group showed significantly higher bone mass, fusion score, and mechanical strength than the control group did. Histological analysis revealed enhanced new bone formation and β-tricalcium phosphate integration. Gene expression analysis revealed osteogenic marker (ALP, osteocalcin, and Runx2) and regenerative factor (BMP-7, IGF-1, HGF-1, and Oct4) upregulation, along with reduced apoptosis. Further, adipose-derived stem cell survival was confirmed at the repair site. These results indicate that adipose-derived stem cells contribute to both paracrine and direct osteogenesis.

Link: https://doi.org/10.1302/2046-3758.1410.BJR-2025-0092.R1

Stem cell therapies have existed for a few decades now, and over that time have moved from experimental use for many conditions in the medical tourism industry to a much more formulaic, controlled use for some conditions in the more regulated markets such as the US and Europe. More experimental use in medical tourism never went away, however. It became a larger industry, more varied, the body of knowledge more widespread, but the existence of a very formalized, robust set of procedures adopted by clinics and companies in more regulated markets where every therapy and its method of manufacture is reviewed in great detail (and consequently at great expense) doesn't make the earlier, less costly, less certain approach go away. Well informed patients continue to have the choice over how they proceed.

The trajectory of the stem cell therapy field is presently to replace the use of cells with the use of extracellular vesicles harvested from those cells. Extracellular vesicles are more cost-effective as a basis for therapy, as they can be manufactured centrally, frozen, shipped, and stored indefinitely with minimal loss of efficacy. In practice, as this move from cells to vesicles is at a fairly early stage in the grand scheme of things, there isn't yet all that much centralization of manufacture. There is certainly very little standardization of manufacture; it is a rerun of the early years of stem cell therapies, but for vesicles this time. This will change. As happened for stem cell therapies, there will be more regulated, more expensive extracellular vesicle therapies, manufactured more robustly, and approved by regulators to treat only some conditions. Meanwhile, the medical tourism industry will continue much as it is at the moment, only more so. Check back in a decade, and this will likely be the state of the field.

Efficacy of extracellular vesicles derived from mesenchymal stromal cells in regulating senescence: In vitro and in vivo insights

Researchers have pointed to stem cell depletion as a key mechanism contributing to cellular senescence in aging. Thus, stem cell-based therapy, especially treatment with mesenchymal stromal cells (MSCs), has become an innovative anti-aging approach. A phase I/II double-blind and placebo-controlled study showed that the application of intravenous exogenous allogenic MSCs can reverse the symptoms of frailty in elderly individuals, significantly improving quality of life, physical performance, and reducing chronic inflammation. However, using MSCs in therapeutic applications poses several challenges, including the risk of cellular rejection, tumorigenesis, and problems related to cell delivery and engraftment. These concerns have led researchers to assess alternative strategies for using MSCs for treatment while mitigating the risks related to their application. One such promising strategy involves using extracellular vesicles (EVs) derived from MSCs (MSC-EVs).

The cargo of MSC-EVs consists of various cytokines, growth factors, bioactive lipids, and regulatory microRNAs (miRNAs) that can participate in cell-to-cell communication and cell signaling and alter the metabolism of cells or tissues at short or long distances in vivo. These vesicles have the therapeutic ability of MSCs and can influence tissue response to injury, infection, and disease. Researchers showed that EVs derived from umbilical cord-derived MSCs (UC-MSCs) can delay the aging of naturally aged mice throughout the body and significantly alter the degenerative functions of various tissues and organs.

Many preclinical studies have shown that multiple sources of EVs, especially those derived from UC-MSCs, are prospective cell-free therapeutic agents for aging therapy. However, key parameters, including quality, reproducibility, and potency, determine the development of therapies based on EVs. Large-scale production of EVs faces multiple challenges, including low yield, heterogeneity, targeted delivery, storage stability, and the lack of standardized protocols to ensure quality, safety, and consistency. Current isolation techniques, such as ultracentrifugation and density gradient methods, suffer from limited yield and insufficient purity, making them inadequate for clinical-scale applications.

This study established a highly efficient technique for extracting and characterizing MSC-EVs. Additionally, we identified and implemented crucial quality control checkpoints for MSC-EVs. These measures were taken to ensure consistent yield, quality, and reproducibility of the MSC-EVs, rendering them suitable for clinical use. Next, we conducted several experiments to determine the effects of MSC-EVs on senescence in senescent cells and aged murine models. We found that MSC-EVs inhibited the aging-related secretory phenotype at the cellular level and reduced the attenuation of age-associated degenerative changes in multiple organs. Moreover, integrated metabolomics and transcriptomics analyses were performed, and the results confirmed the anti-aging mechanism of MSC-EVs.

Macular degeneration is a progressive blindness caused by forms of age-related damage that disable and destroy cells of the retina, such as the accumulation of persistent forms of metabolic waste. The dry variant of macular degeneration, in which there is no great degree of inappropriate blood vessel growth in the retina, has no effective treatment at the present time - and treatments for the wet form typically only slow progression. The materials noted here discuss progress towards a precision heat therapy that uses a laser to induce mild cell stress and consequently greater cell maintenance activities in retinal tissue. If used in the early stages of the condition, animal studies suggest it can significantly postpone the onset of more severe degeneration.

The new heat treatment involves heating the retinal pigment epithelium at the back of the eye (at the fundus) with near-infrared laser and precise temperature control. The objective is to halt the development of the condition in its early stages and to prevent it from progressing to the dry or wet form. Heat treatment of the fundus is not a new invention, but until now, it has not been possible to monitor the temperature of the retinal pigment epithelium while the treatment is administered. This is essential in order to avoid damage to the tissues being treated.

The causes of macular degeneration include oxidative stress and the resulting protein misfolding and aggregation. A heat treatment for the back of the eye strengthens the defence mechanisms of retinal cells. These mechanisms help proteins refold back into their correct forms, and at the same time stimulate the natural healing process. In the new heat treatment, the temperature elevation of the fundus is determined from the acceleration of electrical signalling of retinal nerve cells in response to light stimuli and the signals can be registered in real-time from the surface of the eye using electroretinography. With this method, the voltage change caused by light flashes is measured using electrodes placed on the surface of the eye and the skin near the eye.

The temperature determination method has been shown to work in tissue research on mice and pigs, and preclinical tests for the heat treatment have begun. The goal of the commercialisation project is to enable the use of heat treatment in humans, and the design and construction of the treatment device is currently under way.

Link: https://www.aalto.fi/en/news/new-laser-therapy-seeks-to-halt-the-progression-of-age-related-vision-loss

Brown adipose tissue conducts thermogenesis and its activities have been found to be beneficial to the operation of metabolism. Thus a greater proportion of brown adipose tissue versus other types of fat tissue is protective in the context of aging. Unfortunately brown adipose tissue function declines with age, and here researchers provide evidence for this form of fat tissue aging to be caused by a decline in the efficacy of chaperone mediated autophagy, also a feature of aging. This form of autophagy uses chaperone proteins to shuttle damaged or otherwise unwanted molecules into a lysosome for recycling. Like all forms of autophagy the efficiency of its operation is connected to the pace of aging in animal studies; all of the varied processes that help to clear cells of damaged molecules appears beneficial in this context.

Brown adipose tissue (BAT) protects against obesity, diabetes, and cardiovascular disease. During BAT activation, macroautophagy is inhibited, while chaperone-mediated autophagy (CMA) is induced, promoting thermogenic gene expression, adipokine release, oxidative activity, and lipolysis. Aging reduces BAT function and lowers levels of LAMP2A, the rate-limiting CMA component. Pharmacological CMA activation restores BAT activity in aged mice.

To explore the CMA's role in BAT, we generated LAMP2A-deficient brown adipocytes and found that CMA regulates proteins essential for thermogenesis and metabolism. Blocking CMA in BAT reduced energy expenditure, raised blood triglycerides, impaired secretion, and led to an increase of thermogenesis repressors. These findings show that CMA is essential for maintaining BAT function, especially during adaptive thermogenesis. By degrading repressors of thermogenesis, CMA supports BAT activity under cold or metabolic stress.

This work highlights CMA as a key regulator of BAT plasticity and a promising therapeutic target for treating age-related metabolic disorders.

Link: https://doi.org/10.1126/sciadv.ady0415

The broad category of glial cell includes all of the cells making up the nervous system that are not neurons. This includes the innate immune cells known as microglia, the astrocytes that manage brain metabolism and make up much of the brain's structure, the oligodendrocytes that maintain the myelin sheathing necessary for nerves to conduct electrical impulses, and a few other smaller or more localized populations. These are all very different cell types with very different functions, so one can't really talk about them in sweeping terms. Nonetheless, they all become dysfunctional with advancing age for the same underlying reasons, each population contributing to the complexities of brain aging, and in turn being negatively affected by other aspects of aging.

In today's open access review paper, the authors take a tour of what is known of both the ways in which glial cells contribute to the aging of the brain, and the ways in which the aging of the brain harms glial cell function. Aging is sufficiently complex that it is challenging to fully map all of the ways in which the various known changes and dysfunctions interact with one another. Robustly identifying cause and consequence is difficult when the consequence can in turn interact with the cause, and it isn't just one cause and one consequence, but rather an interacting network of effects and their outcomes, all of which can influence one another.

Interplay Between Aging and Glial Cell Dysfunction: Implications for Central Nervous System Health

At the molecular level, aging induces extensive reprogramming of glial cell gene expression, driven by the cumulative impact of epigenetic drift (defined as stochastic alterations in the epigenome that accumulate over time) encompassing changes in DNA methylation patterns, histone modifications, and chromatin remodeling. In aging glial cells, chromatin accessibility is often reduced at loci associated with neuroprotective and metabolic genes, while pro-inflammatory and stress-response genes might become more accessible, driving a maladaptive transcriptional shift. Mitochondrial dysfunction, a well-established hallmark of aging, plays a central role in this process. In glial cells, compromised electron transport chain efficiency reduces ATP production, impairing the high-energy-demanding functions of those cells. This inefficiency also leads to excessive production of reactive oxygen species (ROS), which induce oxidative damage on lipids, proteins, and nucleic acids.

Astrocytes, which play essential roles in maintaining central nervous system (CNS) homeostasis, supporting neuronal function, and regulating the blood-brain barrier (BBB), undergo a shift toward a reactive phenotype in response to aforementioned insults. Their reactive state is characterized by hypertrophy, increased expression of intermediate filament proteins like GFAP and vimentin, and the secretion of several pro-inflammatory mediators, such as IL-1β, TNF-α, and CCL2. Sustained activation of the NF-κB signaling pathway locks astrocytes into an inflammatory state, further impairing their neuroprotective roles. One functional consequence is the reduction in glutamate clearance due to decreased expression of excitatory amino acid transporters EAAT1 and EAAT2, creating conditions favorable for excitotoxic neuronal damage.

Microglia, the resident immune sentinels of the CNS, undergo a parallel but distinct aging trajectory, a process often known as microglial priming. With aging process, pattern recognition receptor pathways, particularly TLR4 signaling, become dysregulated, making microglia hyperresponsive to secondary insults including infections or trauma. Primed microglia exhibit amplified and sustained inflammatory responses, but paradoxically show reduced phagocytic efficiency, compromising the clearance of myelin debris, apoptotic cells, and aggregated proteins such as amyloid-β. Dysfunction in purinergic signaling, especially through P2X7 and P2Y12 receptors, further disrupts microglial chemotaxis and injury sensing. Autophagic flux declines with age, leading to lysosomal dysfunction, which traps damaged organelles and undigested materials inside the cell. This failure of clearance mechanisms sustains the presence of damage-associated molecular patterns (DAMPs) in the CNS microenvironment, perpetuating a self-reinforcing cycle of inflammation and neuronal stress.

Oligodendrocyte precursor cells (OPCs), the main source of new myelinating oligodendrocytes in the adult CNS, also exhibit significant age-related decline. Aging OPCs show impaired proliferation and differentiation capacity, largely driven by epigenetic repression of the genes implied in myelin synthesis, such as MBP and PLP1. Furthermore, OPCs become less responsive to mitogenic growth factors, including PDGF-A and FGF2, which usually promote OPC expansion and maturation. The loss of regenerative capacity impairs remyelination efficiency and contributes to the progressive degradation of white matter integrity, a crucial substrate for cognitive processing speed and executive function.

These issues are exacerbated by systemic aging factors, including chronic low-grade inflammation (known as inflammaging), characterized by increased levels of circulating pro-inflammatory cytokines, as well as alterations in metabolic hormones such as insulin and IGF-1. These systemic molecules facilitate glial senescence via activation of the cell cycle inhibitors p16 and p21, inducing an irreversible growth arrest that further impairs the CNS reparative and adaptive capacity. Over time, these converging cellular and molecular deficits create a CNS environment more susceptible to neurodegenerative processes. Furthermore, these glial modifications do not occur in isolation but rather within a complex and bidirectional interplay with aging neurons, vascular elements, and the immune system.

Aging begins long before evident loss of function arises. As researchers point out here, efforts to better map and intervene in the progression of these pre-symptomatic changes are not the primary focus of medical research and development. But attaining any degree of control over aging also implies the same degree of prevention of aging, meaning the ability to intervene early with therapies that repair the damage that would otherwise lead to greater dysfunction. Any rejuvenation therapy that shows efficacy in late stage disease should be even better as a way to prevent emergence of disease. Nonetheless, the historical focus on late stage disease in aging has already successful misdirected medical research and clinical practice into less beneficial approaches, and may continue to do so absent a cultural shift to focus more on prevention.

Aging is a multifactorial process that progressively disrupts cellular and tissue homeostasis, affecting all organ systems at distinct rates and predisposing individuals to chronic diseases such as cancer, type II diabetes, and sarcopenia. Among these systems, skeletal muscle plays a central role in healthspan decline, yet the precise onset of its deterioration remains unclear. Most studies emphasize late-life models, overlooking the transitional phase of middle age, when initial alterations emerge. Evidence indicates that middle-aged muscle exhibits aberrant metabolism, impaired insulin sensitivity, and an early, gradual reduction in mass, suggesting that decline begins long before overt sarcopenia, a pathologic loss of muscle mass and functionality after middle age.

Indeed, most of the in vivo research about skeletal muscle aging focuses on comparisons between old and young organisms, creating a gap in the field regarding mid-age alterations. This creates two problems: (i) it overlooks non-linear biomarkers that return to basal values in old age after an organism initiates compensatory response mechanisms, and (ii) it presents treatment mainly as a damage-control strategy after molecular and morphological alterations are already established. These "palliative" treatments may partially promote lifespan but have a limited impact on healthspan.

Therefore, we seek to summarize and identify biomarkers indicative of the onset of skeletal muscle aging from in vivo studies on young adults and middle-aged humans and rodents in an attempt to identify some of the chronological alterations. This review aims to contribute insights for future research seeking to prevent or delay the onset of sarcopenia.

Link: https://doi.org/10.3390/ijms262010145

Researchers here find a potential way to induce greater regeneration in injured heart muscle, normally a tissue that regenerates only poorly following damage, and particularly so in older individuals. Inducing CCNA2 expression appears to promote replication of the cardiomyocyte cells making up heart muscle. Still, a great deal of work remains in order to build a viable gene therapy based on this finding and assess it in a clinical trial. The direct delivery of a gene therapy to heart muscle is perhaps more viable than is the case for other internal organs given the range of established minimally invasive surgical procedures developed for use in the cardiovascular field. One can envisage a therapy that is delivered alongside the procedures normally carried out for patients following a heart attack.

When someone has a heart attack or heart failure, heart muscle cells are lost and the heart cannot replace them. There is no current way to grow new heart muscle cells after damage. Researchers wanted to know if they could reawaken the heart's ability to regenerate itself by using a naturally occurring pathway that enables cardiomyocyte (heart muscle) cell division in utero. They focused on CCNA2 - a gene that is normally silenced after birth - and turned it back on in adults to see if this would help grow new heart cells and help the heart heal.

The research team built a replication-deficient human-compatible virus that carries the CCNA2 gene and delivered it to heart muscle cells. They tested it directly in living adult human heart cells in culture from healthy donor hearts. Researchers used time-lapse imaging to analyze the heart cells with CCNA2 and saw these cells divide successfully, while still keeping their normal structure and function.

More specifically, researchers looked at three healthy hearts from donors who were 21, 41, and 55-years-old. Cyclin A2 therapy triggered these adult human heart cells to divide in the 41- and 55-year-old hearts. Conversely, cells from hearts belonging to a 21-year-old showed no change when given the CCNA2 therapy. This latter finding aligns with previous studies that show younger hearts do have regenerative potential and that their cells are capable of dividing without the stimulus provided by CCNA2.

Link: https://www.eurekalert.org/news-releases/1103140

The use of electromagnetic fields to manipulate cellular biochemistry in favorable ways is a field very much in its infancy in comparison to the well established use of small molecule drugs. At the high level, it is quite similar to exploration with small molecules, in that there is a great deal of freedom to experiment with parameters: intensity, frequency, duration, dosing, a focus on primarily electrical versus primarily magnetic fields, equipment differences, and so forth. Within that vast parameter space, only some combinations will be useful. In general this part of the field is characterized by results that fail to replicate and incomplete information on all of the parameters needed to recreate the exact protocol used. Nonetheless, there are some areas of promise where multiple research groups have achieved positive results, and even brought the work into human trials. The use of electric fields to stimulate more rapid regeneration from injury is one example.

Today's open access paper reports on the use of magnetic fields to stimulate beneficial changes in mitochondrial function that are similar to those that occur following exercise. The authors term it magnetic mitohormesis, and one might take a look at an earlier review paper that discusses the mechanisms thought to be involved. The hundreds of bacteria-like mitochondria present in every cell are vital to cell function, primarily by producing adenosine triphosphate (ATP), a chemical energy store molecule. A vast body of evidence indicates that mitochondrial function declines with age, while the various strategies available to modestly improve mitochondrial function, including exercise, are beneficial to health and slow aging to some degree, at least in animal studies, in part because they improve mitochondrial function.

Investigating the Metabolic Benefits of Magnetic Mitohormesis in Patients with Type 2 Diabetes Mellitus

We, and others, have shown that brief exposures to pulsed electromagnetic fields (PEMF) stimulate mitochondrial respiration via a calcium-mitochondrial axis upstream to PGC-1α transcriptional regulation and recreate biological and metabolic adaptations similar to endurance exercise but without physical stress or strain.

In pre-clinical murine studies, PEMF exposure was shown to activate muscle mitochondrial respiration to induce exercise-related muscle adaptation and mitochondrial biogenesis. These responses resulted in the manifestation of typically exercise-associated positive metabolic adaptations, including improved insulin sensitivity, reduced resting insulin levels, enhanced fatty acid oxidation, and enhanced oxidative muscle expression downstream of the well-established pro-metabolic health pathways largely governed by PGC-1α co-transcriptional regulation.

Related benefits have also been observed in several published human studies employing this same PEMF exposure paradigm. In elderly patients, brief 10-min weekly PEMF treatment for 12 weeks increased skeletal mass and reduced total and visceral adiposity. More recently, it was found that PEMF treatment improved knee muscle strength and reduced pain in elderly patients with end-stage osteoarthritis of the knees. In another example, weekly treatment with PEMF for 16 weeks improved markers of muscle mitochondrial functioning and lowered systemic lipotoxicity in patients who underwent anterior cruciate ligament reconstruction compared to placebo.

Collectively, these data support the ability of PEMF treatment to replicate the metabolic benefits of endurance exercise. However, it is unknown whether low-dose PEMF treatment, which we will refer to as magnetic mitohormesis (MM), improves diabetes control. In this open-labeled exploratory study, we investigated the impact of MM on metabolic control in patients with suboptimally-controlled type 2 diabetes mellitus (T2DM). In addition, because PEMF treatment has been shown to reduce visceral fat, we examined whether patients with central obesity (defined as waist-to-hip ratio, WHR of ≥1.0) exhibit a greater propensity to benefit more from this treatment.

The 40 participants had a mean age of 59.4 years and HbA1c of 8.1%. MM treatment was well tolerated with no adverse events, and 77.5% of patients completed all 12 sessions. There were no significant changes in HbA1c, fasting glucose, or HOMA-IR for the overall cohort. However, in patients with central obesity, 88.9% showed a reduction in HbA1c post-treatment compared to 32.3% without central obesity, and mean HbA1c decreased from 7.5% to 7.1%. Our findings suggest that MM is safe and well-tolerated in T2DM patients and may confer a preferential benefit for individuals with greater central obesity.

There is considerable debate over the degree to which persistent viral infections contribute to neurodegenerative conditions such as Alzheimer's disease. If persistent viral infection causes generalized pathology over time, such as via increased chronic inflammation in later life, one would expect it to increase the incidence and severity of most age-related conditions. With that in mind, researchers here analyze a sizable body of study data to quantify the correlations between viral infection and cardiovascular disease. As one might expect, the results suggest that better control of viral infection could improve late life health.

It is well recognized that human papillomavirus (HPV), hepatitis B virus and other viruses can cause cancer; however, the link between viral infections and other non-communicable diseases, such as cardiovascular disease, is less well understood. Thus researchers set out to systematically review all published studies that investigated the association between any viral infection and the risk of stroke and heart attack, initially screening more than 52,000 publications and identifying 155 as appropriately designed and of high quality allowing for meta-analysis of the combined data.

In studies comparing long-term risk (average of more than 5 years) of cardiovascular events in people with certain chronic viral infections versus similar people without the infection, the researchers found: (a) a 60% higher risk of heart attack and 45% higher risk of stroke in people with HIV infection; (b) a 27% higher risk of heart attack and 23% higher risk of stroke in people with hepatitis C infection, and (c) a 12% higher risk of heart attack and 18% higher risk of stroke in people had shingles.

The findings also suggest that increased vaccination rates for influenza, COVID, and shingles have the potential to reduce the overall rate of heart attacks and strokes. As an example, the researchers cite a 2022 review of available science that found a 34% lower risk of major cardiovascular events among participants receiving a flu shot in randomized clinical trials vs. participants in the same trials who were randomly selected to receive a placebo instead.

Link: https://newsroom.heart.org/news/some-acute-and-chronic-viral-infections-may-increase-the-risk-of-cardiovascular-disease

Fibrosis is a feature of aging, in which the normal processes of tissue maintenance run awry and scar-like structures form to disrupt tissue structure and function. The proximate cause is altered behavior on the part of fibroblast cells that largely responsible for maintenance of the extracellular matrix. After than, one can point to the continual inflammatory signaling that takes place in aged tissue, and disrupts many forms of cell activity, not just this one. As is usually the case in matters relating to aging, a more comprehensive picture of causes and consequences leading to inflammation and altered fibroblast behavior, one that encompasses all of the mechanisms involved and their various layers and interactions, has yet to emerge. Biochemistry is exceedingly complex.

Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix (ECM) remodeling.

The ECM is a complex and dynamic network composed of proteins, proteoglycans, polysaccharides, and biologically active factors. It plays a crucial role in maintaining tissue integrity and function by undergoing remodeling in response to inflammation or injury, adapting its structure and composition to maintain tissue integrity and function. However, a persistent expansion of the ECM may evolve into maladaptive fibrosis and organ dysfunction. This pathological remodeling can be triggered by various factors such as hypoxia, inflammation, biomechanical stress, and excessive neurohormonal activation.

Inflammation contributes to ECM remodeling by releasing cytokines that activate fibroblasts, increasing the production of ECM components. It also upregulates matrix metalloproteinases (MMPs) that degrade ECM proteins. This dual action can lead to pathological ECM remodeling, contributing to fibrosis and tissue dysfunction. Senescence, on the other hand, leads to the accumulation of senescent cells that secrete pro-inflammatory factors known as the SASP. SASP factors, including cytokines, chemokines, growth factors, and proteases, further alter the ECM by promoting degradation, impairing its turnover, and reshaping its composition.

Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of cardiovascular disease.

Link: https://doi.org/10.3390/biom15101452

A growing body of literature is associated with the debate over whether persistent viral infection provides a significant contribution to Alzheimer's disease and other neurodegenerative conditions. Some viruses, such as varieties of herpes simplex virus (HSV), cannot be effectively cleared by the immune system. They linger in the body to continually provoke immune reactions. The contribution of viral infection is clearly not reliable and sizable, however, as the epidemiological evidence is mixed. Some study populations show a correlation between infection status or use of antiviral therapies, while some do not. Some researchers have proposed that significant contributions to neurodegenerative disease require the interacting presence of several viral infections, which if true would explain why studies assessing infection status for a single virus produce mixed results.

If looking at only biological mechanisms, such as HSV-1 driving greater accumulation of amyloid-β in the aging brain, or the disruptions to immune function generated by cytomegalovirus, it all sounds quite compelling. But at the end of the day, researchers have be to able to demonstrate a robust association in epidemiological data for the viral contribution to Alzheimer's disease and other neurodegenerative conditions to be taken seriously. At the moment researchers are still in search of that robust correlation, and as a consequence this remains an exploratory part of the field.

HSV-1 as a Potential Driver of Alzheimer's Disease

Globally, approximately 4 billion people, or 64% of the population under the age of 50, are infected with herpes simplex virus type 1 (HSV-1). Antiviral medications such as acyclovir, famciclovir, and valacyclovir are prescribed to symptomatic patients. A complete cure for HSV-1 remains elusive in 2025, as these medicines do not eliminate the virus. After an initial infection, HSV-1 often enters a latent state, which can be reactivated, causing recurrent outbreaks, symptomatic or asymptomatic. Emerging evidence suggests that HSV-1 may contribute to neurodegeneration, particularly in Alzheimer's disease (AD), potentially through mechanisms such as chronic neuroinflammation, amyloid-beta (Aβ) and hyperphosphorylated Tau accumulation, oxidative stress, and synaptic dysfunction. Moreover, HSV-1 proteins have been detected in the hippocampus and thalamus, both of which are affected in AD. However, the role of HSV-1 in dementia remains unclear.

In this review, we examine current evidence on the potential role of HSV-1 in the pathogenesis of dementia and consider whether targeting HSV-1 could be a viable strategy for preventing progressive neurodegeneration. Although many studies have demonstrated an association between HSV-1 and AD, further exploration is needed to determine whether HSV-1 infection is a cause or a consequence of AD degeneration. Because HSV-1 is latent in the trigeminal ganglion and travels to the brain during reactivation, an animal model that can physiologically mimic human-brain conditions remains a challenge. Thus, future studies should examine possible experimental models in order to determine the causality between HSV-1 and AD.

AD is characterized by progressive memory impairment, executive dysfunction, and visuospatial impairment. Several studies have shown that neurotropic viral infections serve as a risk factor for AD onset and progression. Regarding the contribution of HSV-1 infection to AD onset, the studies started with the observation demonstrating the association between HSV-1 DNA and amyloid plaques. 72% of HSV-1 DNA was associated with plaques, whereas only 24% of HSV-1 DNA was associated with plaques in normal brains. Furthermore, HSV-1 DNA and proteins were found in the central nervous system, particularly in the hippocampus and thalamus, which are predominantly affected in AD, supporting the association between HSV-1 infection and AD.

In an epidemiological study, a meta-analysis revealed a positive correlation between anti-HSV-1 acyclovir treatment and the potential reduction in the risk of AD development or slowing down the progression of AD symptoms. However, the analysis may be limited by the lack of data from prospective randomized controlled clinical trials. A Phase II randomized, double-blind, placebo-controlled trial of valacyclovir in patients with mild AD and evidence of HSV-1/2 infection was recently completed (NCT03282916). After 78 weeks of treatment, valacyclovir did not slow disease progression. However, it remains unclear whether a longer treatment duration or intervention at an earlier disease stage might be required to observe therapeutic effects.

Overall, the mechanisms underlying HSV-1 in regulating AD progression are unclear, and further experimental studies are needed to confirm the epidemiological association between HSV-1 and AD. In addition, it remains unclear whether the increased presence of HSV-1 DNA and proteins in brain regions is a consequence of AD-associated immune dysfunction, making the brain more susceptible to infection.

Sirtuins are involved in the regulation of metabolism in various ways, and are clearly quite important to cell function as their structure is very similar in species as divergent as yeast, flies, and humans. Sirtuin 1 as a target for interventions in aging was intensely overhyped and likely not actually very useful in a practical sense. Sirtuin 3 is more interesting, based on research suggesting that it could have calorie restriction mimetic effects, and is involved in mitochondrial function, well known to have a role in aging. Sirtuin 6 is also interesting, as it slows aging in mice, but the mechanisms involved are less well understood. A company is presently working on gene therapies based on sirtuin 6 upregulation. Here, researchers report on their production of profile of these sirtuins in a small population of people at various ages, which might be of interest in the context of growing efforts to modestly slow aging by targeting sirtuins 3 and 6.

While modulation of SIRT1, SIRT3 and SIRT6 extends lifespan in model organisms, evidence in extreme-age humans is scarce. We quantified protein and mRNA levels, and protein-to-mRNA ratios for SIRT1, SIRT3 and SIRT6 in buccal epithelial cells obtained from healthy young adults, middle/late-aged individuals and nonagenarians/centenarians residing in a longevity-enriched region of south-eastern Azerbaijan. The cohort comprised 23 participants, stratified by sex and cardiovascular disease (CVD) status (5 per sex/CVD subgroup).

Our study has shown that although SIRT1, SIRT3 and SIRT6 levels predictably fell with age, the magnitude of these declines was significantly influenced by both sex and baseline cardiovascular health. Women retained higher absolute pools of SIRT1 and SIRT3 and exhibited a smaller loss of SIRT6 than men; their protein-to-mRNA ratios - our proxy for translational efficiency - rose by ≈30% for SIRT3 and SIRT6, whereas the male increase was modest. This pattern is consistent with hormone-dependent regulation: estrogens acting through estrogen receptor (ER)-α/β up-regulate SIRT1 transcription in endothelial and cardiac cells, via the estradiol-ERα interaction boost SIRT3 expression and mitochondrial targeting, enhancing oxidative phosphorylation, antioxidant defenses, and mitophagy for improved mitochondrial health and enhance SIRT6 activity by shielding critical acetyl-lysine residues, whereas androgens are neutral or even suppressive.

Our findings likewise showed that the presence of cardiovascular disease (CVD) reshapes the sirtuin axis far more dramatically than chronological aging and sex. We observed a decline in SIRT1, SIRT3, and SIRT6 levels, broadly consistent with a ~50% reduction in SIRT1 reported in ischemic heart disease cohorts and a ~35% decline in SIRT3 under pressure-overload conditions. In contrast, SIRT6 behaves differently: although its absolute protein level fell by ~73%, the protein-to-mRNA ratio remained virtually unchanged This pattern exemplifies translational buffering whereby cells upregulate translation of selected proteins to maintain critical functions despite drops in mRNA levels. This is more accurately framed as an emergency protective buffer, rather than a pathological driver.

This pilot study is the first to profile SIRT1, SIRT3 and SIRT6 across sex, age and cardiovascular health, defining a unified "sirtuin phenotype" that integrates nuclear energy sensing, mitochondrial integrity and chromatin maintenance as axes of cellular resilience. Although based on a small, cross-sectional cohort, the large and internally consistent effect sizes pave the way for longitudinal studies to validate sirtuin translational efficiency as a predictive biomarker of healthy ageing and cardiovascular resilience across sexes and as a target for sirtuin-modulating interventions aimed at extending healthspan.

Link: https://doi.org/10.3390/biology14101353

Here find a review of what is known of the ways in which age-related changes in the gut microbiome can contribute to the chronic inflammation of aging and development of neurodegenerative conditions. The ability to accurately map the composition of the gut microbiome by sequencing microbial DNA, in particular species-specific variations in the 16S rRNA gene, has produced a vast and growing body of data. Researchers have linked specific microbial populations to specific age-related conditions, and shown that the balance of populations shifts with age to favor those that provoke the immune system at the expense of those producing beneficial metabolites. This is the first step on the road to creating interventions capable of the lasting restoration of a more youthful gut microbiome, a goal that we know is possible because it can be achieved via fecal microbiota transplantation from a young donor to an old recipient, and approach that improves health and slows aging in animal studies.

Neurodegenerative diseases (NDs) represent a major global health challenge in aging populations, with their incidence continuing to rise worldwide. Although substantial progress has been made in elucidating the clinical features and molecular underpinnings of these disorders, the precise mechanisms driving neurodegeneration remain incompletely understood. This review examines the increasing significance of the gut-brain-immune triad in the pathogenesis of NDs, with particular attention to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It explores how disruptions in gut microbiota composition and function influence neuroinflammation, blood-brain barrier integrity, and immune modulation through microbial-derived metabolites, including short-chain fatty acids, lipopolysaccharides, and bacterial amyloids.

In both Alzheimer's and Parkinson's diseases, a reduced abundance of short-chain fatty acid-producing bacterial taxa has been consistently associated with heightened pro-inflammatory signaling, thereby facilitating disease progression. Although detailed mechanistic understanding remains limited, experimental evidence - primarily from rodent models - indicates that microbial metabolites derived from a dysbiotic gut may initiate or aggravate central nervous system dysfunctions, such as neuroinflammation, synaptic dysregulation, neuronal degeneration, and disruptions in neurotransmitter signaling via vagal, humoral, and immune-mediated pathways.

The review further highlights how gut microbiota alterations in amyotrophic lateral sclerosis and multiple sclerosis contribute to dysregulated T cell polarization, glial cell activation, and central nervous system inflammation, implicating microbial factors in disease pathophysiology. A major limitation in the field remains the difficulty of establishing causality, as clinical manifestations often arise after extended preclinical phases - lasting years or decades - during which aging, dietary patterns, pharmacological exposures, environmental factors, and comorbidities collectively modulate the gut microbiome. Finally, the review discusses how microbial influences on host epigenetic regulation may offer innovative avenues for modulating neuroimmune dynamics, underscoring the therapeutic potential of targeted microbiome-based interventions in neurodegenerative diseases.

Link: http://dx.doi.org/10.14218/JTG.2025.00027

Heart failure is the name given to a category of dysfunctions in which the heart cannot pump enough blood to sustain the body. It is characterized by structural changes in heart muscle, some of which are maladaptive, some of which are compensatory, and a range of increasingly unpleasant consequences throughout the body and brain as the condition progresses in severity. The most prevalent cause of heart failure is the narrowing of important blood vessels by atherosclerotic plaque. The rupture of plaque to cause a transient blockage and heart attack can also sufficiently injure and weaken the heart in survivors to cross the threshold into heart failure. Hypertension is another common cause, as long-term disruption of the feedback mechanisms controlling blood pressure and heart activity causes enlargement and weakening of heart muscle, and thereby heart failure. There are other common contributing causes of heart failure that can in principle be sufficient on their own, such as severe atrial fibrillation and pulmonary hypertension, but in older people these issues are more usually coincident with atherosclerosis and hypertension.

In today's open access paper, researchers identify a harmful population of fibroblasts resident in heart tissue that only emerges in the state of heart failure. Fibroblasts are primarily responsible for generating extracellular matrix structures, and in an aged or damaged heart they also produce the scarring of fibrosis that reduces function. Fibroblasts have other capabilities, however, and the particular population of harmful fibroblasts engages in signaling that detrimentally changes the behavior of cardiomyocyte cells making up heart muscle. Interfering in this signaling may be a basis for therapies to reduce the progression of heart failure, preventing some fraction of the maladaptive changes in cell function that contribute to the condition.

Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC-CXCL1-CXCR2 axis

Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Although CFs are thought to maintain cardiac homeostasis primarily by producing extracellular matrices, CFs communicate with other cell types, including cardiomyocytes, via direct interactions and paracrine signaling. In response to diverse stresses under pathological conditions, CFs dynamically alter their phenotype, transitioning from resident fibroblasts to myofibroblasts and eventually matrifibrocytes after myocardial infarction (MI).

Single-cell RNA sequencing of mouse hearts under pressure overload identified heterogeneity in CFs across sham hearts, pressure-overload-induced hypertrophic hearts, and failing hearts, revealing an HF-specific subpopulation of fibroblasts, here designated as HF-Fibro. HF-Fibro expressed Postn, which is expressed in fibroblasts activated by MI, but not Acta2 or the osteochondral gene Chad, suggesting that HF-Fibro are different from myofibroblasts or matrifibrocytes that appear in MI hearts.

The HF-Fibro population also highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-Fibro CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes and blocking the CXCL1-CXCR2 axis mitigates HF. Additionally, CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls.

These findings reveal that HF-Fibro cells contribute to HF via the MYC-CXCL1-CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes.

A major trend in the world of stem cell therapies is the replacement of stem cell transplantation with the use of extracellular vesicles derived from those stem cells. Extracellular vesicles are much more easily managed as a basis for therapy, they are more easily stored and transported, and their production can be more centralized. Since stem cell therapies produce their benefits largely via the signals generated by the transplanted cells in the short period before they die, the use of stem cell derived extracellar vesicles appears a good substitute. The availability of extracellular vesicle therapies is spreading in the medical tourism community, where good data on outcomes is very hard to come by, and the more mainstream medical development community has started towards clinical trials and robust manufacturing approaches. One should probably expect to see a rerun of the trajectory of stem cell transplants over the past twenty years, slowly moving from initially widespread use in clinics in less regulated regions of the world to more codified and narrower uses within the heavily regulated clinical systems of Europe and the US.

Neuroaging is a complex biological process in which the brain undergoes progressive functional decline marked by synaptic loss, neuroinflammation, and cognitive decline. At the molecular and cellular level, aging is driven by multiple interconnected hallmarks, including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Among these, cellular senescence, a state of irreversible cell cycle arrest, has emerged as a critical contributor to brain aging. Senescent cells accumulate with age, driven by the p53-p21 and p16-pRb pathways, and secrete pro-inflammatory factors via senescence-associated secretory phenotype (SASP), thereby exacerbating neurodegeneration, vascular dysfunction, and cognitive decline.

Extracellular vesicles (EVs) are natural nanocarriers of proteins, lipids, and nucleic acids, and have emerged as key mediators of intercellular communication and therapeutics for aging and age-related conditions. EVs derived from various cell types, such as mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), can modulate senescence-related pathways, reduce inflammation, and promote tissue repair. Preclinical studies demonstrate that stem-cell-derived EVs can improve cognitive performance, enhance neurogenesis, reduce senescence phenotype, improve neuronal survival through neuroprotective miRNAs (miR-181a-2-3p), suppress neuroinflammation via inhibition of NLRP3 inflammasome, and support synaptic plasticity. Stem cell EVs possess natural biocompatibility, the ability to cross the blood-brain barrier (BBB), and targeted delivery mechanisms, making them promising candidates for anti-aging interventions.

Link: https://doi.org/10.20517/evcna.2025.65

That offspring inherit epigenetic patterns of modifications to gene expression that reflect the environmental exposures of their parents was a relatively recent discovery. The evolutionary world is just a little bit Lamarkian, in that the ability to steer the metabolic reactions of immediate descendants provides greater resilience to stressful environments. Short-lived species respond to mild stresses with extension of life span, presumably because this increases the odds of reaching a better environment in which offspring are more likely to survive. As shown here, that extension of life span fades for descendants if the stress is maintained over generations. There is at that point a different set of cost-benefit considerations when it comes to balancing the fitness advantage of a metabolism that ages more slowly versus the fitness advantage of a metabolism geared for early life reproductive success at the expense of faster aging. Evolution has clearly produced a complex set of transgenerational reactions to common stresses in the environment a species finds itself in.

Epigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased parental longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs.

Here, we find that Caenorhabditis elegans adapt to repeated generational stresses. We show that, upon two repeated generational hypoxia exposures, the life-span extension is eliminated, and after four repeated generational hypoxia exposures, the reduced fertility is eliminated. Transgenerational adaptation also occurred in response to changes in glucose availability. Transgenerational hypoxia adaptation is dependent on the H3K27 trimethyltransferase PRC2 complex, and we identified transgenerationally adapted genes. Our findings reveal that transgenerational adaptation occurs and suggest that H3K27me3 is a critical modification for adapting to repeated generational stresses.

Link: https://doi.org/10.1126/sciadv.adv9451

Osteoarthritis is a prevalent degenerative joint disorder, in which cartilage and underlying bone becomes worn and damaged, while the normal processes of repair (even limited as they are in cartilage tissue) are impaired by aging. Neurodegenerative conditions in the brain are a much more complex range of dysfunctions with many different contributing causes, and a less complete understanding of how various mechanisms of aging and measured pathological changes relate to one another. How are these two aspects of aging linked to one another? The first clue is that both are inflammatory conditions, characterized by excessive immune activation and continuous, unresolved inflammatory signaling. The normal short-term processes of inflammation, necessary and helpful in the context of injury and infection, become harmful and disruptive when sustained over the long term.

In today's open access paper, researchers explore the ways in which osteoarthritis and neurodegenerative pathologies may influence one another. Interestingly this isn't just a matter of inflammatory signaling, though that is front and center. There are other, more subtle interactions. Whether these other interactions are important in the bigger picture remains an open question. One of the characteristics of age-related disease is that the causes are multifaceted and complex in their interactions with one another, and it is very hard to assign relative importance to any one cause in the absence of a way to specifically eliminate only that one contributing factor of interest.

The brain-joint axis: links between osteoarthritis and neurodegenerative disorders in aging

Growing evidence suggest a strong epidemiological and pathological link between osteoarthritis (OA) and neurodegenerative diseases. Studies indicate an association between OA with Alzheimer's disease (AD) and Parkinson's disease (PD), driven by common mechanisms such as chronic systemic inflammation, metabolic dysfunction, and bidirectional communication along the brain-joint axis. These overlapping pathways may accelerate neurodegeneration, with meta-analyses indicating that OA patients face a 25% higher risk of developing neurological conditions compared with non-OA individuals.

In longitudinal analyses, OA was significantly linked to changes in hippocampal volume (HpVR) over time among individuals with normal cognition. Individuals with OA exhibited a more rapid decline in HpVR over time compared with those without OA. Furthermore, OA patients, especially those experiencing pain, are more likely to develop memory impairments and AD. Additionally, OA-induced chronic pain was associated with declines in multiple cognitive domains, including memory, attention, processing speed, and executive function, underscoring its critical role in worsening AD-related symptoms. Patients with knee OA show significant abnormalities in grey matter volume and functional brain activity compared with healthy individuals. Moreover, structural changes, such as cortical thinning, and functional disruptions, including altered cerebral blood flow and impaired functional connectivity in pain-related networks, were observed, particularly in the right anterior insula, highlighting an association between brain alterations and knee OA.

OA and neurodegenerative disorders, though clinically distinct, share converging age-related pathophysiological mechanisms, including chronic inflammation, oxidative stress, and mitochondrial dysfunction. We propose that OA is not merely a localized musculoskeletal disorder but part of a broader systemic neuro-immuno-endocrine network whose dysfunction contributes to neurodegeneration. Emerging evidence highlights a bidirectional brain-joint axis, whereby systemic and local inflammatory cascades may reciprocally exacerbate both joint degeneration and neuronal injury, creating a self-perpetuating cycle that accelerates age-related decline.

In OA, a chronic low-grade inflammation leads to the sustained release of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α). Systemic inflammation may increase blood brain barrier permeability and alter tight-junction integrity, as inferred by the reduced expression of tight junction proteins in the brain observed in animal models. This allows inflammatory mediators to infiltrate the central nervous system (CNS), triggering neuroinflammation, microglial activation, oxidative stress, and synaptic dysfunction as key drivers of neurodegeneration. Neurodegenerative processes may also impair endogenous pain modulation, worsening central sensitization and OA-related symptoms. This model underscores that inhibition of peripherial inflammation may attenuate neuronal loss and neurodegeneration.

One of the ways in which the immune cells known as neutrophils attack pathogens is to release structures called neutrophil extracellular traps into the intracellular environment. These traps can disable pathogens, but like much of the activity of the immune system, too much of a good thing becomes harmful. Excessive neutrophil generation of traps in the aged tissue environment promotes chronic inflammation, and here researchers focus specific on the consequences of this activity in the vasculature, where it promotes the onset of cardiovascular disease. While relatively little work has been carried out on approaches to clear traps or reduce the pace of their creation, a range of evidence suggests that this might be a viable strategy to improve the state of the aged vasculature.

Blood vessels are critical in systemic aging with arteries stiffening and calcifying due to chronic inflammation and oxidative stress, driving age-related cardiovascular and cerebrovascular diseases. In this review, neutrophil extracellular traps (NETs) - web-like structures composed of decondensed chromatin, histones, and antimicrobial proteins released by neutrophils - are explored as therapeutic targets in vascular aging.

NETs are vital for pathogen defense, but their excessive activation leads to inflammation and vascular pathologies, promoting endothelial dysfunction, inflammatory aging, and vascular remodeling in diseases such as hypertension, atherosclerosis, myocardial infarction, heart failure, atrial fibrillation, ischemic stroke, and Alzheimer's disease. Increasing evidence supports that modulating NETs through inhibitors or scavengers can reduce inflammatory responses, preserve endothelial integrity, and improve prognosis. As a potential therapeutic target, growing attention has been directed toward exploring the balance between NET induction, inhibition, and degradation.

Link: https://doi.org/10.3389/fimmu.2025.1657938

Researchers here report on a novel approach to slow aging and extend life in mice by interfering in the activity of a protein involved in the regulation of metabolism. The researchers find that SAPS3 expression increases with age, and deletion of this gene slows metabolic aging. SAPS3 is a component of a protein complex that reduces levels of AMPK. Upregulation of AMPK is known to slow aging, and here that is achieved by disabling the SAPS3-related process that acts to reduce AMPK levels. The size of the effect on life span in mice is modest, as one might expect given past work on AMPK and aging. This illustrates the point that biochemistry is complex, and for any given target there are many different ways (upstream and downstream in networks of protein interactions) in which one can intervene to achieve a given result.

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice.

We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.

Link: https://doi.org/10.1126/sciadv.adt3879

Proteins are largely quite delicate structures dependent on being manufactured and correctly folded and localized inside a cell. Thus no-one tries to make recombinant proteins or deliver them as a therapy for the vast majority of proteins. The exceptions are those proteins robust enough to be secreted by a cell and circulate in blood and other fluids in the body. In that case one can develop means of manufacture and build a recombinant protein that can be injected as a basis for therapy, assuming that more of that protein is a desirable goal. So far as I am aware it is unusual to find a protein that can survive oral administration and the harsh environment of the gastrointestinal tract, and then enter circulation to produce the same beneficial effects that the natively manufactured protein is capable of achieving. An energetic portion of the research community is actively engaged in trying to find ways to enable proteins to survive oral administration.

A fair amount has been written on the topic of BPIFB4 and its effects on life span and cardiovascular disease in recent years. The longevity-associated variant of the protein both reduces inflammation and reduces the impact of aging on the ability of blood vessels to contract and dilate. Exploration continues to try to fully understand its effects on the complex regulation of the vascular system. While the longevity-associated variant of BPIFB4 was discovered in humans, researchers have demonstrated in a number of studies that it produces benefits in aged mice. Today's open access paper on this topic is largely interesting because the authors used oral administration of a recombinant longevity-associated variant of BPIFB4. This is not the expected next step after earlier success in mice with BPIFB4 gene therapies, precisely because, as mentioned above, very few proteins can be delivered orally.

In vivo evidence supports the effectiveness of the longevity-associated protein LAV-BPIFB4 in reducing adipose tissue-derived mediators of systemic inflammation to prevent vascular insult and atheromatous change

Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models.

Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied n = 5 ApoE-/- mice on standard diet (SD), n = 5 (VEH-HFD) and n = 6 (LAV-HFD) ApoE-/- mice fed high-fat diet without or with rhLAV-BPIFB4 protein. Primary pre-adipocyte cultures were established from epididymal WAT to evaluate CD45+CD38+ leukocyte infiltration, inflammatory profile of pre-adipocytes, and ex vivo effects of conditioned media on vessels.

Oral administration of rhLAV-BPIFB4 in ApoE-/- mice fed high-fat diet dampens atherosclerosis by preserving endothelial integrity and reducing ICAM+ and CD68+ cell infiltration. Despite unchanged adiposity, systemically rhLAV-BPIFB4 reduces pro-inflammatory cytokines (IL-1α/β, TNF-α, IL-6) while mildly increasing IL-10 levels. Supernatants from pre-adipocytes treated with rhLAV-BPIFB4 demonstrate similar anti-inflammatory cytokine profiles. Conditioned media from rhLAV-treated eWAT ex vivo restores endothelial function in dysfunctional arteries. Collectively our data show that targeting adipocyte-associated inflammation, LAV-BPIFB4 emerges as a promising therapeutic strategy to counteract endothelial dysfunction in obesity.

Researchers here demonstrate that diluting calorie intake with non-digestible fiber produces similar outcomes in the health and longevity of mice as does moderate calorie restriction. The researchers also combined this intervention with exome matching of amino acid composition of dietary protein. Exome matching implies that the amino acid composition of proteins in the body is matched to that of the diet; interestingly, mice prefer such exome matched chow over other options. The degree to which either of these approaches can be implemented on a practical basis in a human diet is an interesting question, certainly some discussion and research would be needed. Adding cellulose starch as non-digestible fiber to the diet is certainly possible, but at 30% of all food intake by weight, the amount used here, that may produce complications, logistical and otherwise.

Caloric restriction (CR) is the most extensively studied dietary approach for delaying ageing and extending lifespan across many taxa. In vertebrates such as mice, rats and nonhuman primates, CR is typically implemented by restricting food intake to 50%-80% of ad libitum-fed consumption, provided as a single daily portion with micronutrient supplementation. This feeding regimen induces both energy restriction and extended fasting periods because animals usually consume all available food within a few hours and then fast until the next feeding cycle.

In our previous work with ad libitum-fed mice, we applied this framework and demonstrated that the ratio of dietary protein to carbohydrates influences lifespan. In that study, we incorporated non-digestible cellulose into certain diets to simulate the effects of CR in ad libitum-fed animals. This marked the first instance of CR achieved by dietary dilution in mice. As anticipated, mice consuming the high-cellulose diets increased their food intake as a compensatory response to nutrient dilution, yet their overall energy intake decreased. However, that previous study did not include a comparison to a conventional CR-treated group.

A recent nutritional intervention that may influence growth and longevity is exome-matching. This involves manipulating dietary protein so that dietary amino acids are at a ratio matched with the exome, thereby meeting (without excess) the predicted requirements for protein translation under physiological conditions. Here, we compared longevity and ageing in mice on three diets: an ad libitum-fed control diet (Con); a conventional 20% CR diet; and a low-protein, high-carbohydrate (LPHC) ad libitum-fed diet, which caused caloric restriction through dilution with non-digestible fibre. The amino acid composition of dietary protein in all diets was exome-matched to reduce variation in food intake caused by an imbalance of amino acids.

Survival curves show that the LPHC and CR diets had similar effects on lifespan compared with the ad libitum control diet. LPHC and CR diets significantly increased median lifespan by 17% and 11%, respectively, compared to the control diet. There was no statistically significant difference between median lifespans of the CR versus LPHC. Maximum lifespans were 1008 days for controls, 1179 days for CR, and 1115 days for LPHC diets. Sex was not a significant effect modifier.

Link: https://doi.org/10.1111/acel.70269

A fair sized body of evidence shows that circadian rhythm, the daily cycle of changed gene expression and behavior in cells, is important to tissue function but becomes disrupted with age and age-related disease. The regulation of circadian rhythm is complex and occurs distinctly the central nervous system and periphery of the body, and so one of the ways in which problems arise is when different cell types and tissues fall out of synchronization of rhythm. Here, researchers show that the aggregation of misfolded amyloid-β thought to be the initiating cause of Alzheimer's disease causes disruption of circadian rhythm in supporting cells in the brain, yet another view of the complex pathology of the condition.

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging.

Our data reveal that astrocytes and microglia have robust and unique circadian translatomes, that circadian gene expression patterns reprogram dramatically in the setting of amyloid pathology or aging, and that changes are cell-type specific and context dependent. The core circadian clock was generally robust in the setting of amyloid plaque pathology in bulk cortex, astrocytes and microglia, although downstream rhythms in AD-relevant gene expression underwent dramatic circadian reprogramming. However, aging caused blunting of core clock gene rhythms in microglia, but not in astrocytes.

Our findings illustrate that circadian rhythms in gene expression are highly dependent on cell type and are reprogrammed in a context-dependent manner, in some cases despite robust core clock oscillation. We find that many transcripts related to metabolism, proteostasis, and AD show rhythmic expression that can be altered by pathology, emphasizing the importance of circadian regulation of gene expression and cellular function in aging and neurodegenerative conditions.

Link: https://doi.org/10.1038/s41593-025-02067-1