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- Towards Better Approaches to Systemic Delivery of Gene Therapies
- The Toxic NMDAR-TRPM4 Interaction in Alzheimer's Disease
- Declines from Peak Cognitive Function Start in Early Adulthood
- The Goal of Reversing Immune Aging
- The CCND1-CDK6 Complex as a Target for Senotherapeutics
- Life Extension in Aged Frail Mice via Reduced TGF-β and Increased Oxytocin
- Treating Neurodegeneration with Monocytes and Macrophages Derived from Induced Pluripotent Stem Cells
- Gene Therapy Delivery of Bacterial Sodium Channels Improves Outcome Following Stroke
- Electrical Stimulation Can Induce Macrophages into the Pro-Regenerative M2 Phenotype
- Erosion of Epigenetic Control in the Alzheimer's Brain
- Repurposing the Normal Clearance of Dead Cells to Target Unwanted Live Cells
- GLP-1 Receptor Agonist Use Reduces Heart Failure Mortality
- Cardiovascular Disease Correlates Robustly with Dementia Risk
- Yet More Mouse Data on Fisetin as a Senotherapeutic
- Reviewing What is Known of Glial Cell Aging in the Cerebellum
Towards Better Approaches to Systemic Delivery of Gene Therapies
https://www.fightaging.org/archives/2025/09/towards-better-approaches-to-systemic-delivery-of-gene-therapies/
The biggest challenge facing the deployment of gene therapies for the treatment of aging and age-related disease is that delivery systems are lacking. There is no well established way to safely and robustly deliver a payload of sufficient size to most organs (or all organs) without multiple direct injections, an approach that bears an unacceptable risk when deployed across very large numbers of relatively healthy people. When delivering a gene therapy via intravenous injection, the bloodstream carries most of the payload to the liver and lungs, and this limits the amount of drug that can be introduced to any given other organ because delivery systems are toxic at higher doses. The amount that ends up in the liver dramatically limits what can be done.
A connected issue is that the options for selective expression of a transgene by tissue type are also limited. Selective expression requires introducing a transgene and an associated promoter structure either into the genome or as a plasmid into the cell nucleus; the promoter structure can usually be cleverly tailored to condition expression of the transgene to the desired cell type. The well-trodden options for vectors today are (a) viral vectors and (b) various forms of lipid nanoparticles (LNPs) delivering messenger RNA (mRNA). Viral vectors have the issue noted in the first paragraph above: while you can specify expression by cell type by tailoring the payload of the virus, if one wants sufficient amount of vector to be delivered to a specific tissue, one either risks toxicity in the liver and lungs or undertakes direct injection. LNP-mRNA vectors have two issues: firstly that selective delivery is only well solved for the liver, and secondly that mRNA cannot perform selective expression. It will express in every cell delivered to.
People are working on these problems. One of the most promising near future advances, generally agreed upon to be possible in principle, would be some form of viral vector or LNP delivering DNA plasmids rather than mRNA that more smoothly distributes to the whole body following intravenous injection. No vast buildup of vector inside liver cells or lung cells with minimal delivery to smaller organs, but a distribution that is closer to being even. In the case of LNP-DNA therapies, this hypothetical improvement would also require a novel technology to allow DNA plasmids to safely and effectively enter the cell nucleus. Clearly this also is possible in principle, as it is exactly what an adeno-associated virus (AAV) does. But engineering one of the existing widely used DNA plasmid structures to do this once dropped into the cell cytosol via uptake of an LNP remains an unsolved problem.
Today's open access paper from the Entos Pharmaceuticals team reports on their progress towards a better LNP, one that is very much less toxic than present standards, and delivers more smoothly throughout the body. To the degree that an LNP has very low toxicity, one can accept more of an excess delivery to the liver, provided that one is delivering DNA plasmids that will only express the transgene in the desired organ. Promisingly, the work reported here is relevant to both mRNA and DNA delivery. Specific optimizations of LNP composition and manufacture will differ between delivery of mRNA and DNA, but the general strategy should work in both cases.
Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles
Non-viral delivery vehicles such as lipid nanoparticles (LNPs) have been widely used for RNA-based therapeutic approaches and have cost, manufacturing, and immunogenicity advantages over viral vectors. The approval of patisiran (Onpattro) as a systemic therapy and the more recent success of LNP mRNA COVID-19 vaccines has set the stage for the development of numerous LNP-based nucleic acid therapies. LNPs are formulated with ionizable lipids, which facilitate endosomal escape. However, formulations containing ionizable lipids are also associated with tolerability challenges such as potentiation of apoptotic cell death and dose-limiting liver toxicity following systemic delivery.
Given the strengths and limitations of current viral and non-viral approaches, we developed a proteolipid vehicle (PLV) platform that incorporates an engineered viral fusion protein into a lipid-based formulation to achieve intracellular delivery of nucleic acid cargoes with low immunogenicity and high tolerability. The PLV platform utilizes fusion-associated small transmembrane (FAST) proteins derived from the non-enveloped fusogenic orthoreovirus. At 100-200 residues in length, FAST proteins are the smallest known viral fusogens. These fusion proteins are expressed inside virus-infected cells and are trafficked to the plasma membrane where they facilitate cell-cell membrane fusion, generating multinucleated syncytia to facilitate viral transmission. FAST proteins function at physiological pH and do not require specific cell receptors, allowing them to fuse almost all cell types.
We previously showed in proof-of-concept experiments that FAST protein-containing liposomes induce liposome-cell fusion and facilitate intracellular delivery of encapsulated membrane-impermeable cargo. Here, we evaluated a panel of chimeric FAST protein constructs for fusion activity to identify a high-activity FAST protein chimera that was formulated into a PLV comprised of well-tolerated lipids. We demonstrate that FAST-PLVs comprise a nucleic acid delivery platform that mediates effective delivery and expression of encapsulated mRNA and DNA in vitro and in vivo, while maintaining excellent tolerability, low immunogenicity, and favorable biodistribution in rodent and non-human primate (NHP) models.
Systemically administered FAST-PLVs showed broad biodistribution and effective mRNA and DNA delivery in mouse and non-human primate models. FAST-PLVs show low immunogenicity and maintain activity upon repeat dosing. Systemic administration of follistatin DNA gene therapy with FAST-PLVs raised circulating follistatin levels and significantly increased muscle mass and grip strength. These results demonstrate the promising potential of FAST-PLVs for redosable gene therapies and genetic medicines.
The Toxic NMDAR-TRPM4 Interaction in Alzheimer's Disease
https://www.fightaging.org/archives/2025/09/the-toxic-nmdar-trpm4-interaction-in-alzheimers-disease/
Alzheimer's disease is a slow progression over time and lost cognitive function, but it does kill people in the end. How exactly does the pathology of Alzheimer's disease cause the widespread death of neurons that is characteristic of the late stages of the condition and the eventual cause of death? There are many ways of building an answer to this question, as one can focus on many different parts of the chain of cause and consequence that must exist in the less well studied spaces that exist between the more well studied aspects of Alzheimer's biochemistry. On the one hand protein aggregation of amyloid-β and tau, and on the other hand disrupted metabolism and cell death in neurons, and in between a great deal of dark matter.
In today's open access paper, researchers focus on a mechanism that is closer to neuronal cell death in the chain of cause and effect than is the case for protein aggregation. Two receptors on the cell surface of neurons combine in the context of other Alzheimer's disease cellular dysfunction to cause cell death via a range of severe downstream consequences. The researchers found a way to specifically interfere in the interaction between these two receptors, a necessary approach to therapy, as both are individually essential to cell function and thus cannot be depleted. This interference appears to slow the pathology of Alzheimer's disease in a mouse model of the condition. Interestingly, it has also shown promise in other neurodegenerative conditions, such as in models of ALS.
The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified.
Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex.
FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains.
Declines from Peak Cognitive Function Start in Early Adulthood
https://www.fightaging.org/archives/2025/09/declines-from-peak-cognitive-function-start-in-early-adulthood/
Cognitive function can be measured in many different ways. It is generally considered to consist of a number of different domains that are influenced by different aspects of brain physiology and biochemistry, and which can improve and decline to different degrees over the course of a lifetime. We should expect the various forms of memory, executive function, sensory processing, and cognitive control to be capable of differing in trajectories as degenerative aging progresses, for example. Indeed, studies show this to be the case. While the story of aging writ large is a story of decline, the details have considerable latitude to vary.
The brain develops, and then the brain declines. There is thus a peak of cognitive function, distributed across some range of chronological ages for a given population. The location of that peak will likely vary for the different domains of cognitive function in any specific study population for the reasons given above. Here, researchers show that cognitive control peaks relatively early in adult life, at least relative to the usual perceptions of the character of growing old. As matters actually progress, a person may be sharply intelligent in their late 20s, then not so sharp but a great deal more experienced in their late 40s. A part of that loss of sharpness is a decline in cognitive control.
When does our brain start getting 'old'? Charting the lifespan trajectories of cognitive control
Cognitive control refers to the cognitive process through which individuals regulate attention, thought, and action to achieve specific goals, allowing them to focus on objectives while excluding distractions. For example, maintaining concentration on reading in a library where people are conversing relies heavily on the cognitive control's regulation of attention. Although the patterns of cognitive and behavioral changes related to cognitive control have been well established and serve as diagnostic criteria for development-related and aging-related diseases, systematic research on the corresponding brain activities' changes with age remains limited.
This study collected 139 neuroimaging studies related to cognitive conflict tasks, encompassing 3,765 participants aged 5 to 85 years. Through systematic meta-analysis using seed-based effect size mapping (SDM), generalized additive models (GAM), and model comparison methods, researchers were able to construct the lifespan trajectory of brain activities associated with cognitive control for the first time. The core finding revealed a significant inverted U-shaped lifespan developmental trajectory, where brain activity gradually increases during childhood and adolescence, peaks during adulthood, and slowly declines in later life. The GAM-fitted peak age was found to be between 27 and 36 years.
This period coincides with the peak of individual intellectual maturity and overall cognitive ability, providing a scientific explanation for the high social productivity and creativity exhibited by humans during this phase from a neural mechanism perspective. Notably, the gradual decline in brain function following this peak period suggests the need to prioritize the maintenance and exercise of brain function during middle adulthood to mitigate potential cognitive decline associated with aging.
The lifespan trajectories of brain activities related to conflict-driven cognitive control
Cognitive control is fundamental to human goal-directed behavior. Understanding its trajectory across the lifespan is crucial for optimizing cognitive function throughout life, particularly during periods of rapid development and decline. While existing studies have revealed an inverted U-shaped trajectory of cognitive control in both behavioral and anatomical domains, the age-related changes in functional brain activities remain poorly understood.
To bridge this gap, we conducted a comprehensive meta-analysis of 139 neuroimaging studies using conflict tasks, encompassing 3765 participants aged 5 to 85 years. We adopted the seed-based d mapping (SDM), generalized additive model (GAM), and model comparison approaches to investigate age-related changes in brain activities to characterize the lifespan trajectories of cognitive control. Our analyses revealed two key findings: (1) The predominant lifespan trajectory is inverted U-shaped, rising from childhood to peak in young adulthood (between 27 and 36 years) before declining in later adulthood; (2) Both the youth and the elderly show weaker brain activities and greater left laterality than young adults. These results collectively reveal the lifespan trajectories of cognitive control, highlighting systematic fluctuations in brain activities with age.
The Goal of Reversing Immune Aging
https://www.fightaging.org/archives/2025/09/the-goal-of-reversing-immune-aging/
It is difficult to overstate the importance of immune system dysfunction as a component of degenerative aging. All of the common fatal age-related diseases are strongly connected to immune dysfunctions, particularly the chronic inflammation that occurs with age. At the high level, researchers tend to divide immune aging into two components: immunosenescence is a loss of the ability of the immune system to defend against pathogens and destroy unwanted cells; inflammaging is a state of continual, unresolved inflammatory signaling, a maladaptive reaction to the altered environment and molecular damage of aged tissues. Both immunosenescence and inflammaging are just different viewpoints into one very complex bundle of dysfunctional mechanisms, signals, behaviors, and cell populations, however. One does not occur without the other, because they both arise from the same underlying issues.
Identifying the underlying issues that give rise to immune aging is an important part of building therapies to reverse the dysfunction. Some areas of focus are more promising than others. For example, attempts to fairly bluntly manipulate the signaling environment to suppress inflammation by inhibiting specific circulating proteins or their interactions with receptors are favored by the research and development communities, even though these approaches also suppress necessary inflammatory signaling and thereby inhibit the effectiveness of the immune system. Better approaches include restoration of hematopoietic stem cell function in bone marrow, regrowth of the thymus, and adjustment of the gut microbiome, where in principle there will be much less in the way of unpleasant trade-offs between benefit and side-effect.
Targeting immunosenescence and inflammaging: advancing longevity research
Aging profoundly affects the immune system, leading to two interrelated phenomena: immunosenescence and inflammaging. Immunosenescence is characterized by the immune system's functional decline, reduced immune surveillance, diminished T cell diversity and a weakened response to new infections and vaccinations. Inflammaging, on the other hand, refers to chronic, low-grade inflammation driven by factors such as senescent cells, damage-associated molecular patterns, and alterations in the gut microbiome. Together, these processes accelerate tissue degeneration, systemic dysfunction, and the development of age-related diseases while further impairing immune function.
Emerging therapeutic strategies targeting immunosenescence and inflammaging offer hope for restoring immune balance, reducing inflammation, and extending healthspan. Interventions such as thymus rejuvenation, hematopoietic stem cell modulation and senolytic therapies can potentially combat immune decline. Additionally, technologies targeting IL-11 inhibition and toll-like receptors (TLR5 or TLR7) activation have effectively reduced chronic inflammation and enhanced immune resilience. Specifically, IL-11 inhibition mitigates systemic inflammation and supports tissue regeneration, while TLR5 or TLR7 activation strengthens immune function and promotes regenerative capacity, collectively contributing to lifespan extension.
However, understanding the complexity of immunosenescence and inflammaging is critical to developing effective therapeutic interventions. While chronic inflammation is often viewed as detrimental, inflammation plays a vital role in immune defense, tissue repair, and vaccine efficacy. The challenge lies in maintaining a balance - promoting inflammation's protective effects while mitigating its chronic, maladaptive impacts during aging. Ultimately, by addressing both immune decline and chronic inflammation, these strategies can potentially transform how aging and age-related diseases are managed. Success in these endeavors could extend lifespan and meaningfully improve healthspan, ensuring healthier aging for future generations.
The CCND1-CDK6 Complex as a Target for Senotherapeutics
https://www.fightaging.org/archives/2025/09/the-ccnd1-cdk6-complex-as-a-target-for-senotherapeutics/
Senescent cells accumulate with age in tissues throughout the body, primarily when a cell reaches the Hayflick limit on replication, but also because of damage or stress. When a cell becomes senescent it ceases to replicate and undergoes profound metabolic changes that cause it to secrete a pro-inflammatory, pro-growth set of signals known as the senescence-associated secretory phenotype (SASP). This serves a useful purpose in the context of potentially cancerous cells, attracting the immune system to destroy them, and aids in regeneration from injury. In youth, senescent cells are efficiently destroyed by the immune system, but with advancing age this clearance slows down. A growing imbalance between creation and destruction allows senescent cells to accumulate, and the inflammatory signaling that is useful in the short term becomes increasingly harmful when sustained for the long term.
One of the possible approaches to the treatment of aging is to destroy senescent cells. While appearing to be beneficial in mice, extending life span and reversing age-related dysfunction in many studies, there are some concerns that removing senescent cells could cause harm in some contexts. For example if senescent cells are supporting the structure of a sizable atherosclerotic plaque then clearing them could increase the risk of plaque rupture and a consequent heart attack or stroke. While not yet supported by a sizable body of evidence, this viewpoint has led a number of research teams to search for ways to reduce the SASP rather than destroy senescent cells. If a senescent cell just sat there and did not signal, then its contribution to degenerative aging would be largely eliminated. One might look at the senescent cells in long-lived naked mole-rats, for example, as they exhibit an attenuated SASP and do not appear to contribute to aging in way that senescent cells do in mice.
Thus one sees papers like today's open access research materials, in which researchers dig into the fine details of the mechanisms by which the senescent state triggers inflammatory signaling. Researchers are looking for potential targets for therapies that could interfere in the generation of the SASP without causing meaningful side-effects in the biochemistry of non-senescent cells.
Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline
Cellular senescence is a stable form of cell-cycle arrest triggered by stresses such as DNA damage, oncogene activation, and telomere shortening. Senescent cells accumulate with age in many tissues and contribute to chronic inflammation, tissue dysfunction, and age-related pathologies through secretion of pro-inflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs), collectively termed the senescence-associated secretory phenotype (SASP). Persistent DNA damage signaling in senescent cells promotes the formation of cytoplasmic chromatin fragments (CCFs) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which sustains SASP and systemic inflammation. Identifying the molecular drivers that maintain this chronic inflammatory state is essential for understanding and targeting age-related dysfunction.
Cyclin D1 (CCND1), classically defined as a regulator of G1 progression through activation of CDK4/CDK6 and phosphorylation of the retinoblastoma protein (pRB), is paradoxically elevated in senescence despite proliferative arrest. The functional significance of CCND1 upregulation in non-proliferating, senescent cells remain unclear. Moreover, whether CCND1's unconventional accumulation contributes causally to persistent DNA damage signaling, cytoplasmic chromatin stress, or inflammatory gene expression has not been explored.
Here, we investigate the role of CCND1 and its associated kinase CDK6 in sustaining DNA damage, cytosolic chromatin accumulation, and inflammatory signaling in senescence. Using complementary in vitro and in vivo models, we reveal an essential role for the CCND1-CDK6 complex in promoting persistent DNA damage, CCF formation, and cGAS-STING-driven inflammation. Mechanistically, we identify previously unrecognized interactions between CCND1 and chromatin-associated kinesin proteins, such as KIF4A, which has been implicated in chromatin architecture and DNA repair. Finally, we show that genetic ablation of CCND1 in aged hepatocytes or pharmacological inhibition of CDK4/6 significantly attenuates chronic inflammatory signaling and ameliorates age-associated functional decline, suggesting broad therapeutic implications.
Life Extension in Aged Frail Mice via Reduced TGF-β and Increased Oxytocin
https://www.fightaging.org/archives/2025/09/life-extension-in-aged-frail-mice-via-reduced-tgf-%ce%b2-and-increased-oxytocin/
You might recall that one of the approaches to emerge from considerations of the differences between old blood and young blood, and why connecting the circulatory systems of an old mouse and a young mouse produces some modest degree of rejuvenation in the old mouse, is to combine a reduction in circulating TGF-β with an increase in circulating oxytocin. This is under development as a potential form of therapy, and along the way researchers are accumulating animal study data. Here find the results of a recent study in frail, aged mice that shows an interestingly large difference in the outcome for male mice versus female mice.
Important studies report acute rejuvenation of mammalian cells and tissues by blood heterochronicity, old plasma dilution, defined factors, and partial reprogramming. And extension of rodent lifespan via single-prong methods was tried in recent years. Here, we examined whether simultaneous calibration of pathways that change with aging in opposite directions would be more effective in increasing healthspan and lifespan. Moreover, we started with the challenging age group - frail 25-months-old mice that are equivalent to ~75-year-old people.
We used an Alk5 inhibitor (A5i) of the age-elevated, pro-fibrotic transforming growth factor-beta (TGF-β) pathway that regulates inflammatory factors, including IL-11, and oxytocin (OT) that is diminished with age and controls tissue homeostasis via G-protein-coupled receptor and ERK signaling. Treatment of old frail male mice with OT+A5i resulted in a remarkable 73% life extension from that time, and a 14% increase in the overall median lifespan. Further, these animals had significantly increased healthspan, with improved physical performance, endurance, short term memory, and resilience to mortality. Intriguingly, these benefits manifested only in the male and not in the female mice, yet OT+A5i had positive effects on fertility of middle-aged female mice.
Mechanistically, metabolic proteomics on the blood serum demonstrated that the acute, 7-day, treatment of the old mice with OT+A5i youthfully restored systemic signaling determinants and reduced protein noise in old mice of both sexes. However, after 4 months of OT+A5i, only old male, but not female, mice remained responsive, showing the youthful normalization of systemic proteome. These findings establish the significant health-span extension capacity of OT+A5i and emphasize the differences in aging and in response to longevity therapeutics between the sexes.
Treating Neurodegeneration with Monocytes and Macrophages Derived from Induced Pluripotent Stem Cells
https://www.fightaging.org/archives/2025/09/treating-neurodegeneration-with-monocytes-and-macrophages-derived-from-induced-pluripotent-stem-cells/
Innate immune cells, particularly monocytes and macrophages, are important to tissue function throughout the body. Like all cell populations, they become dysfunction in various ways with advancing age. A particular issue is that these cells become more inflammatory. These cells are not present in the brain to any great degree; the brain has its own population of analogous cells called microglia. Thus it is interesting to see that delivering functional, youthful monocytes and macrophages into circulation can improve function in the aging brain. There are likely many indirect mechanisms at work beyond the question of the chronic inflammation of aging, but effects on inflammation would be the first place to look.
Young blood or plasma improves cognitive function in aged animals but has limited availability. The current study generates a subtype of young blood cells from easily expandable induced pluripotent stem cells and evaluates their effects on age- and Alzheimer's disease (AD)-associated cognitive and neural decline. In aging mice, intravenous delivery of induced mononuclear phagocytes (iMPs, including monocytes and macrophages) improves performance in hippocampus-dependent cognitive tasks, increases neural health, and reduces neuroinflammation.
Hippocampal single nucleus RNA-sequencing shows that iMPs improve the health of a subpopulation of mossy cells that are critically involved in the type of cognitive task in which iMPs improve performance, and shows that iMPs decrease the transcriptional age of several hippocampal cell types. Plasma proteomic analyses reveal that iMPs can also reverse age-associated increases in serum amyloid levels. This is verified in vitro, where iMP-conditioned media is shown to protect human microglia against cell death induced by serum amyloids. Finally, iMPs improve cognition in both young and aging 5×FAD mice, highlighting their potential as a prevention as well as an intervention strategy.
Together, these findings suggest that iMPs provide a novel therapeutic strategy to target both age- and AD-related cognitive decline.
Gene Therapy Delivery of Bacterial Sodium Channels Improves Outcome Following Stroke
https://www.fightaging.org/archives/2025/09/gene-therapy-delivery-of-bacterial-sodium-channels-improves-outcome-following-stroke/
The research here is notable for having progressed as far as a non-human primate study, as the conventional wisdom is that delivery of bacterial genes into mammals via forms of gene therapy is a bad idea because of the potential for immunogenic reactions. It is hard to find funding for any such project, and almost impossible for it to progress far along the path of development in a biotech company. Investors are more skeptical than regulators and will be very wary even given good data. Nonetheless, this is an interesting project, even if it is a little far on the compensatory side of the house: it is better to aim at prevention of heart attacks than to aim at helping the survivors be less impacted.
Current clinical therapies for myocardial infarction (MI) and sudden cardiac death show limited efficacy. The ability to enhance amplitudes of peak sodium (Na+) current and calcium (Ca2+) transient in cardiomyocytes could uniquely prevent arrhythmias and improve the contractile function of infarcted hearts. Previously, we leveraged the small size of engineered prokaryotic voltage-gated Na+ channels (BacNav, <1 kb) to overcome the adeno-associated virus (AAV) size constraint on delivered sequences and demonstrated that BacNav expression can directly enhance cardiac excitability. Here, we investigated whether cardiomyocyte-specific BacNav expression can provide both antiarrhythmic and inotropic benefits to the injured heart.
Encouraged by the in vitro results, we tested therapeutic efficacy of BacNav delivery in a Cynomolgus macaque model of ischemia-reperfusion (I/R)-induced MI. On the I/R injury, 10^12 vector genome/kg self-complementary AAV9-MHCK7-BacNav-HA (human influenza hemagglutinin tag) or self-complementary AAV9-MHCK7-GFP (green fluorescent protein) virus was injected intramyocardially in and around the infarct. Sham-surgery animals served as control. Immunostaining for HA tag fused to BacNav 4 weeks post-AAV injection demonstrated robust transgene expression around the infarction site, with successful targeting of BacNav channels to the T-tubular sarcolemma.
Longitudinal monitoring of cardiac contractile function by transthoracic echocardiography (ECG) revealed that at 1 week post-MI, left ventricular ejection fraction was similarly decreased in BacNav- and GFP-treated animals compared with sham-injury controls. By 4 weeks post-MI, GFP-treated but not BacNav-treated animals showed further decrease in left ventricular ejection fraction and increase in left ventricular end-systolic volume, with BacNav 4-week values not being significantly different from sham animals. Simultaneously, left ventricular end-diastolic volume did not differ across groups or time points suggesting that AAV-mediated, cardiomyocyte-specific BacNav expression directly counteracted an MI-induced contractile deficit.
We also implanted loop recorders at the time of MI induction and analyzed occurrence of spontaneous arrhythmias from recorded ECG traces during the 4-week follow-up. All 6 animals in the GFP group developed arrhythmic events, whereas only 1 animal in the BacNav group and 2 animals in the sham group exhibited arrhythmias.
Electrical Stimulation Can Induce Macrophages into the Pro-Regenerative M2 Phenotype
https://www.fightaging.org/archives/2025/09/electrical-stimulation-can-induce-macrophages-into-the-pro-regenerative-m2-phenotype/
Why do some applications of electric fields appear to enhance regeneration from injury? The study of the effects of electromagnetism on cell behavior lags far behind the study of biochemistry, the effects of proteins and small molecules. Here, researchers provide evidence for electrical stimulation to be able to shift macrophage cells into a more pro-regenerative state. Macrophages are innate immune cells resident in tissue that conduct a wide range of tasks relating to defense against pathogens, destruction of harmful cells, and coordination of tissue maintenance. Macrophages adopt packages of behaviors dependent on circumstances; the most prominent model for describing those behaviors is the distinction between M1 macrophages (aggressive, inflammatory) and M2 macrophages (regenerative, anti-inflammatory). A fair amount of research effort has been directed towards ways to encourage macrophages to adopt a specific desired state in order to treat disease, particularly inflammatory disease.
Modulation of the immune response, in particular innate immune cells such as macrophages, has emerged as a promising strategy to combat degenerative disease and promote effective tissue repair. Electrical stimulation has the potential to regulate cell function during wound healing and regeneration; however, studies to date regarding the effects of electrical stimulation on macrophages remain limited, particularly regarding primary human cells.
Here, we demonstrate that electrical stimulation exhibits an immunomodulatory effect on primary human macrophages, promoting an anti-inflammatory pro-regenerative phenotype, accompanied by decreased inflammatory macrophage marker expression and enhanced expression of angiogenic genes. Furthermore, we highlight the ability of electrically stimulated macrophages to promote angiogenic tube formation in human umbilical vein endothelial cells (HUVECs), as well as mesenchymal stem cell (MSC) migration in a wound scratch model. Collectively, these findings endorse electrical stimulation as a viable therapeutic strategy for the modulation of macrophages across multiple injury and defense microenvironments.
Erosion of Epigenetic Control in the Alzheimer's Brain
https://www.fightaging.org/archives/2025/09/erosion-of-epigenetic-control-in-the-alzheimers-brain/
The low cost of omics tools combined with the ability to distinguish the behavior of individual cells from a tissue sample allows for the creation of ever larger databases of epigenetic and transcriptional profiles of the aging brain. Creating these databases is one thing, and the results are of great interest, but comparatively little progress has been made on the leap from a mass of data describing how an aged brain differs from a young brain to an understanding of cause and effect in those observed changes. That understanding is necessary in order to build effective therapies, but establishing it is also the hard part of the problem.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals.
We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience.
This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.
Repurposing the Normal Clearance of Dead Cells to Target Unwanted Live Cells
https://www.fightaging.org/archives/2025/09/repurposing-the-normal-clearance-of-dead-cells-to-target-unwanted-live-cells/
Researchers here describe an interesting approach to redirecting the immune system to destroy unwanted cells. The membranes of dead cells are distinctively marked and immune cells contain machinery to recognize those marks. This is an important part of the way in which immune cells are directed to engulf and destroy dead cells and cell debris, helping to keep tissue functional. If immune cells are equipped instead with an altered, engineered sensor mechanism, then in principle their well-established behavior of engulfing and destroying dead cells could be repurposed to attack any specific target live cell population. This has applications to many conditions of aging, as researchers have identified many errant, malfunctioning cell populations that contribute to age-related disease and dysfunction. Efficient and safe ways to remove these cells will provide the basis for an important class of future therapies.
During the process of engulfment, phosphatidylserine is exposed on the surface of dead cells as an 'eat-me' signal and is recognized by Protein S (ProS), a secreted factor that also binds to the Mer tyrosine kinase (MerTK) on phagocytes. Despite its robust activity, this engulfment mechanism has not been exploited for therapeutic purposes. Here we develop a synthetic protein modality called Crunch (connector for removal of unwanted cell habitat) by modifying ProS, inspired by the high engulfment capability of the ProS-MerTK pathway.
In Crunch, the phosphatidylserine-binding motif of ProS is replaced with a nanobody or single-chain variable fragment that recognizes the surface proteins of targeted cells. Green fluorescent protein nanobody-conjugated Crunch eliminates green fluorescent protein-expressing melanoma cells in transplantation mouse models. In addition, CD19+ B cells are eliminated by anti-CD19 single-chain variable fragment-conjugated Crunch, resulting in a therapeutic effect on systemic lupus erythematosus. Both mouse and human versions of Crunch are effective, establishing this synthetic ligand as a promising tool for the elimination of targeted cells.
GLP-1 Receptor Agonist Use Reduces Heart Failure Mortality
https://www.fightaging.org/archives/2025/09/glp-1-receptor-agonist-use-reduces-heart-failure-mortality/
Losing weight improves health outcomes. To put it another way, carrying excess visceral fat tissue causes ongoing harm via a range of mechanisms connected to the disrupted, inflammatory metabolism it induces. Thus a growing number of studies demonstrate that weight loss achieved through GLP-1 receptor agonist use improves outcomes in the presently largely overweight populations of the wealthier regions of the world. It is always possible that GLP1-1 receptor agonist drugs have other effects that are meaningful along the way, but losing weight is so influential on health that very robust data would have to be presented to be convincing that non-weight-loss effects are important in the context of overweight individuals.
Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain.
To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice, five cohort studies were assessed using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks.
The primary end point was a composite of hospitalization for heart failure or all-cause mortality. In analyses using expanded eligibility criteria, 58,333 patients were included in the semaglutide vs sitagliptin cohort, 11,257 for tirzepatide vs sitagliptin, and 28,100 for tirzepatide vs semaglutide. Initiators of semaglutide (hazard ratio, HR, 0.58) and tirzepatide (HR, 0.42) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86).
Cardiovascular Disease Correlates Robustly with Dementia Risk
https://www.fightaging.org/archives/2025/09/cardiovascular-disease-correlates-robustly-with-dementia-risk/
Cardiovascular disease correlates very well with incidence of dementia, and this is well demonstrated via analysis of epidemiological data in papers such as the one noted here. Disruption of the flow of blood to the brain is a possible causal mechanism, but one can also consider that both classes of condition are driven by the same underlying processes, such as chronic inflammation. More generally, aspects of aging correlate because aging is an accumulation of damage throughout the body and damaged systems tend to become dysfunctional and fail. The correlation between cardiovascular disease and dementia is strong enough, however, to suggest an additional bidirectional relationship of direct causation.
Cardiovascular disease (CVD) and dementia represent two of the most pressing global health challenges, particularly in low- and middle-income countries. While vascular pathology is increasingly recognized as a contributor to cognitive decline, few studies have systematically explored the global association between CVD and dementia using standardized, population-level data. This study aimed to investigate the relationship between CVD and dementia incidence across 204 countries, stratified by economic status, development level, and geographic region.
Age-standardized incidence rates for cardiovascular disease (CVD) and dementia in 2021 were sourced from the Global Burden of Disease Study. Globally, CVD incidence was significantly associated with dementia incidence (Pearson r = 0.777; Spearman ρ = 0.868). CVD explained approximately 43.0% of the variance in dementia incidence at the population level (r^2 = 0.4303), even after adjusting for key confounders. The association was notably stronger in low- and middle-income countries and developing regions. Among CVD subtypes, peripheral arterial disease (β = 0.903), cardiomyopathy (β = 0.869), and atrial fibrillation (β = 0.708) demonstrated the strongest independent associations with dementia incidence.
Yet More Mouse Data on Fisetin as a Senotherapeutic
https://www.fightaging.org/archives/2025/09/yet-more-mouse-data-on-fisetin-as-a-senotherapeutic/
Mouse data has consistently shown fisetin to be senolytic, capable of selectively destroying the senescent cells that accumulate in tissues with age. Doses most often used are equivalent to around 20 mg/kg in humans, but dosing strategies range from a one-time course of treatment of a few days to intermittent doses provided over months. Unfortunately, despite planned and actually undertaken human trials of fisetin supplementation, there is still no published data of its senolytic capacity in humans. The dasatinib and quercertin combination and the locally delivered senolytic developed by UNITY Biotechnology before they ran out of funds remain the only senolytics with human data for clearance of senescent cells.
Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging.
Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin.
Reviewing What is Known of Glial Cell Aging in the Cerebellum
https://www.fightaging.org/archives/2025/09/reviewing-what-is-known-of-glial-cell-aging-in-the-cerebellum/
The category of glial cells covers all of the supporting cells of the brain, everything not a neuron, a big tent that includes immune cells such as microglia, the oligodendrocytes that manufacture myelin sheathing for axons, and the sizable astrocyte population, among others. These are very different cell populations with very different functions and behaviors, but all become dysfunctional with age. The present consensus is that glial cell dysfunction is important in aging and neurodegenerative conditions, each population contributing to loss of cognitive function in various ways. Given the size of the topic and the complexity of the brain, a review such as this one can really only skate the surface, however, even when focusing on only one region of the brain.
Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus.
This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored.
Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL's ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging.
View the full article at FightAging
