Fight Aging!

Human epidemiological data exhibits a web of correlations between intelligence, education, wealth, lifestyle choices, social status, and longevity. Correlations are simple enough to discover, but determining causal relationships is much harder, particularly when pulling in the possible role of biological mechanisms. Nonetheless, there is an intriguing thread of research suggesting that there is some biological contribution to the correlation between intelligence and longevity. It may be that some aspects of the natural variation between individuals in physical robustness, or in resilience to age-related cell and tissue damage, can contribute to both intelligence and longevity.

As today's open access paper makes clear, the measurement of intelligence is a tricky business. One can argue about the merits of the various approaches taken in humans, but an entirely different set of issues arises when trying to measure intelligence in lower species. The paper is an addition to the body of knowledge regarding the correlation between intelligence and longevity in flies, but there is room to argue that the assessment used may not be a measure of intelligence per se, or at least not in a way that is easily related to the way we measure intelligence in humans. Flies are presented with a left or right choice in a simple T maze and there is food in one direction that can be sensed by smell. Are flies that head towards the food actually more intelligent, or is this instead a measure of drive, olfactory capability, or some other line item? One sees the challenge. Since the successful flies lived longer, there is clearly some interesting biology here relating to robustness in cell function, but it is far from clear that intelligence is involved.

Genetic association of intelligence with longevity in Drosophila melanogaster

Epidemiological studies in different populations, in different countries, and in different epochs consistently showed that high intelligence is positively correlated with longevity. The link between high intelligence and longevity has remained unknown, only to be assumed as a consequence of the socioeconomic difference associated with intelligence in human population.

Here, we report that genome stability contributes both to lifespan and intelligence in Drosophila melanogaster. The intelligence of the genetically heterogenous flies was determined by T-maze olfactory memory assay, and the flies moving to the right direction defined as intelligent flies (INT) were separated from the flies moving to the wrong direction defined as non-intelligent flies (NINT). INT male and female lived 26.40% and 21.35% longer than NINT male and female, respectively, suggesting a possible genetic linkage between intelligence and longevity.

The bidirectional selective breeding based on intelligence extended lifespans gradually generation by generation in INT breeding contrast to the reversed pattern in NINT breeding. INT of F12 generation lived longer than NINT of F12 generation, 63.91% for male and 67.88% for female, as a result from slower aging. The whole-genome transcriptome analysis showed the activation of the genes in ribosome and autophagy in INT and the pathways of genome stability and immune reaction in NINT. Especially, the genetic pathway associated with genome stability was most noticeable, indicating that genome stability contributes both to lifespan and intelligence in D. melanogaster.

In recent years there has been considerable interest in the inhibition of mTOR signaling as a mechanism to upregulate autophagy, a form of calorie restriction mimetic strategy for drug development. While there are a number of safe, low cost, off-patent small molecules that achieve this goal, rapamycin being the most well studied of these options, interest in a mechanism will ensure that researchers eventually work their way through the entire portfolio of approved drugs and drug candidate libraries in search of more options. Even if two small molecules ostensible target the same mechanism, there will always be differences in tissue specificity, side-effects, cost-effectiveness, and so forth. Here find one example of this sort of work, in which researchers add to the body of knowledge regarding the ability of niclosamide to inhibit mTOR signaling.

Niclosamide (NIC) is a medication that has been included in the World Health Organization's list of essential medicines since the 1960s, and is used to treat tapeworm infection. The mechanism of action of NIC involves uncoupling oxidative phosphorylation in the mitochondria, which disrupts the tapeworm's ability to survive. NIC has also been shown to affect various signal transduction pathways, such as Wnt/β-catenin, mammalian target of rapamycin (mTOR), STAT3, NFκB, and Notch pathways. Recent studies have also explored the potential of NIC as a therapeutic agent against cancer, bacterial or viral infections, and metabolic diseases. Studies have shown that NIC promotes autophagy in both small-cell lung carcinoma cells and mouse model, by inducing tumor cell death through the activation of autophagy and apoptosis via the AMPK/AKT/mTOR pathway. Furthermore, NIC improves insulin and glucose homeostasis by activating autophagy in metabolic disease cells and mouse models.

Despite these promising results, no study has focused on its effects on aging. Therefore, in this study, we aimed to evaluate the effects of NIC on natural aging models. We report that NIC promotes healthy aging in C. elegans and mice. NIC increases physical function and mitochondrial function in skeletal muscles, which are reduced with aging. We found that NIC inhibited the expression of muscle atrophy-related genes by suppressing hyperactivated mTORC1 and enhancing autophagic flux, thereby improving age-related decline. Our results demonstrate a new function of the NIC in contributing to healthy aging, particularly skeletal muscle health.

Link: https://doi.org/10.1016/j.jare.2025.04.027

It has long been established in mice that adult animals exhibit neurogenesis in the brain, the creation of new neurons that integrate into existing neural networks. There remains some debate over whether new neurons are created in the adult human brain, however, despite the consensus being that it would be unexpected to find that humans differ from mice in this way. Neurogenesis is thought to be essential to the function of learning and memory. That this process does occur would in principle make it easier to produce regenerative therapies that generate new neurons in the living brain to restore lost function. Establishing beyond doubt that this neurogenesis occurs in living humans brains has been challenging for a number of technical and logistical reasons. Nonetheless, progress has been made in establishing the necessary data.

The extent and significance of the formation of new neurons (neurogenesis) are still debated. There has been no clear evidence that the cells that precede new neurons, known as neural progenitor cells, actually exist and divide in adult humans. In a new study, the researchers combined several advanced methods to examine brain tissue from people aged 0 to 78 years from several international biobanks. They used a method called single-nucleus RNA sequencing, which analyses gene activity in individual cell nuclei, and flow cytometry to study cell properties.

By combining this with machine learning, they were able to identify different stages of neuronal development, from stem cells to immature neurons, many of which were in the division phase. To localise these cells, the researchers used two techniques that show where in the tissue different genes are active: RNAscope and Xenium. These methods confirmed that the newly formed cells were located in a specific area of the hippocampus called the dentate gyrus. This area is important for memory formation, learning, and cognitive flexibility.

The results show that the progenitors of adult neurons are similar to those of mice, pigs, and monkeys, but that there are some differences in which genes are active. There were also large variations between individuals - some adult humans had many neural progenitor cells, others hardly any at all. "Our research may also have implications for the development of regenerative treatments that stimulate neurogenesis in neurodegenerative and psychiatric disorders."

Link: https://news.ki.se/new-research-confirms-that-neurons-form-in-the-adult-brain

Research into reprogramming aims to induce some aspects of the dramatic change in gene expression and cell function that take place during early embryonic development, when adult germline cells shed the epigenetic changes characteristic of age to become young embryonic stem cells. Cell function becomes youthful, mitochondrial function is restored. Researchers can recapture the entire process, which is what happens when somatic cells are reprogrammed into induced pluripotent stem cells via exposure to the Yamanaka factors, but present efforts are turning to finding effective ways to induce only rejuvenation of function, without inducing pluripotency and loss of cell type.

Exploration of what has come to be called partial reprogramming, rejuvenation without pluripotency or other undesirable cell state changes, started with the use of genetic technologies to produce short-term expression of one or more Yamanaka factors. A few companies are slowly moving in the direction of clinical trials with initial gene therapies that focused on carefully narrow use cases, such as diseases of the eye or aspects of skin aging. Gene therapy vectors cannot at present effectively deliver their cargo to the whole body, and many organs remain impossible to target with vectors in any way other than direct injection. Thus there is interest in the alternative path of development of small molecules that can induce reprogramming, as small molecules are capable of reaching the entire body.

Much of the work on small molecule reprogramming is presently focused on a small number of compounds, those that go into the 7c and 2c combinations discussed in today's open access paper. 7c includes some undesirably toxic molecules, and researchers have thus focused more of their recent efforts on 2c, the combination of RepSox and tranylcypromine. This relatively narrow range of possibilities is characteristic of early stage research and development. Companies and research groups are undertaking the search for other starting points in the design of small molecule reprogramming agents, but one should expect progress on that front to emerge only slowly over a span of years.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

During development, cellular reprogramming induces zygotic and primordial germ cell formation following a dramatic chromatin reorganization to create totipotent and pluripotent cells free of aged molecular defects, demonstrating that both cell identity and age are reversible. Importantly, this manipulation of cell identity has been recapitulated in vitro by several methods, including somatic cell nuclear transfer, forced expression of transcription factors, and most recently treatment with small molecules.

Although restoration of aged phenotypes such as telomere length, mitochondrial function, proliferation, and transcriptomic signature in vitro was demonstrated over a decade ago, application of cellular reprogramming in vivo was initially proven unsafe due to the loss of cellular identity leading to tumor and teratoma formation. To overcome this issue, in vivo partial reprogramming by short-term cyclic induction of Oct4, Sox2, Klf4, and c-Myc (OSKM) was a critical advance as it avoided the detrimental loss of cellular identity. Importantly, this limited cyclic expression of OSKM was sufficient to ameliorate multiple aging hallmarks and extend the lifespan of a progeroid mouse strain. Improved regenerative capacity and function has also been demonstrated following therapeutic application of cellular reprogramming in multiple tissues and organs including the intervertebral disc, heart, skin, skeletal muscle, liver, optic nerve, and dentate gyrus.

Here, we report that short-term treatment of human cells with seven small molecules (7c - CHIR99021, DZNep, Forskolin, TTNPB, Valproic acid, Repsox, and Tranylcypromine), previously identified for their capacity to induce pluripotent stem cells, leads to the improvement of molecular hallmarks of aging. In addition, we show that an optimized cocktail, containing only two of these small molecules (2c - Repsox and Tranylcypromine), is sufficient to restore multiple aging phenotypes, including genomic instability, epigenetic dysregulation, cellular senescence, and elevated reactive oxygen species. Finally, in vivo application of this 2c reprogramming cocktail extends both lifespan and healthspan in C. elegans.

It is a great deal easier to theorize about aging than it is to produce technologies that repair specific forms of damage and disarray in aged tissues. The results of animal studies using those technologies are needed in order to prove or disprove specific lines of thought regarding which mechanisms are and are not important in aging, and thus set the stage for more concrete inferences about the evolution of aging. But this is a far greater challenge than the production of more theory. So the aging research community theorizes a great deal on the nature of aging and its evolution, and these days much of that work is aided by computer modeling of pseudo-organisms and evolutionary scenarios.

Aging is an extensive biological process characterized by morphological and functional alterations in cellular and extracellular components, resulting in a systematic decline in biological functions ultimately leading to death. Although substantial advancements have been made in manipulating lifespan in model organisms like C. elegans and mice through genetic, dietary, and pharmacological means, the fundamental mechanisms driving aging in humans remain elusive and widely debated. In addition, there is no comprehensive computational platform capable of making predictions on aging in multicellular systems and integrating the multiscale competency of lifeforms.

We focus on the processes that build and maintain a complex anatomy toward a specific target morphology, and propose the hypothesis that aging arises even in the absence of accumulated cellular or genetic damage, because a homeodynamic system left without any goal in anatomical morphospace will start degrading. This can occur in biological systems because evolution typically prioritizes development over morphostasis, leaving organisms with limited reinforcement of anatomical goals after development.

Using an in silico model of homeostatic morphogenesis with a multiscale competency architecture and information dynamics analysis, we find: (1) Absence of Long-Term Morphostasis: Aging emerges naturally after development due to the lack of an evolved regenerative goal, rather than just specific detrimental properties of developmental programs (e.g., antagonistic pleiotropy or hyperfunction); (2) Acceleration Factors vs. Root Cause: Cellular misdifferentiation, reduced competency, communication failures, and genetic damage all accelerate aging but are not its primary cause; (3) Information Dynamics in Aging: Aging correlates with increased active information storage and transfer entropy, while spatial entropy measures distinguish two dynamics - loss of structure and morphological noise accumulation; (4) Dormant Regenerative Potential: Despite organ loss, spatial information persists in the cybernetic tissue, indicating a memory of lost structures, which can be reactivated for organ restoration through targeted regenerative information; and (5) Optimized Regeneration Strategies: Restoration is most efficient when regenerative information includes differential patterns of affected cells and their neighboring tissue, highlighting strategies for rejuvenation.

These findings provide a novel perspective on aging dynamics with significant implications for longevity research and regenerative medicine.

Link: https://www.preprints.org/manuscript/202412.2354/v3

The chronic inflammation of aging is a major contribution to the onset and progression of age-related disease. The immune system reacts to forms of molecular damage and dysfunction characteristic of aging in a maladaptive way, and the long-term consequences are unfortunate. Short-term inflammation is necessary and important, needed in contexts ranging from infection to suppression of cancer to regeneration following injury. Sustained, unresolved inflammation is disruptive to tissue structure and function, however.

The biggest challenge in finding ways to suppress long-term inflammation is that it appears to use the same systems of regulation as short-term inflammation, and thus successful approaches not only sabotage undesirable inflammation, but also degrade the effectiveness of the immune system. If there is a way to work around this problem, we should all be very interested, as it could form the basis for therapies that reduce age-related inflammation without harming the necessary functions of the immune system.

Chronic inflammation occurs when the immune system is stuck in attack mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health. A new study identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection.

Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. The researchers confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.

The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.

Link: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/new-protein-targets-chronic-inflammation

Transfusion of blood fractions from young individuals into old individuals has so far produced quite variable animal data and disappointing human clinical trial outcomes. Even so, researchers continue to search for molecules in young blood that might be a basis for therapy. That transfusions have not performed as desired doesn't rule out the existence of specific molecules that might be delivered in larger amounts than exist in a transfusion in order to produce benefits. That stem cell therapies produce benefits based on signals secreted by the transplanted cells indicates that cell signaling is important, a path to favorably altering the behavior of native cells in order to reduce inflammation, improve tissue function, and so forth. It is a question of identifying the right signals and the right doses.

Thus a steady flow of publications is emerging, with today's open access paper as an example of the type, in which researchers report on the discovery of one or more specific molecules mined from young blood that appear to produce benefits in older animals. It is a little early to say whether or not this will lead to a sizable number of novel potential therapies and biotech companies to develop those therapies, but some of the early demonstrations of benefits in mice are quite interesting. As with other investigations of cell signaling derived from young tissues, reduced inflammation is the most common outcome.

Plasma Extracellular Vesicle-Derived miR-296-5p is a Maturation-Dependent Rejuvenation Factor that Downregulates Inflammation and Improves Survival after Sepsis

There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals.

There have been several efforts to characterize these youthful or maturation-associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age-dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti-inflammatory, and reduced cellular senescence markers.

MicroRNA sequencing of the EVs showed an age-associated signature and identified miR-296-5p and miR-541-5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR-296-5p and miR-541-5p showed a reparatory effect in an in vitro wound healing model and the miR-296-5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis.

In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation-dependent. Our observation that miR-296-5p and miR-541-5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these microRNAs in inflammation and age-associated diseases.

It is well established that exposure to particulate air pollution increases mortality and risk of age-related conditions. The primary mechanism is thought to be increased chronic inflammation resulting from the interactions of inhaled particles with the cells of epithelial and other tissues. One of the consequences of chronic inflammation is increased fibrosis, a dysfunction in normal tissue maintenance in which excessive extracellular matrix is created, forming scar-like structures that impair tissue function. Here, researchers correlate increased fibrosis in heart tissue with long-term exposure to particulate matter, an outcome that isn't all that surprising given the established epidemiological data linking cardiovascular disease to particulate exposure.

Fine particulate matter with 2.5-µm or smaller aerodynamic diameter (PM2.5) is the most thoroughly studied component of air pollution. PM2.5 is associated with an increased risk of cardiovascular diseases - including myocardial infarction, heart failure, and stroke - and promotes the development of cardiovascular risk factors such as hypertension and diabetes. The World Health Organization estimates that 31% of cardiovascular disease is attributable to environmental factors.

However, the underlying pathophysiologic mechanisms by which exposure to PM2.5 leads to adverse cardiovascular outcomes are unclear. Hypothesized mechanisms include oxidative stress, inflammation, and autonomic stimulation, potentially leading to activation of cardiac fibroblasts and increased extracellular matrix protein deposition. Given its role in maladaptive left ventricular remodeling, myocardial fibrosis could potentially mediate the adverse cardiovascular effects of particulate air pollution and help explain some of the variability in heart failure progression and other adverse cardiac events that are not explained by traditional cardiovascular risk factors.

This retrospective study aimed to determine the relationship between long-term exposure to ambient PM2.5 air pollution and the extent of diffuse myocardial fibrosis quantified with cardiac MRI. Patients with dilated cardiomyopathy (DCM) or controls with normal cardiac MRI findings were included. Diffuse myocardial fibrosis was quantified using cardiac MRI native T1 mapping z scores. A total of 694 patients (mean age, 47 years) were included. In multivariable models, each 1-µg/m3 increase in 1-year mean PM2.5 exposure was associated with a 0.30 higher native T1 z score in patients with DCM and 0.27 higher native T1 z score in controls. In conclusion, higher long-term exposure to ambient fine particulate air pollution is associated with greater diffuse myocardial fibrosis.

Link: https://doi.org/10.1148/radiol.250331

Researchers here report an advance in understanding the biochemistry of pathological interactions between cell types in the context of vascular dementia. After mapping gene expression levels in healthy and diseased vascular tissue, the researchers find a possible basis for therapy in one specific set of altered expression levels observed in microglia and oligodendrocyte. They present initial evidence for restored expression of two genes to reduce vascular dysfunction and pathology. This sort of approach is inherently compensatory, to eliminate a maladaptive reaction without addressing underlying causes. Is likely to be more limited in benefits than addressing those causes, because the causes will continue to produce other harms. Nonetheless, this is the way that the research community usually proceeds.

Vascular dementia (VaD) accounts for approximately 25% of all dementia cases. Currently, there are no direct treatments for VaD, and existing symptomatic therapies, such as cholinesterase inhibitors and memantine, demonstrate limited efficacy and fail to target the underlying vascular pathology. VaD arises from impaired cerebral blood flow due to cerebrovascular pathologies, including ischemic stroke, microinfarcts, or chronic small vessel disease.

A major barrier to advancing VaD research is the incomplete understanding of cell-type-specific responses within the neurovascular unit (NVU) - a dynamic interplay of multiple cell types. This NVU maintains cellular homeostasis and orchestrates responses to injury through intricate cell-cell interactions mediated by ligand-receptor (L-R) signaling. In VaD, ischemic injury originates in endothelial cells and propagates through the neurovascular niche, disrupting intercellular communication and leading to tissue damage and cognitive decline. The intercellular networks or "interactome" specific to VaD remains largely unexplored.

To address these challenges, we performed cell-type-specific RNA-seq to profile transcriptional changes in glial and vascular cells. Notably, WM glial and vascular cells exhibit specific transcriptional profiles compared with cortical and whole-brain datasets. The ischemic lesions also perturb WM-associated aging genes. We constructed a comprehensive VaD interactome, identifying conserved signaling pathways altered in both human and mouse, and prioritized two candidate L-R systems for functional validation: (1) the extracellular matrix component Serpine2 and its receptor Lrp1, which regulate oligodendrocyte differentiation and myelination, and (2) the CD39-A3AR signaling axis, which modulates microglial activation and tissue repair. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist - currently in clinical trials for psoriasis - restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.

Link: https://doi.org/10.1016/j.cell.2025.06.002

Modern hunter-gatherer populations such as the Tsimane, Hazda, and others, are increasingly of interest to researchers following publications of recent years indicating that these groups exhibit very little cardiovascular disease in comparison to populations in wealthier parts of the world. One might look at high and sustained levels of physical activity as a primary cause of this difference, although diet may also play a role. It is one of the better examples of the degree to which lifestyle influences the progression of aging, even while it fails to extend life out beyond the usual limits.

In today's research materials, the authors focus on differences in inflammation between first world populations and hunter-gatherers. One lesson that we might take away from this is that not all inflammation is the same: the hunter-gatherers exhibit higher levels of inflammation in youth, perhaps due to a greater burden of infectious disease, but nonetheless that burden of inflammation does not increase meaningfully into later life as it does in wealthier populations. As noted above the hunter-gatherers exhibit a far, far lower burden of cardiovascular diseases, age-related conditions well known to be driven by the chronic inflammation of aging.

Researchers analyzed data from four populations: two industrialized groups - the Italian InCHIANTI study and the Singapore Longitudinal Aging Study (SLAS) - and two Indigenous, non-industrialized populations - the Tsimane of the Bolivian Amazon and the Orang Asli of Peninsular Malaysia. While the inflammaging signature was similar between the two industrialized populations, it did not hold in the Indigenous groups, where inflammation levels were largely driven by infection rather than age.

Interestingly, while the indigenous populations, particularly the Tsimane, had high constitutive levels of inflammation, these did not increase with age and, crucially, did not lead to the chronic diseases that plague industrialized societies. In fact, most chronic diseases - diabetes, heart disease, Alzheimer's, etc. - are rare or largely absent in the Indigenous populations, meaning that even when young Indigenous people have profiles that look similar on the surface to those of older industrialized adults, these profiles do not lead to pathological consequences.

Inflammaging, an age-associated increase in chronic inflammation, is considered a hallmark of aging. However, there is no consensus approach to measuring inflammaging based on circulating cytokines. Here we assessed whether an inflammaging axis detected in the Italian InCHIANTI dataset comprising 19 cytokines could be generalized to a different industrialized population (Singapore Longitudinal Aging Study) or to two indigenous, nonindustrialized populations: the Tsimane from the Bolivian Amazon and the Orang Asli from Peninsular Malaysia. We assessed cytokine axis structure similarity and whether the inflammaging axis replicating the InCHIANTI result increased with age or was associated with health outcomes.

The Singapore Longitudinal Aging Study was similar to InCHIANTI except for IL-6 and IL-1RA. The Tsimane and Orang Asli showed markedly different axis structures with little to no association with age and no association with age-related diseases. Inflammaging, as measured in this manner in these cohorts, thus appears to be largely a byproduct of industrialized lifestyles, with major variation across environments and populations.

Transcranial magnetic stimulation has been shown to produce benefits in some studies, but reproduction in this field is challenging. There are many options for equipment, frequency, power, duration of treatment, and so forth, and many of these parameters are (a) likely important in determining whether or not the treatment has any beneficial effect and (b) incompletely specified in publications. Further, the mechanisms by which transcranial magnetic stimulation produces benefits are far from completely understood, making it much harder to calibrate potential therapies than would otherwise be the case. Here find an example of research in this part of the field, in which scientists explore the effects of transcranial magnetic stimulation on some of the smaller structures in neurons and neural connections.

Axonal boutons are specialized endings of an axon, which is the long slender part of a neuron that connects neurons by transmitting neural signals. These are sites where synapses form, allowing neurons to communicate. Therefore, any change in the number or function of these boutons can have profound effects on brain connectivity. In this study, the researchers observed structural changes of two types of excitatory boutons, namely "terminaux boutons" (TBs) (short protrusions from the axon shaft typically connecting neurons in a local area) and "en passant boutons" (EPBs) (small bead-like structures along axons typically connecting distal regions). They used two-photon imaging to visualize individual axons and synapses in the brain of a live animal.

The study was conducted on the APP/PS1 x Thy-1GFP-M strain of mice, which is a cross between the APP/PS1 strain (genetically modified to show Alzheimer's disease (AD)-like symptoms seen in humans) and the Thy1-GFP-M strain, which expresses a fluorescent protein in certain neurons. This combination causes axons to glow during imaging, enabling precise tracking of synaptic bouton changes over time. The team monitored the dynamics of the axonal boutons in these mice at 48-hour intervals for eight days, both before and after a single repetitive transcranial magnetic stimulation (rTMS) session. They then compared these findings to healthy wild-type (WT) mice.

They found that both TBs and EPBs in the AD mouse model had comparable density to those in healthy WT mice. However, the turnover of both bouton types was significantly lower in the AD mouse model before rTMS, likely due to the amyloid plaque buildup, a key marker of dementia, and potentially causing diseases like AD. After a single session of low-intensity rTMS, the turnover of TBs in both strains increased significantly, while there was no change in the EPB turnover. Furthermore, in the AD mouse model, this increased turnover was comparable to the turnover levels in the WT mice seen before stimulation. This indicates that low-intensity rTMS can potentially restore the synaptic plasticity of TBs to those seen in healthy mice. Moreover, the fact that only TBs, and not EPBs, responded to rTMS points to the possibility that the mechanisms of rTMS might be cell-type specific.

Link: https://spie.org/news/low-intensity-brain-stimulation-may-restore-neuron-health-in-alzheimers-disease

As researchers note here, the LAG-3 receptor on T cells acts as a checkpoint to suppress T cell activity. Like other such receptors that reduce T cell activity, it has been explored in the context of checkpoint inhibitor therapies to treat cancer by preventing tumor-induced reductions in immune activity. Interfering in the activity of LAG-3 was not effective enough in the context of cancer for potential treatments to emerge, but LAG-3 becomes more interesting as a target in autoimmune conditions. It remains to be seen as to whether this will lead to useful therapies, but the data presented here is intriguing.

T cells exhibit both T-cell receptors (TCRs) and checkpoints. TCRs, although shaped so that bits of invading bacteria or viruses fit into them to activate the T cell, are turned on by the body's own proteins in autoimmune diseases. Checkpoints like LAG-3 are also turned on by specific signaling partners, but when this occurs they have the opposite effect of TCRs, suppressing the T cell's activity. TCR-triggering molecules must be presented to T cell receptors by another set of immune cells that ingest foreign (e.g., microbial) or bodily substances in order to display on their surfaces, through protein groups called major histocompatibility complexes (MHC-II), just the small protein pieces that activate a given TCR.

Mechanistically, the research team found that the proximity of LAG-3 lets it loosely stick to part of the T cell receptor called CD3ε (like two oily globs interacting). This attachment was found to pull on CD3ε enough to disrupt its interaction an enzyme called Lck, which is crucial for T cell activation. MHC-II can theoretically attach to LAG-3 and TCR at the same time, but not frequently enough to maximize LAG-3's ability to dial down T cells.

LAG-3 turns off T cells, but less easily due to its spatial requirements than another checkpoint called PD-1. This feature makes LAG-3 inhibitors weaker as anti-cancer cancer treatment than PD-1-inhibiting antibody treatments that have become a mainstay, but likely better when the immune system is overactive, and targeted T cell suppression is required for maximum safe effect. Based on their discovery of the critical role of TCR proximity in LAG-3 function, the research team designed a molecule that enforces LAG-3/TCR proximity to achieve better LAG-3-dependent TCR inhibition and suppression of T cell responses. Their "bi-specific" antibody held LAG-3 and the T cell receptor together more strongly than MHC-II, and without depending on it.

The bispecific antibody, named the LAG-3/TCR Bispecific T cell Silencer or BiTS, potently suppressed T cell responses and lessened inflammatory damage to insulin-producing cells in BiTS-treated mice with a version of Type 1 diabetes. In autoimmune models of hepatitis, BiTS treatment reduced T cell infiltration and liver damage. With the diabetes and hepatitis disease models largely driven by one type of T cells (CD8+), the team also used a mouse model of multiple sclerosis known to be driven by a second major T cell type (CD4+). The team treated mice prone to develop multiple sclerosis with short-term, preventive BiTS prior to the onset of disease symptoms, and BiTS-treated mice had reduced disease by a standard measure.

Link: https://www.eurekalert.org/news-releases/1089253

Atherosclerosis is the name given to the growth of fatty plaques in artery walls. It is universal in later life, and the primary cause of human mortality via heart attack, stroke, heart failure, and so forth. Once a plaque grows past a given size, the mechanisms that caused its creation fade in importance in comparison to very simple feedback loop. The plaque is an inflammatory, damaged environment that attracts macrophage cells from the bloodstream and surrounding tissues. The macrophages attempt to ingest cholesterol and cell debris, passing the cholesterol back into the bloodstream to return to the liver for reuse or excretion, but instead become overwhelmed. The plaque environment and cholesterol excess forces macrophages into an inflammatory and dysfunctional state. The cells eventually die to add their mass to the plaque. A plaque is a macrophage graveyard, continually calling more macrophages to their doom.

Given this, some lines of research aim to make macrophages more resilient. In principle, if macrophages were not overwhelmed by excess cholesterol and other toxic aspects of the plaque environment, these cells would in time complete their task, dismantling the plaque and repairing the blood vessel wall. Nobody would die from atherosclerosis. A number of approaches have been suggested to at least modestly increase the resilience of macrophages to the plaque environment, and are in various stages of development. Today's open access paper adds another possibility to the list, another way to manipulate macrophage metabolism to sabotage the maladaptive reaction to the plaque environment in order to maintain repair activities.

Can enzyme behind high cholesterol be turned off?

"We found that by blocking the enzyme IDO1, we are able to control the inflammation in immune cells called macrophages." Inflammation plays a crucial role in the immune system, helping the body fight infections and heal injuries. But when inflammation becomes abnormal it can damage cells, disrupt normal functions and increase the risk of serious diseases. During these periods, macrophages can't absorb cholesterol properly, which can lead to chronic disease. Researchers found that the enzyme IDO1 becomes activated during inflammation, producing a substance called kynurenine that interferes with how macrophages process cholesterol.

When IDO1 is blocked, however, macrophages regain their ability to absorb cholesterol. This suggests that reducing IDO1 activity could offer a new way to help prevent heart disease by keeping cholesterol levels in check. The researchers also found that nitric oxide synthase (NOS), another enzyme linked in inflammation, worsens the effects of IDO1. They believe that inhibiting NOS could provide another potential therapy for managing cholesterol problems driven by inflammation.

HDLR-SR-BI Expression and Cholesterol Uptake are Regulated via Indoleamine-2,3-dioxygenase 1 in Macrophages under Inflammation

Macrophages play crucial roles in inflammation, and their dysfunction is a contributing factor to various human diseases. Maintaining the balance of cholesterol and lipid metabolism is central to macrophage function, and any disruption in this balance increases the risk of conditions such as cardiovascular disease, atherosclerosis, and others. The receptor HDLR-SR-BI (SR-BI) is pivotal for reverse cholesterol transport and cholesterol homeostasis. Our studies demonstrate that the expression of SR-BI is reduced along with a decrease in cholesterol uptake in macrophages, both of which are regulated by the activation of NF-κB.

Furthermore, we have discovered that indoleamine-2,3-dioxygenase 1 (IDO1), which is a critical player in tryptophan (Trp) catabolism, is crucial to the regulation of SR-BI expression. Inflammation leads to elevated levels of IDO1 and the associated Trp catabolite kynurenine (KYN) in macrophages. Interestingly, knockdown or inhibition of IDO1 results in the downregulation of lipopolysaccharide (LPS)-induced inflammation, decreased KYN levels, and the restoration of SR-BI expression as well as cholesterol uptake in macrophages. Beyond LPS, stimulation with pro-inflammatory cytokine IFNγ exhibits similar trends in inflammatory response, IDO1 regulation, and cholesterol uptake in macrophages. These observations suggest that IDO1 plays a critical role in SR-BI expression and cholesterol uptake in macrophages under inflammation.

Aging is an accumulation of forms of cell and tissue damage, and a complex network of downstream consequences of that damage that interact with one another to accelerate further dysfunction. It should not be too surprising to find that other approaches to producing damage in a living individual resemble aging, at least superficially. This is the case in DNA repair deficiency conditions, and, as researchers note here, it is the case in the aggressive use of chemotherapy to treat cancer.

While chemotherapy can be lifesaving, it also damages DNA and leads to cognitive issues known as "chemo brain." These effects resemble the memory and learning problems seen in older adults. There are several parallels in these two situations. In both, there is decreased blood flow in the brain when it is at rest and a smaller increase in blood flow when the brain is active. In addition, the blood-brain barrier, a protective layer that prevents harmful substances from entering the brain, is disrupted, which triggers inflammation in the brain. Finally, there is an accumulation of senescent cells in both brains. Senescent cells are in a suspended state of not being dead nor being able to fulfill their normal function, which also causes inflammation.

The research team studied several chemotherapy drugs in mice for their effects on the brain, including the commonly used paclitaxel and cisplatin. They found that even though the chemo drugs caused DNA damage in different ways, their characteristics were the same in how they affected cognition. Because of the blood-brain barrier, chemotherapy drugs do not directly enter and damage the brain. Instead, chemotherapy harms endothelial cells, the type of vascular cell most susceptible to damage. When the endothelial cells are impaired, they become senescent and produce inflammatory substances that compromise the blood-brain barrier.

The researchers also studied ways to improve cognition. They tested senolytics in aging mice. Senolytics are drugs that can induce senescent cells to die through apoptosis, the typical process by which cells are removed. By selectively removing senescent cells, cognition improved. Researchers took the study a step further to determine the ideal time window for administering senolytics to have the most positive effect on the brain's vasculature and cognition. They tested senolytics in mice of all ages and ultimately discovered the drug was most effective when the mice were about 16 months old, which researchers believe equates to 50 to 55 years old in humans.

Link: https://www.ou.edu/news/articles/2025/june/chemo-brain-and-the-Aging-brain-researchers-examine-similarities-in-search-for-improved-cognition

A burden of lingering senescent cells contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Excess visceral fat tissue is know to generate an increased burden of senescent cells. It does also dysregulate metabolism and provoke chronic inflammation in a range of other ways, however. So while senescent cells appear to be important in the damage done by obesity, it remains unclear as to what degree the use of senolytic drugs to selectively destroy senescent cells will reduce the consequences of obesity. Answers will emerge in time, but, as ever, making progress towards larger clinical trials and sufficient human data is a slow and expensive process. There is little incentive for industry to fund work on the existing cheap, off-patent senolytics, such as the dasatinib and quercetin combination, and the usual alternative path of developing and testing expensive, new, patented drugs takes as long as it takes.

Obesity and type 2 diabetes mellitus (T2DM) represent currently major health threats worldwide owing to their rapidly increasing prevalence and debilitating long-term chronic complications. Senescent cells play an important role in T2DM pathogenesis via direct impact on pancreatic β-cell function, since reduced pancreatic β-cell mass and subsequent defects in insulin secretion are major factors in the pathogenesis and progression of T2DM. Preferential accumulation of senescent cells in visceral adipose tissue (VAT) is then associated with an inappropriate expansion of adipocytes (hypertrophy), insulin resistance, and dyslipidemia and represents the nexus of mechanisms involved in aging and age-related metabolic dysfunctions. On the other hand, changes induced by long-standing, poorly controlled T2DM are linked to the accumulation of premature senescent cells in various tissues, contributing to the development of chronic irreversible complications. Thus, senescence is both a cause and a consequence of obesity and T2DM.

The presence of T2DM and its complications is the major reason for the massive financial burden of the treatment of T2DM. It is estimated that therapy of diabetic complications consumes up to two-thirds of the overall T2DM treatment costs. Despite the availability of novel glucose-lowering drugs, the number of patients with T2DM and related chronic complications keeps increasing at a high rate. Current pharmacological approaches address the pathophysiological defects present in T2DM rather than preventing the processes contributing to its development. Therapeutic targeting and elimination of senescent cells with suppression of the SASP production by senolytics may therefore be an effective strategy for a novel approach in the treatment of metabolic diseases.

Link: https://doi.org/10.3389/fcell.2025.1622107