Fight Aging!

Low density lipoprotein (LDL) particles are a class of cholesterol transporter, carrying cholesterol out from the liver where it is manufactured to the rest of the body via the bloodstream. LDL and its cargo can become oxidized as a result of interactions with the variety of oxidizing molecules produced in the normal operation of metabolism. This oxidized LDL is toxic and places stress upon cells in the blood vessel walls that encounter it. The level of oxidation increases globally with age, one of the known issues in an aged metabolism, and as a consequence there are more oxidized LDL particles and oxidized cholesterol molecules to cause problems in the vasculature. The research community is largely focused the role of oxidized LDL and oxidized cholesterol in the onset and progression of atherosclerosis, meaning the damage done to vascular endothelium that leads to excess accumulations of cholesterol, dysfunction in the macrophage cells drawn to attempt a repair, and the growth of an atherosclerotic plaque. There are other downstream consequences, however.

In today's open access review, researchers largely skate over the topic of atherosclerosis to discuss how oxidized LDL particles can contribute to vascular dementia. This is a matter of inflammation, endothelial dysfunction, and blood-brain barrier compromise in the microvasculature of the brain, issues distinct from the atherosclerotic plaque that forms in large arteries. At the high level, we might envisage the vasculature in the brain as a transformer that converts the biochemical issue of too many oxidizing molecules into chronic inflammation and related dysfunctions in brain tissues. Oxidative stress, mitochondrial dysfunction, and unresolved inflammatory signaling all circle round one another in aging, feeding into one another and downstream issues. It remains to be seen as to what the best points of intervention are, but clearing senescent cells and fixing mitochondrial dysfunction seem the best starting points at the present time.

LDL oxidation and cerebrovascular aging: mechanisms of endothelial dysfunction, inflammation, and vascular cognitive impairment and dementia

Converging evidence indicates that the interplay of aging, LDL, and especially oxidized LDL (oxLDL) is a critical driver of cerebrovascular injury underlying vascular cognitive impairment and dementia (VCID). Epidemiological studies have demonstrated that midlife hypercholesterolemia is associated with an increased risk of dementia, with each ∼1 mmol/L rise in LDL levels linked to an estimated 8% higher incidence of all-cause dementia. Mechanistically, atherosclerosis-prone conditions like high LDL promote intracranial arterial disease that compromises cerebral perfusion and precipitates ischemic injury. Beyond large vessels, cholesterol and its oxidized derivatives can accumulate in the cerebral microvasculature, inciting local inflammation and neurodegeneration.

In the aging brain, these processes are compounded by an intrinsically fragile vasculature, establishing a strong case that aging, LDL, and oxLDL must be studied synergistically in the context of brain microvascular health and VCID pathogenesis. OxLDL emerges as a particularly deleterious player within the neurovascular unit (NVU). Once native LDL particles undergo oxidation, they trigger endothelial dysfunction more potently than native LDL. OxLDL engages endothelial cells to upregulate adhesion molecules and pro-inflammatory pathways, while directly degrading the integrity of the endothelial barrier. This damage to the blood-brain barrier (BBB) permits leakage of neurotoxic blood-derived factors into the brain parenchyma, exacerbating oxidative stress and inflammation within brain tissue.

Indeed, oxLDL creates a vicious cycle: it is readily taken up by macrophages and brain glia, generating foam cells and further reactive oxygen species (ROS) and cytokine release. The result is chronic neurovascular inflammation, reduced nitric oxide bioavailability (impairing vasodilation), and breakdown of microvascular structure, changes that manifest as small vessel disease, microhemorrhages, and ultimately cognitive impairment. Thus, aging-related oxidative stress and oxLDL together destabilize the BBB and cerebral perfusion, linking peripheral dyslipidemia to the hallmark microvascular lesions of VCID.

Cartilage is one of the least regenerative tissues in the body, and thus damage and aging leads to osteoarthritis, disability, and joint pain. There is considerable interest in finding ways to effectively repair or replace cartilage, provoke existing tissue into greater regenerative capacity, or adjust cellular biochemistry to make cartilage more resilient to damage and cell death. Here, researchers report on the manipulation of a regulatory protein in cartilage cells, NR0B2, also known as SHP, that is reduced in expression as osteoarthritis progresses, and appears to be protective. It might prove to be a useful target to slow the progression of cartilage loss and osteoarthritis.

Osteoarthritis (OA), characterised by cartilage destruction, is the most common degenerative joint disease. However, no effective disease-modifying OA therapy is currently available. Herein, we report orphan nuclear receptor small heterodimer partner (SHP, NR0B2) as a novel catabolic regulator of OA pathogenesis. NR0B2 expression was markedly downregulated in cartilage from patients with OA.

Global or chondrocyte-specific Nr0b2 deletion in male mice exacerbated OA-related pain and structural changes following surgical destabilization of the medial meniscus, accompanied by increased matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes. Conversely, adeno-associated virus-mediated Nr0b2 overexpression in knee joints of male mice protected against accelerated knee OA caused by Nr0b2 deficiency. Mechanistically, NR0B2 inhibited IKKβ kinase activity via IKK complex interaction, downregulating NF-κB signalling.

Our results demonstrate that NR0B2 has a chondroprotective role in OA progression by regulating matrix-degrading enzymes in an IKKβ/NF-κB-dependent manner, and gene therapy targeting Nr0b2 may be a promising therapeutic strategy for OA.

Link: https://doi.org/10.1038/s41467-026-69864-5

A range of evidence suggests that severe infection causes lasting damage that accelerates degenerative aging. That damage includes an increased burden of senescent cells and their inflammatory signaling, and changes to the immune system that reduce capacity and increase chronic inflammation. Here, researchers process epidemiological data to show that weathering a severe infection is associated with an increased risk of later dementia. Neurodegeneration is accelerated by the chronic inflammation of aging, as are most of the common, ultimately fatal age-related diseases. Unresolved, constant inflammatory signaling is disruptive to tissue structure and function.

Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association. Using nationwide Finnish health registry data, we examined the role of noninfectious mental and physical illnesses in the association between severe infections and dementia. This register-based study included 62,555 individuals aged 65 or older in Finland in 2016 who were diagnosed with late-onset dementia between 2017 and 2020 and 312,772 dementia-free controls matched for year of birth, sex, and the follow-up period. Analyses were adjusted for education, marital status, employment, and area of residence, with age and sex accounted for through the matched conditional design and analysis.

Applying a 1-year lag period, we identified 29 hospital-treated diseases that occurred 1-21 years before dementia diagnosis in cases (or index date in controls), had a prevalence of ≥ 1% prior to dementia, and were robustly associated with increased dementia risk (confounder-adjusted rate ratio ≥ 1.20). In addition to 2 infectious diseases (cystitis and bacterial infection of an unspecified site), these included 27 mental, behavioural, digestive, endocrine, cardiometabolic, neurological, and eye diseases, as well as injuries. 29,376 (47%) of the dementia cases had at least one of these diseases diagnosed before dementia.

The associations between the two infectious diseases and dementia risk were not attributable to the 27 comorbid dementia-related diseases diagnosed before infections. The adjusted rate ratio for cystitis was 1.22 before and 1.19 after adjustment for comorbidities, while for bacterial infections of an unspecified site, the rate ratios were 1.21 and 1.19, respectively. The findings were comparable across subgroups defined by sex and education, and stronger for cases of early onset dementia.

Link: https://doi.org/10.1371/journal.pmed.1004688

Animal studies show that ascending doses of nanoplastic particle infiltration into tissues eventually rise to the level of inducing dysfunction. Evidently harmful nanoplastic exposure doses are considerably higher than what are thought to be environmental exposure doses in the wild at the present time, but equally it is challenging, costly, and takes a long time to build a body of literature focused on subtle effects that may only emerge over the long term to affect the pace of aging. This is a work in progress.

The difference between nanoplastics and particulate air pollution is that there is a very large body of evidence to quantify the harms done by exposure to air pollution in human populations, alongside convincing mechanistic studies to show how long-term health and pace of aging can be negatively impacted. That body of evidence has yet to be constructed for nanoplastic exposure in human populations, so while there is a great deal of concern around this topic, it is unclear as to how much of that concern is justified. The level of interest in the topic means that the necessary epidemiological and supporting mechanistic data, analogous to the existing body of work covering air pollution, will almost certainly be produced in the years ahead, however.

Micro- and Nanoplastics Exposure Across the Lifespan: One Health Implications for Aging and Longevity

Microplastics and nanoplastics (MNPs) are pervasive environmental contaminants with growing relevance for human health across the lifespan. Older adults may be especially vulnerable to their effects due to cumulative lifetime exposure, age-related physiological changes, and a higher burden of chronic disease. Adopting a One Health perspective, this review synthesizes current evidence on the sources, exposure pathways, and biological effects of MNPs, integrating findings from environmental, animal, and human studies with a specific focus on aging populations.

Experimental studies consistently show that MNP exposure triggers oxidative stress, inflammation, mitochondrial dysfunction, and cellular senescence, mechanisms central to biological aging. These processes are linked to dysfunction of the cardiovascular, nervous, gastrointestinal, and immune systems, suggesting that MNPs may contribute to the development or progression of age-related diseases. Within the One Health framework, MNPs also act as carriers of chemical additives and environmental pollutants, potentially amplifying health risks through combined and cumulative exposures along food chains and ecosystems.

Despite increasing mechanistic evidence, direct epidemiological data in older adults remain limited. This review highlights key knowledge gaps and emphasizes the need for integrative, longitudinal research to clarify the role of MNPs in aging and to inform public health and environmental policy.

Partial reprogramming involves exposure of cells to one or more of the Yamanaka factors, (OCT4, SOX2, KLF4, and MYC, collectively OSKM) in order to induce a shift in epigenetic management of nuclear DNA structure to a more youthful state, while avoiding any dedifferentiation of target cell populations into induced pluripotent stem cells. This strategy has been demonstrated to produce some degree of rejuvenation in mice, but comes with the risk of cancer and tissue dysfunction if not carefully managed, particularly in the liver and intestines. Most of the funding presently devoted to development of rejuvenation therapies is focused on partial reprogramming, concentrated in a small number of well funded organizations, primarily Altos Labs. The first clinical trial of partial reprogramming has commenced, conducted by Life Biosciences. It is narrowly focused on the eye, where exposure can be limited and controlled. Significant challenges remain to be overcome before reprogramming can be reasonably safely applied to more of the body, however.

Despite its therapeutic promise, in vivo partial reprogramming remains far from clinical readiness. The primary obstacle is the risk that cells may inadvertently revert to pluripotency. Even brief or low-level induction of pluripotency factors can, in some cells, cross the threshold into dedifferentiation, producing teratomas and tissue dysfunction in animal models. The tissue microenvironment further complicates this dedicate balance, as certain proinflammatory signals can sensitize cells to reprogramming, which makes it difficult to limit OSKM activity to the desired level or location.

Heterogeneous expression and delivery of reprogramming factors is another concern. Systemic delivery of doxycycline-inducible OSKM often yields unequal induction: some tissues receive too much, while others receive too little. Organs with naturally high plasticity, such as the liver and the intestine, are especially vulnerable, given their rapid uptake of doxycycline, plus their intrinsic epigenetic flexibility, which means they reprogram first and most strongly, leading to malabsorption and toxicity long before other tissues benefit. Achieving precise spatial and temporal control remains technically demanding.

Chemical partial reprogramming avoids genomic integration but introduces new challenges. A deeper molecular understanding of each small-molecule cocktail is needed to minimize off-target effects, as many compounds affect multiple pathways. On top of all this, reprogramming itself is stochastic and inefficient; only a fraction of cells respond as expected, making outcomes unpredictable and raising dosing concerns.

In vivo reprogramming, therefore, reflects an intrinsic trade-off between regenerative plasticity and pathological risk. Transient relaxation of cell identity and proliferative constraints can enhance tissue repair in permissive contexts, yet the same plasticity may drive teratoma formation, tumorigenesis, or organ dysfunction when genetic safeguards are compromised or tissue context is unfavorable. Accordingly, the outcome of OSKM induction is dictated by dosage, duration, tissue context, and genetic background, underscoring the need for precise spatiotemporal control.

Progress will depend on tools that can quantitatively define and monitor the 'safe window' of rejuvenation temporally and spatially, including real-time biomarkers of epigenetic reset, tissue-specific or stress-responsive promoters, and nonintegrating delivery systems. Integrating these advances with single-cell profiling and longitudinal functional assays will be essential to establish whether partial reprogramming can be applied safely and predictably in humans.

Link: https://doi.org/10.1016/j.molmed.2026.01.007

The composition of the gut microbiome changes with age to favor inflammatory microbial species at the expense of those producing useful metabolites. Fecal microbiota transplantation is a way to permanently alter the composition of the gut microbiome, moving that of the recipient much closer to that of the donor. A number of studies in mice and other species have demonstrated that transplantation from young to old produces improved health and greater longevity, while transplantation from old to young has the opposite effect, as in the study noted here. While fecal microbiota transplantation is used in human medicine, only a few small studies have assessed outcomes in older people receiving material from young donors. The size of the effect in animal studies is promising, and thus we might hope that future studies demonstrate meaningful benefits in human patients.

The gut microbiota communicates with the homeostatic systems (nervous, immune, and endocrine). As we age, there is an increase in oxidative stress, which can deteriorate these systems, the microbiota, and the communication between them. It has been suggested that the microbiota influence the aging process, though its specific effects remain unclear. This study aimed to assess the impact of transferring microbiota from old to adult mice on behavioral, immune, and redox parameters, as well as their rate of aging and longevity.

Adult female mice were divided into three groups (N = 10/group): old microbiota (received 200 μL of old mice feces resuspended in PBS/3 days week/2 weeks, after a previous intestinal lavage with polyethylene glycol), adult microbiota (received adult mouse feces following the same procedure), and control (no manipulation). Feces were collected after treatment for microbiota and short-chain fatty acid analyses. After microbiota transfer, behavioral tests were performed, and peritoneal leukocytes were extracted to analyze immune and redox parameters, and to quantify biological age. These parameters were re-evaluated in old age, and the animals' longevity was recorded.

The results showed that old microbiota group was characterized by the increase of Akkermansia, Anaerostipes, Dubosiella, and Ruminococcus, among others. In addition, the group displayed elevated levels of anxiety, impaired immune function, and increased oxidative-inflammatory stress, effects that continued into old age. These changes translated into higher biological age and lower longevity. In conclusion, microbiota transfer from old to adult mice disrupts neuroimmune homeostasis, increases oxidative-inflammatory stress and accelerates aging process, reducing longevity.

Link: https://doi.org/10.1016/j.mad.2026.112177

Astrocytes make up a sizable population of supporting and structural cells in the brain, with a broad portfolio of activities that are collectively necessary for the normal operation of brain metabolism and neural activity. Like all cell populations, astrocytes are negatively impacted by the accumulating damage and dysfunction of aging, both internal to cells and in the tissue microenvironment. An area of focus for the research community is how aging provokes an ever increasing number of astrocytes into (1) a reactive, inflammatory state that harms brain tissue, but also (2) into a senescent state, which is also a source of inflammatory signaling that becomes detrimental to tissue structure and function when sustained over the long term. Reactivity and senescence may overlap in their contribution to neurodegeneration, and in root causes, but they are distinct issues.

Today's open access paper reviews what is known of reactivity and senescence in astrocytes, connecting these states to the bigger picture of how loss of cognitive function and onset of neurodegenerative disease emerges from aging. The present understanding of astrocyte biochemistry is, as for all cell types, incomplete. The goal of medicine is ever more precise control over cell state and cell activities, and this drives the scientific endeavor towards assembling an ever more complete understanding of cellular biochemistry. That is a very long term trajectory, however, with an end goal far out of sight of the present day to day work. In the short term, research is a matter of trying to find single genes, single proteins, single interactions in the cell that act as points of control for aspects of behavior, and thus might lead to novel therapies. Medicine remains at a very crude level of cellular control, as illustrated by our struggles with age-related disease.

Astrocyte States in Brain Aging and Neurodegeneration: At the Crossroads of Senescence and Reactivity

Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles in metabolic support, synapse regulation, proteostasis, neuroinflammation, and blood-brain barrier maintenance. Aging is accompanied by broad transcriptional and functional remodeling in astrocytes, leading to the emergence of distinct cellular states that cannot be defined by classical morphological criteria alone.

This review discusses how aging modifies astrocyte identities toward reactive and senescence-like states. We summarize core features of astrocyte senescence, including altered secretory signaling, impaired neuronal support, and changes in mitochondrial and proteostatic pathways, while integrating recent single-cell and regionally transcriptomic studies that delineate multiple reactive states associated with aging and pathological contexts. We further address evidence that reactivity and senescence are not mutually exclusive endpoints, but may coexist, arise sequentially, or partially overlap depending on timing, brain region, biological sex, and pathological insults. Finally, we define key open questions and experimental priorities required to establish the temporal and causal relationships among astrocyte states.

We argue that resolving these issues is essential for advancing therapeutic strategies that specifically target defined astrocyte phenotypes, rather than nonspecifically suppressing astrocyte activity, in aging and neurodegenerative diseases. In this view, both astrocyte reactivity and senescence represent components of a broader spectrum of astrocyte states, encompassing different degrees of inflammatory signaling, metabolic adjustments, proteostatic imbalance and alteration of homeostatic functions across aging trajectories and disease contexts. Notably, although astrocyte states are becoming increasingly well defined, additional layers of complexity are only beginning to be appreciated.

Importantly, reactive and senescent astrocytes should not be regarded as mutually exclusive identities. Instead, they may coexist within the same tissue, arise sequentially, or partially overlap depending on local conditions and disease stage. This perspective helps reconcile the heterogeneity observed across experimental models and human studies, suggesting that susceptibility to neurodegenerative disease depends not only on the presence of astrocyte dysfunction, but also on how specific astrocyte states interact with neuronal circuits, other glial cells, immune responses, and systemic factors. Moving forward, approaches that combine spatially resolved transcriptomics, longitudinal analyses and functional analyses of defined astrocyte populations will be essential to clarify the temporal and regional dynamics of these states.

The reduced intake of protein is what triggers many of the beneficial changes in cell behavior that result from calorie restriction. One of the many outcomes of calorie restriction is that some white fat tissue transitions to become beige fat via an increase the number of brown fat cells present in the tissue. Brown fat cells are involved in thermogenesis and, on balance, a greater proportion of brown fat in the body leads to incrementally better metabolic health and modestly slowed aging. Interestingly, activity in specific microbial species of the gut microbiome is necessary for the browning of white fat to take place in response to reduced protein intake, suggesting possible paths to the production of novel therapies that induce fat browning.

Interactions between diet and the gut microbiota are fundamental to metabolic health, shaping energy balance and disease susceptibility. However, the underlying mechanisms by which dietary and microbial factors converge to regulate host physiology remain unclear. Here we show that protein availability profoundly modulates the functional landscape of the gut microbiota and promotes remodelling of white adipose tissue (WAT). Specifically, low-protein diets (LPDs) robustly induce signature genes of browning in WAT to a similar extent to that seen in response to classical stimuli, such as cold exposure or β-adrenergic receptor activation.

LPD-mediated browning was markedly diminished in germ-free mice, and this defect was rescued by colonization with defined bacterial consortia made up of strains that were isolated and down-selected from the faeces of either LPD-fed mice or healthy human volunteers with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-confirmed brown- or beige-fat activity. Microbiota-induced browning was mediated both by bile acids driving the activation of the farnesoid X receptor (FXR) in adipose progenitor cells, and by nrfA-encoding commensal-derived ammonia driving the expression of fibroblast growth factor 21 (FGF21) in hepatocytes. The bile acid-FXR and ammonia-FGF21 axes both have non-redundant, essential roles in promoting WAT browning.

These findings highlight a mechanistic link between diet, gut microbial metabolism and adipose tissue remodelling, uncovering microbiota-dependent pathways by which the host responds to dietary cues.

Link: https://doi.org/10.1038/s41586-026-10205-3

Any sufficiently complex set of data that changes with age can be used to produce an aging clock, given a database of measures from people of various ages. Machine learning is applied to discover algorithmic combinations of that data that predict age. This is thought to produce outcomes that reflect biological age; a person with a predicted age higher than chronological age has a greater burden of damage and dysfunction. No clock is fully understood, in the sense that it is unknown at the time of creation as to how exactly the clock will react to a higher or lower burden of any one specific form of cell and tissue damage or consequent dysfunction in aging. This makes clocks hard to use in the way that we would like to use them, to speed up the process of evaluating potential rejuvenation therapies by providing a rapid, low cost measure of the efficacy of a given treatment.

Biological age reflects the current state of the body, considering the aspects of lifestyle, environment, and hereditary component. Currently there is no universal formula for determining it, but there are markers that can be used to calculate it. This study aims to develop and compare two models for calculating biological age based on laboratory blood tests and composition of gut microbiota.

The biochemical model of biological age uses 7 indicators and is gender-specific (general - cystatin-C, IGF-1, DHEAS, only for females - homocysteine, urea, glucose, zonulin, only for males - HbA1c, NT-proBNP, free testosterone, hs-CRP). The microbial model requires the input of percentages of 45 bacterial species as indicators of the gut microbiota. Both methods demonstrate high predictive accuracy (mean absolute error ~ 6 years, R-squared > 0.8) and the degree of agreement of assessments both with each other and with PhenoAge (correlation > 0.89).

Among the selected 45 gut bacterial species, 16 were positively associated with age. Of these, 3 species (Muribaculum intestinale, Ruminococcus albus, Ruminococcus champanellensis) can be considered "beneficial," as they are involved in acetate production, carbohydrate fermentation, and support overall microbiota and metabolic health. However, 5 other species (Catabacter hongkongensis, Clostridium saudiense, Desulfovibrio desulfuricans, Holdemanella biformis, Howardella ureilytica) are potentially pathogenic and may cause infections or contribute to inflammatory bowel disease (IBS) involving an immune component. The remaining 8 positively associated species can be classified as neutral, as they produce acetate, butyrate, and propionate, and modulate metabolic pathways.

The majority of microorganisms (29 species) exhibited a negative correlation with age, meaning their abundance decreases in older age. Among these, 7 species (Anaerobutyricum hallii, Butyricicoccus pullicaecorum, Clostridium leptum, Coprococcus comes, Eubacterium rectale, Fusicatenibacter saccharivorans, Lachnospiraceae bacterium Choco86) can be considered beneficial. They are responsible for synthesizing or fermenting various substances, support barrier function, exert anti-inflammatory effects, and reduce the risk of metabolic disorders. Conversely, only 5 species (Blautia obeum, Blautia producta, Dialister invisus, Enterocloster bolteae, Sutterella wadsworthensis) are potentially pathogenic, potentially contributing to obesity, IBS, and negatively impacting mental health. Most of the remaining age-negatively correlated species can be classified as neutral; they produce and ferment substances but under certain conditions may cause gastrointestinal disorders and metabolic disturbances.

The bacterial species used in the model collectively reflect an age-related decline in protective and metabolic functions, an increase in pro-inflammatory potential, and a disruption and impoverishment of metabolic networks.

Link: https://doi.org/10.18632/aging.206360

It is by now clear that alterations to the composition and activities of the gut microbiome affect function in the rest of the body, including the brain. The composition of the gut microbiome changes with age, a growth in populations that provoke chronic inflammation via metabolites or direct interaction with tissues, versus a reduction in the size of populations that generate beneficial metabolites that are required for normal tissue function. The research community has started to identify specific microbial species and specific metabolites associated with specific age-related conditions, and in some cases have already demonstrated the ability to restore lost function in animal studies via interventions that alter microbial population size or metabolite levels.

This research will continue. The most plausible near term interventions to emerge into widespread use are those involving probiotics. The existing probiotics industry will most likely develop a range of new products as the evidence for benefits in animal studies emerges, and do so well in advance of large human studies of efficacy. Another potentially important approach is the use of fecal microbiota transplantation from a young donor to an aged recipient, as this approach has been demonstrated to produce lasting restoration of a more youthful composition of the gut microbiome following one course of treatment, and significant health benefits in animal models. There are caveats, such as how to screen for species that can be problematic when introduced to an older individual, but these caveats seem unlikely to provoke a replacement of fecal microbiota transplantation initiatives with efforts to develop far more complex probiotic mixtures than can currently be manufactured - synthetic microbiomes in essence.

Gut-brain axis in health and brain disease

The gut-brain axis is a complex, bidirectional network of communication systems that integrates neural, endocrine, and immune pathways, as well as metabolic processes, to regulate homeostasis and maintain physiological and cognitive equilibrium. Central to this axis is the gut microbiota, which exerts a profound influence on brain function through microbial metabolites, including short-chain fatty acids, tryptophan metabolites, and bile acids. Disruption of this microbial balance, known as dysbiosis, has been implicated in the onset and progression of major neuropsychiatric and neurodegenerative disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD).

Probiotics, which are "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host," have shown considerable promise in improving mental health symptoms. Findings suggest that specific species within the Lactobacillus and Bifidobacterium genera exert the most significant impact on alleviating mental health symptoms, particularly those associated with anxiety and depressive disorders. Furthermore, studies suggest that probiotics may enhance cognitive function and potentially slow the progression of AD. In addition, they have been shown to reduce neuroinflammation and influence both blood-brain barrier integrity and neurotransmitter regulation in PD.

Fecal microbiota transplantation (FMT) is a clinical procedure in which fecal material from a healthy donor is introduced into a recipient to help reestablish a balanced and healthy gut microbiota. The primary goal of FMT is to directly alter the recipient's gut microbial composition, thereby conferring a health benefit. This approach has gained recognition for its effectiveness in treating recurrent Clostridium difficile infections. However, its potential applications extend to a range of other conditions, including those affecting the gut-brain axis. By restoring microbial balance in the gut, FMT may lead to improvements in both gastrointestinal and brain health.

Emerging studies have focused on the application of FMT as a potential treatment for various neurodegenerative diseases. For example, preclinical studies conducted in mouse models of PD have shown that FMT from healthy donors can lead to improvements in motor function and a reduction in neuroinflammation, suggesting a promising therapeutic avenue. Animal studies in models of AD have yielded varied results, with some showing improvements in behavioral measures and reductions in amyloid plaques and neuroinflammation following FMT. Although several clinical trials have been completed, ongoing studies continue to investigate the efficacy and safety of FMT in various neurological conditions. For example, clinical studies examining the effects of FMT in patients with PD and MS have shown improvements in both motor and non-motor symptoms.

In summary, early results for FMT are encouraging, but the variability in outcomes and the overall limited data underscore the need for more rigorous and extensive clinical trials. Further clinical trials are crucial for identifying the specific conditions and patient populations that are most likely to benefit from FMT. Likewise, the current body of data on the use of FMT for treating most neurodegenerative disorders remains limited. To definitively establish the efficacy and safety of FMT in this context, large-scale, well-controlled clinical trials are necessary.

Can neurodegenerative conditions be effectively treated by only changing the behavior of cells in the brain? That is an interesting question, particularly given the sizable research focus placed on epigenetic reprogramming in recent years. On the one hand there are clearly issues that occur outside cells, such as formation of aggregates or chemical changes in the extracellular matrix. There are other issues inside cells that no amount of altered cell behavior can fix, such as mutational damage to nuclear DNA. On the other hand, a variety of approaches that focus on altering epigenetic control of nuclear DNA structure and gene expression have led to improved function in animal models of neurodegenerative conditions, such as the example shown here.

Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of neurodegenerative diseases. Unlike irreversible genetic mutations, epigenetic marks such as histone methylation are dynamic and potentially reversible, making them attractive therapeutic targets. In particular, two histone methyltransferases (HMTs), GLP (EHMT1) and G9a (EHMT2), have attracted increasing attention due to their role in catalyzing the dimethylation of histone H3 at lysine 9 (H3K9me2), a repressive mark associated with transcriptional silencing. G9a/GLP-mediated epigenetic repression has been shown to influence critical processes such as neuronal development, synaptic plasticity, and memory consolidation.

Intriguingly, an aberrant upregulation of G9a activity has been linked to increased oxidative stress, neuroinflammation, and neuronal dysfunction, which are hallmarks of Alzheimer's disease (AD) and other neurodegenerative conditions. However, translating G9a inhibition into a viable therapeutic strategy has proven to be difficult. Most known G9a inhibitors, including BIX-01294, UNC0638, and A-366, suffer from poor selectivity, high cytotoxicity, and inadequate blood-brain barrier (BBB) permeability, which are limitations that are less critical in oncology but represent major obstacles for central nervous system (CNS) applications. Consequently, the therapeutic potential of G9a inhibition in neurodegeneration remains largely untapped.

Here, we report the discovery and characterization of FLAV-27, a brain-penetrant, subnanomolar inhibitor of G9a with exceptional selectivity for G9a over the closely related GLP and other methyltransferases. Unlike previously reported G9a inhibitors, FLAV-27 exhibits favorable CNS drug-like properties, including excellent BBB permeability and a strong safety profile. FLAV-27 reduces amyloid beta (Aβ) and phosphorylated tau aggregation and restores neuritic complexity in vitro. In Caenorhabditis elegans, it improves mobility, lifespan, and mitochondrial respiration. In mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD), FLAV-27 rescues memory performance, social behavior, and synaptic structure.

Link: https://doi.org/10.1016/j.ymthe.2025.12.038

Here, researchers review what is known of the aging of heart muscle, and what might be done about it. The heart is more vital to life than any other specific muscle tissue, and thus the panoply of late life dysfunctions and other manifestations of aging are well studied in this organ. Connecting the underlying mechanisms of aging to observed changes in function remains a work in progress, and will likely only advance significantly as therapies to address specific mechanisms of aging are developed and deployed. Consider the accelerated pace at which the understanding of cellular senescence in aging has advanced since the the first senolytic drugs were demonstrated in animal studies fifteen years ago, for example.

The heart, a vital organ, works without interruption and constantly adjusts to the ever-changing demands on our body. It adapts to physiological and pathological changes, including exercise and emotional state, as well as metabolic, respiratory, and vascular abnormalities. The pumping action of the heart is determined by the health of the myocardium, which undergoes changes with ageing that are both under-investigated and incompletely understood, potentially impacting our approach to pathological conditions. Here, the alterations in cellular, tissue, and gross physiological function of the heart with age are discussed.

At the molecular level, non-coding RNAs influence cellular senescence, and extracellular vesicles induce fibrosis through matrix remodelling. Mitochondrial dysfunction and altered fatty acid oxidation reduce cellular energetics, whilst accumulation of reactive oxygen species and steatosis, as well as telomere shortening coupled with reduced autophagy, limit the myocardium's regenerative capability. Loss of cardiomyocytes, combined with senescence, requires compensatory hypertrophy, inducing myocardial stiffness and altered muscle function. In addition to these direct alterations in myocardial characteristics with ageing, other factors that can affect the myocardium indirectly are addressed, including valve calcification, resulting in regurgitation and/or stenosis; vascular abnormalities, reducing compliance and exacerbating hypertension; fibrosis leading to cardiac arrhythmias; and autonomic dysregulation, reducing cardiac adaptability.

Finally, potential modulation of cardiac ageing is discussed whilst also addressing which senescent modifications should be considered as ageing-related physiological changes of the myocardium. A better understanding of myocardial ageing will differentiate physiological changes from early, preventable, and reversible pathological changes, consequently helping to optimize management of individuals with or at risk of myocardial disease by taking into account diverse trajectories of myocardial ageing.

Link: https://doi.org/10.1093/eurheartj/ehag095

Lipid metabolism is a complex area of study. Any given lipid can be transformed into scores of other molecules with quite different properties, and the scientific community's understanding of what each of these lipid products is doing in our biology is far from complete. Even just looking at cholesterol alone quickly becomes a sizable undertaking; if you were under the impression that researchers know exactly what every modified form of cholesterol or transformed product of cholesterol does in detail, you may be surprised to see just how much is left to catalog, map, and comprehend. Cellular biochemistry is very complicated, and there are only so many researchers and only so much time.

So science tends to proceed by establishing points of focus on specific molecules or specific interactions, and incrementally mapping nearby molecules and interactions. The further away from these points of focus one moves, the less complete the understanding. One of the scientific programs first started in the SENS Research Foundation has led to a growing point of focus on 7-ketocholesterol and its effects. 7-ketocholesterol is a oxidized form of cholesterol known to be toxic and thought to have no useful purpose in metabolism. Evidence points to a role for 7-ketocholesterol in atherosclerosis and a range of other conditions, and thus a company, Cyclarity Therapeutics, was formed to develop therapies to clear 7-ketocholesterol from tissues. That program is currently in its early clinical stages.

The scientific process doesn't stop at "7-ketocholesterol is toxic, and thus we should clear it from tissues to improve health", however. 7-ketocholesterol exists in the sizable space of alterations to cholesterol and products of cholesterol. Many of the transformations that can be applied to cholesterol can also be applied to 7-ketocholesterol. Do researchers have a good idea as to what these further derivatives of 7-ketocholesterol are doing to cells? Not really, but the point of focus established on 7-ketocholesterol will expand slowly to these products and their effects.

Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease

Cholesterol is a vital lipid molecule essential for cellular structure and function. Oxidation of cholesterol leads to the formation of biologically active oxidized cholesterols known as oxysterols. Among oxysterols, 7-ketocholesterol (7KC) is a key product, primarily formed by oxidation at the C7 position of the cholesterol molecule. 7KC is notably elevated in conditions such as hypercholesterolemia and within atherosclerotic lesions, often at higher concentrations than other oxysterols. Growing research highlights 7KC's significant involvement in the development and progression of a wide array of diseases and aging cells, where it is widely recognized for its cytotoxic, pro-inflammatory, and pro-apoptotic properties, positioning it as a critical factor in pathophysiology.

While 7KC has traditionally been studied as an end-product of cholesterol oxidation, increasing evidence suggests that it also serves as a precursor or co-product in the generation of more structurally complex oxysterols bearing multiple oxidative modifications. Among these, double-substituted oxysterols such as 7-keto-25-hydroxycholesterol (7-keto-25-OHC) and 7-keto-27-hydroxycholesterol (7-keto-27-OHC) represent an underexplored but potentially significant class of downstream metabolites.

The presence of both a C7 ketone and a side-chain hydroxyl group profoundly alters sterol polarity, membrane partitioning, and reactivity. Compared with mono-substituted oxysterols, double-substituted species are expected to exhibit reduced membrane affinity, enhanced aqueous solubility, and increased accessibility to intracellular targets. These physicochemical properties may influence their transport, cellular distribution, and rate of further metabolism or clearance. Moreover, the coexistence of two oxidative modifications may amplify biological activity, either through additive effects or through the emergence of distinct signaling properties not observed with single modifications. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.

In recent years, researchers have noted that circular RNAs accumulate in cells in old age. It has been unclear as to whether this is only a marker of dysfunction or a change that in and of itself causes further downstream issues. The fastest way to obtain an answer to this sort of question is to repair the problem and see what happens. Researchers here identify that levels of RNASEK, a protein responsible for breaking down circular RNA, decline with age, allowing circular RNA levels to rise. Forcing increased expression of RNASEK slows aging and extends life, which strongly suggests that circular RNAs are harmful in some way. The researchers suggest that harms result from circular RNA aggregation in the cell, but further research is needed on this topic.

Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. Using Caenorhabditis elegans, a short-lived roundworm widely used in aging research, researchers first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.

Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.

The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. When RNASEK is deficient and circular RNA accumulates, "stress granules" form abnormally inside the cell, which can impair cellular functions and accelerate aging. RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=59490

The thymus, a small organ near the heart, is important to the function of the adaptive immune system. Thymocytes migrate from bone marrow to the thymus where they mature into T cells. The thymus atrophies with age, and the loss of active thymic tissue reduces the pace at which new T cells are produced. This leads to an adaptive immune system that, lacking sufficient replacements, is ever more populated with senescent, exhausted, and malfunctioning T cells. That this is an important contribution to the loss of immune function that occurs in later life is illustrated by the data presented here, in which researchers correlate degree of thymic atrophy with mortality and incidence of age-related disease in a large human study population.

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581).

In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex, and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity, and physical activity.

Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Link: https://doi.org/10.1038/s41586-026-10242-y