Fight Aging!

Cytomegalovirus is a form of herpesvirus that is prevalent in the human population. As is the case for other herpesviruses, the immune system struggles to clear cytomegalovirus from the body. It becomes a persistent infection. Few people make it to late life without being infected, at least judging by those regions of the world where there is good data on cytomegalovirus prevalence. Cytomegalovirus infection typically goes unnoticed and produces no evident symptoms, at least in the vast majority of individuals who have a normally functioning immune system. But evidence suggests that the presence of cytomegalovirus infection has a corrosive effect on the immune system in late life. Ever more cells become specialized to focus on cytomegalovirus at the expense of populations needed to conduct other activities.

Researchers have correlated the presence of cytomegalovirus with risk of various age-related diseases, but it is unclear as to whether (a) cytomegalovirus infection selects for individuals with more dysfunctional immune systems and thus a higher burden of inflammation to drive the onset and progression of age-related diseases, or (b) cytomegalovirus is actively contributing to disease progression in some way, whether via promoting immune dysfunction and inflammation, or some other mechanism or mechanisms. It is also unclear as to how great a contribution is provided to disease progression by cytomegalovirus, if it is indeed providing a meaningful contribution. These sorts of questions are hard to definitively answer in human medicine. The most feasible approach is probably to develop the means to clear cytomegalovirus from the body, and see how the uninfected fare versus the infected over the long term.

Human cytomegalovirus infection and cognitive decline: insights from population and experimental studies

Human cytomegalovirus (HCMV), a ubiquitous DNA betaherpesvirus, is capable of persistent infection and immunomodulation, particularly in immunocompromised and elderly hosts. Emerging evidence links HCMV to neurodegenerative diseases through its multifaceted immunomodulatory effects. This review summarizes key viral architectures and mechanisms, epidemiological trends, and experimental data supporting HCMV's role in cognitive decline.

The association between HCMV infection and cognitive impairment has been explored across multiple large-scale studies, though findings remain heterogeneous. In the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort of 1,204 older Mexican Americans (mean age 70.3 ± 6.8), higher HCMV IgG levels - but not HSV-1 - were significantly associated with accelerated cognitive decline over four years, independent of age, sex, education, income, and comorbidities. Postmortem and in vitro studies further implicate HCMV in neurodegenerative processes. In a PCR-based analysis, HCMV DNA was detected in 93% of brain specimens from patients with vascular dementia, compared to 34% of age-matched controls. In AD patients, HCMV seropositivity has been associated with increased neurofibrillary tangle (NFT) burden and elevated interferon-γ levels in cerebrospinal fluid (CSF) - a cytokine detected only in seropositive individuals .

Animal studies have also provided mechanistic insights into how cytomegalovirus infection may contribute to neurodegeneration. In vitro, murine CMV (MCMV) infection induces tau pathology in mouse fibroblasts and rat neuronal cells, dependent on late viral gene expression but independent of glycogen synthase kinase 3β (GSK3β) activity - suggesting an alternative pathway for tau phosphorylation. In vivo, repeated systemic MCMV infection in mice has been shown to elevate neuroinflammatory markers, disrupt mitochondrial function, increase oxidative stress, and impair cognitive performance.

While a causal role for HCMV in neurodegeneration remains unproven, future studies - particularly those leveraging antiviral therapies or vaccines aimed at preventing AD and vascular dementia - may clarify whether the virus functions as an etiological contributor. Additional approaches, including probiotics or fecal microbiota transplantation that influence HCMV latency and reactivation, also warrant close investigation as potential strategies to mitigate cognitive decline in susceptible populations.

The failure of anti-amyloid-β immunotherapies to more than slightly slow the progression of Alzheimer's disease has not much dented the amyloid cascade hypothesis, just clarified that amyloid-β becomes unimportant to disease progression once at the stage of sizable tau aggregration, neuroinflammation, and loss of cognitive function. The consensus continues to be that amyloid aggregation is the originating cause of Alzheimer's disease, the pathology that sets the stage for what comes later. That hypothesis will be confirmed or disproven in the years ahead as anti-amyloid-β immunotherapies are deployed in ever earlier stages of the condition. There may be other approaches to obtaining useful data, however. Here, researchers note that an existing drug, levetiracetam, reduces amyloid-β production in the brain, which will in turn reduce misfolding and aggregation of amyloid-β. This suggests the potential for a trial to directly assess its ability to delay or prevent Alzheimer's disease.

Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ42 in the SV lumen.

Levetiracetam (Lev) is a US Food and Drug Administration-approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ42 levels by reducing amyloidogenic APP processing in an SV-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway.

Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Brains from patients with Down syndrome also displayed presynaptic protein accumulation before the occurrence of substantial Aβ pathology, supporting the hypothesis that protein accumulation is a relevant pathogenic event in amyloid pathology. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.

Link: https://doi.org/10.1126/scitranslmed.adp3984

Academic research is, as a rule, always short of funding. Researchers are consistently strongly motivated to find less costly approaches to animal studies. One aspect of this pressure is that the standard, most widely used animal models of disease tend to be the ones that can be created as rapidly as possible, using various toxic, damaging strategies to reproduce aspects of aging in relatively young mice. Time has its own cost, and budgets don't stretch to waiting around for mice to get old. Thus in this modern era of enthusiasm for targeting the mechanisms of aging, the research community finds itself in the position of knowing too little about how aging interacts with disease processes.

Mouse models of Parkinson's disease (PD) are invaluable for advancing our understanding of the disease, and there is much hope that their use will help develop new therapeutic interventions. PD is a complex multisystem disorder characterized by a spectrum of motor and non-motor symptoms, and numerous mouse models have been developed to study its various aspects. While age is the primary risk factor for PD, the role of biological aging in PD is still unclear, and it is often overlooked in the design and application of these models. This omission risks missing critical insights into disease mechanisms and opportunities for the development and translation of novel interventions, in particular as aging biology is emerging as a therapeutic target.

The International Network for Parkinson's Disease Modelling and AGEing (PD-AGE), funded by the Michael J. Fox Foundation for Parkinson's Research, was established to address critical gaps in our understanding of the role of aging in PD. Its creation was prompted by a workshop that brought together leading experts in PD modeling and aging who collectively highlighted the need for a systematic investigation into how aging contributes to PD.

To achieve its goals, PD-AGE was divided into four working groups, each focusing on different models. Here, we report on the working group that focused on approaches using mouse models and conducted a series of workshops to build consensus on prioritizing models of aging and PD, experimental approaches, and the standardization of protocols for their characterization. The result is a comprehensive roadmap for selecting optimal models, defining relevant measurements, and harmonizing protocols.

Link: https://doi.org/10.1038/s41531-025-01239-x

The immune system is a very complex array of interacting cell populations, constantly changing over time. The inflammatory response is similarly complex, arising from many different inciting events and cascades of signaling and interaction between various immune cell types. Thus there are no simple measures of inflammation, no matter that the medical community has certainly tried very hard to make that goal a reality. Or perhaps it is better to say that simple measures of, say, one signaling molecule (in practice often C-reactive protein), paint a limited picture of what is actually going on. Sometimes that limited picture is useful, sometimes it is misleading.

Today's open access paper is a good illustration of the limits of what one can learn from a single marker, or two related markers. Circulating C-reactive protein and IL-6 are linked mechanistically in that C-reactive protein rises in response to IL-6. These are also the most commonly used measures of inflammation, so the research and medical communities have a fair grasp on the limitations. Nonetheless because they are commonly assessed markers, there is a tendency to continue to use them, as then at least there is a large body of existing data to compare against.

Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact

"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.

We found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts - 36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.

In conclusion, peripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.

Imaging of atherosclerotic plaque, particularly via CT scan, has improved immensely over the past decade in its ability to quantify plaque and discern plaque composition, particularly with advances in machine learning approaches to analysis. Here, researchers demonstrate that plaque volume correlates with risk of severe cardiovascular events. The volume of softer, more fatty plaque also correlates with risk, much as one might expect. It is these less stable plaques that are more likely to fragment, leading to a downstream blockage. Imaging will become more important as cardiovascular therapies improve to point of being able to produce rapid stabilization or even regression of plaque, capabilities that do not currently exist. The best that can be done with the present standard of care, focused on lowering LDL cholesterol, is a slowing of plaque growth and some degree of stabilization over years of sustained use.

Despite the increasing use of coronary computed tomographic angiography (CCTA) in patients with known or suspected coronary artery disease (CAD), comparatively little is known about its predictive value for adverse events or clinical applicability of volumetric plaque analysis. This post hoc analysis involved a prospective randomized clinical trial conducted across 193 clinical sites in North America. Participants were symptomatic outpatients without known CAD who were randomized to receive CCTA. Core laboratory-based quantitative plaque measures including total plaque volume (TPV), calcified (CPV) and noncalcified (NCPV) plaque volume, low-attenuation plaque volume (LAPV), total plaque burden (TPB), and noncalcified plaque burden (NCPB), normalized with vessel volume.

The primary outcome was major adverse cardiovascular events, MACE (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina). Among 4,267 patients, the mean age was 60.4 ± 8.2 years; 2199 patients (51.5%) were female and 2068 (48.5%) were male. Higher total plaque volume (≥87 mm), total plaque burden (≥35%), and noncalcified plaque burden (≥20%) were associated with an increased risk of MACE, independent of atherosclerotic cardiovascular disease risk, statin use, 50% or more stenosis, coronary artery calcium score, and high-risk plaque.

Link: https://doi.org/10.1001/jamacardio.2025.5520

Partial reprogramming involves the short-term expression of Yamanaka factors to restore youthful epigenetic control over nuclear DNA structure and gene expression. The primary challenge is to avoid accidental full reprogramming of cells into induced pluripotent stem cells, or otherwise losing necessary cell state, in a tissue environment in which different cell types require different degrees of exposure to pass various reprogramming-related thresholds. Interestingly, much of the present development of partial reprogramming as a basis for rejuvenation therapies has converged on the central nervous system as a target. For example, here researchers are interested in the neurons that encode memory, and find that partial reprogramming can improve memory function in aged mice.

Partial cellular reprogramming has emerged as one of the most promising strategies in regenerative medicine. Cyclic expression of the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc - OSKM), or a partial combination thereof (OSK), holds the potential to orchestrate rejuvenation of cellular function in aging while at the same time preventing changes in cell identity and tumorigenesis.

Memories are encoded in sparse neuronal ensembles termed engrams, which are found in different brain regions, with specific contributions to recall during memory consolidation. Thus, engrams in the hippocampus, and in particular in the dentate gyrus (DG), are predominantly important for learning and recent recall, whereas engrams in the medial prefrontal cortex (mPFC) become gradually more relevant for remote memory expression. Importantly, during physiological aging and in mouse models of Alzheimer's disease (AD), engram impairments interfere with memory recall, suggesting that engram dysfunction may underlie age- and disease-related memory decline.

Here, we report that partial reprogramming of engram neurons - bona fide memory trace cells - by OSK-mediated gene therapy reversed the expression of senescence-related and disease-related cellular hallmarks in aged mice and models of Alzheimer's disease (AD), re-established aberrant epigenetic-transcriptional patterns pertaining to synaptic plasticity, and counteracted AD-typical neuronal hyperexcitability. Importantly, irrespective of the brain area targeted or the behavioral paradigm employed, engram reprogramming also recovered learning and memory capacities to levels of healthy young animals, suggesting cognitive rejuvenation. These results posit that partial reprogramming of specific cell populations in the brain can be exploited for cognitive restoration in aging and disease.

Link: https://doi.org/10.1016/j.neuron.2025.11.028

APOE is a component of the low density lipoprotein (LDL) particles that carry cholesterol from the liver to where it is needed in the body. Lowering circulating LDL-cholesterol levels to modestly slow the progression of atherosclerosis is the primary approach taken in cardiovascular medicine; in recent years, new forms of LDL-lowering therapy such as PCSK9 inhibitors have been used to dramatically reduce LDL-cholesterol to far below normal levels with no immediately apparent prohibitively negative effects on patients.

In today's open access paper, researchers show that elevated APOE levels are a feature of old age and negatively affect bone regeneration, likely by suppressing the creation of osteoblast cells responsible for producing bone extracellular matrix structures. A near complete elimination of APOE production in the liver (which will also have the consequence of dramatically reducing LDL-cholesterol in circulation) improves the regeneration of fractures in old mice. There is clearly still a sense of caution in making permanent changes of this nature, despite ongoing development such as Verve Therapeutics' gene-editing PCSK9 inhibition therapy.

Neutralizing hepatic apolipoprotein E enhances aged bone fracture healing

In our previously published study, we demonstrated that circulating ApoE levels increase with age in patients and in mice and that by using liver targeted AAV to deliver siRNA for ApoE we decreased circulating ApoE levels and increased bone deposition and mechanical stability of healed tissue. However, the potential negative impact on a patient's cardiovascular health resulting from the permanent lowering of ApoE precludes this therapeutic strategy. Therefore, in the current study we aimed to use a neutralizing antibody against ApoE which would be cleared from the body by immune cells.

In this study we identified the mechanism of action by which hepatic ApoE inhibits fracture healing and identified a translatable non-invasive therapeutic intervention to improve aged bone repair. We knocked out hepatic ApoE expression in mice - this decreased levels of circulating ApoE and increased bone deposition and tissue mineral density within the fracture callus. Using tissue culture models, we found ApoE inhibits bone marrow stem cell to osteoblast differentiation and activity by binding to the cell-surface receptor Lrp4 and inhibiting Wnt/β-catenin signaling. Moreover, the same mechanism of action was identified during ApoE-induced inhibition of human bone marrow stem cells.

Finally, aged wildtype mice underwent tibial fracture surgery and were treated with a neutralizing antibody for ApoE 3 days post-injury which decreased levels of circulating ApoE and significantly improved fracture healing.

Atherosclerosis is the largest cause of human mortality, a growth of fatty plaques in blood vessel walls that narrow and weaken vessels. The structure and composition of plaques can vary considerably between people and within one individual. The most dangerous plaques are those with more fat and less structural material, as these are prone to rupture, leading to a downstream blockage and a heart attack or stroke. A plaque is a toxic environment that draws in macrophage cells that attempt to repair the lesion, but instead are overwhelmed, killed, and add their mass to the plaque. Initially, circulating monocyte cells arrive at a plaque and turn into macrophages, but in later stages an almost cancerous process causes smooth muscle cells in the vascular wall to turn into macrophages to further accelerate plaque growth and instability. Here, researchers find a way to potentially interfere in this process, and thus greatly reduce the formation of unstable plaques that are prone to rupture.

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood.

Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition.

Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE knockout mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion.

Link: https://doi.org/10.1093/pcmedi/pbaf039

The creation of engineered immune cells equipped with what are known as chimeric antigen receptors (CARs) can in principle be used to target any distinctive population of cells or extracellular materials for selective destruction. First introduced as a treatment for leukemia, this remains a very expensive form of therapy, and so is not as widely developed for new uses as might otherwise be the case. Nonetheless, a steady stream of proof of concept studies exists, such as the example here in which CAR technology is applied to target protein aggregates in the context of Alzheimer's disease.

Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8+ cells, CD4+ T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging.

Here, we sought to exploit the beneficial properties of CD4+ T cells while circumventing the need for T cell receptor and peptide / major_histocompatibility_complex antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4+ T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4+ T cells into the brain parenchyma and leptomeninges.

In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4+ CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the central nervous system, paving the way for future development of cellular immunotherapies for neurodegenerative disease.

Link: https://doi.org/10.1073/pnas.2530977123

The retina at the back of the eye is the one part of the central nervous system that can be readily visually inspected, including the state of the network of blood vessels that supports it. Capillary networks of tiny blood vessels are dense and actively maintained; as the character of angiogenesis changes for the worse with aging, these networks become less dense and exhibit other signs of damage. Thus imagery of the retina provides a lot of data that can be employed to, for example, produce aging clocks, or act as a proxy measure for other forms of vascular and nervous system aging.

For retinal imagery to be usefully employed as a proxy measure of any specific aspect of vascular aging or central nervous system aging, or specific form of age-related damage, a robust correlation must first be demonstrated. Thus we have papers such as today's example, in which researchers establish links between retinal imagery characteristics and vascular and brain aging. One might expect this to inform efforts to further advance retinal imaging as a relatively low cost diagnostic tool, a way to better establish risk and the need for more costly forms of assessment in older people.

Cross-organ analysis reveals associations between vascular properties of the retina, the carotid and aortic arteries, and the brain

Doctors often use eye scans to check for signs of heart and brain disease, but the exact link between the tiny blood vessels in the eye and those in major organs is unclear. We aimed to systematically map similarities between blood vessels across the entire body. We compared vascular image-derived phenotypes from the brain, carotid artery, aorta, and retina, using UK Biobank sample sizes ranging from 18,808 to 68,740 participants. We examined phenotypic and genetic correlations, as well as common associated genes and pathways.

Here we show that white matter hyperintensities are positively correlated with carotid intima-media thickness (r = 0.03), lumen diameter (r = 0.14), and aortic cross-sectional areas (r = 0.09), but negatively correlated with aortic distensibilities (r ≤ -0.05). Arterial retinal vascular density shows negative correlations with white matter hyperintensities (r = -0.04), intima-media thickness (r = -0.04), lumen diameter (r = -0.06), and aortic areas (r = -0.05), while positively correlating with aortic distensibilities (r = 0.04). Significant correlations also persist after correcting for hypertension.

In summary, we found strong connections with the health of retinal blood vessels mirroring the health of the brain and major arteries. This suggests that some of the same factors influence vessel health across the body. This suggests that an eye scan could be a fast, non-invasive way to get a complete snapshot of a person's overall cardiovascular and brain health. These findings could help doctors identify health issues, such as early artery stiffness or brain aging, much sooner.

Aging is an accumulation of cell and tissue damage, combined with the dysfunctions resulting from that damage. Damaged systems lose function in a haphazard, random fashion that, averaged out over time and across many systems, tends to be proportional to the burden of damage. This is the case whether the system is a simple mechanical device, an organ, or a human. In aging humans and animals one thus observes correlations between most different examples of lost and degraded function, including those that cause mortality.

We assessed the population distribution of age-related functional impairments (ARFIs) and their associations with mortality and life expectancy (LE). We included 12,906 participants (mean age: 62.6 years) from the China Health and Retirement Longitudinal Study. Visual impairment, hearing impairment, cognitive impairment, sleep disorder, depressive symptoms, and disability in activities of daily living (ADL) were assessed. Cox proportional hazards models were used to estimate the associations of ARFIs with all-cause mortality. Life expectancy at age 50 was estimated by the presence and number of key ARFIs.

The six ARFIs exhibit distinct distributions by ages and provinces across China. During the 9-year follow-up, ADL disability, cognitive impairment, and depressive symptoms are independently associated with 64%, 41%, and 20% higher risks of mortality, corresponding to LE losses of 4.45, 3.08, and 1.59 years at the age of 50 years. A greater number of key ARFIs is associated with higher mortality risk in a dose-response manner (hazard ratios: 1.23 for one, 1.42 for two, and 1.86 for three) and greater LE loss (1.63 years for one, 3.37 for two, and 4.96 for three).

Link: https://doi.org/10.1038/s43856-025-01350-3

Evolution optimizes for reproductive success, and thus it should be no surprise to find that reproductive organs influence the entire body, and thus their aging has sizable effects on the aging of other organs. Researchers here review the mechanisms of aging that act to degrade structure and function of the testes, and in turn affect the production of androgens that influence tissue function elsewhere in the body.

The testis, a male-specific organ, plays a critical role in maintaining spermatogenesis and androgen production. As men age, testicular function declines, compromising not only reproductive capacity but also overall health and quality of life. Testicular ageing is characterized by progressive degeneration of the seminiferous epithelium and interstitial compartments, leading to endocrine dysfunction, impaired spermatogenesis, and heightened risk of age-related disease.

Although mechanistic insights are advancing rapidly, most therapeutic studies remain rooted in reductionist single-cell models that overlook the integrated dynamics of the testicular microenvironment. In reality, testicular ageing reflects a coordinated decline of germ cells, Sertoli and Leydig cells, and their niches. This process is driven by interconnected mechanisms, including oxidative stress, defective DNA repair and autophagy, dysregulated endocrine homeostasis, impaired protein quality control, and aberrant activation of ageing-related signalling pathways, which act synergistically.

Testicular ageing is accompanied by a progressive collapse of energy metabolism. Impaired fatty acid utilisation, reduced glucose uptake, and widespread mitochondrial dysfunction collectively drive metabolic remodelling that deteriorates the testicular microenvironment. Moreover, senescent somatic cells acquire a senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines such as IL-6 and IL-1β, while testicular macrophages adopt a pro-inflammatory state that recruits adaptive immune cells. Together, these changes establish a chronic inflammatory microenvironment that reinforces cellular senescence and accelerates testicular ageing.

Priorities for future research include clarifying cell-microenvironment interactions, establishing non-invasive biomarkers for early detection, and resolving metabolic pathways that may guide senolytic strategies. As therapeutic paradigms evolve, emerging interventions - particularly stem-cell-based approaches - may extend beyond the limits of conventional pharmacology to enable more precise and effective mitigation of testicular ageing.

Link: https://doi.org/10.1080/07853890.2026.2624183

The peptide industry has been growing for some years now, becoming more vocal and visible. It occupies a similar space to the supplement industry, and seems likely to provoke many of the same battles with regulators such as the FDA. Peptide use is characterized by the same lack of rigorous supporting data that attends supplement use, and for many of the same reasons. The lines in the sand dividing peptide from drug are just as arbitrary as those dividing supplement and drug, and just as driven by funding and the high cost of regulatory compliance. Peptides that can be effectively monopolized via intellectual property become drug candidates, as only with that monopoly is it possible to raise enough funding to engage with regulators and run clinical trials. Peptides that cannot remain on the outside, without the robust human data needed to support greater interest.

Against the background of this broader context of a growing market for the use of peptides, you might recall that the peptide FOXO4-DRI was one of the early potential senolytic therapies to be validated in animal studies, back in the mid-2010s. FOXO4-DRI interferes in the interaction between FOXO4 and p53 that normally inhibits apoptosis of senescent cells, and thus results in the selective destruction of senescent cells with very little impact on other cells. Clearance of senescent cells is well demonstrated to improve health in aged animal models, but only relatively small clinical trials of a few senolytic small molecules have yet taken place to validate use in humans.

A company, Cleara Biotech, was formed to commercialize the early academic work on FOXO4-DRI, and appears to still be a going preclinical concern focused more on the FOXO4-p53 interaction than on FOXO4-DRI per se. Other groups have since become involved, such as Numeric Biotech, and it has long been the case that anyone so minded can just up and buy FOXO4-DRI for personal use from any number of peptide sellers. It is unclear as how many people are choosing to do that, and certainly we'll never see any sort of useful data resulting from that use. Meanwhile, academic research groups continue to work with FOXO4-DRI as a tool to explore the FOXO4-p53 interaction in the context of cellular senescence as a driver of degenerative aging.

FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

Endothelial cell dysfunction during aging is a key driver of vascular aging and related diseases; however, effective strategies to selectively eliminate senescent endothelial cells and restore vascular function remain lacking. FOXO4-DRI, a novel peptide-based intervention, specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells. This study innovatively focuses on the mechanism by which FOXO4-DRI induces apoptosis in senescent endothelial cells, demonstrating that it functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of these cells. FOXO4-DRI significantly improves vascular function and delays vascular aging.

This study aims to analyze the vascular function and aging status of the aorta in naturally aged mice and progeroid model mice following FOXO4-DRI injection. Additionally, it investigates changes in endothelial cell function in senescent endothelial cells induced by oxygen-glucose deprivation (OGD), as well as the protein expression and interaction in the FOXO4-P53 signaling pathway. To assess the impact of FOXO4-DRI on endothelial cell senescence, the senescent endothelial cells were treated with FOXO4-DRI, followed by immunofluorescence and Western blotting experiments.

Injection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function. Additionally, we found that FOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function. Through co-immunoprecipitation (CO-IP) experiments, we discovered that FOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells. Ultimately, this mechanism achieves the goal of inhibiting vascular aging.

There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.

O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.

While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

Link: https://doi.org/10.1002/cbic.202500774

Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.

Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.

Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.

A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.

Link: https://doi.org/10.1016/j.celrep.2025.116906