Fight Aging!

In recent years, the research community has developed a number of blood tests to assess risk and progression of Alzheimer's disease, relevant to the earliest, pre-symptomatic stages of the condition. Alzheimer's disease emerges very slowly over time, a process of damage and dysfunction that builds by stages over decades. The present consensus is that these early stages are dominated by amyloid-β misfolding and aggregation with only mild cognitive impairment at worst as the result. Only later is it the case that outright neuroinflammation and aggregation of phosphorylated tau protein come into play as the primary disease mechanisms. Nonetheless, forms of phosphorylated tau circulating in blood have proven useful as a marker of disease progression even in the early stages.

Today's research materials report on the use of one of the Alzheimer's blood tests based on phosphorylated tau to construct an aging clock specifically focused on predicting the time to development of Alzheimer's symptoms. Any set of markers that change with age can be used to produce a predictive clock, given enough data from enough people. The only question is how accurate it is; more data is generally better. Here, researchers work from only one assessment in a few hundred people to produce an estimated margin of error of 3 to 4 years over a time span of 10 to 20 years of disease development to first symptoms - a decent outcome given such a limited set of data.

Blood test "clocks" predict when Alzheimer's symptoms will start

Researchers have demonstrated models that predict the onset of Alzheimer's symptoms within a margin of three to four years. This could have implications both for clinical trials developing preventive Alzheimer's treatments and for eventually identifying individuals likely to benefit from these treatments. The models use a protein called p-tau217 in an individual's blood plasma to estimate the age when they will begin experiencing symptoms of the neurodegenerative disease. Levels of p-tau217 in the plasma can currently be used to help doctors diagnose Alzheimer's in patients with cognitive impairment. These tests are not currently recommended in cognitively unimpaired individuals outside of clinical trials or research.

To identify the interval between elevated p-tau217 levels and Alzheimer's symptoms, researchers analyzed data from volunteers in two independent long-running Alzheimer's research initiatives. The participants included 603 older adults who lived independently in the community. Plasma p-tau217 has previously been shown to correlate strongly with the accumulation of amyloid and tau in the brain as shown on PET scans. The key hallmarks of Alzheimer's disease, amyloid and tau are misfolded proteins that begin building up in the brain many years before Alzheimer's symptoms develop.

The models predicted the age of symptom onset within a margin of error of three to four years. Older individuals had a shorter time from when elevated p-tau217 appeared to the start of symptoms as compared to younger participants, suggesting that younger people's brains may be more resilient to neurodegeneration and that older people may develop symptoms at lower levels of Alzheimer's pathology. For example, if a person had elevated p-tau217 in their plasma at age 60, they developed symptoms 20 years later. If p-tau217 wasn't elevated until age 80, they developed symptoms only 11 years later.

Predicting onset of symptomatic Alzheimerʼs disease with plasma p-tau217 clocks

Predicting not just if, but also when, cognitively unimpaired individuals are likely to develop onset of Alzheimerʼs disease (AD) symptoms would be useful to clinical trials and, eventually, clinical practice. Although clock models based on amyloid and tau positron emission tomography have shown promise in predicting the onset of AD symptoms, a model based on plasma biomarkers would be more accessible. Using longitudinal plasma %p-tau217 (the ratio of phosphorylated to non-phosphorylated tau at position 217) from two independent cohorts (n = 258 and n = 345), clock models were used to estimate the age at plasma %p-tau217 positivity.

The estimated age at plasma %p-tau217 positivity was associated with the age at onset of AD symptoms with a median absolute error of 3.0-3.7 years. Notably, the time from %p-tau217 positivity to onset of AD symptoms was markedly shorter in older individuals. Similar models were constructed with data from one p-tau217/Aβ42 immunoassay and four plasma p-tau217 immunoassays. These findings suggest that the time until onset of AD symptoms can be estimated using a single blood test within a margin of error that is acceptable for use in clinical trials.

Lifestyle choice relating to diet influences the pace of aging over the long term. A great deal of effort has been devoted to understanding why this is the case, focused on the specific effects of excess weight and various dietary components on metabolism. Researchers here make an effort to assess the effects of dietary choices on human life expectancy that emerge from the large amount of epidemiological data recorded in the UK Biobank. The results are in the same ballpark as the benefits to life expectancy indicated by some past large studies of the effects of moderate exercise.

Associations between healthy dietary patterns and life expectancy remain unclear. Here, we reported the prospective associations of five dietary patterns with mortality and life expectancy in 103,649 UK Biobank participants. Over a median follow-up period of 10.6 years, 4,314 total deaths were documented. Alternate Healthy Eating Index-2010, Alternate Mediterranean Diet (AMED), healthful Plant-based Diet Index (hPDI), Dietary Approaches to Stop Hypertension, and Diabetes Risk Reduction Diet (DRRD) were associated with lower all-cause mortality and longer life expectancy, with DRRD showing slightly stronger associations than hPDI.

Compared with the bottom quintile, achieving the top quintile of dietary scores was associated with 1.9 to 3.0 years of life gained at 45 years in men and 1.5 to 2.3 years in women. The life gained was longest in DRRD for males and AMED for females. The significant associations remained when accounting for genetic susceptibility. Our findings underscore the advantages of healthy dietary patterns in prolonging life expectancy, regardless of longevity genes.

Link: https://doi.org/10.1126/sciadv.ads7559

Researchers have in past years established that some degree of transmission of environmental information takes place from generation to generation. The epigenetic response to environmental factors such as abundance of food is partially passed on to offspring to result in changes in the operation of offspring metabolism. Epigenetic and metabolic reactions to abundance of food affect pace of aging and life span, and these outcomes are also changed in offspring, even when the offspring live in a different environment with different abundance of food.

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age.

This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of maternal obesity may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

Link: https://doi.org/10.64898/2026.02.04.703858

A wide variety of stem cell therapies exist at various stages of development and clinical use. A broad range of cell sources and processing techniques are unprotected by intellectual property and are thus employed by clinics both within and outside the more heavily regulated regions of the world. Stem cell therapies have long been a staple of the medical tourism industry. These first generation stem cell therapies may be widely used but do not contribute much in the way of robust data to improve our understanding of how well they work. It appears to be the case, from what little we can see, that the benefits of treatment vary notably between patients and clinics. Even similar approaches can produce very different outcomes in different hands, and it is not well understood as to why this is the case or how to improve the situation.

At the other end of the industry, companies develop their own proprietary, patented approaches to producing stem cell therapies that might have a chance of passing muster with regulatory authorities. The intellectual property and consequent monopoly on the technology used is necessary for a company to raise enough funding to conduct clinical trials, which regulators have made a very expensive process. Developing a therapy for regulatory approval tends to require directly addressing the questions of variability between patients and batches of cells, and so far stem cell therapies have done relatively poorly in clinical trials; robust and sizable benefits beyond a months-long reduction in inflammation remain elusive. Today's open access paper is, I think, largely interesting for a large table of trials and trial outcomes that illustrates that point.

A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges

Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. In recent years, stem cell transplantation therapy has gained attention as a promising treatment approach for neurological diseases. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

This narrative review presents a current synthesis of the most recent experimental and clinical findings on stem cell-based therapies for major neurodegenerative disorders. In contrast to previous reviews that mainly concentrated on individual cell types or specific disease applications, this article combines evidence related to specific diseases, clinical trial results, and innovative technologies such as exosome therapy, nanotechnology, and CRISPR-based enhancements. It thus provides a holistic view that connects molecular mechanisms to practical applications. This review distinctively emphasizes the regulatory and ethical framework, tackling real-world challenges that have often been overlooked in earlier discussions.

Portions of the research community are concerned that the ability to preserve function in the aging brain is not progressing as rapidly as the ability to intervene in the aging of other organ systems in the body. This gives rise to articles such as the one here, which seeks to bring attention to this issue by coining a term for the healthspan of the brain specifically. The brain is complex, inaccessible, and irreplaceable in ways that are not the case for even, say, a heart, liver, or kidney. This constrains the strategies that might be developed to treat the aging of the brain, and those constraints in turn lead to concern regarding the development of future therapies.

Longevity medicine has achieved substantial gains in extending lifespan, yet these advances have not been matched by equivalent preservation of cognitive and functional capacity. As a result, many individuals now live longer while experiencing prolonged periods of cognitive decline, emotional dysregulation, sleep disruption, and loss of independence. Existing constructs, including lifespan and healthspan, insufficiently capture the central role of brain function in determining meaningful aging outcomes.

This article introduces the concept of brainspan, defined as the duration of life during which neural network efficiency remains sufficient to support autonomy, adaptive capacity, and coherent physiological and behavioral regulation. Brainspan is conceptualized as a dynamic systems property emerging from the integrated performance of cognitive, autonomic, sleep, emotional, and behavioral networks. We describe characteristic brainspan trajectories across the lifespan, identify chronic and episodic determinants of brainspan decline, discuss approaches to measuring brainspan using longitudinal, multimodal assessments, and outline implications for longevity medicine. Preserving brainspan reframes longevity from survival alone toward sustained independence, resilience, and functional agency across aging.

Link: https://doi.org/10.7759/cureus.101279

The research community appreciates that our ability to preserve function in the aging brain lags behind our ability to intervene in the age-related degeneration of other organs. The brain is also an organ in which our ability to replace tissues, either actually or in principle, is limited. It is comparatively difficult and expensive to access the brain, and structure in the brain store the data of the mind. The only practical path forward is to find ways to repair existing brain tissue without disrupting its activities and data storage. As the ability of the medical community to maintain the rest of the body advances, it will become ever more pressing to develop the means to restore function to an aging brain.

Longevity research has traditionally emphasized peripheral organ systems, metabolic optimization, and molecular aging pathways, while comparatively neglecting the central nervous system as the primary determinant of healthspan. This editorial advances the thesis that the brain functions as the rate-limiting organ of longevity. Drawing on systems neuroscience, clinical neurology, and evidence from neuropsychiatric and neurodegenerative disease, it is argued that progressive disruption of neural networks governs functional decline across multiple physiological systems, regardless of peripheral biological age.

Cognitive resilience, autonomic regulation, sleep integrity, affective stability, and behavioral capacity are centrally mediated processes that determine an individual's ability to maintain homeostasis over time. When brain function deteriorates, lifespan may persist, but meaningful healthspan collapses. A Brain-First Longevity Framework (BFLF) is proposed that prioritizes preservation and restoration of neural network function as foundational to extending durable, functional longevity. BFLF has direct implications for clinical practice, therapeutic development, and the future architecture of longevity medicine.

Link: https://doi.org/10.7759/cureus.101106

Loss of specialized cells is a feature of aging, exhibited in tissues throughout the body. There are many examples of cell types that could in principle be replaced once lost, but in practice are not replaced. The underlying reasons for this selective lack of regenerative capacity are incompletely understood. Examples of highly specialized cell types that do not regenerate include sensory hair cells in the inner ear and the podocyte cells of the kidney that are the subject of today's research materials. Interestingly, some of the cell types that regenerate poorly or not at all in mammals are in fact restored when lost in other species. While comparative biology allows for an exploration of these differences, cells are enormously complex and expanding the understanding of any specific topic in cellular biology remains a slow and difficult undertaking.

Researchers in the field of regenerative medicine are very interested in finding ways to encourage regeneration of cells and tissues that would not normally occur in our species. As yet, progress towards meaningful enhancement of human regeneration remains in its infancy, however. Despite some limited advances, the research community is not yet capable enough when it comes to controlling the behavior of cells to reliably achieve enhanced regeneration. A future in which transplanted cell and native cell behaviors can be shifted in desired ways to allow replacement of lost cells is entirely plausible, but we are not there yet.

Structural Adaptations in Aging Podocytes

The kidneys are vital organs that sustain life by filtering the blood and producing urine. This filtration process takes place in specialized structures called glomeruli, where podocytes play a crucial role by forming the filtration barrier on the glomerular surface. Mature podocytes cannot regenerate once lost, which means that the podocytes generated during fetal development must be used throughout life. It is well known that the number of podocytes decreases with age; however, lost podocytes are not replaced by newly generated cells, and continued podocyte depletion ultimately leads to loss of glomerular function. Therefore, the remaining podocytes are thought to adapt in order to preserve glomerular function despite a reduction in cell number; however, how podocytes adapt to this loss has long remained unclear.

In this study, the research team employed array tomography (AT), a technique that enables whole-cell observation of podocytes with their complex three-dimensional architecture, to elucidate age-related structural changes in podocytes in rats. As podocytes are lost, podocyte density on the glomerular surface decreases, while the volume of remaining aged podocytes increases markedly. The volume of aged podocytes was found to be approximately 4.6-fold greater, indicating compensatory hypertrophy in response to podocyte loss. In addition, areas lost through fragmentation were repaired by coverage from surrounding podocytes, during which atypical self-cellular junctions were frequently formed. These autocellular junctions are entirely absent in normal glomeruli and are considered to represent structural "footprints" of injury repair in aging glomeruli. Furthermore, although aging cells generally exhibit a decline in intracellular degradation capacity for unnecessary cellular components, podocytes were found to compensate for this functional decline by exporting such materials into the extracellular space rather than degrading them intracellularly.

Structural Plasticity of Aged Podocytes Revealed by Volume Electron Microscopy

Aged podocytes exhibited eight characteristic structural alterations: hypertrophy, pseudocystic changes, irregularity of foot processes, fragmentation, pruning of foot processes, autocellular interdigitation, release of lysoendosomal and multivesicular body contents, and an increase in lysosomal volume. Among these, hypertrophy was particularly notable - it resulted in an approximately 4.6-fold increase in podocyte volume and a 3.0-fold increase in total surface area, enabling adequate coverage of the enlarging glomerular surface. Furthermore, in areas where portions of podocytes seemed to be lost because of fragmentation, adjacent podocytes formed de novo autocellular junctions/interdigitation, thereby preventing exposure of the basement membrane. In addition, aged podocytes showed clustering of lysoendosomes and multivesicular bodies, with evidence of their exocytotic release into the urinary space. This process may compensate for the reduced intracellular degradation capacity associated with aging.

Mitochondrial dysfunction is a prominent feature of aging, particularly in tissues with high energy requirements, such as muscles and the brain. Part of the problem is that autophagy to clear out damaged mitochondria becomes less effective. Here researchers show that the distribution of mitochondria in neurons is important to the operation of autophagy and mitochondrial function. Unlike other cells, neurons have very long projections, the axons, that require a sufficiently large population of localized mitochondria for correct function. Aging impairs the mechanisms involved in ensuring that axons are sufficiently supplied with mitochondria, and this in turn impairs function in the brain.

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution.

We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.

Link: https://doi.org/10.7554/eLife.95576.5

Hematopoietic stem cells are responsible for generating red blood cells and immune cells. With age, this production of cells becomes dysfunctional in a variety of ways, contributing to the aging of the immune system. For example, production of immune cells becomes biased to myeloid cells at the expense of lymphoid cells, a change that contributes indirectly to the more inflammatory behavior of the aged immune system. Identifying specific mechanisms involved in hemotopoietic aging is the first step on the road to finding ways to reverse these issues.

Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitin-conjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging.

Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired T-cell development and reduced HSC function.

Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

Link: https://doi.org/10.3324/haematol.2025.288847

The aging of the oral microbiome is relatively understudied in commparison to the present interest in the aging of the gut microbiome, but there is still a fairly sizable literature on the topic. There is clear evidence for a relationship between the oral microbiome and age-related disease, which one will largely find in the context of the potential effects of inflammatory gum disease on cardiovascular and neurodegenerative conditions, where researchers are interested in the leakage of microbes and their metabolites into the bloodstream via injured gums. The literature is not consistent when it comes to effect sizes, however; it is unclear as to how much of a problem this is.

Today's open access paper presents a different focus on the oral microbiome, more akin to work on the gut microbiome. The authors are concerned with the effects of the oral microbiome and its metabolites on the harmful behaviors of senescent cells. Obviously one can mount a good argument for effects in the mouth and the role of cellular senescence in inflammatory gum disease, but going beyond that it is interesting to think about the possible size of the effect of the oral microbiome on senescent cell behavior elsewhere in the body. Again, the effect size are uncertain, however. Mechanisms might be plausible, but equally they may not as much of an issue as other problems in the aging body. Whether this is the case remains to be concretely determined.

Oral microbiome-SASP-aging axis: mechanisms and targeted intervention strategies for age-related diseases

Cellular senescence is a fundamental hallmark of aging. Triggered by diverse stressors, this process is defined by irreversible cell cycle arrest and the development of a complex senescence-associated secretory phenotype (SASP). The accumulation of senescent cells exerts harmful effects on the tissue microenvironment, including promoting inflammation and tissue dysfunction, thereby playing a unique role in systemic metabolic dysfunction and various age-related pathologies.

The oral microbiome is hailed as the second largest microbial community in the human body and serves as the 'second gut' microbial reservoir for human aging. It features a highly diverse ecosystem comprising bacteria, fungi, and viruses. To date, it has been discovered that the oral microbiome significantly influences host systemic and oral health by modulating metabolic and immune pathways. Recent attention has focused on the crosstalk between cellular senescence and oral microbiome dysbiosis and its consequences for host health.

While evidence indicates that the oral microbiome can accelerate disease progression by stimulating SASP-mediated systemic chronic inflammation, the intricate nature of their interactions and their collective impact on host aging remain unclear. Here, we first explore the correlation between the oral microbiome and aging. Then, we systematically summarize how the oral microbiome promotes the progression of aging-related diseases through the secretion of SASP components to induce chronic inflammation. Finally, we discuss the efficacy of therapeutic measures targeting the SASP in diseases.

The immune system is full of specific examples of what is known as antagonistic pleiotropy, the evolution of systems that are beneficial in youth but become harmful in old age. B cells serve a useful but not absolutely vital role in the immune system; one can survive without B cells if necessary, at the cost of diminished immune responsiveness. Unfortunately, aging brings a growing population of dysfunctional, harmful age-associated B cells that aggravate loss of immune function and age-related disease more generally. Destruction of B cells is readily achieved in animal models, either temporarily or permanently. Temporary clearance of B cells in mice is beneficial, removing the age-associated B cells and replacing them with more functional B cells, while here researchers show that permanent life-long removal of B cells in mice slows aspects of immune aging and improves late-life health.

Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span.

We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.

Link: https://doi.org/10.1126/sciimmunol.adv7615

Researchers here provide evidence for circulating oligodendrocyte myelin glycoprotein (OMG, and the expected joking reference is made in the paper's title) to correlate with the state of neurodegeneration in the aging brain. Interestingly, further investigations indicated that OMG is actively protective, not just a marker of protection, and thus one can envisage efforts to increase its expression in the brain as a basis for future therapies to make the brain more resilient to the damage of aging. That process of development is ever a long one, of course, and it is hard to predict timelines for moving from identification of a target to a viable approach to therapy.

After identifying oligodendrocyte myelin glycoprotein (OMG) as a central nervous system (CNS)-specific protein whose levels in peripheral circulation were inversely associated with cortical amyloid-β deposition in two community-based cohorts, the current study leveraged high-throughput plasma proteomic data from over a dozen independent cohorts to characterize OMG's role in Alzheimer's disease and other age-related dementias. We found lower plasma OMG levels among individuals with dementia, compromised brain structure (measured with MRI), and multiple sclerosis (MS). Additionally, individuals with lower plasma OMG were at elevated risk for future dementia and faster cognitive decline.

Using its multi-cohort, cerebrospinal fluid (CSF) proteomic signature, we demonstrated that higher OMG abundance is reflective of broader neuronal and oligodendroglial mechanisms that primarily promote the maintenance of axonal structural stability, along with cell adhesion, synaptic functioning, and proteostasis. Having identified similar structural- and axonal-integrity pathways in OMG's conserved brain tissue proteomic signature, we used genetic inference techniques to show that the cis regulation of OMG abundance across biofluids and brain tissue is causally implicated as protective against multiple neurodegenerative diseases.

Link: https://doi.org/10.1186/s13024-025-00921-1

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