Fight Aging!

Cerebrospinal fluid is produced constantly, circulates through the brain, and drains into the body. This flow carries metabolic waste from the brain, and researchers are coming to view the age-related impairment of cerebrospinal fluid drainage as an important contribution to loss of cognitive function and the development of neurodegenerative conditions in later life. Several pathways for drainage have been identified, each of which is known to lose function with advancing age.

Firstly, cerebrospinal fluid drains through holes in the cribriform plate behind the nose. This pathway ossifies and closes up with age or injury. Studies conducted by Leucadia Therapeutics have added a weight of evidence to the importance of impairment of this fluid drainage path to the development of Alzheimer's disease, which begins in a part of the brain specifically served by cribriform plate drainage. Secondly, the glymphatic system drains cerebrospinal fluid into lymphatic vessels. The meninges, the layered membrane surrounding the brain and spinal cord, is lined with lymphatic vessels and fluid passes into them from the brain. This system of vessels suffers atrophy and dysfunction with age, just like the rest of the lymphatic system. Analogies can be made to the decline of the vasculature for blood flow throughout the body; the density of small capillary vessels declines with age as the processes of maintenance and creation of new vessels become dysfunctional.

In today's open access paper, researchers show that this analogy holds for the approach of provoking increased vessel creation as a way to address the age-related loss of small vessels. It has been demonstrated that upregulation of VEGF via gene therapy improves angiogenesis in older mice. It also improves late-life health, likely in part by removing some of the loss of capillary density. For lymphatic vessels, the analogous signaling protein to promote generation of new vessels is VEGF-C. Here, researchers demonstrate that delivering VEGF-C as a gene therapy to the the meninges can restore cerebrospinal fluid drainage in old mice, and also improve measures of brain function. They show that inflammatory signaling in the brain is reduced once drainage is improved, lending support to the view that the whole problem of reduced drainage is that an increase in metabolic waste in the brain provokes a maladaptive inflammatory response from microglia, innate immune cells of the central nervous system.

Meningeal lymphatics-microglia axis regulates synaptic physiology

Meningeal lymphatic vessels, located in the dura mater of the meninges, drain cerebrospinal fluid (CSF) together with its content of central nervous system (CNS)-derived waste primarily into deep cervical lymph nodes. Since the discovery of meningeal lymphatic vessels, accumulating evidence from mouse models and humans has linked their dysfunction to various neurodegenerative conditions. Ablation of meningeal lymphatics by chemical, genetic, or surgical means exacerbates behavioral outcomes in mouse models of Alzheimer's disease, traumatic brain injury, and chronic stress. Conversely, enhancing the function of meningeal lymphatics ameliorates cognitive deficits in mouse models of Alzheimer's disease, aging, and craniosynostosis.

Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes. Restoring meningeal lymphatic function in aged mice via intracisternal injection of adeno-associated virus encoding VEGF-C reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.

There are now scores of published aging clocks built on various omics databases containing data for people at different ages. Many measurable aspects of metabolism and cell biochemistry change with age in sufficiently similar ways across the population to build clocks that reflect biological age, the burden of damage and dysfunction that causes mortality. Prior to the development of modern machine learning techniques, assembling such a clock would have been prohibitively difficult and expensive, but machine learning makes it straightforward enough for any small research group to create a new clock in a relatively short period of time. Thus there are now a great many aging clocks.

At this point the focus should shift to validation of clocks, as the whole point of having a measure of biological age is to be able to use it to rapidly assess the quality of potential rejuvenation therapies. At present no clock can be treated as entirely trustworthy; they do have quirks, and it remains unclear as to how underlying processes of damage, such as accumulation of senescent cells, produce changes in specific clock parameters. Without knowing these relationships, a clock might overestimate or underestimate the effects of a specific therapy on aging.

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies.

By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

Link: https://doi.org/10.1016/j.celrep.2024.114913

Many dysfunctions and conditions of aging correlate with one another. For closer correlations, the question is whether this relationship exists because (a) one condition contributes meaningfully to the progression of the other, or (b) both conditions are similar in terms of which forms of underlying age-related cell and tissue damage contribute to their onset and progression. Or both! Here, researchers link the severity of sarcopenia, the age-related loss of muscle mass and strength, with arterial stiffness and hypertension. They review the existing hypotheses for causation in this relationship, noting that mechanisms exist to explain either direction of causation.

This cross-sectional study aimed to determine whether sarcopenia is related to arterial stiffness or hypertension in older adults without underweight and obesity. A total of 2,237 male and female adults in the Korea National Health and Nutritional Examination Survey who were ≥60 years and did not have underweight and obesity (body mass index of 18.5 to 25.0 kg/m2) were involved. Arterial stiffness and systolic and diastolic blood pressure showed an increasing trend from normal to moderate-to-severe sarcopenia. Subjects with moderate or severe sarcopenia were 3.545 or 8.903 times more likely to be in the highest tertile of arterial stiffness, and those with moderate or severe sarcopenia were 2.106 or 11.725 times more likely to be hypertensive.

While the exact mechanisms are not fully understood, several potential explanations for the relationship between sarcopenia, arterial stiffness or hypertension have been proposed. Reduced muscle mass and intramuscular fat infiltration cause a decrease in insulin-responsive target tissue, resulting in insulin resistance; consequently, arterial stiffness increases, which indicates the onset of hypertension. The results of the present study supported this potential mechanism in that insulin resistance, evaluated using the triglyceride-glucose index, showed a significant increasing trend from normal to moderate-to-severe sarcopenia. Additionally, chronic inflammation may be a potential explanation for the relationships of sarcopenia with arterial stiffness and hypertension. This potential mechanism was also supported by the finding in the present study that white blood cell counts showed a significant increasing trend from normal to moderate-to-severe sarcopenia.

Furthermore, individuals with sarcopenia commonly exhibit functional impairment or physical disability, which induces a reduction in muscle contraction-derived anti-inflammatory markers called myokines. Since decreased myokine levels are an independent predictor of increased risk of sarcopenia and arterial issues, myokine deficiency in sarcopenia is more likely to increase the risk of arterial stiffness or hypertension. Unfortunately, the present study does not provide objective data on myokine deficiency in sarcopenia patients. However, given that sarcopenia is a common cause of functional impairment or physical disability, decreased myokine secretion in sarcopenia patients is reasonable.

Finally, increased arterial stiffness may induce pulse pressure amplification in arteries. It may stimulate hypertrophy, remodeling or rarefaction in the microcirculation, which makes blood vessels unresponsive to the demand for changing blood flow, thereby leading to increased oxidative stress in muscles. Oxidative stress damages muscle components, such as reducing the number and function of satellite cells, and may induce muscle mass reduction. Depending on all of these factors, sarcopenia may be a trigger of arterial stiffness or hypertension, and arterial stiffness or hypertension may worsen sarcopenia.

Link: https://doi.org/10.3389/fpubh.2024.1469196

The history of attempts to treat Alzheimer's disease is littered with costly failures. One can blame the complexity of both the brain and the condition, which resists attempts to pick apart its contributing mechanisms. One can blame the fact that Alzheimer's is a condition that only naturally occurs in humans (and perhaps dolphins and chimpanzees, with limited evidence in both cases). Access to the biochemistry of the living brain in humans in the ways needed for Alzheimer's research is essentially impossible for ethical and practical reasons. Equally, any practical animal model of Alzheimer's disease, such as the many mouse models, is artificial and embodies certain assumptions about which pathology and processes are most important. Treatments that address the artificially created pathology in the model tend to be successful in that model. Then they fail in humans, after great expense, demonstrating that some of the assumptions were incorrect.

Today's open access review paper is a concise tour of the major categories of drug development. It does omit a range of therapies targeting pathological neurofibrillary tangles made of hyperphosphorylated tau protein, a feature of late stage Alzheimer's disease, and a number of more recent approaches such as clearance of senescent cells as a way to reduce inflammation and tissue dysfunction. Overall it is a cautionary tale for anyone who might be feeling enthused about any of these other approaches to the condition. At some point, the right mechanism will be targeted, but which one is it? The classic problem for every age-related condition is that there is no shortage of contributing mechanisms to consider, but without having already developed a therapy that can address one mechanism in isolation, it is next to impossible to determine whether that one mechanism is important and a good target.

Therapeutic agents for Alzheimer's disease: a critical appraisal

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disorder, characterized by the degeneration of cholinergic neurons in the nucleus basalis, and the presence of extracellular plaques of beta amyloid (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau. AD presents with an impairment in early episodic memory, followed by a gradual and progressive deterioration in cognition and behavior.

The characteristic features of the familial form (FAD) were originally described by Alois Alzheimer in 1906. In FAD, Aβ-containing plaques appear at least 20 years before any signs of memory impairment. While prevention of Aβ formation could provide a treatment option for FAD if started early enough, it represents only about 1% of subjects with AD. The rest have the sporadic form of AD (SAD), with an age of onset of more than 65 years. Their brains also have Aβ-containing plaques, but so do those of healthy, older people with no overt signs of dementia. Since no correlation was found between the number of Aβ plaques and the degree of cognitive impairment in individuals with SAD, the original hypothesis was changed and soluble oligomers of Aβ proposed as the cause of neurodegeneration.

During the last decade, the pharmaceutical industry has concentrated its efforts to affect the processes leading to neurodegeneration by developing drugs to decrease Aβ. Mutations in genes and precursors of Aβ are found in the familial form of the disease. This led to the evaluation of seven monoclonal antibodies against Aβ in subjects with AD, two of which were approved for use by the FDA. They caused only a small improvement in cognitive function, probably because they were given to those with much more prevalent sporadic forms of dementia. They also have potentially serious adverse effects.

γ-secretase is a multi-subunit protease that was identified as responsible for the generation of Aβ, and thus considered a prime therapeutic target in AD. This led to the development of γ-secretase inhibitors like semagacestat to inhibit the formation of Aβ. However, a phase 3 trial in patients with mild to moderate AD was prematurely stopped because the drug actually worsened several measures of cognitive function. Like other γ-secretase inhibitors, avagacestat and tarenflurbil, semagacestat caused serious adverse effects, including cancer, skin related disorders, hypersensitivity reactions, increase in infections, and renal failure. β-secretase inhibitors also prevent formation of Aβ from amyloid precursor protein and their adverse effects are less serious than those of γ-secretase inhibitors. However, verubecestat, atabecestat, and lanabecestat all worsened cognitive function in subjects with mild-moderate AD.

Oxidative stress and elevated pro-inflammatory cytokines are present in all subjects with AD and are well correlated with the degree of memory impairment. Drugs that affect these processes include TNFα blocking antibodies and MAPK p38 inhibitors that reduce cognitive impairment when given for other inflammatory conditions. However, their adverse effects and inability to penetrate the brain preclude their use for dementia. Rosiglitazone is used to treat diabetes, a risk factor for AD, but failed in a clinical trial because it was given to subjects that already had dementia. Ladostigil reduces oxidative stress and suppresses the release of pro-inflammatory cytokines from activated microglia without blocking their effects. Chronic oral administration to aging rats prevented the decline in memory and suppressed overexpression of genes adversely affecting synaptic function in relevant brain regions. In a phase 2 trial, ladostigil reduced the decline in short-term memory and in whole brain and hippocampal volumes in human subjects with mild cognitive impairment and had no more adverse effects than placebo.

The innate immune cells known as macrophages can be found in tissues throughout the body, where they perform many functions. Macrophages do not just find and destroy pathogens and potentially problematic cells, they also help to coordinate regeneration from injury. They can take on pro-inflammatory or anti-inflammatory states depending on circumstances. Researchers are interested in finding ways to reduce inflammation and promote greater regeneration by manipulating macrophage state and activities, and here the focus is on macrophages resident in the heart, an organ that exhibits relatively little regenerative capacity following injury.

Macrophages are essential factors of the body's innate immune system and mononuclear phagocyte system and are widely present in the structure of the tissues, including the heart. Cardiac macrophages play an integral physiological role to regulate the physiological and pathological processes of the cardiovascular system. Resident macrophages are heterogeneous and plastic, and multiple subsets with different phenotypes and functions are present in the same tissue and are involved in different pathophysiological processes. There is increasing evidence suggesting that cardiac-resident macrophage populations play a critical role in regulating heart development, electrical conduction, and ventricular remodelling processes.

The mechanisms used by cardiac macrophages to influence cardiovascular disease (CVD) vary and include both direct and indirect interactions with other cardiac cells. In particular, the identification of specific targets for cardiac resident macrophages to regulate CVD would be crucial. Due to the development of various exogenous (using delivery of toxic substances, blocking antibodies and small interfering RNAs) and genetic methods (transgenic methods) to broadly and specifically target these macrophage populations, this has provided us with the opportunity to understand the function of various cardiac and pericardial macrophages. Relatively few studies have addressed therapies targeting cardiac resident macrophages in patients with CVD although mechanistic knowledge about cardiac resident macrophages and their contribution to cardiovascular risk have accumulated in recent years.

Link: https://doi.org/10.1136/heartjnl-2024-324333

Advanced glycation endproducts (AGEs) are an undesirable form of metabolic waste. The formation of long-lived AGEs that cross-link molecules in the extracellular matrix can change the physical properties of tissue, such as by contributing to the stiffening of blood vessel walls that occurs with age. Further, most varieties of AGE, while being only short-lived, can interact with cell receptors to provoke a maladaptive inflammatory response, thereby contributing to the chronic inflammation of aging. Inflammation, in turn, alters cell behavior for the worse throughout the body. Here, researchers provide an overview of how AGEs contribute to the age-related loss of muscle mass that leads to sarcopenia.

By binding with receptor for advanced glycation end products (RAGEs), AGEs can activate a series of intracellular signalling pathways in skeletal muscle cells related to the elevated levels of inflammation and oxidative stress, as well as impaired insulin/insulin-like growth factor-1 (IGF-1) signalling and mitochondrial biogenesis, which lead to reduced protein synthesis, increased protein degradation, intracellular lipid accumulation, changes in muscle fibre type composition and muscle energy metabolism, and a higher rate of apoptosis, finally resulting in muscle atrophy and impaired regeneration abilities.

Through directly targeted glycosylation, AGEs can damage the biological properties and functions of proteins which include the functional and structural proteins of skeletal muscle as well as collagens in the extracellular matrix, resulting in muscle dysfunction such as impaired force production and increased stiffness. Furthermore, AGEs can also indirectly affect skeletal muscle by contributing to neuromuscular junction lesion and vascular disorders.

Link: https://doi.org/10.1302/2046-3758.143.BJR-2024-0252.R1

Entropy is one of those slippery concepts wherein the same word has been adopted by different scientific disciplines to mean subtly different things. I'd recommend a recent article that attempts to explain for the layperson how these this different meanings arose, and that they overlap at the concept of measuring our ignorance of the state of a system, our inability to predict the state of that system. Here we'll talk about entropy as a measure of the randomness of a distribution; the more random the distribution, the less our ability to predict its specifics. The distribution of interest for today is the methylation state (methylated or not methylated) at one or more CpG sites on the genome, across many genome copies in many cells.

DNA structure determines whether or not a given gene sequence is exposed to transcription machinery and RNA is produced. One of the mechanisms determining the shape of DNA is whether or not methyl groups are added at specific locations called CpG sites, named because a a cytosine nucleotide (C) is followed by a guanine nucleotide (G) with the two linked by a phosphate group (p). This DNA methylation is the basis for epigenetic clocks that assess chronological and biological age, because the methylation status of some CpG sites is characteristic of the damage and dysfunction of aging. While whether or not a CpG site is methylated is a binary outcome, this data is measured across the many, many cells and genomes in a given blood or tissue sample. Current epigenetic clocks take the average of all of those 1s and 0s as the input of that specific CpG site to the clock algorithm.

In today's open access paper, researchers start instead by considering the entropy of the distribution of methylation status at a CpG site across the many measured genomes. For this purpose, entropy is a measure of how noisy or random the data is. The researchers then show that one can construct an epigenetic clock from the entropy values per CpG site that performs as well as clocks built using average values of methylation state. This suggests that aging is not just resulting in a move of some CpG sites towards one status, but also an increase in noise in DNA methylation, a move in both directions, an increase in randomness. Age-related noise in gene transcription is already a topic for discussion in the field, so why not age-related epigenetic noise as well?

DNA methylation entropy is a biomarker for aging

To measure age associated changes in DNA methylation, we collected buccal swabs from 100 individuals ranging from 7.2 to 84 years old. The DNA methylation profiles were generated using targeted bisulfite sequencing. Our target panel contained approximately 3000 regions that were selected to cover age associated CpG sites that were identified in multiple epigenetic clocks. Each probe is 120 base pairs, and therefore captures a region of DNA that is slightly larger than the probe length. We obtained an average coverage of 293 reads per sample across these regions.

We first calculated the mean methylation of each CpG site in each of the 3000 loci across the 100 samples, and then averaged these levels over a region. We also computed the Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM). This approach computes the read level methylation of a region after reads are dichotomized into methylated or unmethylated based on the presence of one or more methylcytosines. We also computed the methylation entropy for each locus using four CpG sites within each region, using the Shannon entropy formula. With four CpG sites, there are 16 possible methylation states, and we computed the probability of each state as well as the entropy of the four CpG sites.

We next generated scatter plots that compared the values of the three metrics across loci. Age-related changes in mean methylation and CHALM were strongly correlated. By contrast, the scatter plots of entropy versus mean methylation or CHALM resulted in more complex patterns with both positive and negative trends. This demonstrates that methylation entropy is measuring different properties of a locus compared to mean methylation and CHALM, and that loci can become both more or less disordered with age, independently of whether the methylation is increasing or decreasing with age.

We next asked whether we could compare the use of these three metrics to construct epigenetic clocks that predict the age of each individual. Selecting only four CpG sites per region to calculate entropy was sufficient to achieve chronological age estimates that were correlated with the actual age. The mean average error was 5.199 years, which was lower than the other mean-based methods that incorporated many more CpG sites. This suggests that the entropy of a locus is potentially a more useful biomarker of aging than the methylation level of individual sites. Though the 3000 loci analyzed may or may not be representative of the whole genome, this suggests that the entropy of an organism's methylation profile is informative of its epigenetic age.

Non-coding RNA sequences in the genome undergo transcription to produce an RNA molecule, but that RNA is not translated into a protein. Nonetheless, non-coding RNAs collectively form just as complex an interacting environment as proteins, important to the function of the cell. Non-coding RNAs remain poorly explored, as much of the work on cell biology to date has focused on proteins. It is unclear if the present catalog of non-coding RNAs is complete, and many of the known entries have unknown functions. Here, the argument is made for non-coding RNAs to collectively be an important determinant of species life span, based on the differences observed between short-lived and long-lived species.

Lifespan is a complex process that interacts with multifactors, yet it is fundamentally an evolutionary process in which genetic factors evolve to cope with lifespan evolution. Thus, it is essential to uncover the genetic factors that contribute to lifespan variations among different species. Current studies have focused on protein-coding genes in the search for longevity determinants, but the results from these studies have not provided sufficient evidence to explain the evolutionary lifespan disparity, even between a small group of species or individuals. The genetic factors contributing to large-scale lifespan gaps between species remain elusive.

When species genomes evolve, they usually acquire more noncoding RNAs (ncRNAs) than proteins. For example, the human genome contains a larger number of ncRNAs than its mouse counterpart, whereas most proteins remain similar. Importantly, these ncRNAs are actively transcribed with their own functional system and they endogenously execute fundamental functions, including lifespan extensions. Therefore, it is reasonable to hypothesize that ncRNAs play a key role in the evolution of the lifespan of an organism.

The present study analyzed multiple large datasets and revealed that ncRNAs indeed work as the primary evolutionary drivers extending animal lifespans and serve as crucial determinants of reproductive systems. Longevity and reproduction are two most important traits of any organism evolution, suggesting that ncRNAs work as the fundamental drivers driving the long evolutionary process and they carry crucial functions in the organism's genome.

Link: https://doi.org/10.1016/j.gmg.2024.100034

Researchers here outline how it is possible to use what is known of gene regulatory networks in order to design better approaches to slow aging. Proteins interact with one another, and feedback loops involving interactions and changes in expression among many proteins determine each aspect of cell behavior. The key realization is that in such a complex system, one has to think about these networks rather than any one individual protein in order to maximize the chance of producing a useful approach to altering cell behavior.

Earlier aging studies focused on individual genes or pathways in isolation and measured lifespan as a static endpoint. As a result, how aging-related genes interact with one another and how these gene regulatory networks (GRNs) operate dynamically to drive aging remain significant unanswered challenges. GRNs consist of nodes, that symbolize genes or regulatory elements, and edges, that depict the interactions or regulatory connections between these nodes. Highly connected nodes at the center of a GRN are the major orchestrators of the response of a cell to stimuli.

The dynamics of these nodes can often be explained by focusing on a few key local interactions, namely subgraphs. Network motifs are recurrent sub-GRNs, typically including up to four nodes, that have characterized behaviors. Network motifs can be as simple as positive autoregulation which ensures the sustained activity of a node. By contrast, mutual inhibition between two nodes can lead to two distinct cell fates where the system stabilizes in one of two states based on initial conditions. The negative feedback loop is a motif that is especially crucial for ensuring homeostasis, and is activated by deviations from a set point that trigger mechanisms to counteract those changes. These motifs are observed in many GRNs and are reinforced by redundant and compensatory pathways to increase the resilience of the system to perturbations.

Decoding the emergent behavior of aging-related GRNs sets the stage for rational design of new interventional strategies to mitigate age-related diseases and promote healthy longevity. However, the intricate nature of aging-related processes cannot be fully understood through traditional reductionist methods. Instead, systems-level approaches designed to analyze the nonlinear dynamics of gene circuits are required. In addition, such network-based approaches can be naturally integrated with synthetic biology to reveal the design principles of prolongevity strategies.

Link: https://doi.org/10.1016/j.tcb.2025.02.006

Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) to power cellular biochemistry. Mitochondrial function declines with age, in part due to damage to mitochondria DNA and in part due to changes in nuclear gene expression that affect proteins needed by mitochondria. This is considered an important contribution to age-related degeneration, particularly in tissues such as muscle and brain that have high energy needs.

Cells will take up mitochondria from their surroundings and make use of them. Studies in mice have indicated that transplantation of mitochondria harvested from cell cultures can produce lasting benefits. The processes of aging that diminish mitochondrial function take a while to operate, and youthful mitochondria can improve function for an extended period of time. The challenge here is that mice are small and people are large; reliable production of the large numbers of mitochondria needed is the primary hurdle preventing clinical use of this approach in old people.

A number of companies are working on the mitochondrial manufacturing challenge, including cellvie and Mitrix Bio. In today's open access paper, an academic group describes a potential approach to the problem, though this is aimed at local injection into cartilage. The goal of whole-body infusions of replacement mitochondria might require another two orders of magnitude of increased scale, and it remains to be seen if this approach will work at that level.

Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration

Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders. Mitochondrial transplantation serves as a promising clinical therapy. However, its widespread application is hindered by the limited availability of healthy mitochondria, with the dose required reaching up to 10^9 mitochondria per injection/patient. This necessitates sustainable and tractable approaches for producing high-quality human mitochondria.

In this study, we demonstrated a highly efficient mitochondria-producing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells (MSCs). Utilizing an optimized culture medium (mito-condition) developed from our established formula, we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days. These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation, with ATP production levels reaching 5.71 times that of normal mitochondria.

Mechanistically, we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication, characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities. Furthermore, the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model, resulting in significant cartilage regeneration over a 12-week period. Overall, this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.

The age-related dysfunction of the brain is a deep, complicated, and incompletely understood field of study. Even if aging is driven by relatively simple processes of damage, the brain is a very complex organ, and thus the outcome of even simple dysfunctions will be a very complex web of further interacting consequences. Thus there are any number of papers similar to the one noted here, in which researchers focus on one specific protein and what is known of its interactions in the brain. As a rule, discoveries regarding disease-specific mechanisms are usually broadly true, but it is rarely clear (or even easily understood) as to how much these mechanisms contribute to the overall burden of pathology, whether they are in fact useful targets to pursue for the development of therapies, or just minor components of the disease as a whole.

CD2AP is expressed throughout the body. Since the identification of the association between CD2AP and Alzheimer's disease (AD), the function of CD2AP in the brain has been attracting more and more attention. The mRNA data from the Allen Brain Atlas suggest that although CD2AP may be expressed at low levels in neurons, it is relatively enriched in highly plastic brain regions such as the hippocampus, cortex, and cerebellum. In addition, high expression of CD2AP was observed in dendritic endosomes of primary cultured mouse neurons and the absence of CD2AP in neurons was shown to cause synaptic damage. Moreover, we recently discovered that CD2AP was expressed at higher levels in microglia compared to neurons in mice and that CD2AP could regulate microglial activation in response to amyloid-β toxicity.

CD2AP is intricately involved in intracellular protein transport and degradation, vesicle trafficking, cell signaling, and cytoskeleton remodeling. As a risk factor for AD, abnormalities in CD2AP in the nervous system may contribute to the pathogenesis of AD through various mechanisms, including influencing the transport and processing of amyloid precursor protein (APP) and thus amyloid-β generation, participating in Tau-mediated neurotoxicity, disrupting synaptic function and vesicle release, modulating microglial activation, and compromising the integrity of the blood-brain barrier. However, the specific molecular mechanisms by which CD2AP participates in these processes have yet to be fully elucidated.

Link: https://www.doi.org/10.61373/bm025i.0026

Researchers here find that age-related changes in the gut microbiome are quite different by sex, and are influenced by the host's mitochondrial haplotype as well. It is now well known that changes occur in the gut microbiome with age, and these changes contribute to age-related degeneration via reduced production of beneficial metabolites and increased inflammation - but there may well be a great deal of variation from individual to individual. The work noted here was conducted in rats, so it remains to be seen as to whether matters are much the same in humans.

We evaluated the impact of sex and mitochondrial-haplotype on the age-related changes in the fecal gut microbiome of the genetically heterogeneous rodent model, the OKC-HETB/W rat. The age-related changes in the microbiome differed markedly between male and female rats. Five microbial species changed significantly with age in male rats compared to nine microbial species in female rats. Only three of these microbes changed with age in both male and female rats. The mitochondrial-haplotype of the rats also affected how aging altered the microbiome.

Interestingly, most of the microbial species that changed significantly with age were mitochondrial-haplotype and sex specific, i.e., changing in one sex and not the other. We also discovered that sex and mitochondrial-haplotype significantly affected the age-related variations in content of fecal short-chain fatty acids and plasma metabolites that influence or are regulated by the microbiome, e.g., tryptophan derived metabolites and bile acids. This study demonstrates that the host's sex plays a significant role in how the gut microbiome evolves with age, even within a genetically diverse background. Importantly, this is the first study to show that the mitochondrial-haplotype of a host impacts the age-related changes in the microbiome.

Link: https://doi.org/10.18632/aging.206211

16S rRNA is a gene that varies in sequence distinctively by microbial species, and thus can be cheaply sequenced to catalog the contents of the gut microbiome for a given individual, determining the composition of specific species and their prevalence. Given this capability, researchers have determined that the distribution of microbial populations alters with age in ways that are harmful to health, such as via loss of beneficial metabolite production or increased inflammation. Further, researchers are increasingly correlating specific features of the gut microbiome to specific age-related conditions.

All of this is groundwork for a near future in which the gut microbiome can be tailored to a specific composition of populations to produce a desired outcome. Lasting rejuvenation of the composition of the gut microbiome, reversing age-related changes, is possible today via fecal microbiota transplantation using a young donor. It is possible in principle (though not yet reduced to practice) to achieve other forms of long-lasting adjustment of the composition of the microbiome by culturing and delivering a specific mix of microbes. Present approaches to oral delivery of probiotics do not achieve this goal, however.

Today's open access paper is an example of present research into correlations between gut microbiome composition and aspects of aging, here the focus is on progressive loss of bone density and muscle mass. The interesting question is the degree to which gut microbiome composition is causative versus being a consequence of other factors that drive osteoporosis and sarcopenia, such as age-related immune dysfunction or the reduced intake of protein and calories typical of older people.

The association of gut microbiome composition with musculoskeletal features in middle-aged and older adults: a two-cohort joint study

The role of the gut microbiome in the development of osteoporosis and sarcopenia has received increased interest given its promising potential in improving musculoskeletal health. The gut microbiome is commonly assessed in the stool and comprises a collection of microorganisms from the digestive tract that impact human physiology through different biological processes. Previous research has indicated that the community of commensal microbes residing in the gut may represent a potentially modifiable factor contributing to muscle and skeletal health. For instance, the gut microbiome can affect the inflammatory environment through effects on the T-cell landscape, which influences osteoclastogenesis and bone loss in mice, and through the production of complex polysaccharides (e.g., short chain fatty acids (SCFA)). The gut microbiota also interacts with important diet components associated with musculoskeletal health such as vitamin K, vitamin D, and calcium. Moreover, the gut microbiota can modulate lipopolysaccharide (LPS) production and various metabolites that directly or indirectly (i.e., through the brain and liver) affect host skeletal muscle metabolism potentially playing a role in sarcopenia etiology.

We leveraged information from two large population-based cohorts, the Rotterdam Study (mean age 62.7 ± 5.6 years; n=1,249) and the Framingham Heart Study (mean age 55.2 ± 9.1 years; n=1,227). For individuals included in this study, gut microbiome 16S rRNA sequencing, musculoskeletal phenotyping, lifestyle and socioeconomic data, and medication records were available. Using 16S rRNA sequencing data we investigated the association between the human gut microbiome (alpha diversity, genera, and predicted functional pathways) and appendicular lean mass (ALM), femoral neck bone mineral density (FN-BMD), and trabecular bone score (TBS) using multilinear regression models controlling for multiple confounders, and performed a joint analysis from both cohorts. Sex-stratified analyses were also conducted.

The gut microbiome alpha diversity was not associated with either tested phenotype after accounting for multiple-testing. In the joint analysis, lower abundance of Oscillibacter, Anaerotruncus, Eisenbergiella, and higher abundance of Agathobacter were associated with higher ALM. Lower abundance of Anaerotruncus, Hungatella, and Clostridiales bacterium DTU089 was associated with higher ALM only in females. Moreover, the biotin biosynthesis II pathway was positively associated with ALM in females while no associations were observed in males. We did not observe any robust association of bone traits with gut microbiome features. Overall, our study suggests that the gut microbiome is linked to muscle aging in middle-aged and older adults. However, larger sample sizes are still needed to underpin the specific microbiome features involved.

Cell surface proteins distinctive to senescent cells can be used as a foundation for immunotherapies that target these cells for destruction. Partial clearance of the age-related burden of lingering senescent cells via small molecule drugs that provoke apoptosis has been shown to produce rejuvenation in aged mice and promising initial results in small human trials, but researchers continue to search for approaches that can remove a greater fraction of senescent cells. Here, find an example of work on surface features of senescent cells, in which a cell surface marker is identified and exploited to construct a proof of principle immunotherapy.

One of the most well-documented hallmarks of senescent cells is their increased lysosomal content and activity. This hallmark feeds into multiple other features of senescence, such as changes in morphology, the senescence-associated secretory phenotype (SASP), and metabolic alterations. Indeed, early efforts quantifying lysosomal activity resulted in the discovery of senescence-associated β-galactosidase (SA-β-Gal), one of the most widely used biomarkers of senescence.

Lysosomal Associated Membrane Protein 1 (LAMP1, also known as CD107a) is a master orchestrator of the structural integrity of lysosomes. LAMP1, as a type I transmembrane glycoprotein, is mostly localized in late endosomes and lysosomes. In immune cells, CD107a is also a cell-surface marker of immune activation and cytotoxic degranulation; however, its expression on the plasma membrane is transient and the protein is internalized rapidly. LAMP1 is only briefly found at the cell surface of healthy cells due to the fusion of lysosomes with the plasma membrane, and is thus mostly undetectable.

The ability to identify and characterize senescent cells is crucial for understanding their role in aging and developing targeted interventions. Here, we describe LAMP1 as a cell surface-specific marker of senescence. LAMP1's presence on the cellular membrane is highly increased in human and mouse senescent cells. In mouse tissue, cells expressing LAMP1 on their surface showed features of senescence. Additionally, senescence induction in the lungs of mice using bleomycin caused an increase in LAMP1+ cells. Finally, senescent cells are eliminated using a LAMP1-targeting antibody. These findings describe a biomarker that can be leveraged to further understand and target senescent cells.

Link: https://doi.org/10.1101/2025.03.04.640878

Elamipretide was formerly known as SS-31, and is a mitochondrially targeted antioxidant molecule that improves mitochondrial function, and may or may not achieve that result through the antioxidant mechanism. For many of the current stable of small molecules known to improve mitochondrial function, it isn't entirely clear as to whether their known mechanisms of action are actually the important ones. Here, researchers demonstrate that elamipretide improves muscle function in old mice, an expected outcome, but does not affect epigenetic age, which is perhaps surprising. Epigenetic clocks that assess biological age based on changing patterns of epigenetic modifications to DNA are known to have some blind spots, but mitochondrial function should not be one of them, given the importance of mitochondria in the aging process.

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways.

We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation.

Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

Link: https://doi.org/10.1111/acel.70026

Reminiscent of recent work on supplementation of the amino acid taurine as a means to modestly slow aging, the authors of today's open access paper examine the role of the amino acid citrulline in age-related changes occurring in mice. As is true of taurine in mice, blood and tissue levels of citrulline decline to varied degrees with age, while long-term oral supplementation with citrulline both restores youthful levels and improves a number of measures of metabolism. This includes a reduction in age-related chronic inflammation that appears mediated by changes in the behavior of the innate immune cells known as macrophages.

Human trials of taurine supplementation have not produced clearly positive outcomes, but the researchers involved may have been looking at the wrong measures in the years prior to the commonplace use of aging clocks. Taurine touches on many areas of metabolism, and a simple self-experiment for taurine supplementation produced a modest reduction in phenotypic age driven by lower levels of circulating neutrophils, another form of innate immune cell. Increased neutrophil count in a blood sample is representative of inflammation.

Citrulline has been used in a sizable number of human clinical trials versus only the few for taurine, and has shown modestly beneficial results for a range of conditions. Since inflammation contributes to the progression of near all age-related conditions, this is much what one might expect see if it is in fact reducing the contribution of macrophages to the inflammatory environment of aged tissues. Given all of this, one might be tempted to run a similar self-experiment as for taurine, using citrulline supplementation instead, and see what results - it would be straightforward to conduct.

Citrulline regulates macrophage metabolism and inflammation to counter aging in mice

Metabolic dysregulation and altered metabolites are widely recognized as key characteristics of aging. Numerous studies have investigated the roles of endogenous metabolites, such as NAD, taurine, spermidine, and others, as drivers of the aging process. In this study, we conducted a comprehensive analysis of metabolic changes in multiple organs of mice at various ages. Our findings provide the first evidence linking citrulline deficiency to aging. We identified multiple antiaging effects of citrulline, including the reduction of cellular senescence, protection against DNA damage, prevention of cell cycle arrest, modulation of macrophage metabolism, and mitigation of inflammaging. Notably, long-term supplementation of citrulline in aged mice demonstrated significant benefits by alleviating age-associated phenotypes and increasing health span. These findings underscore the critical role of citrulline deficiency as a key driver of the aging process and highlight the potential therapeutic intervention of citrulline supplementation to counteract age-related diseases.

To explore the biological mechanism by which citrulline counteracts aging, we demonstrated that citrulline acts as an endogenous metabolite antagonist to inflammation. Macrophages are primary contributors to age-associated inflammation. Our findings unveil that the decline in endogenous citrulline levels impairs the anti-inflammatory function of macrophages, thereby enhancing susceptibility to inflammatory responses during aging. The anti-inflammatory effect of citrulline has been validated in various mouse models, and its efficacy remains intact even in the context of aging. This observation suggests that the age-dependent deficiency of citrulline, acting as an endogenous antagonist to inflammation, triggers inflammaging and accelerates the aging process. In-depth mechanistic investigations have revealed that citrulline supplementation rescues age-associated metabolic alterations in macrophage metabolism. Specifically, we have demonstrated that citrulline modulates the inflammatory responses by regulating the activities of the mTOR-HIF1α-glycolysis signaling pathway in macrophages. Collectively, these results establish that citrulline governs macrophage metabolism and inflammation as a means to counteract aging.

Our study also underscores the remarkable potential of citrulline as an endogenous metabolite inhibitor of the mTOR pathway in the context of inflammation and aging. mTOR serves as a nutrient sensor that regulates cellular metabolism and is linked to cell proliferation, growth, and survival. Extensive research has established the mTOR pathway as a negative regulator of lifespan and aging. Pharmacological inhibition of mTOR using small-molecule compounds such as rapamycin has been shown to effectively extend longevity in various animal models. However, the discovery of an endogenous metabolite that inhibits mTOR to counter aging has remained elusive. Arginine, leucine, and S-adenosylmethionine (SAM; downstream metabolite of methionine) are the known metabolites that are directly sensed by mTOR components. Restriction of methionine or the three branched-chain amino acids - leucine, isoleucine, and valine - extends lifespan in mice, but the roles of these metabolites in regulating aging and mTOR are complicated. Our metabolomics data confirmed that arginine, leucine, SAM, and methionine levels remained unchanged during aging in mice. In our study, we extensively demonstrated that citrulline inhibits the activation of the mTOR pathway in macrophages in both inflammatory and aging contexts. This finding highlights citrulline as a promising endogenous metabolite with the potential to inhibit mTOR signaling.

The endothelium is the inner lining of blood vessels. It is important to a range of vital functions performed by the vasculature, from the selective passage of molecules enforced by the blood-brain barrier to the ability of blood vessels to properly contract and dilate. Further, localized damage and inflammation of the endothelium is an early step in the formation of an atherosclerotic plaque. In this paper, researchers focus on the endothelium of the microvasculature, the smallest blood vessels. All of the same issues occur here, and may contribute over time to the decline of microvascular density as the mechanisms needed for maintenance of these vessels, such as aspects of angiogenesis, become impaired.

Cardiovascular disease (CVD) is the main cause of morbidity and mortality in the adult and the elderly, with increasing prevalence worldwide. A growing body of research has focused on the earliest stage of vascular decline - endothelial dysfunction (ED) - which at the microvascular level can anticipate in decades the diagnosis of CVD. This review aims to provide a prospect of the literature regarding the development of ED as an indissociable feature of the aging of the cardiovascular system, highlighting the role of inflammation in the process.

Vascular aging consists of a lifelong continuum, which starts with cell respiration and its inherent production of reactive oxygen species. Molecular imbalance is followed by cellular epigenetic changes, which modulate immune cells, such as macrophage and lymphocyte subtypes. These mechanisms are influenced by lifestyle habits, which affect inflammation hotspots in organism, such as visceral fat and gut microbiota. The process can ultimately lead to an environment committed to the loss of the physiological functions of endothelial cells. In addition, we discuss lifestyle changes targeting the connection between age-related inflammation and vascular dysfunction. Addressing microvascular ED represents a critical endeavor in order to prevent or delay vascular aging and associated diseases.

Link: https://doi.org/10.3389/fcvm.2025.1505516

Formation of new neurons and their integration into existing neural networks is necessary for repair and change in the brain. Producing a larger supply of neurons could be beneficial, helping to resist the consequences of age-related damage that builds up over time. Here, researchers find a way to influence one source of new neurons using a diterpenoid compound that can be delivered intranasally to find its way into the brain. They demonstrate increased production of neurons in mice using this approach.

Neural stem cells from the subventricular zone (SVZ) neurogenic niche provide neurons that integrate in the olfactory bulb circuitry. However, in response to cortical injuries, the neurogenic activity of the SVZ is significantly altered, leading to increased number of neuroblasts with a modified migration pattern that leads cells towards the site of injury. Despite the increased neurogenesis and migration, many newly generated neurons fail to survive or functionally integrate into the cortical circuitry. Providing the injured area with the adequate signaling molecules may improve both migration and functional integration of newly generated neurons.

Protein kinases (PK) such as PKA or PKC have an important role in neuroblast migration. Previous reports have revealed that the treatment of mouse cortical injuries with a novel PKC activating diterpenoid resulted in neuroblast enrichment and in their differentiation into mature neurons. Within the injury environment and the SVZ, growth factors that promote proliferation and glial differentiation are highly expressed such as transforming growth factor alpha (TGFα) and they need to be counterbalanced with signals that promote differentiation such as neuregulins to allow regeneration and replacement of the lost neurons. Interestingly, evidence shows that in response to diterpenoid EOF2, which activates novel PKC activity and neuregulin release, these signaling cues may be altered to promote the premature differentiation of neuroblasts and their migration toward the injured area suggesting a role for neuregulin 1 (NRG1) and novel PKC in neuronal replacement in cortical injuries.

We have found that EOF2 treatment of adult mice with mechanical cortical injuries facilitates the delivery of neuroblasts into these injuries. The newly generated neurons develop features of fully functional neurons. Our results show that the newly generated neurons receive electrical inputs, fire action potentials, and undergo complete differentiation into neurons recapitulating the stages that distinguish ontogenic differentiation. These neurons develop features representative of neurons belonging the cortical layer in which they are situated. We have also studied that EOF2 facilitates neuregulin release in SVZ cells, a signaling factor that promotes neuronal differentiation. Neuregulin is expressed in microglial cells that reach the injury in response to the damage and its release is increased by EOF2 treatment.

Link: https://doi.org/10.1186/s13287-024-04105-4

The brain requires a lot of energy to function. Like muscle tissue, it is particularly vulnerable to age-related dysfunction in energy metabolism, the various pathways by which cells make use of nutrients to supply energy for the operation of vital biochemical processes. The brain primarily makes use of glucose as a nutrient, but this process of deriving energy from glucose becomes dysfunctional with age, and this dysfunction tends to be particularly pronounced in patients exhibiting neurodegenerative conditions such as Alzheimer's disease. An alternative to glucose readily used elsewhere in the body is β-oxidation of fatty acids. There are reasonable explanations as to why the brain has evolved not to favor this path, such as the greater degree of oxidative stress it generates. But at the end of the day, if the brain had more access to compensatory sources of energy, dysfunction would be slowed with aging.

So to today's research materials, in which the scientists involved show that people with higher degrees of β-oxidation of fatty acids throughout the body tend to suffer less as glucose metabolism in the brain runs awry with age. Thus one could use biomarkers of β-oxidation and call it a measure of the age of energy metabolism, as the researchers do here, but I think that to be an unhelpful framing obscures the relationships between the underlying processes and capacities. As the researchers note, the beneficial effects of present anti-amyloid immunotherapies are small enough, only a modest slowing of disease progression, that a shift in metabolism to favor β-oxidation can produce a similar outcome. What one should take away from this is not that we should all jump up and focus research efforts on upregulation of β-oxidation of fatty acids, which can be achieved to a reasonable degree by ketogenic and calorie restricted diets, but rather that there remains a great unmet need for actually effective therapies to turn back the progression of neurodegenerative conditions.

Lowering Bioenergetic Age May Help Fend Off Alzheimer's

A person's "bioenergetic age" - or how youthfully their cells generate energy - might be a key indicator of whether they're at risk of developing Alzheimer's disease, new research shows. One of the early warning signs of Alzheimer's is that brain cells start losing their ability to produce and use energy efficiently, such as metabolizing glucose. But some people don't show disease symptoms for years. This delay between abnormalities in energy pathways and the onset of symptomatic disease suggests there is a "bioenergetic capacity" that provides a buffer for these individuals. Their bodies and brains are better at keeping energy levels up even when problems start.

Researchers turned to a group of molecules called acylcarnitines, which are associated with declining cognition and breaking down or metabolizing fats and proteins for energy. To test if high acylcarnitine levels in the blood could predict who's at risk of developing Alzheimer's, the researchers used data from a large-scale study called the Alzheimer's Disease Neuroimaging Initiative. This led the researchers to define a bioenergetic clock based on acylcarnitines - how old a person's metabolism acts, compared to actual age. Higher bioenergetic age is linked to higher acylcarnitine levels, worsened Alzheimer's pathology, cognitive decline, and brain atrophy.

The researchers also quantified cognitive decline using a common test called the mini-mental state examination, on which a score below 24 out of 30 points indicates impairment. They found that people with low acylcarnitine levels to begin with declined more slowly, losing about 0.5 points less per year than people with high acylcarnitine levels. The benefit is on par with the Alzheimer's drug lecanemab. To some degree, a person's bioenergetic clock ticks forward at a rate determined by their genetics, but having a healthy lifestyle - for example, eating a plant-based diet and exercising - can help keep acylcarnitine levels low, which means a younger bioenergetic age.

Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD.

Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

You might recall that the Horvath epigenetic clock did not exhibit differences in biological age when comparing twins, given one twin that is sedentary versus one twin that is active. I blamed that on the epigenetic clock at the time, and it is certainly true that these clocks do exhibit quirks. The results noted here exonerate the Horvath clock and focus instead on the study population itself, however. The observed long-term relationship between exercise and mortality in this group is not what one would expect given the dose-response curve for exercise that has been established by many other, larger epidemiological studies.

Researchers investigated the links between long-term leisure-time physical activity and mortality, as well as whether physical activity can mitigate the increased risk of mortality due to genetic predisposition to diseases. Moreover, they examined the relationship between physical activity and later biological aging. The study included 22,750 Finnish twins born before 1958 whose leisure-time physical activity was assessed in 1975, 1981 and 1990. Mortality follow-up continued until the end of 2020.

Four distinct sub-groups were identified from the data, which was based on leisure-time physical activity over the 15-year follow-up: sedentary, moderately active, active and highly active groups. When the differences in mortality between the groups were examined at the 30-year follow-up, it was found that the greatest benefit - a 7% lower risk of mortality - was achieved between the sedentary and moderately active groups. A higher level of physical activity brought no additional benefit. When mortality was examined separately in the short and long term, a clear association was found in the short-term: the higher the level of physical activity, the lower the mortality risk. In the long term, however, those who were highly active did not differ from those who were sedentary in terms of mortality.

The researchers also investigated whether following the World Health Organization's physical activity guidelines affects mortality and genetic disease risk. The guidelines suggest 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous activity weekly. The study found that meeting these guidelines did not lower mortality risk or alter genetic disease risk. Even for twins who met the recommended levels of PA over a 15-year period, no statistically significant difference in mortality rates was found compared to their less active twin pair.

Link: https://www.jyu.fi/en/news/does-exercise-really-extend-life-finnish-twin-study-offers-new-insights

Greater numbers of the innate immune cells known as neutrophils are characteristic of inflammation, whether transient or chronic. A complete blood count of different immune cell populations in circulation can be used to derive the neutrophil to lymphocyte ratio, and this can be used as a measure of chronic inflammation in older individuals. While there is a lot of variety from individual to individual, on balance either significantly more neutrophils than the average (common) or significantly fewer lymphocytes than the average (uncommon) indicates a worse prognosis for health in the years ahead. Chronic inflammation is disruptive to tissue structure and function, and drives the onset and progression of all of the major age-related conditions, including the progressive loss of muscle mass leading to sarcopenia. Thus one might expect to see correlations like the one noted here, between pace of muscle loss and neutrophil to lymphocyte ratio in older individuals.

Inflammation plays a pivotal role in the age-related decline of skeletal muscle mass, leading to sarcopenia in the elderly. The prevalence of sarcopenia notably increases among males aged ≥ 70. However, it remains unclear whether inflammatory indexes are associated with the reduction in skeletal muscle mass in the elderly population. Thirty-one males aged ≥ 70, without severe diseases or dementia, were enrolled in the study. They underwent muscle mass measurements, physical measurements, and hematological tests at the onset of the study and after a one-year follow-up.

Twenty-eight participants were successfully followed for one year. Appendicular skeletal muscle mass index (ASMI) decreased by 3.30 ± 2.41% in 14 participants and increased by 2.66 ± 1.61% in the other 14 participants compared to baseline levels. The baseline neutrophil-to-lymphocyte ratio (NLR) was 2.14 ± 0.56 in the ASMI-decreased group and 1.66 ± 0.62 in the ASMI-increased group. A statistically significant negative correlation was found between baseline NLR and the change in ASMI in linear regression analyses. NLR emerged as a potential prognostic marker for ASMI reduction in elderly males. However, further studies are necessary to assess its clinical utility.

Link: https://doi.org/10.18632/aging.206217

The manipulation of cell state to produce positive outcomes via either electromagnetic fields or physical stimuli such as pressure are both understudied areas of cell biology, potentially applicable to the production of novel therapies, but with little concrete progress to that end goal. One of the challenges is that there are many, many different ways in which one can apply electromagnetic fields or physical stimuli to cells, and it seems fairly clear from a review of the fairly sparse literature on this topic that (a) most of the choices one can make in this large space of options will not produce the desired results, and (b) replication is hard because researchers do not adequately describe the exact protocol they are using. Small and even unintentional changes in the setup of the experiment can produce large differences in outcomes.

Today's open access paper is quite interesting. In it, researchers present evidence for the application of pulsed pressure to cells via low frequency ultrasound to be capable of reversing cellular senescence. Normally senescence is an irreversible transition, though in recent years researchers have found a few manipulations that can achieve this goal. Low frequency ultrasound is shown to affect mTOR signaling and boost autophagy. Pharmacological approaches to achieve this goal, such as use of rapamycin, do not reverse senescence. They do reduce the number of cells that become senescent, however, and thus allow the number of senescent cells in a tissue or in cell culture to become lower over time. Researchers tested the ultrasound approach in cell culture, but were careful to try to show that formerly senescent cells lost characteristics of senescence, it wasn't just a reduced onset of senescence. The researchers then tested the application of low frequency ultrasound to mice, and report a sizable gain in life span in mice treated with ultrasound throughout their lives, in the same ballpark as the use of senolytic drugs to clear senescent cells.

Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound

Senescent cells, as rigorously defined by many markers, including the expression of β-galactosidase, can be mechanically rejuvenated by low frequency ultrasound (LFU) without transfection or other biochemical manipulations. The ultrasound pressure waves restore normal behavior irrespective of whether senescence is induced by chemical treatment or by repeated replication. There is no apoptosis with LFU, and videos of senescent cells show a dramatic increase in cell and mitochondrial motility, as well as in growth after LFU treatment. Many features of senescent cells are all reversed by LFU, including the increase in β-galactosidase activity, p16 and p21 expression, decreased telomere length, increased H3K9me3 levels, decreased 5mC levels, increased cell size, secretion of senescence-associated secretory phenotype (SASP), and inhibition of growth. Surprisingly, ultrasound treatment of normal cells causes secretion of growth-stimulating factors that partially restore normal behavior in senescent cells. Because replicatively senescent cells are restored to a normal phenotype by LFU, they can be cultured for longer periods to produce increased numbers of cells without major alteration in their phenotype.

It is perhaps surprising that fully senescent cells can be rejuvenated by pressure waves. This raises the question of how a senescent cell is defined. Cells that were made senescent by toxic compounds or repeated replications were incubated for long periods, and time-lapse video microscopy verified the absence of any growth. After such treatments, quiescent cells were not present since over 95% of the cells expressed β-galactosidase and many of the larger senescent cells grew and divided in the videos after LFU. By tracing individual cells, we were able to determine that growth was occurring in over 30% of the originally non-dividing cells after 4-5 days. Such robust growth is inconsistent with the growth of just a subpopulation of cells that are not senescent. Further, there is no apoptosis after LFU treatment of the senescent cells, and over fifteen characteristics of senescence are reversed. Thus, all of these objective criteria indicate that LFU reverses senescence, and we suggest that LFU actually rejuvenates senescent cells.

This opens many new possibilities in the aging research field, including the possibility of rejuvenating aged cells in vivo to inhibit age-dependent disorders, which appears to be true based on the results of the mouse studies reported here. 46 mice were treated over 300 days (some mice reached 3 years of age). In the five LFU-treated groups, the best survivors had the lowest doses of ultrasound with about 50% survival at 1000 days (~33 months of age) and 3 mice survived until 3 years. Autopsies of the mice that died revealed no tumors or obvious cause of death. In terms of the safety of LFU, half of the mice in the longevity study were treated daily with LFU for over 300 days without damage or evidence of harm from the LFU treatment. Further, the treated mice maintained a normal weight, whereas the weight of the sham mice was declining with age.

At this point it is well established that cardiovascular aging correlates with neurodegenerative disease. Even setting aside the point that varied age-related diseases arise from common forms of underlying damage and so tend to loosely correlate with one another, we should note that the brain has high energy requirements. Any sustained reduction in the delivery of oxygen and nutrients to brain tissue via cerebral blood flow, resulting from loss of capillary density, other aspects of cerebral small vessel disease, and heart failure, for example, will contribute to existing issues. Researchers here add to the existing evidence, demonstrating that measures of cardiovascular health correlate with increased levels of established biomarkers of neurodegeneration.

The American Heart Association developed a 7-item tool, Life's Simple 7, to promote cardiovascular health (CVH) in the general population. Life's Simple 7 comprises lifestyle and vascular risk factors, including not smoking; maintaining a normal body mass index (BMI); engaging in regular physical activity; consuming a healthy diet; and managing dyslipidemia, diabetes, and hypertension. An optimal CVH characterized by a higher Life's Simple 7 score is associated with a reduced risk of cardiovascular disease (CVD).

Cardiovascular health (CVH) has been associated with a low risk of Alzheimer disease and less vascular dementia. However, the association between CVH and biomarkers of neurodegeneration remains less understood. This study investigate the association of CVH, assessed by Life's Simple 7 score, with serum biomarkers of neurodegeneration, including neurofilament light chain (NfL) and total tau (t-tau). This cohort study was conducted within the Chicago Health and Aging Project (CHAP) of adults aged 65 years or older between 1993 and 2012. Participants who had measured serum NfL and t-tau levels and data on all components of the CVH score were included.

A total of 1,018 CHAP participants were included in the analysis (mean age, 73.1 ± 6.1 years). Compared with participants with low CVH scores (0-6 points), those with high CVH scores (10-14 points) had significantly lower serum levels of NfL (relative difference, -18.9%). A higher CVH score was associated with a slower annual increase in NfL levels as participants aged (relative difference in rate, -1.7%). Cardiovascular health was not associated with serum levels of t-tau. These findings suggest that promoting CVH in older adults may help alleviate the burden of neurodegenerative diseases.

Link: https://doi.org/10.1001/jamanetworkopen.2025.0527

The research community is steadily accumulating data on the relationship between aging clocks to assess biological age and existing measures of disease and dysfunction. For example, cardiometabolic index is a combined measure of obesity and lipid metabolism dysfunction, and associated with age-related metabolic diseases and consequent mortality. We should expect a good approach to assessing biological age to tend to produce higher biological ages in patients with a higher cardiometabolic index, and researchers here show that this is the case for the Klemera and Doubal aging clock.

The cardiometabolic index (CMI) combines clinical measures of triglycerides, high-density lipoprotein cholesterol, and waist-height ratio. CMI has been related to several metabolic disorders, including diabetes mellitus, atherosclerosis, ischemic stroke, and hypertension. Several studies have investigated the clinical significance of CMI in metabolic disorders, and more significant increases in CMI over time were significantly associated with a greater risk for subsequent cardiovascular events.

Cross-sectional data were obtained from participants with comprehensive CMI and biological age data in the National Health and Nutrition Examination Survey from 2011 to 2018. Biological age acceleration (BioAgeAccel) is calculated as the differences between biological age (determined via the Klemera and Doubal method) and chronological age. Weighted multivariable regression, sensitivity analysis, and smoothing curve fitting were performed to explore the independent association between CMI and the acceleration of biological age. Subgroup and interaction analyses were performed to investigate whether this association was consistent across populations.

In 4,282 subjects ≥ 20 years of age, there was a positive relationship between CMI and biological age. The BioAgeAccel increased 1.16 years for each unit CMI increase, and increased 0.99 years for per standard deviation increase in CMI. Participants in the highest CMI quartile had a BioAgeAccel that was 2.49 years higher than participants in the lowest CMI quartile. In stratified studies, the positive correlation between CMI and biological age acceleration was not consistent across strata. This positive correlation was stronger in female, diabetic patients, and non-hypertensive populations.

Link: https://doi.org/10.1186/s12889-025-22053-3

Birds are much studied in the comparative biology of aging because they are long-lived for their size in comparison to mammals. The present consensus lumps birds and bats together, in that the evolution of flight and its high metabolic demand is thought to also require the evolution of a greater resistance to stresses placed on cells by oxidative molecules and other sources of molecular damage. One of those other forms of damage is glycation by sugar compounds. High blood sugar in mammals increases the production of a range of glycated molecules, such as the well-studied advanced glycation endproducts (AGEs), that can cause a variety of harms, from inflammation via the receptor for AGEs (RAGE) to cross-linking of the extracellular matrix to stiffen arteries.

Today's open access paper notes that birds exhibit high blood sugar relative to mammals, and that the relationship between blood sugar and species life span is not straightforward. It suggests that some longer lived species have evolved means to protect themselves from harmful glycation. This gives researchers something to look for; one of the long term goals in the study of the comparative biology of aging is to find mechanisms that might give rise to therapies that will slow aging in mammals. As ever, it is far to early to tell how this line of research will turn out in the end.

Birds' high blood sugar defies ageing expectations

The pace-of-life syndrome hypothesis proposes that an organism's metabolic rate, lifespan, reproductive strategies, and behaviour evolve in predictable ways. Under this framework, species with fast metabolisms, short lifespans, and high reproductive rates are expected to have higher blood sugar and glycation levels. Conversely, those with longer lifespans and slower developmental times should have lower blood sugar levels and greater resistance to glycation. However, it is unclear how glycation has coevolved with other traits across species, and so it is undetermined whether glycation fits into the framework of the pace of life hypothesis.

"Birds are particularly relevant in this context, given their relatively high blood sugar levels - on average almost twice as high as similarly sized mammals. This is thought to be an adaptation allowing flight, providing birds with the fuel needed to power intense bursts of aerobic exercise. But it is also paradoxical. Despite their higher blood sugar levels, birds show remarkable longevity compared to their mammalian counterparts, living up to three times longer."

Researchers conducted an analysis of 484 individual birds from 88 different species. They compared blood sugar levels and glycation rates in relation to the birds' life history traits. Their results revealed substantial variation in blood sugar levels across species. Smaller birds had the highest blood sugar levels, while larger species had the lowest. Glycation rates followed a similar trend, with smaller birds showing higher levels and larger birds displaying lower levels. However, the relationship between blood sugar levels and lifespan was more complex. While longer-lived birds generally had higher blood sugar levels, this increase plateaued beyond a certain point. This suggests that some species have evolved mechanisms to prevent glycation-related damage, rather than avoiding high blood sugar levels altogether.

Variation in albumin glycation rates in birds suggests resistance to relative hyperglycaemia rather than conformity to the pace of life syndrome hypothesis

The pace of life syndrome hypothesis (POLS) suggests that organisms' life history, physiological, and behavioural traits should co-evolve. In this framework, how glycaemia (i.e., blood glucose levels) and its reaction with proteins and other compounds (i.e. glycation) co-vary with life history traits remain relatively under-investigated, despite the well documented consequences of glucose and glycation on ageing, and therefore potentially on life history evolution. Birds are particularly relevant in this context given that they have the highest blood glucose levels within vertebrates and still higher mass-adjusted longevity when compared to organisms with similar physiology as mammals.

We thus performed a comparative analysis on glucose and albumin glycation rates of 88 bird species from 22 orders, in relation to life history traits (body mass, clutch mass, maximum lifespan, and developmental time) and diet. Glucose levels correlated positively with albumin glycation rates in a non-linear fashion, suggesting resistance to glycation in species with higher glucose levels. Plasma glucose levels decreased with increasing body mass but, contrary to what is predicted to the POLS hypothesis, glucose levels increased with maximum lifespan before reaching a plateau. These results increase our knowledge about the diversity of glycaemia and glycation patterns across birds, pointing towards the existence of glycation resistance mechanisms within comparatively high glycaemic birds.

This open access review paper outlines what is known of the way in which aging, circadian rhythm, and cancer risk interact with one another. Cancer is a well known as an age-related disease; among other contributing mechanisms, the mutation burden in somatic cells increases with age, while the surveillance conducted by the immune system, intended to destroy cancerous cells long before they form a tumor, declines with age. Separately, circadian rhythm regulation also becomes dysfunctional with advancing age, though the causative mechanisms in this case are little understood in comparison to what is known of the causes of cancer. Lastly, circadian rhythm interacts with cancer risk in potentially complex ways, again an area in which more research is needed before we might be able to say it is well understood.

Cancer, circadian rhythms, and aging are three biological processes closely associated with health and disease. While they may appear to be independent, increasing evidence suggests that there are complex interactions among them. The relationship between aging and cancer is very clear. Aging remains to represent the foremost risk factor across various cancer types, correlating with an elevated incidence of cancer that typically reaches its peak around the age of 85 years. On the mechanism, aging and cancer share many common hallmarks, including genomic instability, epigenetic alterations, chronic inflammation, cellular senescence, and so on, which serve as intermediaries between aging and cancer.

Circadian rhythms are 24-hour cycles that govern a range of physiological processes in living organisms, such as sleep-wake cycles, hormone release, metabolism, and cell proliferation. Disruption of circadian rhythms has also been shown to contribute importantly to the development and progression of cancers, although the exact mechanisms are not yet fully understood. Mechanistically, circadian rhythm proteins exhibit physical interactions with molecules implicated in cancer-related pathways, thus exerting influence over cancer initiation and progression.

Furthermore, there also exist complex and multifaceted relationships between aging and circadian rhythms. On the one hand, the aging process reduces the resilience of circadian rhythms, resulting in disrupted sleep-wake cycles, a diminished ability to synchronize circadian rhythms in peripheral tissues, and changes in the molecular functioning of circadian clock outputs. On the other hand, circadian rhythm dysfunction can accelerate the aging process by compromising essential bodily functions. These disruptions lead to increased oxidative stress, which refers to cellular damage caused by an imbalance between the production of reactive oxygen species (ROS) and the cell's ability to neutralize them. This imbalance of ROS can lead to DNA damage, protein denaturation, and lipid peroxidation, ultimately contributing to inflammation and the development of age-related health issues

Link: https://doi.org/10.34133/research.0612

White matter hyperintensities are small volumes of damage and scarring in the white matter of the brain, named for the way they appear in MRI images of brain tissue. They can be caused by rupture of small blood vessels, but also by any other localized cause of cell death and inflammation. Greater numbers of white matter hyperintensitives are generally indicative of a higher risk of neurodegenerative conditions and cognitive decline. Interestingly, researchers here note that the correlation with cognitive decline only exists for larger white matter hyperintensities.

The association between white matter integrity and adverse brain health outcomes is well-established. Increased white matter lesion burden has consistently been linked to higher risk of stroke, cognitive impairment, dementia, and mortality in cross-sectional and longitudinal studies involving diverse patient populations and healthy older adult cohorts.

This study investigates the relationship between white matter hyperintensities (WMHs) and longitudinal cognitive decline in older adults. Using data from The Irish Longitudinal Study on Ageing (TILDA), we examined WMH characteristics, including volume, location, and microstructural integrity, in a community-dwelling population of 497 individuals over a six-year period. WMHs were categorised into phenotypes based on their size, fractional anisotropy (FA), and mean diffusivity (MD), with subtypes for periventricular and deep white matter lesions. We hypothesised that larger, microstructurally compromised lesions would be associated with accelerated cognitive decline.

We isolated 11,933 WMHs, with an average of 24 WMHs per individual. Of these lesions, 6,056 (51%) were classified as Low Volume - High FA, 3193 (27%) were classified as Low Volume - Low FA and 2684 (22%) were classified as High Volume, Low FA. Our findings demonstrate that high-volume, low FA deep and periventricular lesions were significantly linked to cognitive decline, whereas small periventricular lesions with near normal microstructural properties do not predict cognitive decline. These results suggest that distinct WMH phenotypes may serve as markers for differential risks of cognitive impairment, providing potential targets for early intervention in at-risk populations.

Link: https://doi.org/10.3389/fnagi.2025.1520069

The innate immune cells known as macrophages are found everywhere in the body, outside the brain. Inside the brain an analogous population known as microglia exists. A population of monocytes resides in the spleen and circulates in the bloodstream, capable of differentiating into macrophages and entering tissues when needed. But large numbers of tissue resident macrophages also exist, already in place. Macrophages undertake a wide range of tasks, including the destruction of infectious pathogens and senescent and cancerous cells, coordination of tissue regeneration following injury, and clearance of metabolic waste and debris. Macrophages are diverse in the sense that they can adopt different programs of expression and behavior in response to circumstances and environment. With advancing age, some of these behaviors can become maladaptive in response to the damaged tissue environment.

Today's open access paper is focused on one specific population of macrophages that is implicated as a source of inflammatory signaling in aging. Chronic inflammation is a feature of aging, with many contributing causes. When inflammation continues indefinitely without resolution, it changes cell behavior to cause disruption to tissue structure and function, contributing to the onset and progression of a range of age-related conditions. Since necessary short term inflammation and harmful long-term inflammation are governed by the same regulatory pathways, it is likely that the only truly effective solution to the problem of chronic inflammation in aged tissues involves removing the molecular damage that provokes it and either removing or altering the behavior of the immune cell populations that generate the largest amounts of inflammatory signaling.

SPP1 macrophages across diseases: A call for reclassification?

Recent advances in macrophage biology have revealed a remarkable diversity among these immune cells, highlighting the existence of specialized subpopulations with distinct functional roles in health and disease. Among these, SPP1+ macrophages, characterized by elevated osteopontin (SPP1) expression, have garnered significant attention due to their consistent association with pathological states. Originally identified in cancer as tumor-associated macrophages (TAMs), SPP1+ macrophages have since been implicated in various conditions, including aging, chronic inflammatory disorders, neurodegenerative diseases, and tissue remodeling.

Aging presents a compelling context in which SPP1+ macrophages emerge as key players. Single-cell RNA sequencing studies have revealed their abundance in the skeletal muscle of aged mice, where they exhibit hallmarks of senescence and enhanced angiogenic and lipid metabolic activity. Beyond musculoskeletal systems, SPP1+ macrophages also influence neurodegenerative diseases. In Alzheimer's disease, an upregulation of SPP1-positive microglia correlates with inflammation and synaptic loss. Perivascular macrophages with SPP1 profiles modulate microglial phagocytic activity, offering a potential mechanism underlying synapse degradation. This dual contribution to inflammation and neurodegeneration positions SPP1+ macrophages as central figures in aging-related pathologies.

Their conserved traits, such as promoting fibrosis, remodeling the extracellular matrix, and modulating immune responses, suggest they play a pivotal role in sustaining chronic inflammation and tissue dysfunction. Furthermore, their presence often correlates with poor clinical outcomes, underscoring their relevance as potential therapeutic targets. Despite these shared characteristics, SPP1+ macrophages exhibit functional adaptability across different disease contexts, raising questions about their classification and the underlying mechanisms that drive their diverse roles.

In this perspective, we briefly summarize recent discoveries on the multifaceted roles of SPP1+ macrophages across various pathological conditions, emphasizing their shared traits and the critical differences dictated by the tissue microenvironment and pathological inflammatory context. Based on our comparative literature investigation, we also propose a re-evaluation of their classification, advocating for their recognition as a distinct macrophage subtype linked to prolonged inflammatory states rather than specific to tumors. Such a shift in perspective could not only advance our understanding of macrophage biology but also open new avenues for targeted therapeutic interventions.

Why are there more female than male centenarians? The difference in life expectancy between men and women is well known and well explored. The long list of potential causative mechanisms all come with supportive evidence, but are incompletely understood at the detail level. In particular it remains unclear as to the relative importance of each these contributing factors versus all of the others. Here, researchers focus on differences in immune function and the composition of the gut microbiome in extremely old individuals. These are connected items, as the immune system gardens the gut microbiome by removing potentially problematic microbes, while those problematic microbes can induce chronic inflammation and dysfunction in the immune system.

Extreme longevity, particularly reaching the age of 100 years, is an exceptionally rare trait in the human population, exhibiting significant variations in prevalence between genders. Women generally exhibit greater survival rates than men across all age groups, including centenarians, with the gender gap in life expectancy ranging from 4.2 to 6.2 years. Genetic factors and immune responses play a crucial role in achieving longevity; however, there is limited information regarding the mechanisms that regulate the differences in biological aging between men and women.

A strong immune system is a key factor in determining lifespan, and sex plays an important role in its composition and activity. The sex-based diversity in immunity between males and females is regulated by several mechanisms, including X chromosome inactivation, mosaicism, skewing, and dimorphism in the expression of X chromosome-encoded genes, as well as regulatory genes on the Y chromosome. Generally, women exhibit stronger innate and adaptive immune responses than men.

An additional factor that may contribute to gender differences in the immune system is the gut microbiota. Composition of gut microbiota varies between males and females providing sex-specific differences in immune responses. Notably, it has been demonstrated that the ratio of bacterial cells to human cells differs between males and females, with a ratio of approximately 1.3:1 for males and 2.2:1 for females. However, the mechanisms by which the gut microbiome contributes to conditions conducive to successful aging remain unclear. Consequently, future research should prioritize investigating the causal relationship between sexually dimorphic immunity and the microbiota.

Link: https://doi.org/10.3389/fimmu.2025.1525948

Torpor is characteristic of hibernating mammals, involving reduced body temperature and slowed metabolism. Researchers have discovered a way to induce this state in mice, and demonstrate that implementing a schedule of intermittent repeated periods of torpor produces an extension of healthspan. This ties in to an established literature on the relationships between metabolic rate, body temperature, and lifespan in mammals, in that one would expect reduced body temperature to produce a modest slowing of aging.

Torpor is a state of profoundly decreased metabolic rate, driving a decrease in core body temperature that can last from hours to days, whereas hibernation is a seasonal behavior comprising multiple bouts of torpor interrupted by periodic arousals to euthermia. These extraordinary adaptations raise many unanswered fundamental questions of homeotherm biology, one of the most compelling being the link between torpor and longevity. Natural torpor is characterized by tightly coupled, extreme physiological changes that have been individually implicated in aging and longevity, such as decreased core body temperature and metabolic rate, and caloric restriction. Indeed, hibernating species exhibiting long torpor bouts show extended longevity compared to closely related non-hibernators and longer lifespan than would be expected based on body mass alone.

Here we demonstrate that the activity of a spatially defined neuronal population in the preoptic area, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor-like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves healthspan. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature on blood epigenetic aging and find that the decelerating effect of the TLS on aging is mediated by decreased body temperature. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that body temperature is an important mediator of the aging processes.

Link: https://doi.org/10.1038/s43587-025-00830-4

Metabolic syndrome is the precursor to type 2 diabetes, and a direct consequence of being sufficiently overweight to experience the necessary disruptions to metabolism. Sarcopenia is the name given to severe loss of muscle mass and strength when it occurs in older people, though it is worth noting that these losses are universal. While a sizable fraction of the muscle atrophy observed in wealthier regions of the world results from a sedentary lifestyle, the other underlying causes resulting from aging occur for everyone. Everyone would reach a state of sarcopenia eventually, if they did not first die due to some other consequence of degenerative aging.

Since sarcopenia is in part driven by chronic inflammation, and chronic inflammation is characteristic of metabolic syndrome, these two conditions can coexist. In today's open access paper, epidemiologists examine data obtained for this patient population in order to quantify the excess mortality risk that these individuals experience as a result of (a) the underlying damage and dysfunction that contributes to these conditions, and (b) the secondary dysfunctions and further damage resulting from these conditions.

Additive impact of metabolic syndrome and sarcopenia on all-cause and cause-specific mortality: an analysis of NHANES

Metabolic syndrome (MetS) and sarcopenia (SP) are increasingly significant public health issues in aging societies, sharing common pathophysiological mechanisms and being associated with severe health consequences. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. Mortality data were obtained from the National Death Index up to December 2019. Among the 21,962 participants, 61.5% had neither MetS nor SP (MetS-/SP-), 24.6% had MetS only (MetS+/SP-), 12.2% had SP only (MetS-/SP+), and 1.5% had both MetS and SP(MetS+/SP+).

Compared to the group without MetS and SP, the groups with MetS only, SP only, and both MetS and SP showed increased all-cause mortality, with adjusted hazard ratios (HR) of 1.23, 1.63, and 1.61, respectively. The MetS+/SP+ group had the highest overall mortality risk. For cause-specific mortality, the MetS+/SP+ group exhibited increased cardiovascular mortality (HR: 1.89), cardiac mortality (HR: 1.89), respiratory mortality (HR: 2.63), and diabetes mortality (HR: 8.79) compared to the group without MetS and SP.

Overexpression of the transcription factor XBP1 has been shown to extend life in flies. It is thought to achieve this outcome by increasing the efficiency of the unfolded protein response, a cell maintenance process. Its diverse other effects may also be important, as its regulation of transcription touches on immune function, lipid metabolism, glucose metabolism, and other mechanisms. This extensive portfolio of influences is often the case for transcription factors. Here, researchers apply brain-specific XBP1 overexpression to mouse models of Alzheimer's disease, and observe a reduction in pathology.

The decay of the proteostasis network has been pointed out as a primary hallmark of aging, a phenomenon that may contribute to Alzheimer's disease (AD) pathogenesis. Strategies to improve proteostasis have been tested in multiple models of neurodegenerative diseases, observing outstanding protective effects. One of the central nodes of the proteostasis network altered during aging involves the function of the endoplasmic reticulum (ER), the main site for protein production in the cell. The ER is also highly altered in AD. To cope with ER stress, cells activate an evolutionarily conserved pathway known as the unfolded protein response (UPR), which aims to re-establish proteostasis. The UPR reinforces many processes involved in the function of the secretory pathway to improve protein production and sustain cell function, whereas chronic ER stress results in neurodegeneration and cell death.

The most conserved UPR signaling branch is initiated by the ER stress sensor IRE1, which catalyzes the unconventional splicing of the mRNA encoding XBP1. This event results in the expression of an active transcription factor, termed XBP1s, which enables transcriptional reprogramming. We recently reported that the activity of the IRE1/XBP1 pathway declines in the brain during normal aging in mammals and strategies to enhance the activity of the UPR extend brain healthspan. Importantly, we showed that strategies to express XBP1s in neurons either using transgenic mice or gene therapy delayed synaptic dysfunction and cognitive decline during normal aging, in addition to reducing the content of senescence cells in the brain.

With the idea of testing the effects of artificially enforcing UPR adaptive responses in the AD brain, we overexpressed the active XBP1s form in the nervous system using transgenic mice, in addition to the hippocampus using adeno-associated viral (AAV) vectors. Overexpression of XBP1s dramatically reduced the content of amyloid plaques in the brain and improved cognitive performance and synaptic plasticity in a model of familial AD (5xFAD transgenic animals expressing mutant APP and presenilin-1). Additionally, XBP1s overexpression in the brain improved memory performance on a model of sporadic AD based on the injection of amyloid β oligomers. The beneficial effects of XBP1s expression in the context of experimental AD and normal aging involve a substantial correction of gene expression patterns associated with synaptic function, neuronal morphology, and connectivity. Thus, we speculate that a major protective mechanism of XBP1s in AD relates to its function as a regulator of neuronal physiology that may parallel its effects in reducing amyloid deposition.

Link: https://doi.org/10.4103/NRR.NRR-D-24-00658

Being overweight correlates with an increased risk of age-related disease and mortality in later life. The greater the excess weight, the greater the risk. A sizable fraction of this risk appears to be mediated by the metabolic activity of visceral fat cells, which promote chronic inflammation through a range of mechanisms. These include an increased burden of cellular senescence, visceral fat cells mimicking the signaling associated with infected cells, and an greater amount of debris from dying and dead cells that provokes a maladaptive inflammatory response from immune cells. Chronic inflammation is characteristic of aging, and is disruptive to tissue structure and function.

Body fat distribution in women changes as menopause progresses and estrogen levels decrease, causing the adipose tissue concentrated in the hips and thighs to gradually shift to the midsection as harmful visceral fat. This predisposes women to low-grade inflammation and cardiovascular diseases, which increase significantly after menopause. A study investigated the connection between health behaviours and low-grade inflammation. Health behaviours in this study include sleeping, eating and physical activity, and related disorders.

"In line with previous studies, a higher amount of visceral fat was, as expected, associated with low-grade inflammation. Visceral fat accumulated in the midsection secretes cytokines that increase inflammation, and this can increase the risk of metabolic diseases." The results show that those individuals who exhibit more disordered eating behaviour, as well as those who were physically less active, had more visceral fat, and thus the risk of low-grade inflammation was also higher. When eating and physical activity behaviours were examined together, higher physical activity was associated with lower visceral fat, especially in those women who did not display disordered eating behaviour.

Link: https://www.jyu.fi/en/news/exercise-and-healthy-eating-behaviour-together-provide-the-best-protection-against-cardiovascular

People taken en masse are reflexively conservative, grumbling and resistant to all change, whether or not that change is evidently, clearly positive. So if one takes a tour of what the medical community has to say about the prospects of extending healthy life spans via the development of new forms of therapy that target mechanisms of aging, one will find at least as much grumbling and resistance as optimism. It seems self-evident that more healthy life is a good thing. But it is change, and people don't like change.

A clever editorial is presently doing the rounds, pointing out the parallels between the present development of treatments for aging with the early development of anesthesia for surgical patients across the span of the 1800s. That was a development process that we might today, in hindsight, characterize as much delayed past the point of the initial discovery of the first practical approach to anesthesia. Exactly how much of that delay can be attributed to grumbling and resistance on the part of the medical community is up for debate, but the authors of the editorial have uncovered some choice quotes from influential figures of the time.

Turning Fate into Choice: Patient Self-Determination and Life Extension

The foundations of modern medicine rest upon two revolutionary changes in medical practice. The first is the development of effective treatments that have transformed previously fatal diseases into manageable or curable conditions. A child who developed diabetes in 1900 would have died within months, while today, insulin therapy can provide them with a normal lifespan. The second was a fundamental shift in the doctor-patient relationship, replacing physician paternalism with patient self-determination. Whereas physicians once withheld diagnoses and made unilateral decisions, clinical practice now centers on informed consent and shared decision-making.

This progress in expanding patient choice was neither smooth nor inevitable. Consider anaesthesia, the astonishingly slow development of which reveals how physician attitudes can constrain patient autonomy. After the discovery of nitrous oxide's anaesthetic properties in 1799, patients should have been quickly granted the option of avoiding gratuitous surgical and obstetrical pain. Instead, the potential applications were neglected for 50 years, with one prominent surgeon dismissing it entirely when stating that "The abolishment of pain in surgery is a chimera. It is absurd to go on seeking it." When surgical anaesthesia was finally demonstrated successfully in 1846, one might have expected rapid adoption to promptly provide patients the choice of pain-free surgery. Instead, resistance persisted, with some surgeons in 1847 still insisting that "Pain in surgical operations is in a majority of cases even desirable, and its prevention or annihilation is for the most part hazardous to the patient." While skepticism of new treatment safety is understandable - and indeed, anaesthesia-related complications still occur today - it seems clear that 19th century patients would have welcomed the choice of pain-free surgery, had they been granted the opportunity.

Despite medicine's progress since the 1800s, we believe that the aforementioned neglect and paternalism are repeating themselves again today in attitudes towards aging and death. Take the 2022 Report of the Lancet Commission on the Value of Death, which declared that "it is healthy to die" and "without death every birth would be a tragedy" - statements that echo 19th century claims about the necessity of pain in surgery. This philosophical stance is arguably also manifest institutionally: the U.S. Food and Drug Administration does not even classify aging as a disease process, while the National Institutes of Health dedicates less than 1% of its budget to basic research into ageing and senescence. While we welcome the increasing emphasis on patient choice in end-of-life care, these attitudes reveal a troubling disregard for the wish of many dying patients, no matter their age, to live longer if only they were able. Indeed, one survey found that 70% of terminally ill individuals, including those in their eighties, maintained a strong will-to-live even when death was imminent. Just as patients facing amputation in 1825 would likely have jumped at the chance for pain-free surgery, surely many patients today would choose to extend their lives if offered ways to do so while maintaining their quality of life.

The central nervous system is inconveniently situated for those who wish to examine it in detail in living people, but one tiny portion is at least readily available for visual inspection - the retina at the back of the eye. To the degree that the retina is subject to the same mechanisms of aging as the brain, one might expect to be able to use retinal imagery as a measure of brain aging. A number of studies have done just that, and a number of different aging clocks have been derived from standard forms of retinal imagery. Here, researchers look at just one aspect of retinal structure as a measure of age-related degeneration, the thickness of its different layers.

The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results. This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline.

Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline.

Link: https://doi.org/10.1186/s13195-024-01627-0

Macrophages of the innate immune system exhibit a range of different states known as polarizations. M1 macrophages are inflammatory and focused on attacking pathogens and errant cells. M2 macrophages are anti-inflammatory and focused on tissue maintenance, playing an important role in regeneration from injury. Not a vital role, strictly speaking, as wounds still heal in the absence of macrophages, but the presence of macrophages in the M2 polarization accelerates the process. As researchers demonstrate here, ways to guide macrophages into the desired pro-regenerative M2 state can further speed wound healing.

Macrophages play a key role in wound healing. Dysfunction of their transition from the M0 unpolarized state to the M2 polarization leads to disorders of the wound immune microenvironment and chronic inflammation, which affects wound healing. Regulating the polarization of M0 macrophages to M2 macrophages is an effective strategy for treating wound healing. Mesenchymal stem cells (MSCs) deliver endogenous regulatory factors via paracrine extracellular vesicles, which may play a key role in wound healing, and previous studies have shown that apoptotic bodies (ABs) are closely associated with inflammation regression and macrophage polarization. However, the specific regulatory mechanisms involved in ABs remain unknown.

In the present study, we designed an MSC-AB (MSC-derived AB)-loaded polycaprolactone (PCL) scaffold, evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro, and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing. Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs, and drives M0 macrophages to program M2 macrophages to regulate inflammation and angiogenesis, thereby synergistically promoting wound healing. This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immune responses.

Link: https://doi.org/10.1016/j.gendis.2024.101388

Nearly 15 years have passed since the first compelling demonstration of rejuvenation produced by clearance of senescent cells in the tissues of aged mice. At that time the study of senescent cells was fairly slow and sedate, not a major area of research. How things change! At present a very energetic community of academic groups and biotech companies is mining the biochemistry of cellular senescence in search of better ways to selectively destroy these cells, ways to change their behavior to reduce their contribution to systemic inflammation and tissue dysfunction, and even ways to turn back the normally irreversible transition into the senescent state. There are incentives: any new discovery could be the starting point for development of a therapy that significantly slows or reverses aspects of aging.

The damage done by the growing burden of senescent cells found in aged tissues is thought to be near entirely caused by the senescence-associated secretory phenotype (SASP), the mix of pro-growth, pro-inflammatory signaling that is energetically produced by these cells. As the thinking goes, a way to eliminate the SASP could be as beneficial as clearing senescent cells from tissues. There are drawbacks to this approach, which is that the SASP is actually beneficial in the short term, helpful in wound healing and suppression of potentially cancerous cells. Periodic destruction of senescent cells would not interfere in their beneficial short-term behaviors, while chronic dosing to suppress the SASP would do so. Nonetheless, as today's open access paper illustrates, there is a growing interest in finding ways to reduce or even eliminate SASP signaling.

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

The senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. Acetate-dependent acetyl-CoA synthetase 2 (ACSS2) produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear.

Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces deoxyribonucleotide triphosphate (dNTP) pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP.

Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.

This review paper looks at what is known of hypoxia-inducible factor (HIF) signaling in the aging of lung tissue, with a particular focus on the burden of cellular senescence as a measure of age-related dysfunction. In the view of these researchers, chronic expression of HIF with age promotes cellular senescence. Why HIF expression becomes dysregulated with age is one of many questions that are hard to answer; it takes a great deal of effort to trace the chain of cause and consequence that leads to any given alteration in gene expression, and in near all cases the long and winding connection to some fundamental causative mechanism of aging has not been definitively established.

Hypoxia-inducible factor (HIF) is a key transcriptional mediator of cellular responses to low oxygen, which regulates lung physiology and pathogenesis. It is a central regulator of hypoxic adaptation in lung tissues and plays a dual role in maintaining homeostasis and driving pathological processes. At low levels, hypoxia induced activation of HIF is hormetic, triggering adaptive cellular responses that enhance stress resistance and longevity. However, excessive or prolonged HIF activation skews this adaptive response, fostering fibrosis, inflammation, and disease progression.

During normal aging, HIF maintains oxygen homeostasis, regulates mitochondrial activity, and supports adaptive stress responses in lung tissues. With advancing age, HIF signaling efficiency declines, leading to reduced stress tolerance and impaired repair mechanisms in lung cells. Chronic HIF dysregulation in aging lungs has been linked to increased oxidative stress, senescence induction, and pro-inflammatory signalling. In the lungs, HIF is also essential for oxygen homeostasis and adaptation to hypoxic environments. Beyond its role in oxygen sensing, HIF modulates cellular metabolism, inflammation, and senescence pathways, directly influencing lung aging.

Recent studies indicate that HIF and cellular senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression.

Link: https://doi.org/10.1007/s10522-025-10208-z

Age-related cataract formation in the lens of the eye causes blindness. This growing opacity of the lens appears to be driven in large part by a growing burden of cellular senescence in lens cells. Could senolytic therapies to clear senescent cells reduce the need for surgery and the development of cell therapies and tissue engineered replacement lenses? This seems plausible, but cataract are a long way removed from the top of the priority list of conditions that might be beneficially affected by senolytic treatments. It is unclear as to whether any group is working towards clinical trials of senolytics in patients at risk of cataract formation.

Cellular senescence plays a dual role in health and disease, acting as both a guardian against uncontrolled proliferation and a driver of age-related pathologies, including cataract formation. The intricate interplay between oxidative stress, mitochondrial dysfunction, and chronic inflammation underscores the complexity of senescence in lens epithelial cells (LECs), essential for maintaining lens transparency and particularly vulnerable to oxidative stress-induced senescence.

The progressive senescence of LECs represents a critical factor in age-related cataractogenesis. Advances in senotherapeutics may offer promising strategies to mitigate LEC senescence, either by eliminating senescent cells through senolytics or modulating the harmful effects of the senescence-associated secretory phenotype (SASP) with senomorphics. Natural compounds like fisetin, luteolin, and metformin, along with innovative therapies such as FOXO4-DRI and gene editing, highlight the growing potential for targeted interventions to delay cataract progression.

Future research on cellular senescence in cataract formation holds significant potential to uncover novel therapeutic strategies aimed at delaying or preventing lens opacity. A deeper understanding of the molecular drivers of LEC senescence, particularly the role of oxidative stress, mitochondrial dysfunction, and protein aggregation, will be essential for developing targeted interventions. Investigating the interplay between SASP factors and changes in the lens microenvironment could provide insights into how chronic inflammation accelerates cataract progression. Senescence research could pave the way for innovative treatments that preserve lens transparency and prevent age-related cataracts.

Link: https://doi.org/10.3390/ph18020244

The balance of microbial species making up the gut microbiome changes with age in ways that (a) promote chronic inflammation, such as via infiltration of microbes into tissue and production of harmful metabolites, and (b) reduce the supply of beneficial metabolites, such as butyrate. A growing body of work characterizes these changes and links them to specific age-related conditions. A number of studies have demonstrated that common neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, correlate with distinct dysfunctional changes in the aging gut microbiome.

Today's open access paper adds to this body of work, and in addition to assessing cognitive function and composition of the gut microbiome also incorporates a measure of brain biological age derived from imaging of brain tissue. All three of these measures tend to move with one another; those people with greater dysbiosis of the gut microbiome also have an older brain age and greater loss of cognitive function. One might hypothesize that either the changes in the gut microbiome are contributing to neurodegeneration, or that immune aging contributes to all of the above. Or both!

There is a bidirectional relationship between the state of the aging immune system and the state of the aging gut microbiome. On the one hand the immune system gardens the gut microbiome, removing problem microbes. As the immune system falters with age, it becomes less able to conduct this duty. On the other hand, changes in the composition of the gut microbiome can affect the immune system both directly, by provoking chronic inflammation, and indirectly, via metabolites and other signaling that affects the state of tissues and organs needed for immune function, such as bone marrow and the thymus.

Brain age mediates gut microbiome dysbiosis-related cognition in older adults

The human gut microbiome, a complex and dynamic ecosystem of microorganisms, plays a vital role in maintaining host health and influencing disease progression. Central to this understanding is the concept of the "gut-brain axis," a bidirectional communication network linking the enteric and central nervous systems (CNS) through neural, endocrine, immune, and humoral pathways. Through these mechanisms, the gut microbiome has been hypothesized to affect brain development, behavior, and cognitive function.

Emerging research suggests that gut microbiome dysbiosis - a state of microbial imbalance - is associated with accelerated gray matter aging. Dysbiosis has been linked to inflammation and increased intestinal permeability, leading to systemic and neural inflammation that can negatively impact cognitive function. Aging appears to exacerbate these changes, marked by decreased diversity in beneficial microbial species, such as anti-inflammatory Bifidobacterium, and increased prevalence of pro-inflammatory species like Enterococcus. These microbial shifts, coupled with reduced immunological function and heightened release of inflammatory products, may further accelerate brain aging, contribute to cognitive decline, and even promote amyloid and tau deposition associated with Alzheimer's disease.

We recruited 292 participants from South Korean memory clinics to undergo brain magnetic resonance imaging, clinical assessments, and collected stool samples. We employed a pretrained brain age model derived from imaging data - a measure associated with neurodegeneration. Using cluster analysis, we categorized individuals based on their microbiome profiles and examined the correlations with brain age, Mental State Examination (MMSE) scores, and the Clinical Dementia Rating Sum of Box (CDR-SB).

Two clusters were identified in the microbiota at the phylum level that showed significant differences on a few microbiotas phylum. Greater gut microbiome dysbiosis was associated with worse cognitive function including MMSE and CDR-SB; this effect was partially mediated by greater brain age even when accounting for chronological age, sex, and education. Our findings indicate that brain age mediates the link between gut microbiome dysbiosis and cognitive performance. These insights suggest potential interventions targeting the gut microbiome to alleviate age-related cognitive decline.

Regeneration from injury might be thought of as an intricate and scheduled set of interactions between immune cells, various types of somatic cell present in the injured tissue, and the stem cells that support the tissue. On the immune cell side of the house, a great deal of research is focused on the innate immune cells known as macrophages. Altering macrophage behavior to, for example, encourage greater somatic cell replication in poorly regenerative tissues such as the heart, seems a promising approach to regenerative medicine. This is a still an ongoing area of development in its relatively early stages, however. The primary challenge is that macrophage behavior, such as the reactions of macrophage cells to the environment, is complex and incompletely understood at the detail level. Thus attempts to produce favorable changes in macrophage activities based on what is presently known have so far resulted in mixed or unreliable outcomes in animal models.

In the mammalian heart, cardiomyocytes undergo a transient window of proliferation that leads to regenerative impairment, limiting cardiomyocyte proliferation and myocardial repair capacity. Cardiac developmental patterns exacerbate the progression of heart disease characterized by myocardial cell loss, ultimately leading to cardiac dysfunction and heart failure. Myocardial infarction causes the death of partial cardiomyocytes, which triggers an immune response to remove debris and restore tissue integrity. Interestingly, when transient myocardial injury triggers irreversible loss of cardiomyocytes, the subsequent macrophages responsible for proliferation and regeneration have a unique immune phenotype that promotes the formation of pre-existing new cardiomyocytes.

During mammalian regeneration, mononuclear-derived macrophages and self-renewing resident cardiac macrophages provide multiple cytokines and molecular signals that create a regenerative environment and cellular plasticity capacity in postnatal cardiomyocytes, a pivotal strategy for achieving myocardial repair. Consistent with other human tissues, cardiac macrophages originating from the embryonic endothelium produce a hierarchy of contributions to monocyte recruitment and fate specification. In this review, we discuss the novel functions of macrophages in triggering cardiac regeneration and repair after myocardial infarction and provide recent advances and prospective insights into the phenotypic transformation and heterogeneous features involving cardiac macrophages. In conclusion, macrophages contribute critically to regeneration, repair, and remodeling, and are challenging targets for cardiovascular therapeutic interventions.

Link: https://doi.org/10.1016/j.gendis.2024.101332

Neurodegenerative conditions are characterized by chronic inflammation. Does reducing that inflammation help? As researchers here note, studies attempting to find correlations between dementia risk and use of common anti-inflammatory medications have produced conflicting results. This study looks at the duration of use of anti-inflammatory medications and total dose over time, and finds that only consistent long term use is associated with a modestly reduced risk of dementia.

Non-steroidal anti-inflammatory (NSAID) medication could reduce dementia risk due to anti-inflammatory and possibly amyloid-lowering properties. However, the results of observational studies and short-term randomized-controlled trials have been inconsistent, and duration and dose-response relationships are still unclear. We included 11,745 dementia-free participants from the prospective population-based Rotterdam Study (59.5% female, mean age 66.2 years). NSAID use from 1991 was derived from pharmacy dispensing records, from which we determined cumulative duration and dose. We defined four mutually exclusive categories of cumulative use: non-use, short-term use (less then 1 month), intermediate-term use (between 1 and 24 months), and long-term use (longer than 24 months).

During an average follow-up period of 14.5 years, a total of 9,520 (81.1%) participants had used NSAIDs at any given time, and 2,091 participants developed dementia. Use of NSAIDs was associated with lower dementia risk for long-term users (hazard ratio, HR: 0.88), and a small increased risk with short-term use (HR 1.04) or intermediate-term use (HR: 1.04). The cumulative dose of NSAIDs was not associated with decreased dementia risk. Associations were somewhat stronger for long-term use of NSAIDs without known effects on amyloid-β than for amyloid-lowering NSAIDs (HR 0.79 versus 0.89).

Long-term NSAID use, but not cumulative dose, was associated with decreased dementia risk. This suggests that prolonged rather than intensive exposure to anti-inflammatory medication may hold potential for dementia prevention.

Link: https://doi.org/10.1111/jgs.19411

Insofar as I have an opinion on politics, I'm against it. Generally it runs in its own noisy part of the world, involves a lot of unnecessary angst and drama, and at the end of the day has little to no influence on my day to day life. It is best ignored. I'll talk about it a little today because it seems likely that some upheaval lies ahead for the regulation of medical development in the US, and by extension that portion of the rest of the world that has outsourced much of its medical regulation to the US. The Department of Government Efficiency and related factions have yet to turn their eyes in earnest to the FDA, but they seem likely to do so.

One old idea that appears ripe for revival is have the FDA cease to require proof of efficacy for new drugs, and only enforce proof of safety before permitting use in the market. By extension, this also implies preventing the FDA from attempts to sabotage the already permitted off-label use of existing approved therapies for new indications. The various payers in the system, everything from medical insurers to individuals, could then make their own decisions as to the proof and standards of efficacy they would like to see upheld before paying for a treatment. It would go back to being a market with a plurality of opinions on any given drug and use case in question, rather than having to accept the dictates of one set of bureaucrats, one size fits all.

One present manifestation of this ethos is the Right to Try law in Montana, which states that any drug that passes a phase 1 safety trial is open for use by any patient - though in practice obtaining that drug would be challenging for any novel therapeutic, requiring cooperation on the part of the developer that the leadership of that company might justifiably view as a risk to their ongoing relationship with the FDA. However, one could envisage a world in which this Right to Try approach effectively becomes federal law in the US, because that is a fairly simple change from the point of view of the executive branch: just alter the way the FDA behaves, and all clinical trial activity beyond phase 1 is optional. At that point, the incentives on developers change considerably, and the complexity thereafter is left to evolve in the market of consumers and payers.

It seems likely that the immediate response of the largest insurance companies and other payers would be along the lines of "great, but keep on running phase II and phase III clinical trials that demonstrate efficacy if you want us to pay for your medicines." I'd expect this to result in only short-term chaos for the network of investments, valuations, and stock prices that depend upon medicine being very expensive to bring to the clinic, and thus only short-term opposition from large investors, pharma entities, and other vested interests with political influence and lobbying capital to spend. After matters settle down to be more or less a continuation of the status quo, at least at first, greater freedom will emerge over time: payers will selectively defect from the consensus regarding standards for efficacy, where they feel it is justified, biotech and pharma companies will gain a much greater freedom to bring new medicine to the market earlier and at a lower cost than would otherwise be the case, and patients would gain the choice of earlier access. All of this is already happening via medical tourism for a small number of people and organizations; adding the option to do this in the US would greatly broaden access.

Another possible path forward is to make the US clinical trial ecosystem look a lot more like that in Australia. This would require more extensive changes to the regulatory system, which may or may not meet with opposition. In Australia there is no central government body akin to the FDA with the role of assessing and approving every phase 1 safety trial. Instead a competing market of specialized clinical sites and institutional review boards exists to assess and approve proposed new drugs and clinical trials, balancing their incentives to receive business versus their incentives to minimize harm to patients. Since something like 10% of all phase 1 trials worldwide are conducted in Australia, at something like half the cost and a fraction of the time required for approval in the US, it is a system that appears to work fairly well. Setting this up in the US would require dismantling regulations applying to institutional review boards and removing the FDA function of up-front vetting and approving of trials. As before, this change would likely produce short-term chaos and scrambling, but if the end goal remained to work towards the same present format of data and reporting that results from clinical trials, then the existing marketplace of contract research organizations (CROs) that run trials and package data would adapt, form standards, and those standards would likely look very much like the present status quo, at least at first. Moving forward, competition and freedom to choose would allow a greater plurality of options to emerge.

A harder and more disruptive change would be to alter the way in which the production of drugs is regulated in order to reduce the costs of compliance. Regulating manufacture under the banner of Good Manufacturing Practice (GMP) is sizable chunk of the work conducted by the FDA, and conforming to FDA requirements on manufacturing processes is certainly a very large slice of the cost and effort required to bring a drug to the clinic. The guidelines put out by the FDA are standard and vague. Every single class of drug has accumulated over years and decades a deep and very detailed culture and tradition of non-public material and experience among consultants and regulators to describe the precise details of an acceptable interpretation of those vague standards. This cannot be discovered without engaging with regulators and consultants at considerable expense. Further, the requirements for GMP manufacture of any given drug class tend to expand over time, as efforts to remove any novel assay or other addition that regulators and consultants have seen used widely will be opposed.

Trying to change GMP requirements runs into a range of problems: firstly, there will be a great deal of political opposition from those who hold the unreasonable fear that any change to GMP regulation will make drugs unsafe; secondly, there will be a great deal of political opposition from large organizations that use the high cost of compliance to reduce competition, the usual problem of regulatory capture; thirdly, the specific interpretations of compliance that have become so very costly have very little do with the published regulations, vary widely by drug type, are very complicated, are are near entirely documented privately, making them hard to target; fourthly, many smaller countries reference US GMP standards and rely upon them to inform their own medical regulation, essential outsourcing that function.

To return to Australia, for example, the consensus that has emerged among institutional review boards, clinical trial running CROs, and clinical sites, is that the drug used in a phase 1 clinical trial should be manufactured to GMP-like quality. What "GMP-like" means in practice is that the FDA has accepted the proposed technical/scientific details of the manufacturing process and quality control assays, the drug batch is manufactured using that process and those assays, but the manufacture is not conducted with the very expensive addition of the full audit trail, checking in triplicate, form-filling, checkboxes, and validation at every step that is required for a process to be GMP grade. In drug manufacture circles this is called an engineering batch, and in present practice is the last full scale non-GMP batch that successfully tests all of the manufacturing processes and passes all of the quality assurance tests. The engineering batch is usually used for toxicity studies in animals that are conducted as a part of submitting an IND proposal to the FDA - except that in Australia one can also use the engineering batch for a phase 1 safety trial in human volunteers.

If engineering batches are safe enough for humans in Australia, why not everywhere else? Why not have the minimum regulated safety requirement for medicines at any stage of approval or commercial use be that manufactured batches be made as if engineering batches? This would reduce manufacture cost by 50% for many drug classes. The batches would still have to pass quality testing that has been reviewed by regulators, institutional review boards, and others. The answer to the question "why not?" is probably that (a) this would be a hard change to make, politically, and (b) while it is easy to state the change in a single sentence, actually wrangling into shape the vague regulations and hidden details of the present state of the art regarding compliance would be challenging.

But it seems likely that we shall see how this all turns out!

Repositories of well-characterized 20+ year old stored blood samples that can be accessed for analysis are few and far between. Here, researchers make use of one such resource to characterize a proteomic aging clock for its ability to predict future health outcomes. This clock, organage, assesses a biological age for different organs based on levels of circulating proteins specifically produced by each organ. As one might expect, people who later developed an age-related dysfunction of an organ and consequent disease tended towards a higher biological age for that organ in the late 1990s, as measured by organage.

In this observational cohort study, to assess the biological age of an individual's organs relative to those of same-aged peers, ie, organ age gaps, we collected plasma samples from 6235 middle-aged (age 45-69 years) participants of the Whitehall II prospective cohort study in London, UK, in 1997-99. Age gaps of nine organs were determined from plasma proteins. Following this assessment, we tracked participants for 20 years through linkage to national health records. Study outcomes were 45 individual age-related diseases and multimorbidity.

Over 123,712 person-years of observation (mean follow-up 19.8 years), after excluding baseline disease cases and adjusting for age, sex, ethnicity, and age gaps in organs other than the one under investigation, individuals with large organ age gaps showed an increased risk of 30 diseases. Six diseases were exclusively associated with accelerated ageing of their respective organ: liver failure (hazard ratio [HR] per standard deviation increment in the organ age gap 2.13), dilated cardiomyopathy (HR 1.65), chronic heart failure (HR 1.52), lung cancer (HR 1.29), agranulocytosis (HR 1.27), and lymphatic node metastasis (HR 1.23). 24 diseases were associated with more than one organ age gap or with organ age gaps not directly related to the disease location. Larger age gaps were also associated with elevated HRs of developing two or more diseases affecting different organs within the same individual (ie, multiorgan multimorbidity): 2.03 for the arterial age gap, 1.78 for the kidney age gap, 1.52 for the heart age gap, 1.52 for the brain age gap, 1.43 for the pancreas age gap, 1.37 for the lung age gap, 1.36 for the immune system age gap, and 1.30 for the liver age gap.

Link: https://doi.org/10.1016/j.landig.2025.01.006

The glymphatic system of the brain is a recently discovered pathway allowing cerebrospinal fluid to drain from the brain into the body, carrying metabolic waste with it. Another path through pores in the cribriform plate behind the nose also appears important. Both of these drainage pathways decline in efficacy with age. It is thought that this loss of function allows various forms of metabolic waste, such as the protein aggregates characteristic of neurodegenerative conditions, to accumulate in the brain. This provokes cells into dysfunction and inflammatory behavior.

The glymphatic system theory introduces a new perspective on fluid flow and homeostasis in the brain. Here, cerebrospinal fluid and interstitial fluid (CSF-ISF) moves from the perivascular spaces (PVS) of arteries to those of veins for drainage. Aquaporin-4 (AQP4) plays a crucial role in driving fluid within the PVS. The impairment of AQP4 is closely linked to the dysfunction of the glymphatic system. The function of the glymphatic system is less active during waking but enhanced during sleep.

The efficiency of the glymphatic system decreases with aging. Damage to the glymphatic system will give rise to the development and progression of many brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and vascular dementia (VaD). Here, we reviewed previous research associated with the glymphatic system, including its concepts, principles, and influencing factors. We hypothesize that AQP4 could be a target for the prevention and treatment of certain brain diseases through the regulation on the glymphatic system.

Link: https://doi.org/10.3389/fncel.2025.1528995

Cellular reprogramming involves expressing the Yamanaka factors discovered twenty years ago. Given robust expression over days, a somatic cell dedifferentiates into an induced pluripotent stem cell, replicating what happens to germline cells in early embryonic development. But with just a little expression of the Yamanaka factors, partial reprogramming occurs: the cell retains its state but resets its epigenetic control of nuclear DNA structure and gene expression to be more youthful. This is a desirable goal for the medical community, and in recent years a very large amount of funding has poured into early stage development programs aimed at producing rejuvenation therapies based on partial reprogramming. It remains to be seen as to how well this will go.

A hoped-for ideal is body-wide reprogramming, to hit every cell in an aged body and brain to restore youthful function to the degree that this is possible given damage to nuclear DNA, signaling environment, extracellular matrix, and so forth. One of the more interesting lines of research to emerge from the cellular reprogramming field is the use of small molecules to induce the expression of Yamanaka factors. Gene therapies are always going to be more effective at producing the altered gene expression one wants, and are more easily tailored to produce specific outcomes inside a cell, but gene therapies have at present several large disadvantages, all of which revolve around the delivery systems necessary to carry nucleic acids into cells. There is no good way to deliver a gene therapy fairly uniformly to the whole body; even the best approaches largely end up in the liver and lungs when injected intravenously. The delivery systems have dose limiting toxicities that mean that the largest whole body dose one could deliver, so as not to overload the liver and lungs, do not deliver meaningful amounts of the payload to other organs.

Small molecules, on the other hand, largely have this desirable characteristic of body-wide delivery. So there is a growing literature of studies making use of the few small molecules known to induce expression of one or more of the Yamanaka factors. A few companies appear to be quietly conducting screening programs to find more such small molecules, but these are early days yet. Today's open access paper is illustrative of some of the work taking place to assess the capabilities of existing reprogramming small molecules; it is in vitro rather than in vivo, and focused on one specific capability of tissue that declines with age. Researchers would typically move on from here to animal studies or screening for further similar small molecules with better specificity or side-effect profiles.

Restoration of angiogenic capacity in senescent endothelial cells by a pharmacological reprogramming approach

Vascular function is highly impaired during aging, and vascular dysfunction is the underlying cause of cardiovascular diseases, the leading cause of death worldwide. Clinically these alterations are among others observable by an increased systolic blood pressure and increased size and stiffness of the large arteries. Recent studies indicate that these alterations mainly result from a dysfunctional endothelium developing with advancing age. The existence of senescent endothelial cells can draw a causal correlation between aging, endothelial dysfunction, and cardiovascular diseases. Senescent cells accumulate over the life span in the vasculature, in older healthy humans and in diseased tissue in the pathogenesis of heart failure or ischemic heart disease. Senescent cells negatively impact several downstream pathways such as inflammation, DNA damage, molecular regulators as well as cell cycle regulation. Together, these processes lead to an impaired function of the aged endothelium by mainly minimizing the angiogenic and regenerative potential.

This makes reversing and rejuvenating senescent endothelial cells a highly interesting target to improve vascular regeneration in old individuals. Currently, different approaches to counteract cellular senescence are under intensive investigation, such as the use of senolytics to induce cell death or the process of cellular reprogramming mainly relying on viral transduction. The concept of cellular reprogramming was originally used to illustrate the transformation of somatic cells into induced pluripotent stem cells using retroviral overexpression of OCT3/4, SOX2, KLF4, and c-MYC (OSMK). This reprogramming has exhibited therapeutic promise and has also indicated the potential to reverse aging-related traits, particularly evident in initial experiments conducted on senescent and centenarian cells. However, prolonged induction of OSKM using viral methods in living organisms has led to teratoma formation and changes in DNA methylation patterns. In the context of aging and cellular senescence, the term cellular reprogramming has been more commonly associated with the rejuvenation process of senescent cells rather than the generation of pluripotent stem cells.

Here, we aimed to develop a pharmacological strategy to improve senescent endothelial cell function, especially in the context of angiogenesis. Recently, a cocktail of small pharmacological compounds was presented, that contributed to liver regeneration and hepatic function in vivo by promoting cellular reprogramming. This cocktail is composed of three compounds, namely tranilast, valproic acid, and lithium carbonate. All three substances are not only described for their supporting regenerative effect but also for beneficial effects on aging. Indeed, here we are the first to demonstrate that the cocktail favors a reversion of the EC senescent phenotype in vitro. Importantly, all three substances are FDA-approved drugs already in use in clinical settings or at least clinical trials simplifying a potential transition from bench to bedside.

A diabetic metabolism is widely considered to accelerate aging, on the basis of very good evidence, and to the point at which researchers have often used diabetic mice as a faster, cheaper stand-in for aged mice in their studies. Reasonably, one should expect any decent measure of biological age to report accelerated biological aging in diabetic animals or people. Indeed, that is what is shown here for two of the commonly used aging clocks developed in recent years. This is one of the many yardsticks that an aging clock should be able to meet in order to give confidence that it reflects biological age sufficiently well to be broadly useful.

Insulin resistance (IR) has been reported to be associated with aging; however, few studies have investigated the relationship between IR and biological age. The Triglyceride-glucose (TyG) index is a recognized marker of IR. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES), including 12,074 adults (aged 20 and older) from the 2001-2010 and 2015-2018 cycles. Comprehensive TyG and biological age data were extracted for analysis.

We included 12,074 participants with a mean age of 46.91 years; of these, 50.25% were female and 49.75% were male. Each 1-unit increase in the TyG index was associated with a 1.64-year rise in Klemera-Doubal method (KDM) biological age and a 117% higher risk of accelerated aging. Similarly, each 1-unit increase in the TyG index corresponded to a 0.40-year increase in phenotypic age, resulting in a 15% higher risk of accelerated aging. The analysis also revealed nonlinear positive relationships between the TyG index and biological aging, particularly for KDM biological age and phenotypic age, with a turning point at 8.66. Across all subgroups, the TyG index consistently showed a positive correlation with biological aging, even in the presence of significant interactions.

Link: https://doi.org/10.1186/s12933-025-02631-w

Researchers here produce a mouse model incorporating a DNA sequence that produces a luminescent protein only in the case of a readthrough error, where the translation machinery ignores a stop codon in the DNA sequence. This is a way to gauge the degree to which readthrough errors increase with age, producing aberrant RNA molecules and consequent dysfunction. A range of evidence supports an age-related increase in translation errors in the production of RNA from DNA, though as is always the case in these matters understanding how much of degenerative aging results from this sort of dysfunction in gene expression is a challenge. One would have to fix just this one problem without affecting other mechanisms, a difficult prospect.

The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due to codon-anticodon mispairing than missense amino acid incorporation. Subsequently, we developed knock-in mice for in-vivo detection of stop-codon readthrough using a gain-of-function Kat2-TGA-Fluc readthrough reporter which combines fluorescent and sensitive bioluminescent imaging techniques.

We followed expression of reporter proteins in-vivo over time, and assessed Kat2 and Fluc expression in tissue extracts and by whole organ ex-vivo imaging. Collectively, our results provide evidence for an organ-dependent, age-related increase in translational error: stop-codon readthrough increases with age in muscle (+ 75%) and brain (+ 50%), but not in liver. Together with recent data demonstrating premature ageing in mice with an error-prone ram mutation, our findings highlight age-related decline of translation fidelity as a possible contributor to ageing.

Link: https://doi.org/10.1038/s41467-025-57203-z

Whenever reading about the effects of an intervention and environmental influence on aging clocks, one has to spend a little time thinking about what it is that these clocks measure and what is known of how the clocks behave. An aging clock is produced from a reference data base of biological measures taken at various ages. If an individual has a pattern of data that matches up to people with an older chronological age in the reference database, then that individual is said to exhibit accelerated biological aging. Is it accelerated biological aging? That is where one has to be careful with definitions.

For most clocks, particularly epigenetic clocks, there is next to no understanding of how the measures making up the clock, such as whether a CpG site on the genome is methylated or not, relate to forms of molecular damage and dysfunction related to aging. The clock measures something, but then researchers have to prove that the something is relevant. We might think that a clock is broadly good and useful if it accurately reflects the known epidemiological data regarding risks of age-related mortality and disease that result from interventions and environmental influences. But we'll never know in certainty that a clock is broadly good and useful; even a few good results fail to tell us how a clock will perform for some other, different intervention.

Nonetheless, researchers are testing all sorts of interventions and environmental factors for their effects on aging clocks in the hope that a large enough pool of data will provide confidence in the use of clocks to assess novel interventions aimed at slowing or reversing aging. Today's open access paper is an interesting example of the type, in which clocks are assessed for their ability to reflect the known effects of heat exposure on mortality and late life health.

Ambient outdoor heat and accelerated epigenetic aging among older adults in the US

Extreme heat contributes to a range of health conditions. Health impacts from heat are particularly adverse among older adults due to age-related declines in thermoregulatory functions. Although links between extreme heat and morbidity and mortality are well established, knowledge of the biological underpinnings is limited. The physiological toll exacted by heat events may not manifest immediately as clinical conditions. Rather, these environmental insults may elicit subclinical deterioration at the biological level, accelerating biological aging, which precedes the subsequent development of diseases and disabilities. Animal studies suggest that epigenetic alteration is a strong candidate for a potential biological mechanism. Severe heat stress can induce a "maladaptive epigenetic memory," which can be coded through changes in DNA methylation (DNAm) patterns. DNAm, arguably the most well-studied epigenetic marker, is known to be responsive to environmental stressors, modulating gene expression and exerting downstream effects on morbidity and mortality risks.

This study examines the association between ambient outdoor heat and epigenetic aging in a nationally representative sample of US adults aged 56+ (N = 3,686). The number of heat days in neighborhoods is calculated using the heat index, covering time windows from the day of blood collection to 6 years prior. Multilevel regression models are used to predict acceleration in principle component (PC) versions of PhenoAge (PCPhenoAge) and GrimAge (PCGrimAge), and in DunedinPACE. More heat days over short- and mid-term windows are associated with increased PCPhenoAge acceleration (e.g., B for prior 7 days: 1.07 years). Longer-term heat is associated with all clocks (e.g., B for prior 1 year: 2.48 years for PCPhenoAge, B for prior 1 year: 1.09 year for PCGrimAge, and B for prior 6 years: 0.05 years for DunedinPACE). Subgroup analyses show no strong evidence for increased vulnerability by sociodemographic factors.

The temporal patterns may reflect different magnitudes and types of biological responses to heat stress occurring in varying time frames. The observed short- and mid-term associations of heat on PCPhenoAge acceleration may be indicative of immediate physiological responses to heat stress. Previous research has identified specific methylation pathways that may potentially underlie these observations.

Researchers here make inroads into mapping a relationship between EDA2R expression and age-related inflammation. They show that EDA2R expression robustly increases with age and correlates with inflammation in multiple tissues types in mice as well as in muscle biopsies from a human study. When overexpressing EDA2R in cells in culture, those cells become more inflammatory. The next step is to established a way to reduce the expression of EDA2R or inhibit its activity and assess in aged mice the degree to which this approach to therapy can reduce inflammation and improve function. No small molecule is known to target EDA2R's interactions in a useful way, so the fastest path ahead to mouse data is likely RNA interference to reduce EDA2R expression.

Ectodysplasin A2 Receptor (EDA2R) is a member of the tumor necrosis factor receptor (TNFR) superfamily which selectively binds to Ectodysplasin-A2 (EDA-A2), a protein encoded by an alternative splicing isoform of EDA (Ectodysplasin A) gene. EDA2R receptor has been recognized as a target of TP53, and EDA2R/EDA-A2 signaling has been observed to mediate activation of JNK, NF-kB pathways and to promote apoptosis and cell death. Moreover, EDA2R messenger RNA expression was reported to be elevated in the aging lungs, and several studies indicated that polymorphisms in the EDA2R gene locus are linked with age-associated androgenetic alopecia (AGA).

Despite these observations, the broader role of EDA2R in aging remains poorly understood. Here, we implement a bioinformatics approach revealing that aging-associated increase of the transmembrane EDA2R is a prominent tissue-independent alteration occurring in humans and other species, and is particularly pronounced in models of accelerated aging. We show that strengthening of EDA2R signalling axis in myogenic precursors and differentiated myotubes suffices to trigger potent parainflammatory responses, mirroring aspects of aging-driven sarcopenia. Intriguingly, obesity, insulin-resistance, and aging-related comorbidities, such as type 2 diabetes, result in heightened levels of the EDA-A2 ligand. Our findings suggest that targeting the Ectodysplasin-A2 surface receptor represents a promising pharmacological strategy to mitigate the development of aging-associated phenotypes.

Link: https://doi.org/10.1038/s41467-025-56918-3

Tau protein becomes phosphorylated and aggregates into neurofibrillary tangles in the aging brain. This harms neurons, and along with inflammation is the dominant pathology in later stages of Alzheimer's disease and other tauopathies. Researchers here engineer neurons to harbor each of the six possible tau isoforms, one by one, and demonstrate that only one of those six different isoforms of tau is a cause of pathology. It remains to be seen as to how this will shape further work leading to new forms of therapy.

The formation of neurofibrillary tangles (NFTs) by hyperphosphorylated tau is the hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases. Under pathological conditions, such as in the presence of toxic amyloid beta (Aβ) oligomers (AβOs), tau becomes hyperphosphorylated, altering axonal microtubule dynamics, causing axonal transport deficits, synapse loss, and ultimately neuronal death and cognitive decline.

In the adult human brain, six tau isoforms originate from alternative splicing of exons 2, 3, and 10 of the MAPT gene. Notably, in the adult human brain 1N tau isoforms (1N3R/1N4R) account for 50% of tau, and 2N tau isoforms are the least expressed isoforms (5%-10%), while in rodents 2N isoforms account for the majority of expressed tau. In rodents and derived neurons, the isoforms differ in intracellular localization, suggesting isoform-specific tau functions. The significance of the isoform expression ratio for neuronal health is underscored by mutations in the MAPT gene that affect its splicing: Changes leading to an imbalance of 3R to 4R tau expression have been directly associated with frontotemporal dementia (FTD) and tauopathies can be classified by the isoforms present in the pathological NFTs.

Rodents, which express almost exclusively 4R tau isoforms (whereas human neurons express 3R and 4R tau), are often used to better understand disease pathology and identify potential therapeutic targets. However, rodents do not naturally develop dementia, and tauopathy models rely on the overexpression of single (mutant/ human) tau isoforms to study disease mechanisms. The contribution of the different tau isoforms to tau physiology and toxicity in disease remains unclear.

Here, we generated tau knockout (KO) human induced pluripotent stem cells (hiPSCs) modified to be easily differentiated into glutamatergic neurons. Tau KO neurons showed impairments of neurite growth and axon initial segment formation, restored by re-expression of individual tau isoforms. Tau KO neurons were protected against AβO-induced neuronal dysfunction and transcriptomic changes, and only the 1N4R tau isoform fully restored the AβO vulnerability of tau KO neurons, based on the higher basal phosphorylation levels of 1N4R tau within the microtubule binding domain, suggesting that this isoform is less microtubule bound compared to other isoforms. All in all, we describe a human tau KO neuronal model and identify 1N4R as a critical mediator of tau toxicity in hiPSC-derived neurons, implying 1N4R tau to be a potential therapeutic target for Alzheimer's disease.

Link: https://doi.org/10.1002/alz.14403

A chimeric antigen receptor (CAR) T cell has been genetically engineered to express a receptor that both binds to a desired target, such as a distinctive surface feature on a cancer cell, and activates the T cell once bound, provoking it into destroying the target. Making this technology into a therapy involves sampling a patient's T cells, incorporating the new CAR gene, then expanding the cells in culture, and introducing them back into the patient. This is an expensive proposition, but has performed well in blood cancers.

Unfortunately, blood cancers are very different in character from the many other forms of cancer that form solid tumors. The cells making up a solid tumor deploy many different strategies to hide from, subvert, suppress, and co-opt the immune system, even inducing immune cells to aid in its growth in some cases, and can rapidly evolve new strategies. Throwing more immune cells at the tumor, even immune cells specifically equipped to recognize tumor cells as a target, often fails.

Nonetheless, CAR-T therapies have worked so very well in their initial uses that a great deal of effort is going into trying to make them work for solid tumors - or if this fails, to understand why it failed, and how to work around the problem. As today's open access paper notes, some of these efforts are aimed at equipping different types of immune cell with chimeric antigen receptors. How well this will work given the nature of the relationship between tumors and the immune system remains to be seen, but hope springs eternal.

Chimeric Antigen Receptor Cell Therapy: Empowering Treatment Strategies for Solid Tumors

CAR-T cell therapy has revolutionized blood cancer treatment, but its application in solid tumors faces challenges, resulting in limited effectiveness and inconsistent outcomes in real-world situations. The disparity between clinical trial results and real-world outcomes underscores the complexity of CAR-T cell therapy for treating solid tumors. Second and third generations of CAR-T cell therapy mark advancements in solid tumor treatment. Second-generation cells incorporate co-stimulatory domains, enhancing T cell activation and persistence in the fight against cancer cells. Third-generation cells combine multiple domains, which may enhance the anti-tumor response. These advancements aim to overcome limitations in solid tumors.

The design of CARs is modular, comprising an antigen-binding domain, a hinge, and a transmembrane domain, along with an intracellular signaling domain. CAR-T cell therapy is a promising cancer treatment that targets specific antigens on tumor cells, enabling the identification of cell surface proteins without depending on the major histocompatibility complex (MHC). However, the effectiveness of CAR-T therapy depends on the presence of specific human leukocyte antigen (HLA) types, limiting its application to a restricted patient population. CAR-T cells exhibit sensitivity to reduced HLA expression and flaws in the antigen processing pathway, tactics employed by tumor cells to escape immune responses. Initial iterations of CARs featured solely a T cell activation domain; however, subsequent designs have incorporated signaling domains from co-stimulatory molecules. CARs are classified as either second- or third-generation based on the quantity of co-stimulatory molecules present.

Despite these challenges, understanding real-world experiences is crucial in optimizing CAR-T cell therapy for solid tumors. Tumor heterogeneity and immune evasion are crucial concepts in cancer biology and treatment resistance. Tumor heterogeneity refers to the diverse characteristics of cancer cells within a single tumor, influencing their interactions with the immune system. Cellular plasticity, particularly dedifferentiation, helps tumors to evade detection. Further exploration and innovation are needed to enhance its effectiveness in this area.

When CAR-T therapy fails, the exploration of alternative options like CAR-NK, CAR-iNKT, or CAR-M therapies becomes increasingly relevant in the landscape of cancer treatment. CAR-NK cells retain natural cytotoxicity, allowing them to target tumors even when cancer cells downregulate antigen expression. CAR-iNKT cells combine natural killer T cells with CAR technology, enhancing effectiveness against various tumors while minimizing toxicity. CAR-M cells, derived from macrophages, penetrate tumors more effectively and exhibit enhanced antitumor efficacy with reduced toxicity. These therapies offer distinct advantages for personalized cancer immunotherapy.

CAR-NK cells present numerous benefits when contrasted with CAR-T cells. Production can occur using established cell lines or allogeneic NK cells that lack matched MHC. Furthermore, they possess the ability to eradicate cancer cells through both CAR-dependent and CAR-independent pathways, while demonstrating diminished toxicity, especially regarding cytokine release syndrome and neurotoxicity. Macrophages infiltrate tumors adeptly, act as crucial immune regulators, and are plentiful within the tumor microenvironment. There is significant enthusiasm surrounding the advancement of CAR macrophages for cancer immunotherapy, aimed at tackling critical challenges associated with CAR T/NK therapy, especially in the context of solid tumors.

The blood-brain barrier surrounds blood vessels passing through the brain and tightly controls which molecules are allowed to pass. It separates the metabolism of the brain from that of the rest of the body. With age, the blood-brain barrier becomes dysfunctional, allowing unwanted cells and molecules to leak into the brain, where they contribute to the chronic inflammation of brain tissue. Researchers here focus on the structure of one specific thin layer of the blood-brain barrier, note that it becomes dysregulated with age, and find a way to improve its function via gene therapy.

The blood-brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis. The brain endothelial glycocalyx layer, a carbohydrate-rich meshwork composed primarily of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen, is a key structural component of the BBB. This layer forms the first interface between the blood and brain vasculature, yet little is known about its composition and roles in supporting BBB function in homeostatic and diseased states.

Here we find that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. We identify significant perturbation in an underexplored class of densely O-glycosylated proteins known as mucin-domain glycoproteins. We demonstrate that ageing- and disease-associated aberrations in brain endothelial mucin-domain glycoproteins lead to dysregulated BBB function and, in severe cases, brain haemorrhaging in mice. Finally, we demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses overexpressing two age-downregulated mucin-type O-glycan biosynthetic enzymes, C1GALT1 and B3GNT3.

Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.

Link: https://doi.org/10.1038/s41586-025-08589-9

In the wet form of age-related macular degeneration, damage and dysfunction gives rise to a maladaptive growth of leaky blood vessels into the retina, destroying its cells, structure, and function. Researchers here report on an early stage clinical trial of a twofold approach to the problem, combining surgery to remove blood vessels with delivery of retinal cells derived from stem cells in order to replace damaged tissue. Efficacy has yet to be determined rigorously, but initial results are encouraging, at least for those patients in which the surgery was successful in achieving the goal of clearing out the unwanted blood vessels.

Wet age-related macular degeneration (AMD) in its early stages can be treated with drugs to reduce the formation of new blood vessels, but this treatment is inefficient in cases where blood vessel formation is already in its advanced stages. A new, alternative treatment for those patients may be surgical removal of the abnormal blood vessels followed by the transplantation of stem cell-derived retinal cells.

In their clinical study, involving 10 patients with wet AMD, researchers first developed a method for safely removing the newly formed blood vessels followed by the transplantation of stem cell-derived retinal cells to replace the patients' damaged or lost retinal cells. The retinal structure improved in those patients where blood vessel patches were completely removed during surgery, suggesting that the transplanted cells survived and repaired the damaged retina. Further, visual acuity remained stable or improved in those patients during the 12-months follow-up, with limited side effects. In contrast, patients where the blood vessel patches could only partially be removed experienced persistent bleeding and inflammation in the eye and an incomplete regeneration of the retina, and vision did not improve in those patients.

Researchers concluded that complete and safe removal of the blood vessel patches prevents inflammation and generates a milieu favorable for transplant survival and integration. Follow up studies with larger groups of patients are required to confirm the clinical efficacy and favorable safety profile of this type of treatment.

Link: https://www.isscr.org/isscr-news/stem-cell-transplant-clears-clinical-safety-hurdle-for-the-treatment-of-wet-age-related-macular-degeneration

The combination of the chemotherapeutic drug dasatinib and the widely used plant extract supplement quercetin was the first senolytic therapy to clear senescent cells from aged tissues to be assessed in mice and humans. The degree of clearance of senescent cells and degree of reversal of aspects of aging and age-related disease produced by dasatinib and quercetin treatment remain comparable to the best of the later panoply of senolytic therapies for which published data exists. Dasatinib produces unpleasant side-effects when used as a chemotherapeutic with dosing regiments sustained over months, but short term use as a senolytic treatment over the course of a few days appears to have a favorable side-effect profile, judging from the published clinical trials. The dose makes the poison.

The challenge with dasatinib and quercetin (as well as the alternative of fisetin) is that there is no financial incentive for any organization to run extensive clinical trials to conclusively prove to the medical community that that these treatments are meaningfully beneficial in older people. These are very cheap compounds, with no patent protection. Without patent protection, and the consequent government-enforced monopoly in the market, it is impossible to obtain the sort of elevated program valuation and elevated drug prices needed to make a profit after spending hundreds of millions of dollars on clinical trials. The fault here is the regulatory burden that causes clinical trials to be so expensive. There must be a better path forward; as things stand, even very good low-cost drugs can languish in this state of being understood to be potentially great, prescribed off-label by some physicians, but never reaching any sort of widespread use or validation sufficiently comprehensive to convince the world at large.

That the dasatinib and quercetin senolytic therapy is understood by the research community to be potentially great is why one sees any clinical trials at all for this approach to the problem of senescent cell accumulation in later life. Various research institutions agitate behind the scenes to obtain philanthropic and other funding to try to move the needle. There is never enough of this funding, and the clinical trials are always too small, but one might hope that at some point a critical mass is reached and a more earnest clinical program is funded by one of the world's larger alternative sources of funding.

A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease

Cellular senescence is one of the hallmarks of ageing that theoretically contributes to the development of age-related diseases. Senolytic agents such as Dasatinib and Quercetin promote the elimination of senescent cells and may provide a viable strategy for the prevention or treatment of diseases of ageing. Studies have demonstrated that co-administration of Dasatinib and Quercetin improved aspects of both physical and cognitive function in mice. However, to our knowledge, the safety, feasibility, and preliminary efficacy of Dasatinib and Quercetin to improve function in humans with mild cognitive impairment (MCI) and slow gait speed is unknown.

This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease. Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.

Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point, but increased significantly by 2.0 points in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0%. Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores, such that reductions in TNF-α were correlated with increases in MoCA scores.

This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.

The more data that is accumulated on the behavior of aging clocks in response to interventions and lifestyle choices known to correlate with life expectancy in humans, the more useful these clocks become. The challenge in the use of the aging clocks established to date is that there is no good understanding of how the measurements making up the clock algorithm, such as the methylation status at specific CpG sites on the genome, relate to mechanisms of aging and disease. Without a great deal more data, researchers cannot predict whether or not a clock will perform well in assessing the effects of a novel intervention intended to slow aging or produce rejuvenation. In the worst case, the only way to calibrate a clock against a specific intervention is to run long studies to assess mortality risk.

Physical inactivity and sedentary behavior are associated with higher risks of age-related morbidity and mortality. However, whether they causally contribute to accelerating biological aging has not been fully elucidated. Utilizing the largest available genome-wide association study (GWAS) summary data, we implemented a comprehensive analytical framework to investigate the associations between genetically predicted moderate-to-vigorous leisure-time physical activity (MVPA), leisure screen time (LST), and four epigenetic age acceleration (EAA) measures: HannumAgeAccel, intrinsic HorvathAgeAccel, PhenoAgeAccel, and GrimAgeAccel

Shared genetic backgrounds across these traits were quantified through genetic correlation analysis. Overall and independent associations were assessed through univariable and multivariable Mendelian randomization (MR). A recently developed tissue-partitioned MR approach was further adopted to explore potential tissue-specific pathways that contribute to the observed associations.

Among the four EAA measures investigated, consistent results were identified for PhenoAgeAccel and GrimAgeAccel. These two measures were negatively genetically correlated with MVPA (r = -0.18 to -0.29) and positively genetically correlated with LST (r = 0.22-0.37). Univariable MR yielded a robust effect of genetically predicted LST on GrimAgeAccel (β = 0.69), while genetically predicted MVPA (β = -1.02) and LST (β = 0.37) showed marginal effects on PhenoAgeAccel. Multivariable MR suggested an independent association between genetically predicted LST and GrimAgeAccel after accounting for MVPA and other important confounders. Tissue-partitioned MR suggested skeletal muscle tissue associated variants to be predominantly responsible for driving the effect of LST on GrimAgeAccel.

Findings support sedentary lifestyles as a modifiable risk factor in accelerating epigenetic aging, emphasizing the need for preventive strategies to reduce sedentary screen time for healthy aging.

Link: https://doi.org/10.1111/sms.70014

Parkinson's disease occurs twice as often in men versus in women, but why this is the case remains a question. Researchers here identify one possible reason, an autoimmune reaction to the PINK1 protein that is much more pronounced in male Parkinson's patients than in female patients. The discovery may be useful as a biomarker, and it may prove to be a target for therapies to reduce the pathology of the condition, at least in men. PINK1 is involved in mitochondrial function and quality control, critical in the motor neurons that are lost to Parkinson's pathology in the brain. PINK1 mutations are associated with early onset of Parkinson's disease, the familial form of the conditions.

In recent years, scientists have found increasing evidence that autoimmunity plays a role in the onset of Parkinson's disease. A recent study shows that PINK1 appears to mark some brain cells for immune cell attack. PINK1 means no harm. The protein actually helps brain cells regulate their mitochondria - the cellular structures that provide energy for a cell. The researchers found that some people with Parkinson's disease have T cells that mistakenly see PINK1 as a red flag. These T cells may target brain cells that express PINK1, contributing to inflammation and brain cell death.

The new research may help explain why Parkinson's disease is around twice as common in men versus women. The team found that men with Parkinson's disease had a 6-fold increase in PINK1-specific T cells, compared with healthy male study participants. Women with Parkinson's disease showed only a 0.7-fold increase in PINK1-specific T cells, compared with healthy female study participants. These PINK1-targeting T cells may also prove valuable as a biomarker of Parkinson's disease, allowing for earlier diagnosis in patients at-risk of developing the neurodegenerative disease.

PINK1 is not the only important T cell target. Previous research showed that many Parkinson's disease patients have T cells that target a protein called alpha-synuclein. This T cell response was linked to inflammation in the brain and the onset of Parkinson's disease. But not all Parkinson's patients show this T cell response to alpha-synuclein, so researchers expanded their hunt for additional antigens that might trigger harmful autoreactive T cell responses. The new research suggests PINK1 is one such antigen.

Link: https://www.lji.org/news-events/news/post/immune-cells-may-lead-to-more-parkinsons-cases-in-men/

A recent paper noted that the dramatic enlargement in senescent cells relative to their non-senescent counterparts isn't just a side-effect of the senescent state, but actually necessary for the inflammatory signaling that is characteristic of senescent cells. In delving into some of the mechanisms involve in this link, the researchers demonstrated that preventing enlargement also largely prevented inflammatory signaling. Since this inflammatory signaling is the mechanism by which accumulating senescent cells contribute to age-related disease, this line of research might lead to novel forms of therapy.

We should bear in mind that the activities of senescent cells are useful in the proper context, as is the case for all inflammatory signaling. Senescent cells serve to draw the attention of the immune system to potentially cancerous cells, as well as coordinate regeneration following injury. Suppress the senescent cell inflammation that contributes to aging, and those benefits are suppressed as well. It all runs through the same pathways and regulatory mechanisms. Separating desirable from undesirable activity may never be a practical concern in the context of applying small molecules or gene therapies to change cell behavior. The only alternative is to address the underlying causes that produce undesirable activation of inflammation or undesirable accumulation of senescent cells.

Following up on the question of senescent cell size, we have today's open access paper, which also describes interesting discoveries regarding specific mechanisms that link senescent cell enlargement to inflammatory signaling. The authors of today's paper are a little quick to use the word "rejuvenation", but it makes for an interesting addition to the discussion, including additional molecule targets for those who feel inclined to develop therapies based on preventing cell enlargement as a means to reduce the impact of senescent cells. For my part, I remain inclined to think that selectively destroying senescent cells via senolytic drugs remains a better option. Senolytic treatments can be intermittent, and thus less costly, and also avoid suppression of the necessary functions of senescent cells between treatments.

AP2A1 modulates cell states between senescence and rejuvenation

Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. The regulation of cell morphology and migration is closely associated with the state of stress fibers. Stress fibers are actomyosin-based bundles, which are composed mainly of actin filaments cross-linked by α-actinin and non-muscle myosin II. Stress fibers localize between separate cell adhesion sites to generate contractile force on the underlying extracellular matrix - points of anchorage.

The organization of stress fibers is known to be altered in cells undergoing senescence. While the proteome of stress fibers has only been partly investigated, our group recently revealed that those in human fibroblasts are comprised of at least 135 proteins, and 63 of them are upregulated with replicative senescence. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers.

Using human fibroblasts undergoing replicative senescence, we found that the expression level of AP2A1 modulates the extent of the senescence progression, specifically influencing the expression of senescence markers, morphological, and migratory phenotypes, and thickness and turnover of individual stress fibers. Notably, knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation. Similar functions of AP2A1 were identified not only in replicative senescence but also in UV-induced or drug-induced senescence and were found in epithelial cells as well as fibroblasts.

We also showed that AP2A1 plays a role in integrin β1 translocation along the length of stress fibers, a process enhanced in aged fibroblasts to strengthen cell adhesions. These results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.

Many studies have demonstrated that modestly increasing the generation of oxidative molecules by mitochondria slows aging. The prevailing view is that this is a form of hormesis; a slight increase in cell stress produces an overcompensating increase in the activity of cell maintenance processes. The outcome is a better function of cells and tissues than is normally the case, greater resilience to molecular damage characteristic of aging than is normally the case, and thus slowed aging. Interestingly, researchers here show that in nematode worms it is only necessary to stress the intestinal cells in this way to obtain the slowing of aging. Flies are also very centered on their intestines when it comes to aging and mortality, but it is quite unclear as whether this sort of lesson can be applied to mammals.

Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, suggesting that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan.

We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality, and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for disruption of mitochondrial superoxide dismutase to increase longevity.

Link: https://doi.org/10.1016/j.freeradbiomed.2025.01.032

While an atherosclerotic plaque initially emerges because too much cholesterol finds its way into one small portion of an artery wall, after a certain point that plaque increases in size by attracting attracting immune cells, stressing them into an inflammatory state, and ultimately killing them to add their mass to the plaque. This is not just the macrophages of the innate immune system, the cell type primarily responsible for attempting to clean up excess lipids and debris, but also T cells of the adaptive immune system. Like macrophages, T cells are attracted by the signaling associated with the inflammatory, damaged plaque environment, and promptly make the problem worse. Later still, there is a cancer-like phenomenon whereby surrounding smooth muscle cells multiply and enter the plaque, accelerating growth still further. That said, and as illustrated here, researchers are interested in trying to slow the development of plaque by reducing the attraction of immune cells to the plaque environment.

Atherosclerosis is the most common cause of life-threatening cardiovascular diseases. The disease involves chronic inflammation of the inner walls of blood vessels and within atherosclerotic plaques. For a long time, macrophages and foam cells were considered the principal agents in the formation of plaques. More recent studies, however, have focused on other immune system cells, CD8+ T cells, as it transpired that these are the immune cells most commonly found in human atherosclerotic plaques.

Scientists cultivated human atherosclerotic plaques together with CD8+ T cells from the same patient in a specially developed 3D tissue culture model. They discovered that the added CD8+ T cells were located primarily in the vicinity of newly formed blood vessels within the plaques. Further analyses using single-cell RNA sequencing and 3D microscopy revealed that the endothelial cells of these vessels express large amounts of the signaling protein CXCL12.

Following up on this discovery, the researchers investigated whether CXCL12 is involved in the recruitment of CD8+ cells by blocking the corresponding receptor (CXCR4) for this signaling protein in the T cells. "This did indeed lead to a significant reduction in CD8+ T cell migration into atherosclerosis plaques. These findings furnish new lines of approach for therapeutic strategies that could influence immune cell infiltration in atherosclerotic plaques."

Link: https://www.lmu.de/en/newsroom/news-overview/news/atherosclerosis-how-immune-cells-migrate-into-plaques.html

Late life depression is a condition perhaps not as rigorously defined as it should be in all of the places it is used, but here I'll take it to mean the onset of major depressive disorder (commonly called "depression") in old age. The biochemical causes of major depressive disorder are not well understood, as both the brain itself and the countless influences on its subtle function are very complex. Many lines of evidence point to altered, usually inflammatory immune system behavior, however. Many of the interventions assessed in clinical trials to be beneficial for patients with major depressive disorder, such as sustained programs of physical activity, are known to influence immune function. Nonetheless, it is complex, and people vary widely. An intervention that works for one person fails in another, and for reasons yet to be understood.

Given the focus on biochemical causes of major depressive disorder more generally, it shouldn't be surprising to see researchers investigating connections between age-related dysfunction of the brain and major depressive disorder. Chronic inflammation is characteristic of old age, and the brain suffers from this and many other degenerative changes. Today's open access paper takes a look at what is know of the relationships between vascular aging in the brain and late life depression. The researchers find the usual varied data, leaning in the direction of indicating that cerebrovascular disease contributes to late life depression, or both conditions can arise from shared underlying pathology.

Cerebrovascular Disease and Late-Life Depression: A Scoping Review

Cerebral small-vessel disease (CSVD) is an umbrella term encompassing chronic, progressive conditions that affect the brain's vasculature. Diverse pathological and neurological factors lead to various clinical and neuroimaging patterns in elderly patients. While depression in the elderly is not uncommon, the connection between CSVD and late-life depression (LLD) remains unclear. CSVD is significant because it is closely linked to chronic hypertension, contributing to microvascular damage and impaired cerebral perfusion. Our objective was to synthesize evidence, evaluate relevant literature to synthesize, and present information relating to the underlying pathophysiology and factors linking CSVD to depression in older adults.

Twenty papers met our criteria and were analyzed, including using statistical correlation. Of the 20 studies, 15 reported a statistically significant correlation between CVSD and LLD, whereas five of the studies found no significant correlation. In the 15 studies that reported a significant relationship between CSVD and LLD, there were a total of 15,158 participants, or an average of approximately 1,011 participants per study. The five studies that did not find a correlation included 2,222 participants, averaging about 444 participants per study. Thus, this review's overall findings are consistent with a significant relationship between CSVD and LLD.

White matter hyperintensities (WMHs), one of the findings of CSVD, were found to be a common finding in patients with CSVD and LLD. Increased WMH volume led to an increase in depressive symptoms. However, some studies highlight counterpoints, emphasizing the complexity of the relationship and the influence of non-vascular factors such as neuroinflammation, neurodegeneration, and systemic comorbidities. These findings underscore the importance of early detection of CSVD and interdisciplinary approaches to mitigate the burden of depression and cognitive decline in aging populations. Future research should focus on advanced neuroimaging, genetic profiling, and longitudinal studies to unravel the multifaceted mechanisms linking CSVD and LLD and improve clinical outcomes.

The early detection of Alzheimer's disease only makes a difference if there is something that can be done about it. Knowing that one is on track for Alzheimer's disease shouldn't make much difference to one's lifestyle choices; if every other looming dysfunction of old age has failed to convince someone to better maintain his or her health, then what is one more item to add to that list? The cost-benefit equation for anti-amyloid immunotherapies that modestly slow the decline into dementia if used in the early stages of the condition may work out for some people, but these treatments have potentially severe side-effects and are expensive. All told, it shouldn't be surprising that in the present environment there is little incentive to make use of the options on the table to detect Alzheimer's disease in its earliest stages.

Despite the potential benefits of early detection and increasing treatment options for Alzheimer's disease and related dementias, there is limited use of valuable screening and testing tools. Researchers studied responses from nearly 1,300 participants in the National Poll on Healthy Aging to understand experiences and views of cognitive screening and blood biomarker testing among adults aged 65-80. Consistent with previous research, their study found that only about 1 in 5 older Americans reported having cognitive screening in the past year.

Even with recognition of potential benefits and Medicare coverage of cognitive testing for beneficiaries, the underuse of cognitive screening persists, the researchers say. Millions of dementia cases go undiagnosed and untreated, fueled by multiple barriers to diagnosis at the patient, provider and health care system levels. "Treatments are now available to help slow the course of Alzheimer's disease, if started early enough, and there are promising clinical trials and risk reduction strategies available. So for many older adults, talking to your doctor about your cognitive health can be as important as talking to your doctor about your physical health."

Link: https://sph.umich.edu/news/2025posts/alzheimers-disease-dementias-chronically-undiagnosed-yet-early-detection-rarely-used.html

Astrocytes are supporting glial cells in the brain, and help to maintain much of the metabolism and structure of brain tissue. A sizable fraction of the brain is made up of astrocytes. In response to stress, infection, or injury astrocytes change to adopt a reactive state. Much like the inflammatory reaction of immune cells, this is helpful in the short term, but when sustained over the long term in response to the cell and tissue damage that drives aging, it contributes to the chronic inflammation and lost function of the aging brain.

Normal aging leads to a decline in homeostasis maintenance across tissues, particularly in regulation of organelle functions and response to damage. Across organ systems, key mitochondrial, proteostatic, and damage handling pathways decline during aging. In the central nervous system many of these regulatory functions are allocated to astrocytes under homeostatic conditions to enable efficient neuronal functioning. Astrocytes are key regulators of metabolism and energy generation that also sense and handle damage downstream of these and other cellular processes. Astrocytes are required for maintenance and regulation of synapse stability and neuronal activity, which become perturbed in advanced aging. Neurons also offload damaged species like dysfunctional organelles and reactive oxygen species-affected lipids to astrocytes for degradation. Understanding how astrocytes regulate these processes under homeostatic conditions and how normal functions decline during aging is crucial to our analysis of brain aging phenotypes and degeneration.

Astrocytes are perhaps best described for their roles in responding to insults, such as disease, infection/inflammation, neuronal trauma, and perturbations of organismal metabolism. In addition to the many functions performed by these cells under homeostasis, astrocytes under stress react to unique circumstances by enacting unique responses. These stress-responsive astrocytes, termed "reactive astrocytes," can lose homeostatic capabilities and/or gain additional functions such as proliferation and scar formation, neurotoxicity, or immune cell regulation, among others. The context dependent and multifaceted nature of astrocyte reactivity suggests that states of astrocytes during normal aging are likely reliant on extrinsic cues that accumulate across the lifespan. For example, aging is associated with increased inflammation and infection, as well as senescence and metabolic disease. How astrocytes synthesize these cues during aging and alter their baseline states is largely unknown.

Specific changes in aged astrocytes, both intrinsic and related to their long-term cell-cell interactions as organisms age, are poorly understood and have been difficult to interrogate with high fidelity. New and developing analytical tools such as single cell sequencing and multi-omic characterization strategies have begun to describe aged astrocytes, but more work is needed to fully understand the functional consequences of these alterations and how changes occur in different contexts and disease conditions. Improved functional characterization of aged astrocytes will likely provide insight into aging-related disease mechanisms and propose avenues to address aging brain phenotypes moving forward.

Link: https://doi.org/10.1186/s13024-025-00810-7