Fight Aging! Newsletter, March 3rd 2025
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- Partial Depletion of Microglia in the Brain Improves Cognitive Function in Aged Mice
- Reprogramming Helps Retinal Ganglion Cells Resist Inflammation-Mediated Neurodegeneration
- Enlargement is Necessary for the Harmful Signaling Generated by Senescent Cells
- Data Continues to Indicate Only a Small Role for Genetics in Life Expectancy
- Greater Ability to Recognize Human Endogenous Retrovirus K Correlates with Greater Longevity
- Reviewing What is Known of Structural Deterioration of Lymph Nodes with Aging
- The Aging of Meibomian Glands
- Contact Between Mitochondrion and Endoplasmic Reticulum in the Context of Aging
- Aging of the Gut Microbiome as a Contribution to Sarcopenia
- Hevin Overexpression in Astrocytes Slows Cognitive Decline in Alzheimer's Model Mice
- A View of Immune Cell Gene Expression Changes Characteristic of Alzheimer's Disease
- Reviewing the Present State of Cancer Vaccines
- m6A RNA Modifications in Cellular Senescence
- Regular Exercise Correlates with Decreased Dementia Risk
- Age-Associated B Cells Contribute to Autoimmune Conditions
Partial Depletion of Microglia in the Brain Improves Cognitive Function in Aged Mice
https://www.fightaging.org/archives/2025/02/partial-depletion-of-microglia-in-the-brain-improves-cognitive-function-in-aged-mice/
Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. They attack pathogens, remove damaged cells, clear up debris, and assist in some aspects of the function of neural networks. With age, microglia become more prone to inflammatory behavior. Chronic, unresolved inflammation is harmful to tissue structure and function. Some of this is a maladaptive reaction to growing levels of molecular waste present in the brain, such as protein aggregates characteristic of neurodegenerative conditions, some the result of other processes of aging operating inside microglia, such as mitochondrial dysfunction.
Inhibiting CSF1R kills microglia (and macrophages), and there is a small molecule cancer drug that can achieve this in practice, called pexidartinib or PLX-3397. Clearance of microglia requires a much lower dose than is used in cancer patients, and so the side-effect profile is much more reasonable. The population of microglia and macrophages regenerates from progenitor populations within a few weeks following clearance, and in animal studies of neurodegeneration and brain aging this treatment has been shown to reduce the number of inflammatory microglia, reduce inflammation in the brain, and otherwise improve function. In today's open access paper, researchers try a lower dose and lesser degree of clearance of microglia, and still see benefits to cognitive function in aged mice.
Partial microglial depletion through inhibition of colony-stimulating factor 1 receptor improves synaptic plasticity and cognitive performance in aged mice
Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporary ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling.
This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory synapses in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.
Reprogramming Helps Retinal Ganglion Cells Resist Inflammation-Mediated Neurodegeneration
https://www.fightaging.org/archives/2025/02/reprogramming-helps-retinal-ganglion-cells-resist-inflammation-mediated-neurodegeneration/
The eye is relatively isolated from the rest of the body. The potential scope of adverse effects resulting from treatments targeting the eye is much reduced relative to treatments that enter the body as a whole, or are targeted to one internal organ. Thus eye conditions tend to be a testbed for novel advanced forms of therapy. Further, the state of the more accessible retina is a convenient window into the state of the less accessible central nervous system, and so you'll find researchers focused on retinal cells as a way into gain insight into the mechanisms and progression of neurodegenerative conditions.
In today's open access paper, the authors discuss the effects of multiple sclerosis on the neurons of the retina and optic nerve. Multiple sclerosis is an autoimmune condition characterized by central and peripheral nervous system inflammation and loss of the myelin sheathing needed for nerves to function. The consequent damage also extends to the retina. In an animal model relevant to this pathology, the researchers demonstrate that features of cellular senescence are prevalent in retinal ganglion cells, a type of neuron in the retina. Further, exposure to Yamanaka factors to induce partial reprogramming in retinal cells can reduce this senescence and improve function.
Cellular rejuvenation protects neurons from inflammation-mediated cell death
Multiple sclerosis (MS) is an immune-mediated disease with a neurodegenerative component. While immune-mediated demyelination of axons constitutes a primary pathogenic mechanism in MS, sustained clinical deficits are associated with neuronal degeneration, including loss of neurons in the gray matter and loss of axons in white matter lesions and normal-appearing white matter. Notably, the retina and optic nerve acquire extensive pathology in MS. Optic nerve lesions are frequently detected in patients with MS by MRI. Additionally, there is significant retinal nerve fiber layer and ganglion cell layer thinning evidenced by optical coherence tomography, and this correlates with clinical deficits and brain volume loss. This is mirrored in the experimental autoimmune encephalomyelitis (EAE) mouse model, where there is optic nerve demyelination, immune cell infiltration, and gliosis, retinal nerve layer thinning, neuron loss, and axonal pathology, making the EAE mouse retina and optic nerve a useful model to study inflammation-mediated neurodegeneration.
Recent studies have explored the relationships between aging, cellular senescence, and MS. Cellular senescence is also highly correlated with aging and age-related disease. Although cellular senescence was originally defined by aberrant cell cycle exit, it is also characterized by other features, including altered autophagy, the senescence-associated secretory phenotype (SASP), accumulation of DNA damage, and epigenetic changes. Targeting aging and senescence programs in MS may be a beneficial strategy to address immune cell or glial dysfunction; however, there is limited data about the neuronal gene signature in MS and thus whether rejuvenating therapies may promote neuroprotection.
Here, we profile the transcriptome of retinal ganglion cells (RGCs) in EAE mice. Pathway analysis identifies a transcriptional signature reminiscent of aged RGCs with some senescent features, with a comparable signature present in neurons from patients with MS. This is supported by immunostaining demonstrating alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 adeno-associated virus (AAV) to rejuvenate the transcriptome enhances RGC survival in EAE and improves visual acuity. Collectively, these data reveal an aging-like phenotype in neurons under pathological neuroinflammation and support the possibility that rejuvenation therapies or senotherapeutic agents could offer a direct avenue for neuroprotection in neuroimmune disorders.
Enlargement is Necessary for the Harmful Signaling Generated by Senescent Cells
https://www.fightaging.org/archives/2025/02/enlargement-is-necessary-for-the-harmful-signaling-generated-by-senescent-cells/
Cells become senescent constantly throughout the body and throughout the life. These are largely somatic cells reaching the Hayflick limit on replication, but cells can also become senescent in response to excessive stress or damage. A senescent cell ceases to replicate and begins to secrete pro-growth, pro-inflammatory signals. Most senescent cells are destroyed by immune cells that are attracted by this signaling. It serves as a useful mechanism to draw the attention of the immune system to regions of damage and dysfunction in tissue. It helps to prevent cancer, for example, and assists in regeneration from injury.
With age, however, the immune system becomes less able to clear senescent cells. Senescent cells linger, their numbers growing. The inflammatory secretions of senescent cells become disruptive to tissue structure and function when sustained over time. This is an important mechanism of degenerative aging, and a number of companies are presently developing senolytic therapies that are intended to selectively destroy senescent cells. Animal studies show that clearing senescent cells produces some degree of rapid reversal for many aspects of aging and age-related disease.
One of the more interesting features of senescent cells is that they grow in size quite dramatically, relative to their non-senescent counterparts. Researchers have used this feature to sort circulating senescent cells for analysis. As noted by the authors of today's open access paper, this isn't just a side-effect. The growth in size is essential for the energetic signaling produced by senescent cells. Interestingly, one can find ways to sabotage this enlargement of cells on entering the senescent state, and doing so dramatically reduces the harmful senescent cell signaling.
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype
Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU.
Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.
Data Continues to Indicate Only a Small Role for Genetics in Life Expectancy
https://www.fightaging.org/archives/2025/02/data-continues-to-indicate-only-a-small-role-for-genetics-in-life-expectancy/
It is interesting to compare the level of interest in mapping genetic variations to effects on aging and life expectancy with the results of studies that use the largest databases of genetic material. The more data used, the more it becomes apparent that gene variants have very little effect on life expectancy, considered across the breadth of the population. The average person is very little different from their associates when it comes to the interaction between genotype and mortality risk. The effects of lifestyle choices far outweigh the effects of genes.
There are rare genetic variants capable of bestowing additional years of life. The small effect of genetics on life expectancy is the consequence of the fact that neither you, I, nor near the the entire population of the world is blessed with such a variant. Yet even looking at the inherited mutation with the largest known effect size on mortality risk in humans, PAI-1 loss of function, which appears to influence later life burden of cellular senescence and adds seven years of life expectancy for the very few people known to exhibit it, that is still a gain that that most people could achieve via suitable lifestyle choices. Exercise a great deal more, eat a very optimal diet, and so forth.
Lifestyle and environmental factors affect health and ageing more than our genes
Researchers used data from nearly half a million UK Biobank participants to assess the influence of 164 environmental factors and genetic risk scores for 22 major diseases on ageing, age-related diseases, and premature death. Environmental factors explained 17% of the variation in risk of death, compared to less than 2% explained by genetic predisposition (as we understand it at present). Of the 25 independent environmental factors identified, smoking, socioeconomic status, physical activity, and living conditions had the most impact on mortality and biological ageing. Early life exposures, including body weight at 10 years and maternal smoking around birth, were shown to influence ageing and risk of premature death 30-80 years later. Environmental exposures had a greater effect on diseases of the lung, heart and liver, while genetic risk dominated for dementias and breast cancer.
Integrating the environmental and genetic architectures of aging and mortality
Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify the environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors.
Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate, and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.
Greater Ability to Recognize Human Endogenous Retrovirus K Correlates with Greater Longevity
https://www.fightaging.org/archives/2025/02/greater-ability-to-recognize-human-endogenous-retrovirus-k-correlates-with-greater-longevity/
Transposable elements in the genome are capable of hijacking cellular machinery to copy themselves into new locations in the genome. Many of these sequences are clearly the remnants of ancient infections by retroviruses, degraded and disabled by millions of years of evolutionary mutational change. In other cases, the origin is less clear. An infectious retrovirus arriving from the environment copies its own genetic material into the genome in order to replicate. Alteration of the genome by retroviral infection and unfettered activation of transposable elements is both a cause of pathology and an important mechanism of evolutionary change. It has been going on for a long time: a sizable fraction of any given mammalian genome is made up of transposable elements.
Transposable elements, including the genetic remains of ancient retroviruses, are repressed in youth. These sequences are packaged away in compact DNA and hidden from transcriptional machinery. Aging brings changes to the epigenetic control of the structure of DNA, however. Transposable elements begin to be exposed, allowing replication to cause genetic damage. Perhaps worse, the engagement of the machinery of gene expression with retroviral transposable elements can produce molecules that the immune system recognizes as foreign, in some cases appearing similar to viral particles. This provokes harmful inflammation, disruptive to cell and tissue function.
It was recently noted that expression of the transposable element human endogenous retrovirus K (HERVK) increases with age and can be implicated in age-related inflammation and an increased burden of cellular senescence. This is one of many lines of evidence in support of significant harm arising from a greater activation of transposable elements in later life. Importantly, inhibiting the activity of HERKV and analogous retroviruses reduces the burden of cellular senescence and slows aging in animal models. Today's open access paper is interesting to read in this context, as the authors look at the capacity of the immune system in human study participants to recognize HERVK retroviral particles, and find that a greater capacity correlates with survival to very old age. That said, one should bear in mind that it requires only a small reduction in mortality risk for specific gene variants to appear significantly more often in older people.
Immunogenetics of longevity and its association with human endogenous retrovirus K
The human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality.
We utilized high-resolution genotyping to characterize HLA and in a large sample (N = 986) of participants ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. We determined in silico the median predicted binding affinity for each individual and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW).
The analyses yielded only one statistically significant effect - namely, a positive association between age and HERVK. Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses. Taken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.
Reviewing What is Known of Structural Deterioration of Lymph Nodes with Aging
https://www.fightaging.org/archives/2025/02/reviewing-what-is-known-of-structural-deterioration-of-lymph-nodes-with-aging/
Researchers have shown that the aging of lymph nodes prevents restoration of immune cell populations from improving the immune response. The immune system uses lymph nodes as centers of coordination, but with age these structures deteriorate and become fibrotic. Here, researchers review what is known of this structural and functional lymph node aging. At this point it is unclear as to the best approaches to restore aged lymph nodes, as fibrosis in general remains an unsolved problem. Clearing senescent cells may help, but other strategies may be needed, such as the creation and transplantation of artificial lymph nodes.
Studies have indicated that as individuals age, there is a reduction in the size of the lymph node (LN), accompanied by degenerative changes such as the development of fibrosis and lipomatosis. There is also evidence of changes in the structure of the LN endothelium, leading to decrease in immune cell recruitment. As a result, the immune cell number present in the LN diminishes. Furthermore, during ageing, the number and size (area) of germinal centres (GC) is reduced by approximately 30%-50% . This deficit results in reduced humoral immunity, leading to impaired antibody production and an increased susceptibility to infections in individuals over the age of 65. Consequently, it can be speculated that the disorganisation of the LN structure play a significant role in the ageing of the immune system.
The architecture of the LN is created and supported by LN stroma cells (LNSCs), comprising heterogeneous populations of mesenchymal cells and endothelial cells. LNSCs organise the LN into distinct compartments to support immune cell retention, activation, proliferation, and differentiation in homeostatic conditions and in response to antigenic stimulation. To support and maintain the distinct yet diverse immune cell niches within the LN, LNSCs secrete various growth factors and chemokines to ensure immune cells are correctly localised to their unique niches and receive appropriate survival signals. Thus, LNSC plays an important role in ensuring immune cell homeostasis, activation of immune responses during infection, and accordingly, any age-associated changes to LNSCs may significantly hamper the overall function of the LN as a hub for immunosurveillance.
As a matter of fact, studies performed in the recent years have begun to shed light how age-associated changes to LNSCs impairs the generation of protective immunity against infection and after vaccination. The observation that the older adults are not able to generate effective long-term protective immunity after vaccination highlights the necessity to comprehend how underlying age-associated changes to LNSC precipitates into impaired immune responses, and further research may potentiate development of therapeutic strategies that could enhance immune responses by targeting the aged LNSCs.
The Aging of Meibomian Glands
https://www.fightaging.org/archives/2025/02/the-aging-of-meibomian-glands/
The age-related failure of the glands around the eye to generate the right mix of compounds to form tears is not given a great deal of thought by most people, at least until it happens to them. Dry eye syndrome is unpleasant to experience, but in world in which cardiovascular disease and cancer exist, the causes of the age-related onset of dry eye syndrome are perhaps not as well studied as they might be. Resources are directed to more severe issues.
Researchers here note age-related changes in a stem cell population that supports one of the glands around the eye. Stem cell populations in general decline in function with age, and much of this appears to be an inappropriate reaction to the aged environment. Evidence accumulated in the study of muscle stem cells and hematopoietic stem cells suggests that aged tissue maintenance could be improved by forcing stem cells back to work, but the specific approaches needed are likely to vary widely from tissue to tissue.
Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined.
Using single cell RNA sequencing, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
Contact Between Mitochondrion and Endoplasmic Reticulum in the Context of Aging
https://www.fightaging.org/archives/2025/02/contact-between-mitochondrion-and-endoplasmic-reticulum-in-the-context-of-aging/
Mitochondria are the power plants of the cell, generating chemical energy store molecules to power cellular operations. The endoplasmic reticulum is a structure studded with ribosomes for protein assembly, and where protein folding and transport within the cell takes place. Nothing in the cell has only one function, however, and both of these structures influence many cell processes. Researchers here discuss what is known of the direct interactions that take place between mitochondrion and endoplasmic reticulum, and the possible relevance of this still largely unexplored activity to aging and disease.
For decades, scientists viewed the various compartments within cells, called organelles, as relatively independent entities. This perspective, while useful for understanding basic cellular structure, has proven to be an oversimplification of the complex and dynamic nature of cellular organization. Recent research has revealed a far more interconnected and fluid cellular landscape, where organelles interact and communicate in sophisticated ways.
At the heart of this paradigm shift is the discovery of specialized regions where two critical organelles - mitochondria and the endoplasmic reticulum (ER) - are in close apposition. These regions, known as mitochondria-associated ER membranes (MAMs), are revolutionizing our understanding of cellular function and disease. MAMs act as cellular 'communication hubs', allowing for rapid and precise exchange of signals and molecules between mitochondria and the ER. This communication is crucial for maintaining cellular health, responding to stress and regulating energy production. The strategic positioning of MAMs allows for efficient transfer of molecules and signals, facilitating precise control of cellular functions.
Alterations in MAM structure and function have been implicated in a wide range of conditions, including neurodegenerative diseases, metabolic disorders, and cardiovascular disease. Disruption of MAMs impairs the structural and functional connectivity between the ER and mitochondria, leading to significant cellular dysfunction. For instance, studies have shown that high glucose levels can disrupt MAM integrity through the pentose phosphate pathway, resulting in mitochondrial fragmentation and altered respiration. While some age-related changes in MAMs have been observed, such as alterations in calcium signalling and mitochondrial function, the full impact of these changes on cellular function and organismal health remains an open question. Understanding how MAMs change throughout the lifespan could provide insights into the ageing process and potentially lead to interventions to promote healthy ageing.
Aging of the Gut Microbiome as a Contribution to Sarcopenia
https://www.fightaging.org/archives/2025/02/aging-of-the-gut-microbiome-as-a-contribution-to-sarcopenia/
Here find a review of what is known of relationships between the aging of the gut microbiome and aging of skeletal muscle. With age, everyone loses muscle mass and strength, leading eventually to sarcopenia and frailty. A perhaps surprisingly large fraction of this is a consequence of too little physical activity, as judged when comparing hunter-gatherer populations with the much more sedentary developed world. Other mechanisms of aging are important, however. The gut microbiome changes in composition with age, and this both increases chronic inflammation and reduces the supply of beneficial metabolites to tissues in the body. It remains to be seen as to how large this effect is versus others, but it is at least a contribution that can be addressed more readily than most.
Sarcopenia is a skeletal muscle disorder, with primary sarcopenia defined as an age-related progressive loss of skeletal muscle mass, strength, and physical function. This condition is notably prevalent, ranging from 10% to 27% in individuals aged 60 years and older. At present, it is known that primary sarcopenia is multifactorial and not limited to age-related lifestyle changes (e.g., physical inactivity and low-protein diet), inflammation, and insulin resistance. These factors contribute to alterations in muscle protein turnover as well as the development and progression of sarcopenia. However, the extent of other factors that may contribute to sarcopenia development is not fully understood, and the precise underlying mechanisms of sarcopenia remain elusive.
The gut microbiota, consisting of over 100 trillion bacterial cells, plays a vital role in human metabolic and immunological health. The gut microbiota can produce a wide range of bioactive compounds, mainly including short-chain fatty acids (SCFAs), secondary bile acids, branched-chain amino acids, and many others, to impact host physiology and health via different host-microbe metabolic pathways. Once in the bloodstream, SCFAs exhibit epigenetic and immunomodulatory effects on various organs, contributing to the development of a range of human diseases, including primary sarcopenia.
Gut dysbiosis, an imbalanced gut microbiota resulting from compositional changes, has been associated with aging as well as various age-related health conditions and diseases, including sarcopenia. Gut dysbiosis and sarcopenia commonly occur in older individuals. Convincing evidence from animal and human studies has linked gut dysbiosis to sarcopenia, with a recent study suggesting a causal relationship. While the factors influencing human gut microbiomes are complex throughout the lifespan, age itself has been shown to adversely affect the diversity of gut microbiomes and their beneficial metabolites. This impact may contribute to age-related diseases, including sarcopenia.
Studies have demonstrated that Bifidobacterium and Lactobacillus supplements enhance muscle mass and strength in aged mice, and similar benefits have been observed with a prebiotic formulation in elderly individuals. However, it remains unclear whether there is a direct impact of gut microbiota on muscle mass, function, and the development of sarcopenia. It is also challenging to pinpoint the specific gut microbiomes and their metabolites that are beneficial to muscle health and could serve as therapeutic targets. Additionally, it is still elusive how the gut microbiome and its metabolites regulate the gut-muscle axis, a topic of ongoing investigation. Further research is needed to fully understand the mechanisms and to explore potential therapeutic interventions targeting the gut microbiota to prevent or treat sarcopenia, thus promoting healthy aging.
Hevin Overexpression in Astrocytes Slows Cognitive Decline in Alzheimer's Model Mice
https://www.fightaging.org/archives/2025/02/hevin-overexpression-in-astrocytes-slows-cognitive-decline-in-alzheimers-model-mice/
Hevin is a circulating signal molecule that appears to be involved in the regulation of connectivity between neurons in the brain, inducing the formation of synapses. To the degree that this increases neuroplasticity, one would expect it to help resist the harmful effects of Alzheimer's disease pathology. It does this not by reducing the ongoing damage to neurons and their connections, but by allowing the brain to better adapt to or recover from that damage. This sort of approach is a losing game in the long term, as pathology will grow to outpace attempts to compensate, but it is better than nothing.
Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. Hevin has been reported to induce the development of structurally formed but functionally silent synapses. Importantly, Hevin has been pointed out as a candidate factor that reverts age-associated cognitive decline following administration of blood from young to aged animals.
By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of amyloid-β plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance that follows astrocytic Hevin overexpression.
A View of Immune Cell Gene Expression Changes Characteristic of Alzheimer's Disease
https://www.fightaging.org/archives/2025/02/a-view-of-immune-cell-gene-expression-changes-characteristic-of-alzheimers-disease/
Researchers here assess the transcriptomes of immune cells in blood samples taken from hundreds of older patients with and without Alzheimer's disease. It is a good illustration of the capabilities and limitations of these studies. One can obtain interesting insights into what is going on in the immune system, but meaningfully connecting these insights to disease processes and the development of therapies is challenging. For example, pointing to changes in ribosomal function is all well and good, but the ribosome, where messenger RNA is used as a blueprint to produce proteins, is such a fundamental part of the cell that its activity influences everything else. It is following a trail into a swamp, there is no good way forward towards specific answers.
The prevalence of Alzheimer's disease (AD) is increasing as society ages. The details of AD pathogenesis have not been fully elucidated, and a comprehensive gene expression analysis of the process leading up to the onset of AD would be helpful for understanding the mechanism. We performed an RNA sequencing analysis on a cohort of 1227 Japanese blood samples, representing 424 AD patients, 543 individuals with mild cognitive impairment (MCI), and 260 cognitively normal (CN) individuals. A total of 883 and 1169 statistically significant differentially expressed genes (DEGs) were identified between CN and MCI (CN-MCI) and between MCI and AD (MCI-AD), respectively.
Pathway analyses using these DEGs, followed by protein-protein interaction network analysis, revealed key roles of ribosomal function in MCI progression, whereas immune responses, cell cycle, and protein processing in endoplasmic reticulum were involved in AD progression. Our findings indicate that the onset of AD might be associated with gene expression changes in the immune system, cell cycle, and protein processing following alterations in the expression of ribosomal protein genes during the MCI stage, although validation using brain tissue samples will be necessary in the future. Given the known effectiveness of delaying MCI progression in preventing AD, the genes related to ribosomal function might emerge as biomarkers for early diagnosis.
Reviewing the Present State of Cancer Vaccines
https://www.fightaging.org/archives/2025/02/reviewing-the-present-state-of-cancer-vaccines/
Cancer vaccines are an area of active development, but have yet to succeed in obtaining clinical approval. The principle is much the same as any vaccine: deliver a suitably designed molecule or combination of molecules that will provoke the immune system into recognizing a distinctive feature of the target cell, pathogen, or other structure as a candidate for attack and destruction. Unfortunately tumor cells employ a wide range of mechanisms to suppress, co-opt, and subvert the activities of immune cells, and so it may well be the case that cancer vaccines will remain poorly effective without the addition of means to block these mechanisms.
Despite advancements in traditional cancer treatments such as surgery, chemotherapy, and radiotherapy, many cancers remain difficult to cure, particularly in advanced stages where treatment options are limited. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), and cancer vaccines have emerged as promising approaches to leverage the host immune system against malignancies. While ICIs and ACT have shown efficacy in specific patient populations, their success remains limited, with only a subset of patients achieving sustained responses. Cancer vaccines, however, offer a unique advantage by priming new T cells, potentially targeting a broader array of tumor antigens and inducing more durable immune responses.
Cancer vaccines deliver target antigens, often in combination with adjuvants, to evoke or amplify the host immune system, especially T-cell immunity, to recognize and eliminate malignant cells. They are broadly categorized into two types: therapeutic and prophylactic cancer vaccines. Therapeutic cancer vaccines are post-exposure treatments that induce potent cellular immune responses to eliminate existing cancer cells and establish long-lasting immune memory to prevent recurrence. In contrast, prophylactic cancer vaccines are designed to stimulate the immune system in tumor-free individuals, generating antibodies and immune memory cells that reduce the risk of cancer development.
Numerous cancer vaccines have progressed to clinical evaluation, demonstrating the ability to elicit strong immune responses. However, despite some early successes, the majority have not achieved durable responses or significant clinical efficacy in large phase III trials, presenting both opportunities and challenges for future development. Decades of research have greatly deepened our understanding of cancer vaccines, and the design of an optimal vaccine remains a delicate process. This process requires careful consideration of antigen selection, adjuvant incorporation, administration methods, combination with other therapies, and identification of the appropriate patient population.
m6A RNA Modifications in Cellular Senescence
https://www.fightaging.org/archives/2025/02/m6a-rna-modifications-in-cellular-senescence/
In the years since the first demonstration that clearance of senescent cells produces rejuvenation in old mice, and the first programs to develop senolytic drugs that can selectively destroy senescent cells, ever more research has been directed into better understanding the distinctive biochemistry of senescent cells. Any novel feature could turn out to be the basis for a better senolytic drug, or a way to suppress the inflammatory signaling of senescent cells. Here, for example, researchers focus on the relevance of one specific aspect of RNA processing in cells that appears relevant to senescence.
m6A (N6-methyladenosine) RNA modification has emerged as a key regulator of cellular processes, including senescence. m6A is the most prevalent internal modification in eukaryotic mRNA and is dynamically regulated by "writers" (methyltransferases, such as METTL3 and METTL14), "erasers" (demethylases, such as FTO and ALKBH5), and "readers" (m6A-binding proteins, such as YTHDF1 and YTHDC1). By modulating RNA stability, splicing, translation, and decay, m6A modifications influence a wide array of biological functions, including cell proliferation, differentiation, and stress responses. Recent studies have highlighted the role of m6A in regulating the pathways associated with cellular senescence, including p53, NF-κB, and senescence-associated secretory phenotype (SASP) components. However, the intricate interplay between m6A modifications and senescence remains incompletely understood, warranting further exploration.
While targeting m6A modifications holds great potential for senescence therapy, several limitations and challenges must be addressed before its clinical translation. First, the dynamic and reversible nature of m6A modifications, mediated by "writers" (methyltransferases), "erasers" (demethylases), and "readers" (binding proteins), adds significant complexity to their regulation. Targeting these components may lead to off-target effects due to the widespread role of m6A in various cellular processes beyond senescence, such as stem cell maintenance, immune responses, and tumor progression. This non-specificity could result in unintended disruptions to normal physiological functions. Furthermore, the heterogeneity in senescence mechanisms across cell types and tissues complicates the development of universal m6A-targeted therapies. A therapy effective in one cellular context may exhibit limited efficacy or even adverse effects in another.
Finally, the detection and quantification of m6A modifications remain challenging due to the lack of standardized and highly sensitive tools. Current techniques, such as m6A-seq, provide valuable insights but have limitations in resolution and scalability. Without precise detection methods, identifying specific m6A targets for therapeutic intervention is difficult, which hinders progress in the field. Developing small molecules or RNA-based therapeutics targeting m6A modulators poses challenges related to specificity and toxicity. Ensuring efficient delivery to senescent cells while avoiding off-target effects in non-senescent cells remains a major hurdle. Advanced delivery systems, such as nanoparticle-based or cell-specific delivery platforms, are needed but require further optimization for clinical use. Overcoming these limitations requires a multidisciplinary approach, integrating advances in molecular biology, bioinformatics, drug delivery systems, and clinical research. Continued efforts to refine m6A-targeted strategies and deepen our understanding of m6A's role in senescence will pave the way for safer and more effective therapies.
Regular Exercise Correlates with Decreased Dementia Risk
https://www.fightaging.org/archives/2025/02/regular-exercise-correlates-with-decreased-dementia-risk/
Studies of correlations between physical activity and long term health tend to show a large difference in outcomes between people who are sedentary versus people who exercise even a little; it is a big step up to go from no exercise to a little exercise. The dose response curve for physical activity as an intervention starts out quite steep, and then further activity even beyond the present recommendations of 150 minutes per week continues to add benefits in terms of reduced mortality and reduced risk of age-related disease.
Dementia, usually from Alzheimer's disease, is one of the most common conditions of old age. It is estimated to affect about seven million people in the U.S., including about a third of those who are 85 years or older. Although the risk of dementia rises with age, studies in recent years have suggested that dementia is somewhat preventable, within a normal lifespan, by lifestyle changes that include better control of cholesterol, blood pressure, and blood sugar, and being more active.
Researchers analyzed data on British adults generated as part of the UK Biobank project, a long-running, ongoing study of approximately 500,000 individuals. The dataset for the new study covered 89,667 adults, mostly in their 50s and older, who used wrist-worn accelerometers to track their physical activity for a week during the period from February 2013 to December 2015. Follow-up of their health status extended for an average of 4.4 years, through November 2021, during which 735 of the participants were diagnosed with dementia.
The analysis compared individuals whose trackers showed some weekly moderate to vigorous physical activity to those whose trackers showed none and accounted for age and other medical conditions. The associations between higher activity and lower dementia risk were striking. Participants in the lowest activity category, ranging from one to 34.9 minutes per week, had an apparent risk reduction of about 41% versus sedentary individuals. When the researchers took into account participants who met their definitions of frailty or pre-frailty, they found that the association between more activity and less dementia was essentially unchanged. Dementia risk decreased further with higher amounts of physical activity. Dementia risks were 60% lower in participants in the 35 to 69.9 minutes of physical activity/week category; 63% lower in the 70 to 139.9 minutes/week category; and 69% lower in the 140 and over minutes/week category.
Age-Associated B Cells Contribute to Autoimmune Conditions
https://www.fightaging.org/archives/2025/02/age-associated-b-cells-contribute-to-autoimmune-conditions/
Age-associated B cells are a distinct population of B cells that grows in number with age. Evidence suggests that these cells are meaningfully dysfunctional and contribute to immune aging, including an impaired immune response and the chronic inflammation characteristic of later life. As researchers note here, there is plenty of evidence for age-associated B cells to contribute to autoimmune conditions as well. Temporary clearance of B cells is possible and has been demonstrated in animal models. The B cell population regenerates rapidly afterwards, but lacking the age-associated B cells that were present beforehand. This approach to therapy should be developed for widespread use.
As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c.
Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis.
Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.