Fight Aging! Newsletter, March 10th 2025
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- A Relationship Between Cerebrovascular Disease and Late Life Depression
- AP2A1 is Important in the Enlargement (and thus Inflammatory Signaling) of Senescent Cells
- Results from a Small Trial of Dasatinib and Quercetin in Patients with Mild Cognitive Impairment
- Reviewing Progress in the Adaptation of CAR-T Therapies to Solid Cancers
- Heat Stress from Hot Weather Produces Accelerated Epigenetic Aging
- The Contribution of Aging Astrocytes to Brain Inflammation and Disease
- The Underdiagnosis of Early Alzheimer's Disease
- An Approach to Reduce T Cell Infiltration into Atherosclerotic Plaques
- Reduced Expression of Superoxide Dismutase in Intestinal Tissue Extends Life in Nematode Worms
- T Cells Targeting PINK1 May Explain the Greater Incidence of Parkinson's in Men
- Effects of Exercise and Sedentary Behavior on Aging Clocks
- Cell Therapy Plus Surgery as a Treatment for Wet Macular Degeneration
- Restoration of the Glycocalyx Layer of the Aged Blood-Brain Barrier Improves Function
- One of the Six Isoforms of Tau Protein is Responsible for the Harms Done to Neurons
- EDA2R is Upregulated with Aging and Promotes Inflammatory Signaling
A Relationship Between Cerebrovascular Disease and Late Life Depression
https://www.fightaging.org/archives/2025/03/a-relationship-between-cerebrovascular-disease-and-late-life-depression/
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.
AP2A1 is Important in the Enlargement (and thus Inflammatory Signaling) of Senescent Cells
https://www.fightaging.org/archives/2025/03/ap2a1-is-important-in-the-enlargement-and-thus-inflammatory-signaling-of-senescent-cells/
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.
Results from a Small Trial of Dasatinib and Quercetin in Patients with Mild Cognitive Impairment
https://www.fightaging.org/archives/2025/03/results-from-a-small-trial-of-dasatinib-and-quercetin-in-patients-with-mild-cognitive-impairment/
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 a 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.
Reviewing Progress in the Adaptation of CAR-T Therapies to Solid Cancers
https://www.fightaging.org/archives/2025/03/reviewing-progress-in-the-adaptation-of-car-t-therapies-to-solid-cancers/
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.
Heat Stress from Hot Weather Produces Accelerated Epigenetic Aging
https://www.fightaging.org/archives/2025/03/heat-stress-from-hot-weather-produces-accelerated-epigenetic-aging/
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.
The Contribution of Aging Astrocytes to Brain Inflammation and Disease
https://www.fightaging.org/archives/2025/03/the-contribution-of-aging-astrocytes-to-brain-inflammation-and-disease/
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.
The Underdiagnosis of Early Alzheimer's Disease
https://www.fightaging.org/archives/2025/03/the-underdiagnosis-of-early-alzheimers-disease/
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."
An Approach to Reduce T Cell Infiltration into Atherosclerotic Plaques
https://www.fightaging.org/archives/2025/03/an-approach-to-reduce-t-cell-infiltration-into-atherosclerotic-plaques/
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."
Reduced Expression of Superoxide Dismutase in Intestinal Tissue Extends Life in Nematode Worms
https://www.fightaging.org/archives/2025/03/reduced-expression-of-superoxide-dismutase-in-intestinal-tissue-extends-life-in-nematode-worms/
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.
T Cells Targeting PINK1 May Explain the Greater Incidence of Parkinson's in Men
https://www.fightaging.org/archives/2025/03/t-cells-targeting-pink1-may-explain-the-greater-incidence-of-parkinsons-in-men/
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.
Effects of Exercise and Sedentary Behavior on Aging Clocks
https://www.fightaging.org/archives/2025/03/effects-of-exercise-and-sedentary-behavior-on-aging-clocks/
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.
Cell Therapy Plus Surgery as a Treatment for Wet Macular Degeneration
https://www.fightaging.org/archives/2025/03/cell-therapy-plus-surgery-as-a-treatment-for-wet-macular-degeneration/
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.
Restoration of the Glycocalyx Layer of the Aged Blood-Brain Barrier Improves Function
https://www.fightaging.org/archives/2025/03/restoration-of-the-glycocalyx-layer-of-the-aged-blood-brain-barrier-improves-function/
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.
One of the Six Isoforms of Tau Protein is Responsible for the Harms Done to Neurons
https://www.fightaging.org/archives/2025/03/one-of-the-six-isoforms-of-tau-protein-is-responsible-for-the-harms-done-to-neurons/
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.
EDA2R is Upregulated with Aging and Promotes Inflammatory Signaling
https://www.fightaging.org/archives/2025/03/eda2r-is-upregulated-with-aging-and-promotes-inflammatory-signaling/
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.