Fight Aging! Newsletter, May 27th 2024

Fight Aging! Newsletter, May 27th 2024

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
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Tracing Contributions to Neuroinflammation Back to the Bone Marrow

In today’s open access paper, researchers discuss the role of bone marrow aging in the chronic inflammation observed in the aging brain. This inflammation is clearly of great importance in the onset and development of neurodegenerative conditions such as Alzheimer’s disease; it is disruptive to the function of the brain. The immune system of the body originates in the hematopoietic cell populations of bone marrow, where cells of the innate immune system are created, as well as the thymocyte precursors to adaptive immune cells. With age, the production of immune cells becomes biased towards innate immune cells (myeloid cell lineages) over adaptive immune cells (lymphoid lineage), but this is far from the only change that takes place.

The immune system of the brain is distinct from that of the body, and originates from different progenitor populations established during early development. Microglia of the central nervous system, for example, are analogous to the macrophages found in the rest of the body, but are thought to originate in the yolk sac during embryonic growth. Still, the immune system of the brain is influenced by that of the body, both by the passage of inflammatory signal molecules, and by the transport of some small number of immune cells into the brain. This transfer appears to increase with age, either due to dysfunction of the blood-brain barrier, or as an adaptive process in response to some aspect of aging. Regardless, while the immune system of the brain is distinct, it is far from isolated from the state of the body, and is thus affected by aspects of aging taking place in the bone marrow.

Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation

Aging is a complex process characterized by a myriad of physiological changes, including alterations in the immune system termed immunosenescence. It exerts profound effects on both the bone marrow and the central nervous system, with significant implications for immunosenescence in neurological contexts. Our mini-review explores the complex relationship between bone marrow aging and its impact on immunosenescence, specifically within the context of neurological diseases.


The bone marrow serves as a crucial hub for hematopoiesis and immune cell production, yet with age, it undergoes significant alterations, including alterations in hematopoietic stem cell function, niche composition, and inflammatory signaling. These age-related shifts in the bone marrow microenvironment contribute to dysregulation of immune cell homeostasis and function, impacting neuroinflammatory processes and neuronal health.


In our review, we aim to explore the complex cellular and molecular mechanisms that link bone marrow aging to immunosenescence, inflammaging, and neuroinflammation, with a specific focus on their relevance to the pathophysiology of age-related neurological disorders. By exploring this interplay, we strive to provide a comprehensive understanding of how bone marrow aging impacts immune function and contributes to the progression of neurological diseases in aging individuals. Ultimately, this knowledge can hold substantial promise for the development of innovative therapeutic interventions aimed at preserving immune function and mitigating the progression of neurological disorders in the elderly population.


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Investigating the Mechanisms by which the Aged Gut Microbiome Provokes Chronic Inflammation

In recent years, it has become clear that the gut microbiome contributes meaningfully to long-term health, perhaps to much the same degree as exercise, diet, and other common lifestyle choices. Unlike those choices, the composition of the gut microbiome is more inscrutable, however. While commercial services employing 16S rRNA sequencing can cost-effectively list the microbial species present in the intestines, and their relative proportions, it remains a work in progress to (a) reliably connect differences in the list to pathologies of aging, and (b) reliably alter the gut microbiome in deterministic and lasting ways.

Which is not to say that we know nothing! It is clear that the relative proportions of the microbial species making up the gut microbiome change with age, and some of those changes provoke chronic inflammation. Pro-inflammatory microbes grow in number at the expense of microbial species responsible for producing beneficial metabolites such as butyrate. It is also clear that fecal microbiota transplantation from a young individual produces a lasting reset of the gut microbiome, and consequent improvements in health, even if the full details of what matter in that reset have yet to be determined.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin.


Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge, with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-antibiotic cessation.


Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.


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Exercise Improves Neurogenesis via Restoration of Microglia to a More Youthful Phenotype

Exercise is known to improve cognitive function and neurogenesis, the process by which new neurons are created by neural stem cells and then mature to integrate into existing neural networks. Neurogenesis is best studied in the hippocampus, where it is necessary for learning and memory function to take place. It is also likely important in the very limited ability of the central nervous system to recover from injury and in general maintenance of brain tissue over time.

In today’s open access paper, researchers demonstrate that exercise reverses age-related changes in the gene expression and behavior of microglia, innate immune cells of the brain that are analogous to macrophages elsewhere in the body. They also show that microglia are necessary for the benefits of exercise to emerge. Microglia assist neurons in altering and maintaining synaptic connections in the brain, and this is one way in which the aging of microglia might be detrimental to cognitive function.

Microglia also become more inflammatory with age, however, and chronic inflammation tends to change cell behavior for the worse in all tissues. In this context, it is worth noting that exercise is known to dampen inflammation, among its many other benefits. The study here says little about the signaling mechanisms by which exercise might induce a temporary rejuvenation in microglia, however.

Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain

Exercise may be useful for preventing (or reversing) age-related hippocampal deterioration and maintaining neuronal health. However, the mechanisms underlying the beneficial effects of exercise on the ageing brain remain poorly defined. We provide here a comprehensive single cell RNA-seq dataset and unbiased analyses characterising the effects of both natural ageing and exercise on cell types within the female mouse hippocampus. We show that ageing alters the relative abundance and transcriptional phenotypes of different cell types in the hippocampus.


We further demonstrate that exercise profoundly and specifically impacts the transcriptional state of microglia, reverting the gene expression signature of aged microglia towards that observed in young animals. In particular, the transcriptional profile of disease-associated microglia was markedly rejuvenated by exercise. We went on to demonstrate that microglia are required for the pro-neurogenic effects of exercise in the aged hippocampus. Importantly, however, global depletion of microglia did not affect the cognitive benefits conferred by exercise in our experimental paradigm.


Prior analyses of microglia have indicated that ageing is associated with increased expression of inflammatory factors. Here, we identified similar microglial differentially expressed genes in association with ageing, including type II interferon and immune genes Ccl2, Ccl3, Ccl4, Ccl5, Ccl7, and Ccl8. We also identified pathways enriched in aged microglia, including those regulating the TYROBP causal network, chemokine signalling, and type II interferon signalling. Strikingly, the number of microglial differentially expressed genes identified between young sedentary mice and aged exercising mice was small, reflecting their transcriptional similarity and hence the restorative impact of exercise on the microglial phenotype. Indeed, our linear regression analyses revealed that exercise had a profound and specific effect on the transcriptional signature of aged microglia, reverting their gene expression profile back towards that seen in young microglia.


Recent work from our group highlighted that microglial phenotypes can profoundly influence hippocampal neurogenesis in the injured brain. The process of adult neurogenesis itself is otherwise also well known to be regulated and/or influenced by exercise. We previously demonstrated that exercise supports both the activity and survival of neural precursors, and that microglia may play a role therein. With our unbiased single-cell transcriptomics analyses identifying microglia as the cells mostly modulated by exercise, we probed the in vivo significance of this phenomenon in relation to hippocampal neurogenesis. Here, our depletion experiments showed that the loss of microglia annulled any stimulatory effects of exercise on hippocampal neurogenesis. As technological advances progress, future studies could explore more specifically what microglial subset (or state) inhibits adult neurogenesis and/or drives the pro-neurogenic effects of exercise.


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A Brief Tour of the Development of Senolytic Therapies to Clear Senescent Cells

Senescent cells accumulate with age as the immune system falters in its ability to clear these cells in a timely fashion. Senolytic therapies selectively destroy some fraction of senescent cells, and first generation senolytic drugs have been demonstrated to rapidly and impressively reverse age-related disease and extend life in mice. The best of these first generation drugs are repurposed cancer therapeutics such as dasatinib and navitoclax, with the jury still out on whether plant extracts like fisetin can be competitive on their own rather than in combination with the chemotherapeutics.

The second generation senolytics presently under development aim to be more selective, have fewer side-effects, require lower or more infrequent doses, or be able to target a greater range of senescent cell types. It is becoming clear that senescence is a varied collection of states, and first generation senolytics are only effective in destroying senescent cells for some of those states, and in some tissues. With this in mind, today’s popular science article takes a look at some of the companies and research groups working on a broad range of second generation senolytic treatments. There are promising programs under development; we might expect a much more diverse range of options to exist for patients and self-experimenters a decade from now than is presently the case.

Researchers are using new molecules, engineered immune cells and gene therapy to kill senescent cells and treat age-related diseases

Lurking throughout your body, from your liver to your brain, are zombie-like entities known as senescent cells. They no longer divide or function as they once did, yet they resist death and spew out a noxious brew of biological signals that can slow cognition, increase frailty and weaken the immune system. Worst of all, their numbers increase as you age. For more than a decade, researchers have been trying to see whether they can selectively destroy these cells with a variety of drugs. In a pivotal study published in 2015, a team discovered that a combination of two compounds, called dasatinib and quercetin, killed senescent cells in aged mice. The treatment made the mice less frail, rejuvenated their hearts and boosted their running endurance. The finding opened the door to a new area of medicine called senolytics.


Now, fresh results from animal studies and human clinical trials have added momentum to the field. In mice and monkeys, researchers are using genetic tools to reprogram and kill senescent cells. Others are engineering senolytic immune cells. And about 20 clinical trials are ongoing. Researchers are testing new and repurposed drugs that could have senolytic properties, in the hope of combating age-related conditions, including Alzheimer’s disease, pulmonary fibrosis, and chronic kidney disease.


One key strategy in senolytics involves designing drugs that stop senescent cells from resisting apoptosis. Usually, the cells survive by producing anti-death proteins. Blocking these with drugs can force the cells to succumb to death. Unity Biotechnology is at the forefront of this approach. In a recent study, researchers found that senescent cells were more abundant in the retinas of diabetic mice than in those of healthy mice. It was possible, the team predicted, that senescent cells in the blood vessels of the eye play a part in diabetes-related vision loss. The researchers designed a drug, called foselutoclax, which blocks the action of BCL-xL, a key anti-death protein that is abundant in senescent cells. When they injected the drug into the eyes of diabetic mice, it killed senescent cells in the blood vessels supplying the retina, but not healthy cells.


Rather than making senolytics from scratch, some scientists are testing drugs that already exist. In a 2019 study, researchers used dasatinib and quercetin to remove senescent brain cells in a mouse model of Alzheimer’s disease. Mice treated with the senolytics had reduced brain inflammation and improved memory compared with animals that were given a placebo. Spurred on by these promising data from mice, researchers last year conducted the first safety trial of the drug combination in people with early stage Alzheimer’s disease. The team gave five people dasatinib and quercetin intermittently for three months. The researchers found that the drugs were safe and that dasatinib was present in samples of cerebrospinal fluid, suggesting it could cross into the brain. Quercetin was not detected in brain fluid samples, but researchers suspect that it did reach the brain and was rapidly broken down. The team is now conducting a larger trial to track the cognition of people with and without Alzheimer’s disease for nine months after they take a placebo or the drug combination. The results should be released in 2025.


When it comes to killing cells in the body, the immune system could be of help. And some researchers have latched on to the idea of using genetically engineered immune cells called chimeric antigen receptor (CAR) T cells. These can target and kill specific cells on the basis of the molecules they display on their surface. Researchers found that old mice treated with the CAR T cells selective for a marker of senescence had reduced blood-sugar levels – a sign of improved metabolic health – and that the animals ran faster and for longer. But CAR-T-cell therapies are expensive to make. Deciduous Therapeutics is also developing a more affordable approach that harnesses a different kind of immune cell called a natural killer T cell. In 2021, researchers at Deciduous Therapeutics demonstrated the senolytic role of these cells, which naturally become less effective with age. They also found that drugs that can activate the immune cells helped to eliminate senescent cells in the damaged lungs of mice, reducing lung scarring and improving survival. Safety tests will be conducted in dogs and non-human primates later this year, and clinical trials should begin in the next two years.


Other teams such as Oisin Biotechnologies are using gene therapy to kill senescent cells. In this approach, researchers package a gene that encodes a lethal protein called caspase-9 into fatty capsules studded with proteins derived from a virus. In mice and monkeys, the capsules have been found to deliver the gene to cells in the lungs, heart, liver, spleen and kidneys. Healthy cells are spared, because the gene is activated only in senescent cells that have high levels of one of two proteins called p16 and p53. The researchers found that, over four months, a monthly dose of the therapy reduced frailty and cancer rates in old mice without causing harmful side effects.


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FOXF1 Gene Therapy Improves Regeneration of Intervertebral Discs Following Injury

Intervertebral disc degeneration is a feature of aging, and injury can produce further challenges. A range of approaches have been assessed to enhance the regenerative capacity of disc tissue, useful not just after injury, but also to reverse some of the declines in disc structure and function produced by aging. Stem cell therapies have been attempted, and are widely available via medical tourism, but unfortunately that diverse population of patients contributes next to no publicly available data to help researchers understand whether or not this is a viable approach, and how to improve on it. First generation stem cell therapies are gradually being replaced by exosome therapies, as these are logistically easier to manage. Exosomes can be harvested and stored, it is easier to produce consistent batches from one central location for manufacture, and the benefits of stem cell therapies are in any case mediated by the signaling produced by these cells, largely carried in extracellular vesicles such as exosomes.

Thus in today’s open access paper, we see an example of researchers building on the exosome therapy approach rather than the cell therapy approach. Beyond the logistics, another advantage of exosomes is that they can be readily engineered to carry additional cargo into cells. In this case, researchers are delivery a DNA plasmid to express FOXF1. The usual challenge with DNA plasmids is that they express poorly, as passage into the cell nucleus and access to transcriptional machinery that can read the plasmid only efficiently occurs during cell division. The researchers used an injury model in mice, so there will tend to be more cellular replication in this circumstance as regeneration takes place. In any case, the researchers observed improvements in the treated mice versus controls. We are likely to see a range of similar approaches based on the use of extracellular vesicles as a gene therapy vector emerge in the years ahead.

Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain

Painful musculoskeletal disorders such as chronic low back pain (LBP) are leading causes of disability worldwide and their prevalence and societal impact continues to rise with expansion of the aging population and growing opioid crisis. Intervertebral disc (IVD) degeneration is a major cause of LBP, often referred to as discogenic back pain (DBP), with epidemiological studies estimating that approximately 40% of cases are attributed to IVD degeneration. The IVD functions as an avascular and aneural joint, sandwiched between adjacent vertebral bodies of the spinal column. It is comprised of a gelatinous proteoglycan-rich nucleus pulposus (NP) core encapsulated by rings of collagen that form the annulus fibrosus (AF). In degeneration, mechanical imbalances, loss of critical extracellular matrix (ECM) components such as proteoglycans, increased catabolism, inflammation, and neurovascular invasion contribute to a detrimental shift in homeostasis that leads to the loss of tissue function and increased pain.


n previous studies, we have demonstrated the potential of developmental transfection factors such as Brachyury (T) and Forkhead Box F1 (FOXF1), both of which are healthy immature NP markers involved in growth during development, to drive cellular reprogramming of diseased human NP cells to a pro-anabolic phenotype in vitro. These studies also highlight the feasibility of using engineered extracellular vesicles (eEVs) to mediate the delivery of FOXF1 to diseased cells, and their potential to be used as a minimally invasive gene delivery mechanism.


Here we have developed a novel non-viral gene therapy, using eEVs to deliver FOXF1 to the degenerated IVD in an in vivo model. Injured IVDs treated with eEVs loaded with FOXF1 demonstrated robust sex-specific reductions in pain behaviors compared to control groups. Furthermore, significant restoration of IVD structure and function in animals treated with FOXF1 eEVs were observed, with significant increases in disc height, tissue hydration, proteoglycan content, and mechanical properties. This is the first study to successfully restore tissue function while modulating pain behaviors in an animal model of DBP using eEV-based non-viral delivery of transcription factor genes. Such a strategy can be readily translated to other painful musculoskeletal disorders.


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Stochastic Changes are Sufficient to Produce the Behavior of Aging Clocks

That it is possible to produce aging clocks from omics data, that some omics changes map very well to chronological age, biological age, and risk and presence of age-related disease, has been used to argue for aging to be an evolved program. Researchers here use a modeling approach to show that random events, the accumulation of molecular damage, can still produce the outcome observed in aging clocks.

Aging clocks have provided one of the most important recent breakthroughs in the biology of aging, and may provide indicators for the effectiveness of interventions in the aging process and preventive treatments for age-related diseases. The reproducibility of accurate aging clocks has reinvigorated the debate on whether a programmed process underlies aging. Here we show that accumulating stochastic variation in purely simulated data is sufficient to build aging clocks, and that first-generation and second-generation aging clocks are compatible with the accumulation of stochastic variation in DNA methylation or transcriptomic data.


We find that accumulating stochastic variation is sufficient to predict chronological and biological age, indicated by significant prediction differences in smoking, calorie restriction, heterochronic parabiosis, and partial reprogramming. Although our simulations may not explicitly rule out a programmed aging process, our results suggest that stochastically accumulating changes in any set of data that have a ground state at age zero are sufficient for generating aging clocks.


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Correlating Gut Microbiome Characteristics with Changed Behavior in Aging Mice

The composition of the gut microbiome influences health and aging. In addition to variations between individuals, the relative abundances of different microbial populations making up the gut microbiome change with age in ways that contribute to chronic inflammation and the loss of useful metabolite production. Researchers here demonstrate that it is possible to correlate aspects of this gut microbiome aging with changes in behavior normally observed in aged mice. The gut microbiome is becoming an attractive target for intervention, given that strategies such as fecal microbiota transplantation can produce a lasting restoration of a more youthful gut microbe configuration.

In this study, we evaluated the locomotor activity, sensory function, and cognitive level of young (3 month old) and aged (22 month old) female C57BL/6J mice through a series of behavioral tests. The physiological functions, gut microbiota, and their metabolites of young and aged mice were comparatively analyzed from the perspective of the microbiota-gut-brain axis (MGBA). Our study focused on the alterations in the microbiota and metabolites induced by aging, and whether such alterations affect systemic inflammation and inflammation of related brain region through the MGBA to mediate abnormal behaviors.


Decreased locomotor activity, decreased pain sensitivity, and reduced respiratory metabolic profiling were observed in aged mice. High-throughput sequencing revealed that the levels of genus Lactobacillus and Dubosiella were reduced, and the levels of genus Alistipes and Bacteroides were increased in aged mice. Certain bacterial genus were directly associated with the decline of physiological behaviors in aged mice. Furthermore, the amount of fecal short-chain fatty acids (SCFAs) in aged mice was decreased, accompanied by an upregulation in the circulating pro-inflammatory cytokines and increased expression of inflammatory factors in the brain.


Aging-induced microbial dysbiosis was closely related with the overall decline in behavior, which may attribute to the changes in metabolic products, e.g., SCFAs, caused by an alteration in the gut microbiota, leading to inflammaging and contributing to neurological deficits. Investigating the MGBA might provide a novel viewpoint to exploring the pathogenesis of aging and expanding appropriate therapeutic targets.


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Demonstrating an mRNA Cancer Vaccine

One of the consequences of the COVID-19 pandemic is that the biotech industry is now geared up for the use of messenger RNA (mRNA) as a basis for therapy. The broadest use at present is vaccination, as doses can be very low and the experience gained during the pandemic is directly applicable, but many other forms of mRNA gene therapy are under development. Given the ability to produce novel mRNA vaccines, the most obvious use beyond infectious disease is to force the immune system to engage with cancerous tissue. This line of development appears to be making good progress.

In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumor. While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected. The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumors whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. The breakthrough now will be tested in a Phase 1 pediatric clinical trial for brain cancer.


This is a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient’s own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine. “Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions. The reason we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”


In a cohort of four patients, RNA was extracted from each patient’s own surgically removed tumor, and then messenger RNA, or mRNA – the blueprint of what is inside every cell, including tumor cells – was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream and prompt an immune-system response. The vaccine was personalized to each patient with a goal of getting the most out of their unique immune system.


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Exosome Therapy as a Way to Improve Angiogenesis in the Context of Bone Tissue

Angiogenesis, the complex set of processes by which new blood vessels are produced, becomes less efficient with advancing age. One important consequence is a loss of capillary density, which has a range of detrimental effects on tissue function, particularly in energy-hungry tissues such as the brain and muscle. Regeneration from injury is also dependent on the quality and efficiency of angiogenesis. Researchers here take a narrow focus on the question of angiogenesis relevant to bone tissue maintenance and regeneration, and the use of exosome therapies to improve angiogenesis. To the degree that treatment with exosomes harvested from stem cells can improve angiogenesis throughout the body, this approach to therapy should produce broad benefits.

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions.


After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.


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Why is Thrombosis an Age-Related Condition?

Thrombosis is the inappropriate clumping of platelets to form blood clots in blood vessels, leading to potential blockage and serious injury as tissues are deprived of blood flow. This undesirable situation occurs more readily with age. Platelets are produced by megakaryocyte cells, and the count of platelets in the blood tends to increase in older people. Why does this happen? Researchers here dig in to some of the details, and find that age-related changes in hematopoiesis in the bone marrow produce a distinct population of megakaryocytes that manufacture a greater number of platelets. Further, those platelets are more easily triggered into clot formation. Restoration of youthful hematopoiesis is already an important goal in the treatment of aging, and this adds one more reason for that to be the case.

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors.


The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.


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miR-519a-3p as a Circulating Marker for Early Alzheimer’s Disease

There is considerable interest in developing biomarkers to detect the earliest stages of Alzheimer’s disease, well prior to symptoms. To the degree that Alzheimer’s is a lifestyle condition, it might be postponed or averted if discovered early on. To the degree that it is not a lifestyle condition, then the first viable anti-amyloid immunotherapies offer some chance, the odds yet to be determined, of averting Alzheimer’s in the earliest stages. Some progress has been made on predictive biomarkers that can be assessed a decade or more prior to symptoms, but work continues to broaden and improve upon these options.

A recent study has identified a new biomarker for Alzheimer’s disease in asymptomatic stages of the disease. The molecule is miR-519a-3p, a microRNA directly linked to the expression of the cellular prion protein (PrPC), which is dysregulated in people suffering from some neurodegenerative diseases such as Alzheimer’s. The search for biomarkers that are stable and easily detectable in biofluids, such as microRNAs, offers hope for detecting Alzheimer’s disease in its early, asymptomatic stages. Early detection could significantly improve the diagnosis and treatment of this disease, which affects more than 35 million people worldwide.


The amount of PrPC changes over the course of Alzheimer’s disease, with higher levels in the early stages of the disease and lower levels as the disease progresses. Although the mechanism responsible for these changes is not known in detail, it has been observed that certain microRNAs bind to a specific region of the PRNP gene that controls PrPC expression, reducing it. For this reason, and based on comparisons of previous studies and computational analyses in various genomic databases, the researchers selected the microRNA miR-519a-3p for their study.


“If our goal is to use miR-519a-3p as a biomarker to detect Alzheimer’s dementia in hypothetically healthy people, it is essential to ensure that its levels are not altered in other neurodegenerative diseases. In our study, we compared the levels of this biomarker in samples from other tauopathies and Parkinson’s disease, confirming that the changes in miR-519a-3p are specific to Alzheimer’s disease. The next step is to validate miR-519a-3p as a biomarker in blood samples from different cohorts of patients, in order to start using it in the clinical diagnosis of Alzheimer’s disease in peripheral samples.”


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Rare Individuals Exhibit Alzheimer’s Pathology but No Symptoms

In a tissue bank of more than 5,000 donated brains, researchers found 12 in which there were signs of Alzheimer’s disease pathology but for which the donors had exhibited none of the symptoms of Alzheimer’s disease. Here find a report on some of the biochemical differences found in these resilient brains; it is hoped that pursuing this line of research might aid in the understanding of the condition and strategies for the development of effective therapies.

Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer’s disease (AD). This phenomenon has been referred to as ‘resilience’. The molecular and cellular underpinnings of resilience remain poorly understood. To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals, and age-matched controls (n = 11-12 per group).


897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors. Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia.


As changes in MT, mitochondria, heat shock proteins, and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes. MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors.


Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males. Taken together, these results show possible mechanisms involving MTs, mitochondrial processes, and the UPR by which individuals might maintain cognition despite the presence of AD pathology.


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Senescent T Cells Contribute to Neurodegenerative Conditions

T cell senescence is a noted feature of the aging immune system. T cells mature in the thymus, which atrophies with age. Absent a supply of new T cells, the existing populations are forced into greater cellular replication in order to (a) maintain a steady number of cells, and (b) continue to respond to infection with an expansion of the number of T cells equipped to attack the pathogen. Cellular senescence occurs when a cell reaches the Hayflick limit to replication. With each cell division, telomeres at the ends of chromosomes shorten. When telomeres become too short, a cell either self-destructs or becomes senescent. In some subsets of the immune cell population, almost half of all T cells are senescent in old people.

Senescent cells generate a pro-inflammatory, pro-growth mix of signals, the senescence-associated secretory phenotype (SASP). These cells serve a purpose when present in the short term, but when they linger the SASP becomes highly disruptive to tissue structure and function. As today’s open access paper points out, even though T cells are not present in the brain in any great number, their state of senescence does matter. Inflammatory signaling moves throughout the body, and can and does link the distinct immune systems of the body and brain.

With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence.


T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4+ T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4+ T-cells in NDs. In this review, we summarize the classification and function of CD4+ T-cell subpopulations, the characteristics of CD4+ T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4+ T-cell senescence.


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Calorie Restriction Slows the Aging of Stem Cells in Subcutaneous Fat

The practice of calorie restriction is well known to slow aging, though the effects on life span are much larger in short-lived species. In humans calorie restriction is demonstrated to be beneficial to long-term health, certainly on a par with the results obtained from maintenance of physical fitness. Calorie restriction has noteworthy effects on the distribution and biochemistry of fat tissue. Researchers here report that one aspect of this outcome is a slowing of age-related changes in adult stem cells associated with subcutaneous fat.

With advancing age, there is a gradual loss of subcutaneous adipose tissue volume, leading to diminished glucose and lipid uptake. This phenomenon is known as “lipid overflow hypothesis,” which results in the ectopic deposition of lipids in muscles and the liver, ultimately contributing to the development of insulin resistance. Long-term calorie restriction (CR) has been found to result in reduced adipocyte size and a beneficial remodeling of body fat composition, shifting away from visceral white adipose tissue towards subcutaneous white adipose tissue. This shift is significant as subcutaneous fat tends to have positive effects on aging and obesity, whereas visceral is associated with detrimental health outcomes.


Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Aging is associated with increased adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of reactive oxygen species (ROS). Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in the subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs.


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Why Are Extraocular Muscles So Resilient to Aging?

Most of us put little thought into the muscles that control the movement of the eye. They just work. Researchers here ask the interesting question: why are these extraocular muscles so resilient? Why does their function decline so little with age, when other muscles throughout the body lose strength and mass, leading ultimately to sarcopenia? There is no complete answer to this question, but it is suggested here that this resilience might have something to do with the fact that the extraocular muscles are much more heavily innervated than other muscles in the body. That in turn might direct a greater focus towards the effects of aging on neuromuscular junctions and consequent loss of innervation in muscles elsewhere in the body. This loss of innervation has been suggested as a contributing cause of sarcopenia.

The extraocular muscles (EOMs) are unique in several aspects: They represent the fastest and most fatigue-resistant muscles within the human body. Extraocular muscles (EOMs) predominantly exhibit impairment in conditions such as myasthenia gravis and mitochondrial myopathies, yet, remarkably, they are spared from various muscular dystrophies, including Duchenne, Becker, limb-girdle, and congenital muscular dystrophies, as well as aging. Furthermore, EOMs demonstrate particular resistance to amyotrophic lateral sclerosis (ALS).


he complexity of the actions performed by the extraocular muscles (EOMs) is reflected in their anatomical and physiological characteristics. Morphologically and in terms of their molecular composition, they significantly differ from the muscle fibers (MFs) of other skeletal muscles. The gene expression profile of the EOMs is distinct from that of limb muscles, with differences encompassing over 330 genes involved in metabolic pathways, structural components, development markers, and regenerative processes. Unlike skeletal muscles, the EOMs predominantly utilize an aerobic pathway for carbohydrate metabolism and relies directly on the glucose influx from the blood. This metabolic strategy enables them to be among the fastest muscles in the body while also being exceptionally resistant to fatigue.


Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles.


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