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- Suppression of the Senescence-Associated Secretory Phenotype as a Basis for Therapy
- Circulating Proteins Secreted by Senescent Cells Correlate with Risk of Mild Cognitive Impairment
- A Mechanism by Which TDP-43 Aggregation Causes Pathology in the Aging Brain
- Contrasting the Strategies for Engineered Negligible Senescence and the Hallmarks of Aging
- A High Level Tour of Environmental Contributions to Aging
- Towards Regeneration of a Lost Sense of Smell
- The Promise of Induced Pluripotent Stem Cells in Regenerative Medicine
- Why Would the Nasal Microbiome Correlate with Mild Cognitive Impairment and Loss of Sense of Smell?
- An Example of Visceral Fat Accelerating the Progression of Aging
- Macrophages Accumulate in the Aging Brain to Promote Dysfunction
- Low Levels of Selenium Biomarkers Correlate with Accelerated Epigenetic Age
- Clusterin Expression is a Signature of Age-Related Hematopoietic Stem Cell Dysfunction
- Tau Aggregation in the Aging Brain Causes Blood-Brain Barrier Dysfunction
- Replacing an Extracellular Matrix Component to Treat Degenerative Disc Disease
- Towards PET Scan Detection of α-Synuclein for Early Diagnosis of Parkinson's Disease
Suppression of the Senescence-Associated Secretory Phenotype as a Basis for Therapy
https://www.fightagi...is-for-therapy/
Senescent cells accumulate with age in tissues throughout the body. Senescent cells are created throughout life, largely because somatic cells reach the Hayflick limit on replication, but also as a result of various stresses. In youth, newly created senescent cells are cleared rapidly by the immune system. In later life, that capability declines, and senescent cells begin to linger as a result. While senescent cells never make up more than a tiny fraction of all cells in a tissue, they energetically produce inflammatory signaling, in what is known as the senescence-associated secretory phenotype (SASP). It is this signaling that causes harm when sustained over time, disruptive to cell and tissue function, and a contributing cause of age-related conditions.
There are a few different approaches to the problem of senescent cells. Firstly one can try to selectively destroy senescent cells via the use of senolytic therapies. This is the most well developed and most easily implemented approach, and has the largest set of animal and human data to suggest that it will be beneficial. In mice, certainly, it produces by far the largest and most rapid reversal of specific age-related conditions so far observed. The second approach is to prevent cells from becoming senescent, and thus allow the immune system to catch up and reduce the burden of lingering senescent cells. Therapies that upregulate autophagy, such as mTOR inhibitors, are the best example of this strategy.
The third approach is to interfere in the ability of senescent cells to generate the SASP. This is likely the most challenging of the options on the table, as it requires a much greater understanding than presently exists of the regulation of the SASP and its most important component molecules. Further, what is known of the SASP suggests that both it and its regulation are very complex. Any one protein or protein interaction target is unlikely to address more than a modest fraction of the overall problem. It seems doubtful that SASP modulation could be more effective than clearance of senescent cells, which obviously reduces the SASP quite readily, to the degree to which it reduces the burden of senescence.
SASP Modulation for Cellular Rejuvenation and Tissue Homeostasis: Therapeutic Strategies and Molecular Insights
Modulation of the SASP has gained attention as a therapeutic strategy for combating age-related diseases, tissue degeneration, and cancer progression. While preclinical studies show promise, clinical translation remains limited due to the heterogeneous and context-specific nature of SASP, as well as its complex crosstalk with immune pathways. Addressing these challenges requires integrated efforts in molecular biology, pharmacology, and computational sciences to develop targeted, tissue-specific therapies.
The SASP is not a uniform signature but varies depending on cell type, senescence trigger, tissue environment, and duration. While core components like IL-6, IL-8, and CXCL1 are commonly expressed, others such as extracellular vesicle-derived microRNAs and long non-coding RNAs show high tissue specificity. This molecular diversity complicates biomarker discovery and universal therapy design. Advances in single-cell RNA sequencing and spatial transcriptomics have enhanced our understanding of SASP heterogeneity, although technical limitations persist. Machine learning tools capable of integrating multi-omic datasets may help create personalized approaches for SASP modulation.
Therapeutically, SASP displays both beneficial and detrimental roles depending on context. Acute SASP promotes regeneration, wound healing, and embryonic development, but chronic SASP contributes to inflammaging, fibrosis, and cancer. For instance, senescent fibroblasts secrete pro-angiogenic factors, aiding repair while also facilitating tumor growth and immune evasion in epithelial tissues. Mitochondrial dysfunction, particularly via the cGAS-STING pathway, may drive chronic SASP and associated inflammation, yet targeting mitochondria raises concerns over the long-term effects on metabolic integrity.
The immune system is both influenced by and responsive to the SASP. Early SASP supports immune recruitment through cytokines like IL-6 and CXCL2, promoting senescent cell clearance. However, a persistent SASP can drive immune exhaustion and chronic inflammation, suppressing anti-tumor responses through elevated levels of IL-6 and TGF-β. Immunotherapies such as PD-1/PD-L1 inhibitors offer partial success but require a deeper understanding of SASP-immune dynamics to improve consistency and efficacy.
Translating preclinical findings into clinical applications presents further obstacles. Murine models often fail to replicate human senescence biology due to species-specific differences in SASP and immune responses. Emerging platforms such as humanized organoid systems and grafts of patient-derived aged tissues offer better fidelity but are hampered by inconsistent induction methods and limited standardization. Collaborative research frameworks and harmonized protocols will be essential for achieving reproducible clinical outcomes.
Circulating Proteins Secreted by Senescent Cells Correlate with Risk of Mild Cognitive Impairment
https://www.fightagi...ive-impairment/
Animal study data makes it very clear that senescent cells are actively involved in producing the age-related dysfunction that leads to disease and mortality. Senescent cells grow in number with age and generate signaling, the senescence-associated secretory phenotype, that disrupts tissue structure and function. Selectively destroying senescent cells via the use of senolytic therapies removes this influence to produce a profound and rapid reversal of many measurable aspects of aging in mice. Some of these therapies are used by a growing number of patients with access to anti-aging physicians, and human trials have taken place to produce promising early results. Nonetheless we are still some way from a good enough understanding of dosing in humans and enough rigorous human data to convince the world that this is as impressive as it appears to be in the laboratory.
Clearance of senescent cells should help to, at the very least, slow the progression towards neurodegenerative conditions, such as the prevalent mild cognitive impairment in older individuals. In today's open access materials, researchers report on the ability to correlate circulating markers of the burden of senescent cells with the risk of mild cognitive impairment. Beyond the point that more ways to assess the risk of neurodegeneration improve the ability to prevent such conditions via early intervention, this adds to the body of evidence to suggest that presently available senolytic therapies with a good safety profile, such as intermittent treatment with the dasatinib and quercetin combination, should be widely used as preventative medicine in the older population.
Plasma senescence associated secretory proteins: A new link to mild cognitive impairment
Cellular senescence is widely acknowledged hallmark of aging that has been implicated in the progression of several age associated disorders. The secretome of senescent cells, termed as senescence associated secretory phenotype (SASP), consists of a number of inflammatory cytokines as well as growth factors and proteases that can lead to paracrine disruption of normal tissue structure and function and propagate senescence in neighboring cells. Moreover, many SASP molecules have been identified as potential biomarkers of aging and associated traits. In cases of age associated neurodegenerative diseases that can lead to dementia or cognitive impairment, increased senescence has been observed in multiple cell types in brain.
Mild cognitive impairment (MCI) is defined as a condition defined by cognitive impairment with minimal impairment of daily activities. It is observed in about 10-20% of individuals over 65 years of age and about 10% of individuals with MCI can progress to dementia every year. There are few potential plasma biomarkers that have been reported, particularly senescence-associated protein biomarkers. Therefore, there is a need to identify new robust potential plasma biomarkers that can be applied clinically for diagnosis of MCI.
A new study explored the connection between cellular senescence and MCI by analyzing the plasma levels of certain SASP markers to predict risk of MCI among older adults. The study is based on the data from the Lifestyle Interventions for Elders (LIFE), a large cohort study designed to assess the effects of physical activity and health education on mobility in sedentary older adults. The authors assessed a panel of 27 SASPs that were previously identified as markers associated with mobility disability. Among these, higher plasma levels of myeloperoxidase (MPO) and Membrane metalloprotease-7 (MMP7) and reduced levels of MMP1 reportedly led to increased risk of MCI in older adults. Importantly, MPO and MMP7 were longitudinally associated with future MCI (24 months later), underscoring their predictive potential. These markers had been previously reported to be associated with different neurological disorders including Alzheimer's disease. However, the current study points to a potential mechanistic connection with cellular senescence and SASP as players in development of MCI. If certain cases of MCI are driven by cellular senescence, a possibility that needs to be further explored, then senotherapeutic interventions may offer a novel therapeutic opportunity.
A Mechanism by Which TDP-43 Aggregation Causes Pathology in the Aging Brain
https://www.fightagi...he-aging-brain/
TDP-43 is one of the few proteins capable of becoming altered in ways that allow it to form solid aggregates. Like many of the other examples, it is involved in the onset and progression of neurodegenerative conditions. This form of pathology in the brain was a more recent discovery than, for example, the involvement of amyloid-β and tau in Alzheimer's disease or α-synuclein in Parkinson's disease. It was only a few years ago that researchers clearly defined limbic-predominant age-related TDP-43 encephalopathy (LATE) as a novel form of neurodegenerative condition. Separately, TDP-43 also appears important in amyotrophic lateral sclerosis (ALS). As research into TDP-43 aggregation broadens, it appears likely that it causes neurodegenerative pathology to some degree in a large fraction of the older population.
In today's open access paper, researchers report on one of the ways in which TDP-43 aggregation can cause harm to the brain. Problems start because aggregation depletes TDP-43 in the cell nucleus, where it serves useful functions. This depletion alters cell behavior in pathological ways. When this happens in cells making up the blood-brain barrier, it causes the blood-brain barrier to leak. Normally the blood-brain barrier prevents unwanted cells and molecules from passing from the circulation into the brain. Leakage produces persistent inflammatory reactions to those unwanted cells and molecules in brain tissue, and this chronic inflammation is disruptive to brain function.
Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects
Loss of nuclear TDP-43 (TAR DNA-binding protein 43) is a common feature in a wide range of neurodegenerative diseases. These include Alzheimer's disease (AD), limbic-predominant age-related TDP-43 encephalopathy, and amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Across these diseases, a common feature is aggregation of ubiquitinated TDP-43 in the cytosol and nuclear loss of TDP-43 in neurons. The identification of familial FTD mutations in TDP-43 that exacerbate this process highlights TDP-43 dysfunction as a driver in disease progression. Mechanistically, the reduced nuclear levels of TDP-43 are associated with impaired nuclear splicing functions. In a dose-dependent manner, the loss of nuclear TDP-43 results in the aberrant inclusion of exonic junctions into transcripts, often leading to transcript destabilization and degeneration through nonsense-mediated mRNA decay. In neurons, the loss of specific transcripts alters the expression of proteins critical for axonal projection, which is thought to contribute to the progression of motor neuron deficits in ALS.
Early in the course of neurodegenerative diseases, increased flux across the blood-brain barrier (BBB) is detected. BBB leakage alone can exacerbate neurodegenerative changes in animal models. While not all the subsequent consequences of BBB leakage are fully understood, fibrin deposition has been linked to reactive changes in brain microglia. The BBB is part of a complex neurovascular unit comprising endothelial cells (ECs) lining the lumen of vessels, an underlying basement membrane, associated pericytes, astrocytes, and perivascular fibroblasts. Although each of these components contributes to the barrier, it is the ECs that provide the functional barrier.
Here, we show that TDP-43 has a critical function in the maintenance of the BBB. We recently identified reduced nuclear TDP-43 in capillary ECs of donors with ALS-FTD. Because BBB permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 and that this leads to loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phosphorylated Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.
Contrasting the Strategies for Engineered Negligible Senescence and the Hallmarks of Aging
https://www.fightagi...marks-of-aging/
The Strategies for Engineered Negligible Senescence (SENS) was the original attempt to produce a list of important mechanisms in aging, created in an era in which the aging research community leadership was actively hostile towards the concept of treating aging as a medical condition. A great deal of patient advocacy and hard work was required to create the much more receptive research community that exists today, in which the treatment of aging is accepted as a legitimate goal, and the inflamed discussion has moved on to how exactly one should go about it. In this more receptive environment, SENS was followed by other lists of mechanisms: the Hallmarks of Aging, echoing the much earlier Hallmarks of Cancer, and the Seven Pillars of Aging.
To my eyes the important difference between SENS and the hallmarks of aging is that SENS was framed as a call to action from the very start. It attempts to list the root causes of aging, conceptualizing aging as an accumulation of specific well-established forms of cell and tissue damage, points at which intervention will plausibly produce rejuvenation - and rejuvenation is the goal, the point of the exercise, to eliminate age-related suffering and death. The hallmarks of aging is just a list, attempting to be scientifically neutral. One can use both as starting points for directions in research and development of means to treat aging, but SENS was from the beginning intended to be used that way, and its creation was biased towards achieving the greatest expectation of extended healthy life span given viable therapies.
SENS vs. the hallmarks of aging: competing visions, shared challenges
In response to the complexity of aging, a range of pluralistic frameworks have emerged to address its challenges. Two particularly relevant proposals in this regard are Strategies for Engineered Negligible Senescence (SENS), which advocates repairing accumulated damage in the body to reverse its effects, and the Hallmarks of Aging (HoA), which identifies and classifies the key biological processes driving age-related decline. Given their prominent roles, both SENS and the HoA are the subject of ongoing debate and scrutiny. SENS has been criticized regarding the burden of proof, an epistemological principle stipulating that those who propose a novel hypothesis must provide robust evidence to substantiate it. The HoA has also faced considerable criticism, particularly for lacking a clear framework to prioritize therapeutic targets.
We contend that, despite their divergences, a comparative analysis of the conceptual and methodological foundations of SENS and the HoA is both feasible and valuable. There are several considerations that support the relevance of such analysis. First, SENS and the HoA rest on a remarkably similar theoretical foundation: both conceptualize aging as a multifactorial phenomenon driven by interconnected biological mechanisms, primarily at the cellular and molecular levels. Second, both proposals have played a pivotal role in shaping the idea that aging is a plastic process - one that, in principle, can be modulated through biotechnological interventions - insofar as it is conceived as amenable to targeted manipulation. Third, while sharing the overarching goal of addressing aging, SENS and the HoA have engaged in a form of intellectual and material competition, seeking to influence the conceptual direction and the allocation of recourses in aging research. Finally, both proposals have achieved sustained prominence.
SENS adopts an explicitly interventionist stance rooted in a technological solutionist perspective, framing aging as a technical problem that necessitates practical solutions rather than a deeper theoretical understanding. It does not provide a strict definition of aging, as its main focus is on the effectiveness of treatments rather than conceptual debates. It argues that a precise definition of aging is unnecessary from a biomedical perspective, emphasizing the importance of focusing on the repair and prevention of accumulated damage. From this standpoint, semantic debates are not only unproductive but also delay the development of effective interventions.
The HoA explicitly defines aging, as its approach necessitates a clear conceptualization to integrate and systematize the existing body of biological knowledge. Aging is described as a "progressive deterioration of physiological integrity, leading to impaired function and increased vulnerability to death". Unlike SENS, which emphasizes intervention over definition, the HoA regards a precise understanding of aging as essential for identifying the key biological processes that underlie its progression.
This paper seeks to contribute to a deeper understanding of the core principles and assumptions underpinning SENS and the HoA. We consider that previous literature has not sufficiently addressed the conceptual and methodological foundations of these proposals. Addressing these dimensions is essential not only for a more nuanced understanding of the frameworks themselves but also for a more accurate evaluation of their theoretical and practical contributions.
A High Level Tour of Environmental Contributions to Aging
https://www.fightagi...tions-to-aging/
Primary aging derives from mechanisms inherent to our biology, such as the damaging mechanisms listed in the Strategies for Engineered Negligible Senescence (SENS) view of aging. Secondary aging derives from lifestyle choices (such as diet and exercise) and environmental exposures (such as particulate air pollution or persistent viral infections), harmful factors that can interact with the mechanisms of primary aging to accelerate the path to loss of function, age-related disease, and mortality. Epidemiological studies suggest that many people are losing at least a few years of life to poor choices, poor luck, or poor living circumstances.
Today's open access paper offers a high level tour of some of the major categories of environmental pollution. While extensive data indicates air pollution is harmful and increases the incidence of age-related diseases, data is somewhat lacking for many other areas of potential concern. Exposure to microplastic and nanoplastic particles, for example, may turn out to be as harmful as air pollution, but the few existing studies are by no means enough to say in certainty one way or another. Those studies can only collectively suggest that it would be wise to gather enough data to be sure.
Environmental Health Is Overlooked in Longevity Research
Environmental pollutants constitute an often-overlooked factor in the aging process. The mechanistic insights presented in this manuscript provide a snapshot of how specific classes of pollutants - including heavy metals, particulate matter, and endocrine-disrupting chemicals - induce oxidative stress through multiple pathways. These pollutants disrupt redox balance, impair mitochondrial function, and damage critical biomolecules such as DNA, proteins, and lipids, ultimately affects epigenetic aging. The cumulative impact of these events has significant implications for the overall trajectory of organismal aging. Epidemiological evidence linking pollutant exposure to cardiovascular, neurodegenerative, and oncologic outcomes further supports the concept that environmental health is an integral component of the longevity equation. In a recent study comparing genetic and environmental influences for 22 major diseases, polygenic risk scores explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points.
Environmental factors are estimated by the World Health Organization (WHO) to account for approximately 25% of the total burden of disease globally, which translates into a substantial loss of healthy life years on a population level. Using a back-of-the-envelope calculation based on WHO metrics, one can approximate that environmental exposures result in loss of several years of good health over the lifespan. This environmental burden is quantified using Disability-Adjusted Life Years (DALYs), which represent the total number of years lost due to ill health, disability, or premature death. WHO estimates that approximately 1.7 million DALYs are lost annually in France due to environmental factors.
To translate this population-level burden into an individual context, we can estimate annual per capita loss by dividing the annual 1.7 million DALYs by France's population of approximately 66 million which yields an average loss of about 0.0258 DALYs per person per year. Since one DALY equates to one lost year of healthy life, this corresponds to roughly 9.4 days of healthy life lost per person each year. Over an average lifespan of 80 years, this annual loss accumulates to approximately 2.1 years of healthy life lost per individual due to environmental exposures. This estimation reaches 3-4 years for the most polluted countries like China. This calculation does not take into account interindividual variations and it is likely that individuals who are exposed to pollution levels orders of magnitude higher than others will suffer in proportion.
Towards Regeneration of a Lost Sense of Smell
https://www.fightagi...sense-of-smell/
One of the less frequently discussed aspects of aging, perhaps because it is seen as a less critical function, is the progressive loss of the sense of smell. When arising from the underlying cell and tissue damage of aging, this can be considered a form of neurodegeneration. Strategies in the development of regenerative medicine that are aimed at regrowth of neurons and axonal connections between neurons are applicable to this form of age-related dysfunction, and here find a review of some of this ongoing work.
Olfactory loss impacts more than 12% of the population and increases with aging. Multiple conditions can cause loss of smell (hyposmia or anosmia), including post-viral damage from COVID-19 or influenza, head injuries, sinusitis, or neurodegenerative conditions such as Alzheimer's or Parkinson's disease. While treatments including surgery, anti-inflammatories or olfactory training may be of benefit in specific cases, there is an unmet need for effective therapies for many common causes of olfactory dysfunction, especially those thought to be due to damage to the olfactory neurons that have failed to recover spontaneously.
Broadly, regenerative medicine approaches may exert a therapeutic effect by (a) delivering signals to endogenous cells in a damaged tissue that promote a necessary process that has been inhibited or blocked, such as cell division or differentiation; or (b) delivering exogenous cells capable of engrafting appropriately into the damaged tissue and functioning as stem or progenitor cells that can divide and differentiate appropriately.
In either scenario, the organ system must be capable of integrating the newly regenerated cells properly. For instance, a newly produced olfactory sensory neuron in the olfactory epithelium (OE) of the nose must extend an axon through the cribriform plate, enter the central nervous system, and establish a synapse at an appropriate glomerulus in the olfactory bulb of the brain. Because the OE continually produces new olfactory neurons from resident stem cells as needed throughout life, evidence suggests that the presence of local guidance cues and a permissive microenvironment may support repair.
The Promise of Induced Pluripotent Stem Cells in Regenerative Medicine
https://www.fightagi...ative-medicine/
The authors of this review paper have a positive view of the future of regenerative medicine built on the ability to generate induced pluripotent stem cells from any patient cell sample. That should be tempered by a realistic expectation on timelines. At this point almost two decades have passed since the discovery of the first approach to reprogramming adult cells into induced pluripotent stem cells, but relatively little progress has been made on bringing therapies into even initial clinical trials. Perhaps the biggest challenge is that working with cells is very expensive and very challenging, far more so than development of small molecule drugs. Higher costs means fewer programs, slower progress.
Aging-related diseases often involve the dysfunction or loss of specific cell types, leading to organ and tissue degeneration. Due to their "young" characteristics, induced pluripotent stem cells (iPSCs) offer a promising solution by enabling the reprogramming of adult cells into a pluripotent state, which can then be directed to differentiate into various cell types needed to replace damaged or dysfunctional cells and thus make a difference in aged bodies. In addition, the advent of iPSCs has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells.
Despite the promising potential of iPSC technology, several challenges remain to be addressed before its full therapeutic potential can be realized. These include ensuring the safety and stability of iPSC-derived cells, overcoming potential immune rejection issues, and refining differentiation protocols to produce fully functional and mature cell types. Additionally, establishing robust protocols for large-scale production and rigorous quality control will be essential for the successful clinical translation of iPSC-based therapies. The field of iPSC-based cell therapy is advancing rapidly, with genetic engineering and cellular manipulation techniques significantly enhancing the functionality and therapeutic potential of iPSC-derived cells. As research progresses, the integration of cutting-edge iPSC technology with discoveries in aging biology promises to revolutionize treatments for aging-related diseases.
Beyond merely treating aging symptoms, iPSCs offer the transformative potential to intervene in fundamental aging processes, ushering in a new paradigm of regenerative medicine focused on extending both lifespan and healthspan. As these technologies advance, it is crucial to maintain a focus on ethical considerations and regulatory frameworks to ensure that these groundbreaking therapies are developed responsibly and equitably.
Why Would the Nasal Microbiome Correlate with Mild Cognitive Impairment and Loss of Sense of Smell?
https://www.fightagi...sense-of-smell/
Researchers here show that the distribution of microbial populations in the nasal microbiome correlates with mild cognitive impairment and age-related loss of sense of smell. Both of these are manifestations of neurodegenerative processes that degrade function in the central nervous system. While we know that age-related changes in the gut microbiome are probably influential on age-related conditions via, at the very least, provoking increased chronic inflammation. But is the nasal microbiome large enough to have the same sort of effect on the function of parts of the brain? It seems more plausible that both nasal microbiome and neurodegeneration are influenced by the state of the aging immune system. Either way, more research is needed if a concrete answer is wanted.
Emerging evidence has highlighted that olfactory dysfunction, a common feature of aging, is increasingly linked to cognitive decline in older adults. However, research on the underlying mechanism, particularly the role of nasal microbiome, remains limited. In this study, we investigated the associations between olfactory function, the nasal microbiome, and cognition among 510 older adults with an average age of 77.9 years. Olfactory function was assessed using the brief Chinese Smell Identification Test, and cognitive assessments were conducted via the Mini-Mental State Examination and the Revised Hasegawa Dementia Scale. Nasal microbiome profiles were generated through 16S rRNA gene sequencing.
We observed that olfactory dysfunction (i.e., hyposmia) was associated with a higher richness of nasal bacteria, and such observation was replicated in an external dataset. A total of 18 nasal bacterial genera were identified to be associated with olfactory function, with eight genera such as Acidovorax and Morganella being enriched in the hyposmic group. A composite microbial index of nasal olfactory function significantly improved the reclassification accuracy of traditional risk model in distinguishing hyposmic from normosmic participants. Furthermore, participants with a nasal biotype dominated by Corynebacterium had a lower prevalence of mild cognitive impairment compared to those dominated by Dolosigranulum or Moraxella.
Our findings suggested that the nasal microbiome may play a role in the association of olfactory function with cognition in older adults, providing new insights into the microbial mechanisms underlying hyposmia and cognitive decline.
An Example of Visceral Fat Accelerating the Progression of Aging
https://www.fightagi...ssion-of-aging/
People with excess visceral fat tissue suffer more age-related disease, develop those conditions earlier, and exhibit a higher mortality risk. But is this accelerated aging, an increased burden of the defined forms of damage and dysfunction that drive aging, or is it a different set of damaging processes? There is a fair amount of evidence to suggest that being overweight does literally accelerate aging, such as the fact that greater amounts of visceral fat produce a greater burden of senescent cells, and studies such as the one noted here that correlate higher aging clock measures with the amount of visceral fat. But this isn't a concretely answered question.
Cardiometabolic multimorbidity (CMM), as one of the most prevalent and representative multimorbidity forms, is characterized by the coexistence of at least two cardiometabolic diseases (CMD), typically including coronary heart disease (CHD), type 2 diabetes (T2DM), and stroke. Obesity is widely recognized as a significant risk factor for CMM. A growing consensus holds that the accumulation of visceral adipose tissue is more deleterious to health than the expansion of subcutaneous adipose tissue. The body roundness index (BRI) is a novel anthropometric measure that integrates height and waist circumference (WC) to characterize body shape. Compared to the traditional body mass index (BMI), it provides a more accurate reflection of visceral fat distribution.
Using data from the UK Biobank, a nationwide cohort study was conducted using the available baseline BRI measurement. Biological aging was assessed using the Klemera-Doubal method for biological age and the phenotypic age algorithms. The association between the BRI and CMM was estimated using the Cox proportional hazards regression model, while the roles of biological aging were examined through interaction and mediation analyses.
During a median follow-up of 14.52 years, 6,156 cases of CMM were identified. A significant association was observed between the BRI and CMM. The hazard ratio (HR) for CMM was 3.72 for individuals in the highest quartile compared with those in the lowest quartile of the BRI. More importantly, the BRI demonstrated superior predictive performance relative to body mass index. Furthermore, the BRI exhibited additive interactions with accelerated biological aging on the risk of CMM, and accelerated biological aging partially mediated the association between the BRI and CMM. These findings provide evidence for the application of the BRI as a novel and readily accessible screening tool associated with CMM, suggesting that the effective management of visceral fat and biological aging deceleration may hold promise for reducing CMM risk.
Macrophages Accumulate in the Aging Brain to Promote Dysfunction
https://www.fightagi...te-dysfunction/
The immune system of the brain is distinct from that of the rest of the body, at least to a first approximation. Given improved tools and more research, scientists are finding that immune cells from the body do find their way into the brain. This seems to occur to a limited degree normally, in young people, but becomes more pronounced in later life. This is likely due to increasing dysfunction of the blood-brain barrier, specialized cells that line blood vessels that pass through the brain and collectively determine which cells and molecules are allowed to pass to and from the brain. When the barrier leaks, allowing unwanted cells and molecules to enter the brain, the result is usually harmful persistent inflammation in the nearby brain tissue.
Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment derived from the yolk sac that resists seeding with cells derived from adult hematopoiesis occurring in the bone marrow. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles.
Unlike yolk-sac-derived microglia in the brain, due to their derivation from hematopoietic stem cells MoMΦs are exposed to somatic mutations that are associated with age-related clonal hematopoiesis. Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human clonal hematopoiesis variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with clonal hematopoiesis, can cause brain pathology.
Low Levels of Selenium Biomarkers Correlate with Accelerated Epigenetic Age
https://www.fightagi...epigenetic-age/
A growing body of work has found correlations between selenium deficiency and suggestions of accelerated aging: increased epigenetic age, increased mortality, increased incidence of age-related disease. Selenium is incorporated into a range of proteins called selenoproteins, and it is possible to argue that too little selenium, leading to a lower production of these proteins, impairs functions relevant to aging, such as antioxidant capacity and immune system activities. As is usually the case in these matters, there is correlation and inference, but no concrete data on which of these proteins and mechanisms are more versus less important.
In this study, we analyzed the association between serum biomarkers, namely total serum selenium, selenoprotein P (SELENOP), the selenocysteine-containing glutathione peroxidase 3 (GPx3), and biological age measured by epigenetic clocks in 865 participants of the observational Berlin Aging Study II. Lower values in all three selenium biomarkers were associated with an increased pace of aging measured with the DunedinPACE clock. Our analyses do not allow to draw any conclusions on cause-effect relationships between selenium levels and accelerated biological aging. However, our results corroborate recent findings on aging phenotypes assessed by other clinical and phenotypic outcomes that show an association between selenium biomarkers and mortality.
In a recent prospective study with ~17 years of follow-up, serum concentrations of the selenium transporter SELENOP were inversely associated with all-cause and cardiovascular mortality, independent of biologically relevant confounders. In line with this finding, serum selenium was inversely associated with mortality and incident heart failure in the Dutch PREVEND study comprising ~6000 individuals. Similar results were observed in other recent large prospective European studies for all-cause mortality as well as cardiovascular outcomes. Besides all-cause mortality and cardiovascular outcomes, serum selenium biomarkers were shown to be inversely associated with prognosis in several cancer entities. Moreover, an effect of selenium levels on epigenetic age is also biologically plausible since changes in the methylome in dependence to the selenium levels in rodents, cell-lines (human, mouse) and human tissue are well established.
Clusterin Expression is a Signature of Age-Related Hematopoietic Stem Cell Dysfunction
https://www.fightagi...ll-dysfunction/
Hematopoietic stem cells in the bone marrow generate red blood cells and immune cells. Immune cells can be roughly divided into myeloid lineages of the innate immune system and lymphoid lineages of the adaptive immune system. With advancing age, the generation of myeloid cells becomes favored over lymphoid cells, and this is one source of dysfunction in the aged immune system. Here, researchers find a signature of age-related dysfunction in hematopoietic cells that favor myeloid cell production. This could be a first step towards targeting these malfunctioning hematopoietic cells in order to restore a more balanced generation of immune cells and thus improve immune function in older individuals.
Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging-associated proteins or reporter systems of aged HSC signature genes.
Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis.
The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.
Tau Aggregation in the Aging Brain Causes Blood-Brain Barrier Dysfunction
https://www.fightagi...er-dysfunction/
The blood-brain barrier consists of specialized cells that line blood vessels passing through the central nervous system, only selectively allowing passage of molecules and cells between the circulation and the brain. Dysfunction of the blood-brain barrier allows unwanted molecules and cells into the brain, where they cause chronic inflammation and become an important contribution to the onset and progression of neurodegenerative conditions. While blood-brain barrier dysfunction appears early in the aging of the brain, and thus seems a good candidate for the position of primary causative mechanism, many studies - such as the one noted here - suggest that other pathologies associated with neurodegenerative conditions can cause blood-brain barrier dysfunction.
Problems with blood vessels in the brain are recognized as some of the earliest changes that can lead to memory loss and other symptoms in Alzheimer's disease and other forms of dementia. These problems generally center around the neurovascular unit - a group of different cell types, including blood vessel cells, support cells, and neurons - that work together to keep the brain healthy. This system helps regulate blood flow in the brain, controls how nutrients and energy are delivered, and helps protect the brain from inflammation and harmful substances.
Until now, scientists did not fully understand what tau protein aggregates were doing at the brain's blood vessels. To uncover the mystery, researchers ran a series of experiments in vitro using a cell model that mimics the brain's protective barrier. When they exposed the cells to protofibrillar tau - a form of tau that appears early in Alzheimer's disease - they discovered that it weakened the barrier, making it more "leaky" and less able to protect the brain. The researchers also found that right after exposure to protofibrillar tau, brain blood vessel cells quickly changed how they make energy. This shift triggered inflammation and weakened the protective barrier, suggesting these damaging changes happen very early in the disease process.
Replacing an Extracellular Matrix Component to Treat Degenerative Disc Disease
https://www.fightagi...e-disc-disease/
The extracellular matrix is a complex structure of molecules generated and maintained by cells to support themselves and determine the physical properties of a tissue, such as load-bearing capacity or elasticity. The extracellular matrix changes with age in ways that are not fully explored, but which harm cells and tissue function. Comparatively little effort is focused on finding ways to repair the aged extracellular matrix, in part because it seems a hard problem. There are few points of intervention that can be as simple as the one noted here, where delivering a novel substitute molecule allows it to be incorporated into the matrix to improve matters. In most cases, providing the raw materials is not enough; there are issues of cell activities, problematic alterations to existing structures, or toxic debris from chemical interactions in the matrix, to pick a few of the many issues.
Intervertebral disc degeneration (IDD) accounts for nearly half of the cases of low back pain (LBP), a leading cause of disability worldwide. The progression of IDD is characterized by decreased intervertebral disc height and water content in the nucleus pulposus (NP) tissue which lies in the center of the intervertebral disc and is surrounded by annulus fibrosus (AF).
A key change to the NP tissue along IDD development is the increasing loss of glycosaminoglycan (GAG) polysaccharides. GAGs are a main component of the gel-like extracellular matrix (ECM) that maintains the morphology and phenotypes of NP cells (NPCs). Although replenishing GAGs has emerged as a promising strategy, its efficacy remains unclear, with hardly any clinical success achieved. Recent findings have raised questions that the NP tissue under degeneration is maintained as a catabolic microenvironment by the elevated presence of enzymes that can degrade native GAGs. An alternative approach is to implant a biomaterial substitute of GAGs - serving as a glue to the damaged ECM of NP. This glue material should avoid recognition by the enzymes in the pathological niche, and meanwhile, mimic native GAGs in exerting specific bioactivities to support NPC functionality.
Accordingly, we synthesize a glucomannan octanoate (GMOC) with robust resistance to ECM-cleaving enzymes. GMOC injected into the degenerated intervertebral disc leads to NP tissue regeneration in a rat and a rabbit model, which represent two clinical scenarios of pre-surgical intervention and post-surgical regeneration of IDD, respectively. In summary, we report enriching the ECM with a glycan glue as a mechanism to promote NP regeneration for IDD treatment.
Towards PET Scan Detection of α-Synuclein for Early Diagnosis of Parkinson's Disease
https://www.fightagi...insons-disease/
Researchers here note recent progress towards assessment of the burden of misfolded α-synuclein in a living brain via contrast imaging. This would provide a way to reliably diagnose Parkinson's disease in advance of symptoms. Unlike imaging for the protein aggregates associated with Alzheimer's disease, this is not an established capability. It seems likely that imaging approaches will fade in importance in the years ahead, however, as blood assays with a much lower cost are now demonstrated to be able to detect neurodegenerative diseases in their earliest stages.
The abnormal accumulation of α-synuclein protein is a defining pathological feature of several neurodegenerative conditions collectively known as synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Until recently, confirming the presence of these protein aggregates required post-mortem examination, severely limiting early diagnosis and treatment monitoring capabilities.
A recent paper meticulously reviews recent advances in positron emission tomography (PET) tracer development, with special attention to promising candidates that have shown effectiveness in both laboratory and clinical settings. The researchers highlight tracers such as [18F]F-0502B, [18F]C05-05, and [18F]ACI-12589, which have demonstrated encouraging results in distinguishing patients with synucleinopathies from healthy controls.
One particularly significant breakthrough came when [18F]C05-05 successfully visualized synucleinopathies in ten patients meeting clinical diagnostic criteria for Parkinson's disease or dementia with Lewy bodies. This tracer showed increased binding in the midbrain - an area commonly affected by Lewy body pathologies - and this binding correlated well with the severity of motor symptoms.
Despite these developments, several challenges that remain in developing optimal α-synuclein PET tracers. The heterogeneous distribution and conformation of α-synuclein aggregates across different synucleinopathies, along with the relatively low density of these pathological features, complicate the development of universally effective imaging agents.
View the full article at FightAging
