Fight Aging! Newsletter, February 5th 2024
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- Interactions Between Innervation, Vascular Aging, and Loss of Capillary Density in the Heart
- Amyloid-β Biochemistry as a Cause of Blood-Brain Barrier Leakage in Alzheimer's Disease
- More on CCL17 as a Target to Reduce Inflammation in Cardiovascular Disease
- DEL-1 Upregulation Promotes Bone Regeneration in Aged Mice
- Making a Mouse that Exhibits Human Telomere Dynamics
- Modest Effects on Cognitive Decline from Multivitamin Use
- Mechanisms for the Benefits to Long Term Vascular Health Provided by Exercise
- The Prospects for Treating Neurodegenerative Conditions by Modifying the Gut Microbiome
- Measuring Myelin Loss in the Aging Brain
- Building Biological Age Clocks from Immune and Redox Markers
- Senolytic CAR T Cell Therapy Improves Health in Aged Mice
- Removing Senescent Cells Makes Chemotherapy More Effective
- Age-Related Changes in the Prefrontal Cortex Associate with Loss of Memory
- CISD2 Upregulation Reduces the Senescence-Associated Secretory Phenotype in Aged Skin
- Biomarkers for Immunosenescence
Interactions Between Innervation, Vascular Aging, and Loss of Capillary Density in the Heart
https://www.fightaging.org/archives/2024/01/interactions-between-innervation-vascular-aging-and-loss-of-capillary-density-in-the-heart/
One noted aspect of vascular aging is that the processes of angiogenesis become less effective with age, and as a consequence aged tissues lose capillary density. This harms function by reducing the supply of nutrients and oxygen to energy-hungry tissues such as muscles and brain, as well as putting stress on the remaining vasculature due to changes in the dynamics of blood flow. Accompanying this form of vascular aging is a progressive innervation, a loss of peripheral nervous system connections. These two complex processes interact strongly with one another, given the proximity of blood vessels and nerves, and signaling that passes back and forth between the cell types involved.
In today's open access commentary, researchers discuss recent findings regarding the interaction of blood vessel aging and peripheral nervous system aging, with a focus on the heart, where the consequences of these processes include various forms of arrhythmia. Interestingly, innervation precedes loss of capillary density, something that might form the basis for further investigation in and of itself, given the importance of this loss to tissue function. The primary result, however, is that researchers found one specific signal that appears to be released by endothelial cells in aged tissues, and which is disruptive to peripheral nerve formation and maintenance. This gives a target for drug development and further research into this form of degenerative aging.
Endothelial cell dysfunction: the culprit for cardiac denervation in aging?
During cardiac development, nerves grow in close anatomic proximity to blood vessels due to their need for oxygen and nutrients. Vice versa, blood vessels require closeness to nerves for tight control of vasodilation and vasoconstriction. However, their interdependence also means that malfunction of one cell type may result in dysregulation of the other. Two important sources of cardiac innervation are the parasympathetic and sympathetic nervous systems, and under- or hyper-activity of either system can lead to heart failure or arrhythmias. One common condition associated with autonomic nervous system deterioration and a predilection for cardiac arrhythmias is aging. Researchers recently demonstrated that aging-dependent vascular endothelial cell dysfunction reduces the density of neuronal axons in the heart, which in turn increases the risk of arrhythmias.
For these groundbreaking studies, researchers utilized 18-20-month-old male and female wild-type (WT) mice as the primary model of aging. Compared to young (3-month-old) mice, old mice exhibited ventricular diastolic dysfunction. Immunohistochemical staining of heart cross-sections revealed that all three major types of nerve fibers - parasympathetic, sympathetic, and sensory - were decreased in old vs. young mice. In conjunction, there was a higher incidence of inducible ventricular tachycardia in hearts isolated from old vs. young mice.
A time-course experiment revealed that nerve degeneration presented at 16 months prior to the onset of capillary rarefaction at 20 months - suggesting that nerve degeneration is not caused by loss of capillaries but rather may be due to alterations in vascular-derived neuroguidance cues. RNA sequencing (RNA-seq) of cardiac endothelial cells (ECs) isolated from old mice revealed upregulation of genes encoding pathways involved in neuronal death and axon injury, in particular semaphorin 3A (Sema3a). Interestingly, prior work had revealed that both deletion and overexpression of Sema3a can cause ventricular arrhythmias and sudden death in mutant mice. The researchers uncovered a new mechanism that involves aging ECs releasing more Sema3a, which reduces neuronal axon density in the heart, thereby promoting ventricular arrhythmias.
Amyloid-β Biochemistry as a Cause of Blood-Brain Barrier Leakage in Alzheimer's Disease
https://www.fightaging.org/archives/2024/01/amyloid-%ce%b2-biochemistry-as-a-cause-of-blood-brain-barrier-leakage-in-alzheimers-disease/
Alzheimer's disease is a complex degenerative failure of a complex system, the brain. This complexity is illustrated by the continuing debate over which of the many identified mechanisms are the primary cause. Is it amyloid-β aggregation, or some aspect of the halo of biochemistry associated with that aggregation, or is it chronic inflammation, or cellular senescence in supporting cells of the brain, or vascular dysfunction and leakage of the blood-brain barrier, or neurofibrillary tangles, or the presence of persistent viruses. All of these mechanisms interact with one another, and the direction of causation between any specific pair of mechanisms is also up for debate. Researchers are in many cases challenged by the inability to affect one mechanism in isolation of the others; even immunotherapies to clear amyloid-β have side-effects on tissues and the immune system.
In today's open access paper, researchers point out that most Alzheimer's patients exhibit cerebral amyloid angiopathy, deposition of amyloid-β into blood vessel walls leading to dysfunction, leakage, and rupture of microvessels. This results in damage to surrounding brain tissue and passage of inappropriate cells and molecules into the brain, provoking inflammation, among other consequences. The paper delves into mechanisms by which amyloid-β aggregation might cause dysfunction of the blood-brain barrier wrapping blood vessels in the brain and thus also the problems that arise from leakage of the blood-brain barrier. This is one example of an argument for a specific direction of causation between processes known to be involved in Alzheimer's disease. There are many such arguments, and not all of them agree with the one set out in this paper!
Endothelial leakiness elicited by amyloid protein aggregation
The most influential paradigm concerning Alzheimer's disease (AD) pathology is the amyloid cascade hypothesis and its modifications thereafter, where amyloid beta (Aβ) evolves from disordered monomers to toxic oligomers and amyloid fibrils through molecular self-assembly, modulated by environmental factors such as pH, temperature, metals, chaperones, and cell membranes. Accordingly, much effort over the past three decades has been made towards inhibiting or clearing the toxic Aβ aggregates, employing small molecules, peptidomimetics, antibodies, and, more recently, nanoparticles. A lack of clinical success, however, has shrouded these efforts, suggesting the pathophysiology of AD is multifactorial as its triggers.
Indeed, it has now been realized that, in addition to Aβ amyloidogenesis, tauopathies, apolipoprotein E, and neuroimmune activation are all causative to neurodegeneration in AD. The great (80-90%) correlation between AD subjects and patients carrying cerebral amyloid angiopathy (CAA) further suggests an important role of endothelial integrity in the development of AD pathogenesis, also evidenced by observations of cerebral endothelial dysfunction and microvascular injury induced by Aβ. Intriguingly, while Aβ originates from the proteolytic cleavage of amyloid precursor protein (APP) in endosomal membrane, deposits of Aβ are seen throughout the central nervous system, cerebral blood vessels, cerebrospinal fluid, and the plasma. Aβ-mediated vasoactivity, vascular capillary constriction, blood flow reduction, and paracellular transport have been reported with endothelial monolayers, blood-brain barrier (BBB), and biopsied human and rodent brain tissues, in connection with the production of reactive oxygen species (ROS), modified cytoskeletal network, altered tight-junction protein expression, and signaling to pericytes.
Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogenesis of AD and Parkinson's disease.
More on CCL17 as a Target to Reduce Inflammation in Cardiovascular Disease
https://www.fightaging.org/archives/2024/01/more-on-ccl17-as-a-target-to-reduce-inflammation-in-cardiovascular-disease/
Atherosclerosis is the buildup of fatty plaques in the walls of blood vessels, impeding blood flow and eventually rupturing to produce a heart attack or stroke. It is the single largest cause of human mortality. Atherosclerosis is in part an inflammatory condition, accelerated by the state of chronic inflammation that arises in later life. In this context, levels of CCL17 have been shown to rise with age, while inhibition of CCL17 has been shown to reduce chronic inflammation and slow the progression of atherosclerosis. This outcome is achieved via effects on T cell behavior; CCL17 is expressed on the surface of dendritic cells and interacts with CCR4 on the surface of T cells. In doing so it represses the anti-inflammatory activity of regulatory T cells.
Researchers continue to investigate the biochemistry involved in this relationship. The authors of today's open access paper here report that CCR4 isn't the only receptor involved, and CCL17 also binds to CCR8. This sort of investigative work is necessary to understand how and where to target a specific mechanism. As researchers note, CCL17 does have a normal, useful role in coordinating transient immune activity where it is needed. As is the case for most age-related dysregulation of immune function, one can't just inhibit an overactive mechanism without consequences, as excessive immune activate uses the same pathways as normal immune activation. The aim of tracing the various interactions involved like this is to find a point of intervention that only affects pathology, rather than also suppressing necessary immune system activity. The results reported here are likely only one step of many needed to reach that goal, if it can be attained.
New signaling pathway uncovered, shedding fresh light on atherosclerosis
A chronic inflammatory disease of the inner walls of blood vessels, atherosclerosis is responsible for many cardiovascular conditions. Dendritic cells, which act to recognize foreign substances in the body and mount an immune response, play an important role in the disease. They produce the signaling protein CCL17, a chemokine, which influences the activity and mobility of T cells, which track down infected cells in the body and attack the pathogens. However, CCL17 can also promote cardiovascular pathologies. People who suffer from cardiovascular diseases, or are particular susceptible to such diseases, have elevated levels of the signaling protein. In humans and mice, elevated CCL17 serum levels are associated with increased risk of atherosclerosis and inflammatory diseases of the cardiovascular and digestive systems.
"We know from our previous work that a genetic deficiency or an antibody blockade of CCL17 impedes the progress of atherosclerosis." Before now, only one signal receptor was known to contribute to the recruitment and functions of T cells. If this receptor is lacking, however, the body is not protected from the negative effects of CCL17. Mice that did not possess the receptor in question continued to have the same extent of disease driven by CCL17. If the signaling protein acted directly and exclusively on this receptor, then silencing it should have the same effects as the absence of CCL17. Consequently, there must be another signaling pathway in which CCL17 is involved, and the researchers demonstrated and described just such a pathway in the course of the new study. "We furnish clear evidence that CCL17 acts through an alternative receptor with high affinity, thereby triggering a signaling pathway that results in the suppression of anti-inflammatory, so-called regulatory T cells."
Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis
CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4.
Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, whereas FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Treg cells.
DEL-1 Upregulation Promotes Bone Regeneration in Aged Mice
https://www.fightaging.org/archives/2024/02/del-1-upregulation-promotes-bone-regeneration-in-aged-mice/
Bone is constantly remodeled throughout life. The extracellular matrix making up bone tissue is continually broken down by osteoclast cells and built up by osteoblast cells. In youth, these activities are balanced. With aging, however, the activity of osteoclast cells progressively outweighs the activity of osteoblast cells. The consequence is an ever greater loss of bone mineral density leading to osteoporosis. This process is also found in the bone loss characteristic of advanced periodontitis. There are many contributing factors leading to the imbalance in bone remodeling, and it isn't all that clear as to which of them are more or less important than the others, even given the existence of treatments, such as bisphosphonates, that can slow the progression of osteoporosis. There is certainly a need for better therapies, those with the ability to dramatically increase bone mineral density.
In today's open access paper, researchers discuss the role of DEL-1 in bone loss related to periodontitis. They demonstrate an approach to upregulation of DEL-1 expression, showing that it can regenerate bone in this context of gum disease. The researchers do a good job of laying out the various interactions along the way, and demonstrate that the treatment requires DEL-1 to function. Thus DEL-1 is the critical link, and expression of DEL-1 declines with age, perhaps an important contribution to loss of bone mineral density. This mechanism may additionally be worth exploring in the broader context of all bone loss experienced with age. Whether that is the case remains to be seen.
A novel macrolide-Del-1 axis to regenerate bone in old age
Development endothelial locus-1 (DEL-1) is a homeostatic protein secreted by tissue-resident cells in the gingiva and the periodontal ligament (PDL), endothelial and mesenchymal stromal/stem cells (MSCs) and some macrophage subsets, and contributes to inflammation resolution and tissue repair. Specifically, during the resolution phase of experimental periodontitis in mice, DEL-1 promotes efferocytosis and the emergence of the macrophage pro-resolving phenotype as well as stimulating alveolar bone regeneration. The pro-regenerative function of DEL-1 is largely independent of its efferocytic/pro-resolving function and involves activation of a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitor cells. Alveolar bone regeneration fails in DEL-1-deficient mice or in mice that express a DEL-1 point mutant that cannot bind β3 integrins. The expression of DEL-1 is severely diminished in old age, both in mice and humans.
Given that DEL-1 levels decline severely in old age and mice ≥18 months of age are DEL-1 deficient, it is important to develop potential therapeutic approaches to stimulate DEL-1 expression, thereby restoring the levels of this important homeostatic protein in the elderly. We have recently shown that the macrolide antibiotic erythromycin (ERM) - but not other antibiotics, such as penicillin and josamycin - stimulates the production of DEL-1 in vascular endothelial cells. Specifically, erythromycin interacts with the growth hormone secretagogue receptor (GHSR) and activates JAK2 and p38 MAPK signaling, leading to C/EBPβ-dependent DEL-1 expression. Moreover, systemic erythromycin treatment in mice increased DEL-1 expression in the PDL, which connects the tooth to the surrounding alveolar bone. The PDL of humans and animals, including mice, contains a mostly perivascular MSC niche involved in periodontal tissue regeneration and includes progenitor cells that can differentiate into osteoblasts.
We show that erythromycin and other macrolides restore DEL-1 expression in old mice and promote regeneration of bone lost due to naturally occurring, aging-related periodontitis. The same treatment increased the bone mass in the femurs of old mice. Importantly, EM-523, a non-antibiotic derivative of erythromycin, that retains the ability to activate a homolog of the GHSR, motilin receptor, reproduced the DEL-1-dependent effect of erythromycin on bone regeneration. Mechanistically, macrolide and EM-523 treatments induced the formation of new bone by upregulating alkaline phosphatase (ALP) activity and the expression of osteogenic genes in periodontal tissue while reducing the number of osteoclasts, thereby favorably influencing the osteogenesis/osteoclastogenesis balance. Periodontal bone lost due to periodontitis has limited capacity for regeneration even after standard treatment (scaling and root planing) and surgical periodontal therapy, especially in elderly patients. Therefore, the non-antibiotic compound EM-523 may represent a safe, effective, and affordable new approach to regenerate bone lost due to periodontitis in humans and perhaps for increasing the mineral content of the skeletal bone in the elderly.
Making a Mouse that Exhibits Human Telomere Dynamics
https://www.fightaging.org/archives/2024/02/making-a-mouse-that-exhibits-human-telomere-dynamics/
Telomerase acts to extend telomeres, the repeated DNA sequences at the ends of chromosomes. With every cell division, some of the telomere repeats are lost. Cells with critically short telomeres become senescent or undergo programmed cell death, having reached the Hayflick limit on replication. Some cells employ telomerase to adjust the countdown of telomere length. In humans, only stem cells use telomerase. In other species, such as mice, telomerase is much more widely expressed. There has been some interest in the research community in upregulation of telomerase as a way to improve stem cell and tissue function in old age.
One of the points of risk in bringing telomerase gene therapies to the clinic is that while the results to date in mice have been impressive, gene therapies producing extended life, improved function, reduced cancer incidence, mice have very different telomere dynamics from humans. Will the risk of extending the functional life of damaged, potentially cancerous somatic cells be offset by improved immune function in humans as it seems to be in mice? While some number of people have undergone telomerase gene therapy, largely via medical tourism, results for most of those patients will never be published, and long-term data on cancer risk will in any case take years to emerge.
In today's open access paper, researchers report on the development of a mouse lineage with a humanized telomerase gene and more human-like telomere dynamics. This will be a useful tool in the continued development of telomerase gene therapies. If telomerase gene therapy in this lineage turns out to produce much the same benefits as it does in wild type mice, with particular attention to cancer incidence, then one could be more convinced that risks in human patients are lower.
Humanization of the mouse telomerase gene reset telomeres to human length
Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene.
Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Tert(h/-) mice, telomere length progressively declined, stabilizing below 10-kb. Tert(h/h) mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert(h/h) mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres.
Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.
Modest Effects on Cognitive Decline from Multivitamin Use
https://www.fightaging.org/archives/2024/01/modest-effects-on-cognitive-decline-from-multivitamin-use/
Setting aside cases of vitamin deficiency, the consensus on supplement use (including vitamins) in essentially healthy individuals is that it does little to nothing, or is even mildly harmful to long-term health. That mild harm might include use of antioxidants that diminish the beneficial response to exercise that is mediated in part by oxidative stress. As a counterpoint to the consensus, researchers here provide evidence for multivitamin use to modestly improve cognitive function in later life. Whether this result will hold up in other study populations is a question, and we'll likely be waiting a while on the answer. It tends to take a long time for studies involving hundreds or thousands of participants to be organized, conducted, and analyzed.
The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a large-scale, nationwide, randomized trial rigorously testing cocoa extract and multivitamin supplements. Two previously published studies of cognition in COSMOS suggested a positive effect for a daily multivitamin. COSMOS researchers now report the results of a third study of cognition in COSMOS, which focused on participants who underwent in-person assessments, together with the results of a combined analysis from the three separate studies.
In the in-clinic study the researchers administered detailed, in-person cognitive assessments among 573 participants in the subset of COSMOS known as COSMOS-Clinic. In their prespecified analyses of data from COSMOS-Clinic, investigators observed a modest benefit for the multivitamin, compared to placebo, on global cognition over two years. There was a statistically significant benefit of multivitamin supplementation for change in episodic memory, but not in executive function/attention. The team also conducted a meta-analysis based on the three separate studies, with non-overlapping COSMOS participants (ranging 2-3 years in treatment duration), which showed strong evidence of benefits for both global cognition and episodic memory. The authors estimate that the daily multivitamin slowed global cognitive aging by the equivalent of two years compared to placebo.
Mechanisms for the Benefits to Long Term Vascular Health Provided by Exercise
https://www.fightaging.org/archives/2024/01/mechanisms-for-the-benefits-to-long-term-vascular-health-provided-by-exercise/
The vascular system responds favorably to exercise at any age. A large portion of the benefits of exercise derive from improvements to vascular function throughout the body, and physical fitness can be maintained further into old age than most people believe to be the case. The flip side of this point is that a sizable fraction of the declines of later life are a matter of disuse, people living a more sedentary life than is optimal for the health and function of muscles, heart, and brain. These the most energy-hungry tissues and those that see the worst outcomes from a decline in vascular function and consequently reduced delivery of nutrients and oxygen. Beyond the matter of blood supply, exercise is also protective against mechanisms involved in development of hypertension and atherosclerosis, as well as other conditions related to the vasculature. Overall, it is a good idea to maintain physical fitness for as long as possible in life, for these and other reasons.
Exercise-induced hemodynamic changes lead to mechanical stress of the vascular wall, the release of circulating growth factors from the endothelium, and the release of exerkines from the exercising skeletal muscle and other organs. These three main adaptive stimuli lead to an increased activity of several molecular pathways within the vascular endothelial and smooth muscle cells, culminating in a better vasodilation and vasoconstriction responsiveness, reduced arterial stiffness, arteriogenesis, and angiogenesis, higher antioxidative capacities, and reduced oxidative stress. Recent research revealed a potential role of enhanced mitochondrial biogenesis and mitophagy, substrate metabolism, and insulin sensitivity in the vascular smooth muscle cells for exercise-induced vascular adaptations.
Some vascular adaptations, such as a favorable balance of angiogenesis and angiostasis as well as of vasodilator and vasoconstrictor responsiveness, require regular exercise, ideally throughout the entire life span. Therefore, individualization of exercise according to objective and subjective factors should be sought to achieve the best possible long-term training adherence. Repeated stimuli, at least every other day at initial stages and progressively increasing to 5-7 days per week, might be necessary to use the full potential of favorable physiological alterations, such as elevated blood pressure and improved glycemic control, which last for about 24 hours post exercise.
The cumulative volume of elevated shear stress seems more important than peak shear stress in terms of stimulating vascular remodeling. Thus, prolonged moderate-intensity workouts may be favored over shorter sessions with very high intensities, especially if injury prevention and long-term training adherence are important. High-intensity interval training may have additional benefits in the long-term, such as increased antioxidative and metabolic capacities, and thus should also be part of vascular exercise training. Resistance and aerobic exercise induce distinct macro- and microvascular adaptations; thus, both types of exercise should be implemented in comprehensive training for optimal vascular health.
The Prospects for Treating Neurodegenerative Conditions by Modifying the Gut Microbiome
https://www.fightaging.org/archives/2024/01/the-prospects-for-treating-neurodegenerative-conditions-by-modifying-the-gut-microbiome/
The gut microbiome interacts with the body via a wide range of mechanisms, including induction of chronic inflammatory responses and delivery of both harmful and beneficial metabolites. With advancing age, the balance of populations making up the gut microbiome changes in ways that increase the harms while reducing the benefits. This may happen because the aged immune system becomes less able to clear problem microbes, but other mechanisms such as lifestyle changes and intestinal tissue aging may also contribute meaningfully. Fortunately, studies have demonstrated that making sizable, lasting changes to the gut microbiome is possible, such as via fecal microbiota transplant using a young donor. In animal studies, this can restore a more youthful balance of populations and thereby improve health and extend life.
Trillions of microbes live symbiotically in the host, specifically in mucosal tissues such as the gut. Recent advances in metagenomics and metabolomics have revealed that the gut microbiota plays a critical role in the regulation of host immunity and metabolism, communicating through bidirectional interactions in the microbiota-gut-brain axis (MGBA). The gut microbiota regulates both gut and systemic immunity and contributes to the neurodevelopment and behaviors of the host. With aging, the composition of the microbiota changes, and emerging studies have linked these shifts in microbial populations to age-related neurological diseases (NDs).
Preclinical studies have demonstrated that gut microbiota-targeted therapies can improve behavioral outcomes in the host by modulating microbial, metabolomic, and immunological profiles. In this review, we discuss the pathways of brain-to-gut or gut-to-brain signaling and summarize the role of gut microbiota and microbial metabolites across the lifespan and in disease. We highlight recent studies investigating 1) microbial changes with aging; 2) how aging of the maternal microbiome can affect offspring health; and 3) the contribution of the microbiome to both chronic age-related diseases (e.g., Parkinson's disease, Alzheimer's disease and cerebral amyloidosis), and acute brain injury, including ischemic stroke and traumatic brain injury.
Measuring Myelin Loss in the Aging Brain
https://www.fightaging.org/archives/2024/01/measuring-myelin-loss-in-the-aging-brain/
Myelin acts as an insulating sheath for the axonal connections that exist between neurons, and is necessary for the correct function of these connections. Demyelinating diseases such as multiple sclerosis are particularly debilitating due to the spreading and progressively worsening failure of the nervous system caused by loss of myelin. Unfortunately myelin is also lost to a lesser degree with advancing age, one of many consequences of accumulated molecular damage and maladaptive reactions to that damage. Here, researchers report on efforts to better measure the loss of myelin that occurs with age, comparing established with novel approaches to the challenge of measuring specific structural aspects of the living brain via imaging technologies.
The study of myelination in the brain is essential due to its profound impact on neural function. Myelin acts as an insulator, significantly increasing the speed and efficiency of electrical signal transmission within the nervous system, facilitating information processing and precise neuron communication. Myelination is crucial during early development and continues to influence learning, memory, and cognitive function throughout life.
Recent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelin-weighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry.
Our results show that the changes occurring in myelin network architecture due to aging have critical effects on network connection strength and efficiency. Specifically, we found that efficiency and mean strength extracted from myelin-weighted connectomes reach their highest point of development around 40 years of age; after this peak, the natural degeneration of axonal microstructure begins. In the broader context of our study, which explores the overall architecture of the myelin-weighted connectome, MySD outperforms traditional Tractometry-based approaches in detecting myelin network changes during normal aging.
Building Biological Age Clocks from Immune and Redox Markers
https://www.fightaging.org/archives/2024/01/building-biological-age-clocks-from-immune-and-redox-markers/
Any sufficiently large set of biological data can be used to produce clocks that measure biological age, where a clock is some weighted combination of measurements that produces age as an output. At this point novel clocks are much less interesting than standardizing on one clock and working towards a better understanding of how exactly the clock measurements relate to underlying processes of aging. Without that understanding it is impossible to use clock assessments of biological age to accelerate research and development of therapies to treat aging as a medical condition. One has to know that they clock does in fact correctly assess the burden of damage that is targeted specifically by the therapy, whether it is senescent cells, or mitochondrial dysfunction, or any of the many other options, or the clock results are simply not actionable. Nonetheless, researchers continue to produce new clocks at a fair pace these days, with this paper being an example of the type.
Immune function and redox markers are used for estimating the aging rate, namely biological age (BA). However, it is unknown if this BA and its changes can be reflected in longevity. Thus, we must quantify BA in experimental animals. In peritoneal immune cells of 202 female mice (ICR/CD1) in different ages, 10 immune and 6 redox parameters were evaluated to construct two mathematical models for BA quantification in mice by multiple linear regression. Immune and redox parameters were selected as independent variables and chronological age as dependent, developing two models: the Immunity and the Redox Clocks, reaching both an adjusted coefficient of determination of 80.9% and a standard error of 6.38 and 8.57 weeks, respectively.
Both models were validated in a different group of healthy mice obtaining a Pearson's correlation coefficient of 0.844 and 0.800 between chronological age and BA. Furthermore, they were applied to adult prematurely aging mice, which showed a higher BA than non-prematurely aging mice. Moreover, after positive and negative lifestyle interventions, mice showed a lower and higher BA, respectively, than their age-matched controls. In conclusion, the Immunity and Redox Clocks allow BA quantification in mice and both the ImmunolAge and RedoxAge in mice relate to lifespan.
Senolytic CAR T Cell Therapy Improves Health in Aged Mice
https://www.fightaging.org/archives/2024/01/senolytic-car-t-cell-therapy-improves-health-in-aged-mice/
To the degree that senescent cells in a tissue exhibit distinctive surface features, one can deploy technologies such as chimeric antigen receptor T cells to selectively destroy them. T cells will destroy whatever cell binds to the chimeric antigen receptor they are equipped with. This approach has been used with great success to treat cancers, and may also see some use in the clearance of senescent cells provided that the cost is somehow greatly reduced. At present it is a very expensive therapeutic modality, given that a patient's cells must be extracted, genetically engineered, cultured for weeks or more to expand their numbers, and then reintroduced into the patient. The use of universal cells may allow a more efficient therapy, but a gene therapy that targets only T cells is perhaps a more plausible near term approach.
Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals.
We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.
Removing Senescent Cells Makes Chemotherapy More Effective
https://www.fightaging.org/archives/2024/02/removing-senescent-cells-makes-chemotherapy-more-effective/
Cellular senescence is protective against cancer, at least initially. When cells become senescent due to potentially cancer-inducing damage, shutting down replication and secreting pro-inflammatory signals reduces the risk of cancer and attracts the immune system to clear out other potentially cancerous cells that have not become senescent. When senescent cells linger in larger numbers, however, they begin to aid cancer by changing the environment into one that favors the growth of cancerous tissue. Thus clearing senescent cells in conjunction with traditional cancer treatments is more effective for patients than the treatment on its own. Additionally, the established approaches of chemotherapy and radiotherapy produce a lasting burden of senescent cells in the course of killing the cancer. This harms patients, increasing their risk of age-related disease and reducing life expectancy, but senolytic therapies to clear those senescent cells may remove this well-established cost to successful cancer treatment.
Cancer treatments, including chemotherapy, in addition to killing a large number of tumour cells, also result in the generation of senescent tumour cells. While senescent cells do not reproduce, they do, unfortunately, generate a favourable environment for the expansion of tumour cells that may have escaped the effects of the chemotherapy and eventually result in tumour regrowth. Researchers have described how cancer cells that have become senescent after chemotherapy activate the PD-L2 protein to protect themselves from the immune system while recruiting immune suppressor cells. The latter creates an inhibitory environment that impairs the ability of lymphocytes to kill cancer cells.
Based on these findings, scientists wondered what would be the effect of inactivating PD-L2. Interestingly, senescent cells lacking PD-L2 are rapidly eliminated by the immune system. This intercepts the capacity of senescent cells to create an immunosuppressive environment and, as a result, lymphocytes retain their full capacity to kill those cancer cells that may have escaped the effects of chemotherapy. "By blocking PD-L2 in mouse models, we have seen that chemotherapy is more effective against cancer. This finding paves the way to consider the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease."
Age-Related Changes in the Prefrontal Cortex Associate with Loss of Memory
https://www.fightaging.org/archives/2024/02/age-related-changes-in-the-prefrontal-cortex-associate-with-loss-of-memory/
Researchers here investigate age-related changes correlating with loss of working memory. They work with mice, but produce results that line up with observations made in other species. How neural circuits function is one distinct way of looking at the brain. Like all such approaches, it is challenging to connect it to other distinct views of the aging brain, such as proteomic or transcriptomic or cell behavior or signaling changes, or the accumulation of specific forms of age-related molecular damage. Measuring one aspect of a complex system is one thing, figuring out how many different aspects fit together into a web of interacting causes and consequences is quite another.
Cognitive aging is the natural and gradual decline in cognitive function that occurs as people age and emerges as a major challenge for maintaining quality of life and employment. It is hence crucial to understand the neurobiology underlying cognitive aging in detail. Working memory (WM) decline is a fundamental aspect of cognitive aging and has the earliest onset among age-related cognitive deficits. Executive function is susceptible to aging. How aging impacts the circuit-level computations underlying executive function remains unclear. Using calcium imaging and optogenetic manipulation during memory-guided behavior, we show that working-memory coding and the relevant recurrent connectivity in the mouse medial prefrontal cortex (mPFC) are altered as early as middle age.
Population activity in the young adult mPFC exhibits dissociable yet overlapping patterns between tactile and auditory modalities, enabling crossmodal memory coding concurrent with modality-dependent coding. In middle age, however, crossmodal coding remarkably diminishes while modality-dependent coding persists, and both types of coding decay in advanced age. Resting-state functional connectivity, especially among memory-coding neurons, decreases already in middle age, suggesting deteriorated recurrent circuits for memory maintenance. Optogenetic inactivation reveals that the middle-aged mPFC exhibits heightened vulnerability to perturbations. These findings elucidate functional alterations of the prefrontal circuit that unfold in middle age and deteriorate further as a hallmark of cognitive aging.
CISD2 Upregulation Reduces the Senescence-Associated Secretory Phenotype in Aged Skin
https://www.fightaging.org/archives/2024/02/cisd2-upregulation-reduces-the-senescence-associated-secretory-phenotype-in-aged-skin/
CISD2 expression declines with age, while upregulation of CISD2 expression has been shown in mice to improve liver function and extend life span. This strategy is expected to have broad effects on function in many tissues beyond the liver. At least some of those benefits result from an increase in the efficiency of the complex cell maintenance processes of autophagy, recycling damaged and unwanted proteins and cell structures. As is the case for other approaches to slowing aging that function via autophagy, CISD2 upregulation has the effect of reducing senescent cell burden and suppressing the harmful senescence-associated secretory phenotype (SASP). Researchers here demonstrate this benefit in aged skin.
CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy.
We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging.
Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice.
Biomarkers for Immunosenescence
https://www.fightaging.org/archives/2024/02/biomarkers-for-immunosenescence/
The aging immune system exhibits a declining ability to destroy pathogens and dysfunctional, harmful cells. This is known as immunosenescence. There are ways to assess immune cell populations and their characteristics to measure the degree of immunosenescence, but this is comparatively costly and cannot be used on banked samples. Researchers here ask whether combinations of circulating proteins can instead be used to assess the degree of immunosenescence from a blood sample, and propose a few such biomarkers based on their analysis.
Inflammaging, the characteristics of immunosenescence, is characterized by continuous chronic inflammation that could not be resolved. It not only affects older people but can also occur in young individuals, especially those suffering from chronic inflammatory conditions such as autoimmune disease, malignancy, or chronic infection. This condition led to altered immune function and as consequent immune function is reduced. Detection of immunosenescence has been done by examining the immune risk profile (IRP), which uses flow cytometry. These tests are not always available in health facilities, especially in developing countries and require fresh whole blood samples. Therefore, it is necessary to find biomarkers that can be tested using stored serum to make it easier to refer to the examination.
Here we proposed an insight for soluble biomarkers which represented immune cells activities and exhaustion, namely sCD163, sCD28, sCD80, and sCTLA-4. Those markers were reported to be elevated in chronic diseases that caused early aging and easily detected from serum samples using ELISA method, unlike IRP. Therefore, we conclude that these soluble markers are beneficial to predict the pathological condition of immunosenescence.