Fight Aging! Newsletter, June 26th 2023

There is substantial evidence that most diseases in older age involve inflammation in the brain and/or body due to a chronic over-activation of pro-inflammatory cytokines over anti-inflammatory cytokines ("inflammaging"). By contrast, individuals in young adulthood and middle age have an immune system balanced in these two components, as do many centenarians (100+ years), effectively providing immune protection from environmental and body insults. We have therefore proposed that a gerotherapeutic that can "rebalance" pro- and anti-inflammatory cytokines in aged individuals will reduce the risk or severity of age-related diseases and increase healthy longevity. This perspectives paper provides clinical evidence that such a "rejuvenating" gerotherapeutic is not a drug, but rather a bioengineered medical device that provides Transcranial Electromagnetic Wave Treatment (TEMT), the MemorEM. In that regard, TEMT administration to aged/diseased individuals could be comparable to them receiving continual blood infusions from young adult or middle-aged individuals who have a balanced (youthful) immune system in their blood-the result being much reduced systemic inflammation and increased longevity through TEMT.

The results presented, and conclusions reached in this paper are based on our three published clinical papers involving the same mild/moderate Alzheimer's disease subjects given TEMT for a period of 30 months and evaluated at 2 months, and 14-31 months into that period. At 2 months into treatment, analysis of 11 cytokines in blood and 7 cytokines in brain/CSF revealed an extraordinarily consistent ability of TEMT to "rebalance" the largely pro-inflammatory status of the immune system in these subjects. Specifically, if a given cytokine's level was high in blood plasma or cerebrospinal fluid, TEMT reduced its levels to normal aged individuals, and vice versa if they were low. The mechanism for blood rebalancing of cytokines by TEMT appears to involve the unique ability of red blood cells to concentrate cytokines and to respond to electromagnetic waves by increasing their membrane fluidity to rebalance plasma cytokines with an appropriate flux of cytokines in or out across their membranes. We believe that the same rebalancing of blood/plasma cytokines by TEMT will occur in both normal aged and age-diseased individuals. This is because those cytokine levels in individual subjects that were near normal levels at baseline did not show a TEMT-induced change in their levels thereafter.

In its Phase III clinical trial, lecanemab became the first therapy to unambiguously put the brakes on the trainwreck of neurodegenerative aging. The monoclonal antibody cleared beta-amyloid protofibrils from patients' brains and slowed the downward plunge of Alzheimer's disease by some 27%, leading to FDA approval. And now comes donanemab, a monoclonal antibody that for the first time specifically targets beta-amyloid that has been cut down to and modified into pyroglutamate at position 3 (pE3-Abeta). While we are still awaiting publication in a peer-reviewed journal, the press release from Eli Lilly tells us that over the course of a relatively short trial, donanemab passed the goalpost of slowing the progression of Alzheimer's-type neurodegenerative aging (AD).

The people expressing disappointment with the donanemab trial results are absolutely right to insist that the ultimate goal should be to prevent AD from emerging - and to reverse it in its early stages if it does. As we've been highlighting for years, achieving this triumph will require the application of one of two "damage-repair" strategies. One approach is to begin removing beta-amyloid as soon as it starts to accumulate in the brain - meaning, in a person's forties or fifties. This would prevent beta-amyloid from driving tau aggregates widely across the brain, and thus prevent the destruction of neurons downstream. It would also likely prevent some of the excess senescent cell burden in the AD brain and better-preserve brain mitochondrial function.

Of course, that is not how these medicines are being used today. But while the clinical trials for these amyloid-clearing therapies didn't start that early in the disease process, part of the reason they succeeded was exactly that they began treating patients earlier in the disease process than had been done in previous trials. Starting to clear the brain of beta-amyloid alone in people experiencing "mild" cognitive impairment or early-stage AD was still not an early enough start to head off the cascade of horrors in the AD brain entirely - but it was early enough that doing so could still have a substantial effect.

To realize the full potential of removing beta-amyloid alone, you would want to begin treatment before the cascading destruction downstream of beta-amyloid had set in earnest - before people even began questioning whether they might be starting to slip. Happily, after the success of lecanemab in Phase III, the National Institutes of Health joined forces with Esai and decided to take this next logical step. Together, they have launched the AHEAD Study. This clinical trial will test lecanemab in volunteers with no evidence of cognitive impairment, but who have either intermediate (in one trial) or higher (in another) levels of beta-amyloid in their brains. The goal will be to see if starting at this early stage can keep people free from ever developing MCI and dementia in the first place.

Beta-amyloid clearance can potentially be made safer and more effective by replacing the current generation of binding antibodies with catabodies. Catabodies are catalytic antibodies that cleave their targets directly where they encounter them instead of having to bind to them and drag them to the circulation for eventual disposal via the liver or passive degradation. Catabodies offer the potential of greater safety since they break up their target on site, instead of having to drag it out through the brain's vasculature, where it may cause damage and inflammation. Indeed, the damage inflicted by wrenching beta-amyloid out of the brain is the most worrisome risk associated with the current beta-amyloid targeting antibodies, taking the form of vascular swelling and microbleeds.

Alzheimer's disease (AD), a neurodegenerative condition that affects approximately 24 million people worldwide, accounts for 60 to 70% of all dementia cases. Despite tremendous recent advancements in neurodegenerative disease research, the understanding of AD biology remains incomplete. Although amyloid-beta (Aβ) plaques and tau neurofibrillary tangles are considered hallmark features of AD, the past two decades have seen a surge in genomic studies that consistently point to the central role of microglia and neuro-immune dysfunction in the pathogenesis of AD. Concurrently, a large body of work has highlighted the potential relevance of peripheral immune changes, particularly pro-inflammatory signaling, in AD pathogenesis.

Evidence for a relationship between peripheral immune factors and AD has come primarily from epidemiological and observational research studies that demonstrate associations between (a) circulating inflammatory markers and (b) neurocognitive features. However, there is a growing body of literature supporting the role of acute inflammatory insults as potential catalysts for cognitive decline and AD. Here, we define acute inflammatory insult as an immune challenge - typically tissue injury or exposure to a pathogen - that produces, in most cases, a time-limited inflammatory response.

This review focuses on the evidence from clinical and translational research linking acute inflammatory insults to cognitive decline and AD. We review evidence for the role of both pathogen- and damage-mediated inflammatory insults in AD and provide current conceptualizations of mechanisms for and treatment of immune-mediated cognitive decline. Importantly, we outline critical next steps for understanding how acute inflammatory insults might impact AD pathological processes and influence clinical presentation. We provide guidelines to address gaps in the literature, outline methods for appraisal of infection-mediated outcomes, and highlight future studies that may accelerate therapeutic interventions.

Why do individuals manifest such wide differences in lifespan, health status across age, and susceptibility to infectious diseases? One possibility is that variations in an immune trait contribute to these differences. Given that infections are among the most impactful environmental factors that shape the human genome, optimal host responses to these microbial drivers of natural selection may have played a role in increasing longevity. Hence, immune mechanisms may have evolved based on conferred resistance to the ancestral burden of inflammatory stress associated with infectious diseases. Resistance mechanisms could include higher immunocompetence and prevention of uncontrolled inflammation. In contemporary times, these infection-resistance mechanisms may confer advantages for a lower comorbidity burden and longevity.

Our hypothesis regarding the identity of this advantageous trait is immunologic resilience (IR). We define optimal IR as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance and longevity (immunocompetence), as well as control inflammation during acute, repeated, or chronic immune (antigenic) stimulation associated with inflammatory stressors (e.g., infections or autoantigens). IR is rooted in the principle that repeated inflammatory (antigenic) exposures are inevitable throughout life, necessitating allostatic processes that mediate adaptation, ideally returning immunocompetence and inflammation to optimal or pre-exposure levels. With this definition, optimal IR is linked to a conjoined high immunocompetence (IC)-low inflammation (IF) state.

Individuals preserving optimal IR metrics manifested advantages for longevity and survival as well as resistance to severe COVID-19, HIV-AIDS, common acute respiratory viral infections, recurrent skin cancer, and sepsis-associated mortality. These advantages were observed after controlling for age, sex, and/or level of antigenic stimulation. Collectively, our findings suggest that the lower immune status observed with age may be driven by two distinct mechanisms, one being dependent on age and the other attributable to IR erosion/degradation, which occurs concurrently with age but is not dependent on age per se. Thus, among persons of similar age, an individual's susceptibility to disease risks/severity and mortality may relate to their antecedent and current capacity for preservation and/or restoration of optimal IR when experiencing inflammatory stress.

When cooking with biomass and fossil fuels, their incomplete burning can lead to air pollution, which can trigger pernicious effects on people's health, especially among the elderly, who are more vulnerable to toxic and harmful environmental damage. This study explored the association between different cooking fuel types and the risk of cancer and all-cause mortality among seniors constructing Cox regression models. Data were obtained by linking waves of 6, 7, and 8 of the Chinese Longitudinal Healthy Longevity Survey, which included a total of 7,269 participants who were 65 years old and over. Cooking fuels were categorized as either biomass, fossil, or clean fuels. And the effects of switching cooking fuels on death risk were also investigated using Cox regression models.

The results indicate that, compared with the users of clean fuels, individuals using biomass or fossil fuels were at a greater death risk for cancer [hazard ratios: biomass, 1.13; fossil, 1.16] and all causes [hazard ratios: biomass, 1.29; fossil, 1.32]. Furthermore, compared with sustained users of biomass fuels, individuals converting from biomass to clean fuels significantly reduced death risk for cancer [hazard ratio: 0.81] and all causes [hazard ratio: 0.76]. Similarly, all-cause death risk [hazard ratios: 0.77] was noticeably reduced among these participants converting from fossil to clean fuels than persistent users of fossil fuels.

Every cell in the human brain possesses a unique genome that is the product of the accumulation of somatic mutations starting from the first postzygotic cell division and continuing throughout life. Somatic mosaicism in the human brain has been the focus of several recent efforts that took advantage of key technological innovations to start elucidating brain development, aging, and disease directly in human tissue. On one side, somatic mutation occurring in progenitor cells has been used as a natural barcoding system to address cell phylogenies of clone formation and cell segregation in the brain lineage. On the other side, analyses of mutation rates and patterns in the genome of brain cells have revealed mechanisms of brain aging and disorder predisposition.

Accumulation of somatic mutations in aging brain cells informs on cell-type-specific disease predisposition. Somatic mutation in neurons is linked to neurodegeneration. In glial cells, however, somatic mutation may play a role in predisposing to tumor insurgence as we become older. Since there is very little neuronal turnover in the postnatal brain, clonal expansions are either congenital or the product of postnatal expansions within the glia lineage. Indeed, an increase in clonal oncogenic somatic mutations was observed in the white matter of the normal human cerebral cortex compared to the adjacent grey matter.

Recent studies have shown how certain pathological states are associated to increased somatic mutation rates in the human brain and to disease-specific mechanisms. Although current knowledge seems to suggest that increased somatic mutation in Alzheimer's disease is due to oxidative damage due to the disorder, the exact role of increased rates of somatic mutation in neurodegeneration remains unclear, as well as the limit beyond which somatic mutations are not tolerated, thus leading to cell death.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain, or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. "Due to a solid tumor's physical properties, it is challenging to design molecules that can enter these masses. Instead of creating a new molecule to do the job, we propose using cells that 'eat' invaders - macrophages."

Macrophages, a type of white blood cell, immediately engulf and destroy - phagocytize - invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage's innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine. "Macrophages recognize cancer cells as part of the body, not invaders. To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway - a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all 'self' cells - was the key to creating this therapy."

The engineered macrophages were put to the test on "tumoroids," conglomerates of mouse melanoma cells in culture plates. The macrophages cooperatively clustered around the cancer cells, picked them apart and progressively destroyed the tumor. When tested in vivo, the engineered cells were able to eliminate tumors in 80% of mice. Importantly, tumor elimination triggered an adaptive immune response. Weeks later, the anti-cancer immunoglobulin G antibody increased. This engineered macrophage therapy works best in combination with existing antibody therapy. One day, patients may be able to rely on these engineered cells to eliminate solid tumors as well as the need for future treatments.

Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis, and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin, and oleandrin in human cell lines under various modalities of senescence.

The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.

Transthyretin amyloidosis (ATTR) is caused by amyloid deposits composed of a blood protein called transthyretin (TTR). It can be hereditary or non-hereditary ("wild-type"). The build-up of these protein deposits in the heart is called ATTR amyloid cardiomyopathy (ATTR-CM). Current treatments aim to relieve the symptoms of heart failure, but do not tackle the amyloid, although a number of "gene-silencing" therapies are currently being trialed which reduce TTR protein concentration in the blood and thereby slow ongoing amyloid formation.

Advances in imaging techniques has meant substantially more people being diagnosed with the disease than was the case 20 years ago. Previously, diagnosis needed a biopsy (involving tissue taken from the heart). The imaging techniques also mean the burden of amyloid on the heart, and consequently the progression of the disease, can be more precisely monitored, making it easier to detect cases where the condition has reversed, rather than merely remaining stable. The latest study began when one man aged 68 reported his symptoms improving. This prompted the research team to look through records of 1,663 patients diagnosed with ATTR-CM. Out of these patients, two more cases were identified.

The three men's recoveries were confirmed via blood tests, several imaging techniques, and, for one patient, an assessment of exercise capacity. Scans showed heart structure and function had returned to a near-normal state and amyloid had almost completely cleared. An in-depth look at the records and assessments for the rest of the 1,663 patient cohort indicated that these three patients were the only ones whose condition had reversed.

One of the three men underwent a heart muscle biopsy that revealed an atypical inflammatory response surrounding the amyloid deposits (including white blood cells known as macrophages), suggesting an immune reaction. No such inflammatory response was detected in 286 biopsies from patients whose disease had followed a normal progression. Investigating this further, the researchers found antibodies in the three patients that bound specifically to ATTR amyloid deposits in mouse and human tissue and to synthetic ATTR amyloid. No such antibodies were present in 350 other patients in the cohort with a typical clinical course. If these antibodies could be harnessed, they could be combined with new therapies being trialed that suppress TTR protein production, enabling clinicians to clear away amyloid as well as preventing further amyloid deposition.

The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases.

This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited.

In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process.

We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks.

Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function.

Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.

Researchers have published the first Aging Fly Cell Atlas (AFCA), a detailed characterization of the aging process in 163 distinct cell types in the laboratory fruit fly. Their in-depth analysis revealed that different cell types in the body age differently, each cell type following a process involving cell type-specific patterns. As the flies aged, the researchers took samples when the animals were 30, 50 and 70 days old (the latter is equivalent to an 80-year-old person). At each time point, the team conducted single-nucleus RNA sequencing to analyze gene expression changes in individual cells in different organs and compared the results to those of young flies (5 days old).

The team examined four different aging features: cell composition changes, number of differentially expressed genes, change in the number of expressed genes and decline of cell identity. They found that as flies age, these features change as a group according to cell type-specific patterns. Aging impacts cellular composition across the whole fly. Fat body cells were among the cell types that increased in number the most, while muscle cells decreased the most. Neurons, however, did not show major changes in the number of cells during the fruit fly's life. In addition, the analysis of the genes expressed by different cell types in time revealed that fat cells show the largest difference between the number of genes expressed in young versus old fruit flies. The researchers also found that about 80% of all the cell types analyzed decreased the number of genes expressed, and 20% increased this number.

"A critical observation of this study is that cell type-specific aging patterns in cells can be used to gauge biological age, that is the relative aging status of an organism, independent of its chronological age. This will provide further insight into factors, such as diets, drugs and diseases, that may change the aging trajectory and hence make an organism 'younger' or 'older' than its chronological age."

Aging is the major risk factor for chronic disease development. Cellular senescence is a key mechanism that triggers or contributes to age-related phenotypes and pathologies. The endothelium, a single layer of cells lining the inner surface of a blood vessel, is a critical interface between blood and all tissues. Many studies report a link between endothelial cell senescence, inflammation, and diabetic vascular diseases.

Here we identify, using combined advanced AI and machine learning, the Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B (DYRK1B) protein as a possible senolytic target for senescent endothelial cells. We demonstrate that upon induction of senescence in vitro DYRK1B expression is increased in endothelial cells and localized at adherens junctions where it impairs their proper organization and functions. DYRK1B knock-down or inhibition restores endothelial barrier properties and collective behavior. DYRK1B is therefore a possible target to counteract diabetes-associated vascular diseases linked to endothelial cell senescence.