The immune system matures by deploying a number of responsive lymphocytes in the body and leaving behind memory cells after infection. However, the function of the immune system declines gradually with age, while chronic inflammation and autoimmune responses are enhanced, resulting in metabolic diseases, cardiovascular diseases, cancer, diabetes, and other attributable age-related diseases.

The radiation from the atomic bombs (A-bombs) dropped on Hiroshima and Nagasaki in 1945 has increased the risk of developing certain cancers and non-cancer diseases, including heart disease. Long-term epidemiological and clinical studies of A-bomb survivors have shown that there are significantly increased risks of age- and immune system/inflammation-related diseases among the A-bomb survivors. Although there is no direct evidence that radiation exposure-accelerated immunological aging increases the risk of certain cancers or cardiovascular diseases, it has been presumed that accelerated immunological aging due to radiation exposure is associated with increased risk of age-related diseases.

Reactive oxygen species (ROS) play an important role in immune responses; however, their excessive production and accumulation increases the risk of inflammation-related diseases. Although irradiation is known to accelerate immunological aging, the underlying mechanism is still unclear. To determine the possible involvement of ROS in this mechanism, we examined 10,023 samples obtained from 3,752 atomic-bomb survivors in Hiroshima and Nagasaki, who participated in repeated biennial examinations from 2008 to 2016, for the effects of aging and radiation exposure on intracellular ROS (H2O2 and O2-) levels, percentages of T-cell subsets, and the effects of radiation exposure on the relationship between cell percentages and intracellular ROS levels in T-cell subsets.

The percentages of naïve CD4+ and CD8+ T cells decreased with increasing age and radiation dose, while the intracellular O2- levels in central and effector memory CD8+ T cells increased. Additionally, when divided into three groups based on the percentages of naïve CD4+ T cells, intracellular O2- levels of central, and effector memory CD8+ T cells were significantly elevated with the lowest radiation dose group in the naïve CD4+ T cells. Thus, the radiation exposure-induced decrease in the naïve CD4+ T cell pool size may reflect decreased immune function, resulting in increased intracellular ROS levels in central and effector memory CD8+ T cells, and increased intracellular oxidative stress.

Based on the results of this study, we hypothesize that past radiation exposure, particularly high-dose exposure, affects T-cell function and enhances the persistent inflammatory state, thereby increasing T-cell ROS levels in the blood. To test this hypothesis, we continue to investigate changes in the immune and clinical status with radiation exposure and aging, as well as, an increased risk of disease onset due to radiation exposure in A-bomb survivors, based on interactions between intracellular ROS levels and immune and inflammatory biomarkers. We expect that these studies will provide concrete evidence for the hypothesis of "accelerated immune aging due to radiation exposure".

Glycogen phosphorylase (Pyg) catalyzes the first and rate-limiting step in the process of glycogen degradation (glycogenolysis). Inhibition of Pyg was shown to block memory formation in young chickens and induction of the Long Term Potentiation (LTP, a cellular/molecular mechanism of memory formation) in hippocampi and hippocampal slices isolated from young rodents. It was also shown that impairment of synaptic plasticity after Pyg inhibition was associated with decreased transport of glycogen-derived lactate from astrocytes to neurons in a process called the astrocyte-neuronal lactate shuttle (ANLS). The impact of the astrocytic glycogen-derived lactate on neuronal metabolism is the subject of ongoing debate and the mechanism by which this pool of lactate stimulates the LTP is not fully understood. However, it is commonly accepted that disruption of the ANLS affects memory formation.

In contrast to the young animals, inhibition of glycogen breakdown in hippocampal sections isolated from adult and aged rodents was shown to improve the LTP formation, elevating significantly its magnitude. Moreover, in hippocampal slices isolated from old animals, significant alterations in morphology of dendritic spines were observed after inhibition of Pyg, indicating changes in dendritic spines maturation. Mechanisms underlying this different response to Pyg inhibition remain to be discovered but they might be associated with a different organization of hippocampal formation in young and aged animals and global changes in the expression of hippocampal proteins, and in the NAD+/NADH metabolism during aging.

Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice. This was accompanied by changes in morphology of dendritic spines in hippocampal neurons, and by "rejuvenation" of hippocampal proteome. In contrast, in young animals, inhibition of glycogen degradation impaired memory formation; however, as in old mice, it did not alter significantly the morphology and density of cortical dendritic spines. Our findings provide evidence that prolonged inhibition of glycogen phosphorolysis improves memory formation of old animals. This could lead to the development of new strategies for treatment of age-related memory deficits.

Recent insights suggest that remnant cholesterol (RC) plays a role in cellular senescence, yet its specific contribution to frailty remains indeterminate. Through the integration of observational and Mendelian randomization (MR) studies, this research explores the impact of elevated serum RC levels on frailty susceptibility. The observational study included 11,838 participants from the National Health and Nutrition Examination Survey. To circumvent observational study limitations, a two-sample MR analysis was conducted using the inverse-variance weighted method, leveraging genome-wide association studies (GWAS) data.

After adjusting for potential confounding variables, the observational study identified a significant association between high serum RC levels and frailty in middle-aged and older adults (odds ratio [OR] = 1.67), exhibiting a non-linear dose-response correlation. This association persisted after propensity score matching (OR = 1.53). The MR study echoed these results, demonstrating a causal association of RC with the frailty index (β = 0.059), consistent with the observational findings (β = 0.017).

Despite a lack of direct epidemiological evidence linking serum circulating RC levels to frailty, recent MR studies have spotlighted the influential role of elevated LDL-C levels in inducing frailty. Substantial increases in RC levels have been documented in adults consuming high-fat diets. The same diets administered to mice resulted in a heightened frailty level, while simultaneously diminishing the anti-frailty benefits of intermittent fasting. Consequently, this indirect evidence suggests a connection between higher RC levels and a heightened frailty risk, which this study substantiates.

Although increased serum RC levels are regarded as a potent independent risk factor for CVD, this analysis reveals that the association between serum RC levels and frailty persists, even after adjusting for CVD and T2DM. This suggests that the contribution of RC to frailty risk is not exclusively attributed to a higher susceptibility to CVD. Furthermore, the results from our epidemiological studies and multivariable MR confirm that this association remains significant, regardless of total cholesterol or LDL-cholesterol levels.

DNA methylation is a mechanism by which cells can control gene expression - turning genes on or off. In these studies, the researchers focused on DNA methylation differences across species at locations where the DNA sequence is generally the same. To study the effects of DNA methylation, the nearly 200 researchers - collectively known as the Mammalian Methylation Consortium - collected and analyzed methylation data from more than 15,000 animal tissue samples covering 348 mammalian species. They found that changes in methylation profiles closely parallel changes in genetics through evolution, demonstrating that there is an intertwined evolution of the genome and the epigenome that influences the biological characteristics and traits of different mammalian species.

Methylation, as evidenced by the epigenetic "marks" it leaves, bears a substantial correlation with maximum life span across mammalian species. Maximum life span of a species is associated with specific developmental processes, as suggested by the involvement of certain genes and genetic transcription factors. Cytosines whose methylation levels correlate with maximum life span differ from those that change with chronological age, suggesting that molecular pathways pertaining to average life span within a species are distinct from those determining the species' maximum life span.

Researchers used a subset of the database to study the methylation profiles of 185 species of mammals. Identifying changes in methylation levels that occur with age across all mammals, they developed a "universal pan-mammalian clock," a mathematical formula that can accurately estimate age in all mammalian species.

Comparative epigenomics is an emerging field that combines epigenetic signatures with phylogenetic relationships to elucidate species characteristics such as maximum life span. For this study, we generated cytosine DNA methylation (DNAm) profiles (n = 15,456) from 348 mammalian species using a methylation array platform that targets highly conserved cytosines. We first tested whether DNAm levels in highly conserved cytosines can capture phylogenetic relationships among species. We constructed phyloepigenetic trees that paralleled the traditional phylogeny. To avoid potential confounding by different tissue types, we generated tissue-specific phyloepigenetic trees. The high phyloepigenetic-phylogenetic congruence is due to differences in methylation levels and is not confounded by sequence conservation.

We then interrogated the extent to which DNA methylation associates with specific biological traits. Both the epigenome-wide association analysis (EWAS) and eigengene-based analysis identified methylation signatures of maximum life span, and most of these were independent of aging, presumably set at birth, and could be stable predictors of life span at any point in life. Several CpGs that are more highly methylated in long-lived species are located near HOXL subclass homeoboxes and other genes that play a role in morphogenesis and development. Some of these life span-related CpGs are located next to genes that are also implicated in our analysis of upstream regulators (e.g., ASCL1 and SMAD6). CpGs with methylation levels that are inversely related to life span are enriched in transcriptional start site and promoter flanking associated chromatin states. Genes located in chromatin state TSS1 are constitutively active and enriched for nucleic acid metabolic processes. This suggests that long-living species evolved mechanisms that maintain low methylation levels in these chromatin states that would favor higher expression levels of genes essential for an organism's survival.

Despite the intriguing connection between lipid metabolism and aging, it is still unknown whether and how inter-individual differences in lipid profiles contribute to different rates of biological aging in the general population. The heterogeneous chemical structure of lipids poses challenges for their accurate quantification, and until now only a few lipid species have been investigated in the context of human aging and age-related health outcomes. We investigated 14 complex lipid classes, covering 964 molecular species and 267 fatty acid composites, with biological aging. We found complex lipid species to be differently associated with different rates of biological aging. Higher levels of molecular species belonging to the neutral lipids (MAG, DAG, TAG), phospholipids (PE, PE(O), PE(P)), and sphingolipids (CER, DCER) classes were associated with accelerated biological aging, whereas higher levels of distinct other molecular species (i.e., LPC, HCER, and LCER) were associated with slower biological aging. CE, PC, and LPE molecular species with odd-numbered (i.e., 15 and 17) fatty acid tail lengths were associated with slower biological aging, yet even-numbered fatty acid tail lengths were associated with faster biological aging. Importantly, in silico pathway analysis revealed that lipids that were associated with biological aging estimators were mainly involved in known longevity and aging-related pathways, revealing their role as potential determinants of biological aging across the lifespan in the general population.

Very little work has explicitly assessed the value of LPC species as potential human blood-derived biomarkers of human aging. Circulating LPCs are generated by phospholipases A2 from the PC. The most abundant LPC in human plasma is 16:0, followed by 18:2, 18:0, 18:1, 20:4, and other minor species. Here we found that higher levels of 13 out of 19 LPC species exhibit a robust association with slower biological aging, suggesting that LPC species may contribute to healthy aging. Our findings expand on those from recent epidemiological studies, which assessed a limited number of LPC species, and reported low concentrations of certain circulating LPCs (i.e., 18:2 and/or 17:0) to be associated with several aging-related phenotypes and disorders, including memory impairment, gait speed decline, and incident myocardial infarction. Moreover, elevated LPC (18:1) levels have been reported in centenarians. Potential biological mechanisms through which LPCs could contribute to slower biological aging and less age-associated functional decline are anti-oxidative stress and anti-inflammatory responses.

The major phospholipids in eukaryotic biomembranes are phosphatidylcholine (PC), and phosphatidylethanolamine (PE), which were also quantified in our study. PC can be synthesized by a three-step methylation of PE. We found that higher levels of various PE species were related to accelerated biological aging across the lifespan, whereas higher levels of polyunsaturated PCs were associated with slower biological aging. Higher levels of species with fewer double bonds tended to be associated with accelerated biological aging. These findings are in line with previous studies that found associations between higher levels of saturated and monounsaturated PCs and increased risk of cardiovascular diseases and type 2 diabetes. Conversely, polyunsaturated PC species have been linked to longevity, which might be due to their antioxidative and cardioprotective properties. PE species, the second most abundant membrane phospholipids, have been identified as modulators of inflammation and apoptosis, yet little is known about the properties of specific PE species.

Higher TAG levels are linked to an increased risk of cardiovascular diseases and Alzheimer's disease. Small-scale lipidomic profiling in longevity studies also found lower levels of TAG species (including TAG 46:5, 47:5, 52:1, 54:7, 54:6, 56:6, 56:7, 57:2) to be associated with healthy aging. Our findings extend these previous reports by showing that 361 out of 519 TAG species across different chain lengths and double bonds were associated with accelerated biological aging. Few studies have investigated the association between other neutral lipids (including CE, MAG, and DAG) and longevity or healthy aging. We found that higher levels of DAG species or lower levels of CE species were related to an accelerated rate of biological aging, indicating that almost all neutral lipids could potentially influence longevity.

We recently published selective destruction theory (SDT), which suggests a mechanism of ageing which is both independent of accumulating damage and consistent with epigenetic rejuvenation. We argue that in multicellular organisms, neighbouring cells are in constant competition. When mutations arise that increase a cell's growth rate, they bestow a selective advantage (an extreme example would be cancer, but most will not be). If these cells are uncontrolled, their growth advantage will allow them to spread, and their overactive metabolism could result in a host of detrimental or even lethal overactivity disorders. For example, in β-cells where growth is tied to insulin production, fast mutants spreading could produce a lethal drop in blood glucose. Another less tissue-specific example is the increased propensity of fast growing/metabolising fibroblasts to reach the critical threshold required for fibrosis.

Fast mutants are also likely to be more tumorigenic, while slow mutants will be less active, less fibrotic, and less tumorigenic even compared to wildtype cells. We therefore proposed that a maintenance mechanism which selectively destroyed fast cells might undergo positive selection even if it caused the spread of slow mutants as it would reduce the risks of overactivity disorders. The mechanism of selective destruction is currently theoretical. In our most developed model, we demonstrated that if slow cells induced epigenetic changes in faster cells causing their metabolism to slow (rather than killing them) it not only reduced unnecessary cell death, but also further reduced the likelihood of overactivity disorders by preventing the spread of fast cells. The resulting epigenetic growth suppression could therefore reflect a kind of ageing program designed to prevent overactivity disorders, and may explain why the methylation of specific CpG islands provides such accurate ageing clocks. It would also explain epigenetic rejuvenation by Yamanaka factors and parabiosis, so we predict that methylation of CpG islands will affect cell growth.

Visuospatial processing speed underlies several cognitive functions critical for successful completion of everyday tasks, including driving and walking. While it is widely accepted that visuospatial processing speed peaks in early adulthood, performance across the lifespan remains incompletely characterized. We developed a novel visuospatial processing speed (VIPS) task adapted from two tests sensitive to visuospatial processing speed declines in older adults, the Useful Field of View paradigm and the PERformance CEntered Portable Test. The VIPS task requires participants to make a central orientation discrimination and complete a simultaneous peripheral visual search task.

Data were collected from 86 in-lab volunteers (18-30 years) to compare performance to traditional neuropsychological measures. Consistent with previous literature, performance on the novel VIPS task significantly correlated with measures of selective attention, executive functioning, visual speed, and working memory. An additional 4,395 volunteers (12-62 years) were recruited on TestMyBrain.org to establish lifespan trajectories of visuospatial processing speed and associations with functional disability. VIPS task performance peaked in the early 20's, and steadily decreased such that thresholds doubled in 60-year-olds relative to 20-year-olds (817 ms vs. 412 ms).

VIPS task performance significantly correlated with self-reported cognitive functioning deficits broadly across the lifespan but was specifically related to mobility issues in middle-age. These findings have important implications for early detection of cognitive decline and provide insights into potential early intervention targets for younger and middle-aged adults.

Emerging evidence indicates the critical roles of microbiota in mediating host cardiac functions in ageing, however, the mechanisms underlying the communications between microbiota and cardiac cells during the ageing process have not been fully elucidated. Bacterial DNA was enriched in the cardiomyocytes of both ageing humans and mice. Antibiotic treatment remarkably reduced bacterial DNA abundance in ageing mice. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into cardiomyocytes in ageing mice, causing cardiac microbial DNA enrichment.

Vsig4+ macrophages efficiently block the spread of gut mEVs whereas Vsig4+ cell population was greatly decreased in ageing mice. Gut mEV treatment resulted in cardiac inflammation and a reduction in cardiac contractility in young Vsig4-/- mice. Microbial DNA depletion attenuated the pathogenic effects of gut mEVs. cGAS/STING signaling is critical for the effects of microbial DNA. Restoring Vsig4+ macrophage population in ageing WT mice reduced cardiac microbial DNA abundance and inflammation and improved heart contractility.

Frailty is a geriatric syndrome that results from multisystem impairment caused by age-associated accumulation of deficits. The frailty index is used to define the level of frailty. Several studies have searched for molecular biomarkers associated with frailty, to meet the needs for personalized care. Cyclase-associated protein 2 (CAP2) is a multifunctional actin-binding protein involved in various physiological and pathological processes, that might reflect frailty's intrinsic complexity.

This study aimed to investigate the association between frailty index and circulating CAP2 concentration in 467 community-dwelling older adults (median age: 79; range: 65-92 years). The selected robust regression model showed that circulating CAP2 concentration was not associated with chronological age, as well as sex and education. However, circulating CAP2 concentration was significantly and inversely associated with the frailty index: a 0.1-unit increase in frailty index leads to ~0.5-point mean decrease in CAP2 concentration. Furthermore, mean CAP2 concentration was significantly lower in frail participants (i.e., frailty index ≥0.25) than in non-frail participants.

This study shows the association between serum CAP2 concentration and frailty status for the first time, highlighting the potential of CAP2 as a biomarker for age-associated accumulation of deficits.

Dietary restriction (DR) is the most reproducible and effective nutritional intervention tested to date for delaying the aging process and prolonging the health span in animal models. Preventive effects of DR on age-related diseases have also been reported in human. In addition, highly conserved signaling pathways from small animal models to humans mediate the effects of DR. Recent studies have reported that DR-induced longevity is regulated by innate immune signaling components.

In C. elegans, the transcription factor ZIP-2 is an innate immune signaling component molecule that is upregulated in response to infection by Pseudomonas aeruginosa (PA14), and is necessary for survival against PA14 infection. It has been reported that ZIP-2 is a key mediator of the effects of DR on healthy aging in C. elegans. ZIP-2 activity increased in response to DR, and zip-2 was necessary for DR-induced longevity and physical activity improvement in worms subjected to DR. ZIP-2 activity was increased by inhibition of the TOR signaling pathway and rapamycin treatment. It was concluded that zip-2 extends longevity through TOR/S6K inhibition by DR.

Consistent with the results in C. elegans, acute DR boosts innate immunity in Drosophila. DR via yeast restriction enhanced Drosophila survival against PA14 infection, and reduced TOR signaling protected flies from pathogenic bacterial infection. In addition, researchers confirmed the beneficial effects of yeast restriction on Drosophila immunity following rapamycin treatment.

The p38-MAPK signaling pathway is an important innate immune pathway that is highly conserved from C. elegans to human. It was reported that the p38-MAPK signaling pathway is related to longevity extension by DR in C. elegans. They found that DR maintained the level of the p38-ATF-7 (ATF-7 is a transcription factor downstream of p38) innate immune response at the basal activation level, and that maintaining p38-ATF-7 activity at the basal level is an important factor for longevity in C. elegans. Thus, these results imply that the regulation of immune signals by DR is an important mechanism for extending longevity.

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as in the use of machine learning for analysing ageing-related data. In this work, we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four types of datasets for predicting whether or not a compound extends the lifespan of C. elegans (the most frequent model organism in DrugAge), using four different types of predictive biological features, based on: compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBase's Phenotype Ontology.

To analyse these datasets, we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. In addition, we interpreted the most important features in the two best models in light of the biology of ageing. One noteworthy feature was the GO term "Glutathione metabolic process", which plays an important role in cellular redox homeostasis and detoxification. We also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds. These include nitroprusside, which is used as an antihypertensive medication. Overall, our work opens avenues for future work in employing machine learning to predict novel life-extending compounds.

For a long time, reactive microglia have been considered a consequence of Alzheimer's disease (AD) pathology; however, they are now regarded as potentially playing a role in disease progression and maybe initiat$ion. Sustained microglia inflammation has been identified as a contributor to AD pathogenesis, as the release of inflammatory cytokines, chemokines, and complement proteins increases amyloid-β (Aβ) production. In addition, microglia have been shown to be involved in the clearance of Aβ plaque, which is impaired in AD due to mutations in microglia-related genes, including P2ry12, Apoe, and Trem2. Furthermore, with impaired microglia clearance, debris and other byproducts are diverted for clearance to other brain cells, such as endothelial cells, which do not proliferate efficiently and exhibit similar dysfunction, resulting in cell death and impaired blood flow.

Thus, targeting microglia offers a potential therapeutic opportunity for AD. We have previously demonstrated that a single systemic transplant of wild-type hematopoietic stem and progenitor cells (HSPCs) led to long-term rescue in both mouse models for cystinosis, a lysosomal storage disease, and Friedreich's ataxia, a neurodegenerative disease. In Friedreich's ataxia mouse model, transplanted HSPCs engrafted and differentiated into microglia in the brain and spinal cord, and into macrophages in the dorsal root ganglions (DRGs), resulting in the preservation of the neurons and locomotor function. Efficient replacement of microglia in the central nervous system (CNS) by bone marrow stem cell transplantation has previously been described. Therefore, because microglia may play an important role in AD, we hypothesized that wild-type (WT) HSPC transplantation could result in the generation of healthy microglia that may have a beneficial impact on AD.

Our study showed that single systemic wild-type (WT) hematopoietic stem and progenitor cell (HSPC) transplantation rescued the AD phenotype in 5xFAD mice and that transplantation may prevent microglia activation. Indeed, complete prevention of memory loss and neurocognitive impairment and decrease of β-amyloid plaques in the hippocampus and cortex were observed in the WT HSPC-transplanted 5xFAD mice compared with untreated 5xFAD mice and with mice transplanted with 5xFAD HSPCs. Neuroinflammation was also significantly reduced. Transcriptomic analysis revealed a significant decrease in gene expression related to "disease-associated microglia" in the cortex and "neurodegeneration-associated endothelial cells" in the hippocampus of the WT HSPC-transplanted 5xFAD mice compared with diseased controls. This work shows that HSPC transplant has the potential to prevent AD-associated complications and represents a promising therapeutic avenue for this disease.

Parkinson disease (PD) is the most common neurodegenerative movement disorder, characterized pathologically by the abnormal accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites and resulting in the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Due to activation of tissue-resident macrophages and the infiltration of both innate and adaptive immune cells, neuroinflammatory mechanisms have been strongly implicated in the neurodegeneration associated with α-syn accumulation.

Central nervous system (CNS) resident macrophages (CRMs) may be key antigen-presenting cells that orchestrate neuroinflammatory and neurodegenerative responses. CRMs include microglia in the parenchyma and border-associated macrophages (BAMs) that reside in the choroid plexus, dural and subdural meninges, and are adjacent to the vasculature within the perivascular space. It is important to note that BAMs have also been referred to as CNS-associated macrophages (CAMs) to highlight their anatomical location.

We found that border-associated macrophages (BAMs) play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen-presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation.

Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

While medical science has prodigiously slashed death from atherosclerosis, very little progress has been made against other kinds of "heart disease." Deaths from pulmonary heart disease, heart valve disease, and notably disordered heartbeat (arrhythmia) have remained at the same stubborn levels for decades. Worse yet: after years of making at least incremental progress against heart failure and hypertensive heart disease, the number of people suffering from these degenerative heart conditions is now rising again. In the face of this rising threat, the really good news at the center of this post is that the biotech company Neurimmune and their pharma partner AstraZeneca have just run an early-stage trial of a new AmyloSENS therapy that directly removes a malformed protein from patients' hearts. The study was small, but it found no signal for danger, and the data suggest that the antibody successfully pried its target loose from the patients' heart tissue - and that their hearts beat more freely as a result.

Cardiac amyloids are chains of malformed proteins that have twisted out of shape, bound together in chains, and worming its way into the gaps between the heart muscle cells. These deposits then physically impede the heart muscle as it attempts to expand and contract to keep the precious blood of life flowing to our tissues. The most common kind of amyloid afflicting the aging heart is composed of malformed transthyretin (TTR). Mutations in the TTR gene cause a tiny fraction of all the cases of life-threatening cardiac amyloid heart disease. But even the standard-issue TTR protein is inherently unstable and occasionally contorts out of its proper conformation, with the result that TTR cardiac amyloid accumulates in all of us progressively with age. The vast majority of cardiac amyloid disease is caused by the accumulation of this molecular aging damage, which impairs the function of our hearts, even in people who are technically below the threshold at which it is diagnosed as a "disease."

Scientists recently reported the results of a phase 1 clinical trial of NI006, an antibody designed to latch on to TTR amyloid and pry it loose from the heart. This is a critical difference between NI006 and other TTR amyloid treatments that are either in use or currently in development. Previous therapies have been designed to merely slow down the rate at which new cardiac amyloid accumulates, either by partially stabilizing the rattletrap TTR protein or by throttling down the body's ability to produce the protein in the first place. By contrast, NI006 is a true "damage-repair" therapy: if it works, it could prevent and even reverse cardiac amyloid by directly removing existing deposits of mangled TTR from the heart. We can't fully hang our hats on the results of a study with so few patients - but all the results they did see were encouraging. In just the initial four months of treatment, imaging scans of volunteers who got real NI006 showed that much of the amyloid that had invaded their heart muscles had been cleared out - and the amyloid continued to disappear as they continued to receive NI006 during the eight months of all-comers treatment.

By definition, Phase I trials are preliminary - but the Phase I trial for NNC6019 was even more tentative than that for NI006. This author guesses that the reason for this was budgetary constraints. NNC6019 was developed by immunizing mice with a short stretch of TTR protein that is normally shielded from the immune system through its appropriate folding, but which can be exposed when TTR has twisted out of its normal conformation. They then harvested the antibodies the mice produced in response to the normally-shielded fragment and screened them for properties that would make an antibody useful as an AmyloSENS therapy for TTR amyloidosis. With only seven subjects to fully evaluate and no placebo control group, we have to be careful not to cling too tightly to the results of this trial - but those results were quite positive. The seven subjects who had received all doses of NNC6019 suffered barely any worsening on the score of their neuropathy: an increase of 1.29 points, versus a typical 9.2-point exacerbation over a comparable time. And neuropathy didn't progress at all in the two subjects who were receiving only NNC6019 and no other anti-amyloid therapy.

T regulatory cells (Tregs) have the important job of stopping the other T cells from releasing too many inflammatory, or cytotoxic, molecules as they fight infection. Some T cells contribute to atherosclerosis by attacking a molecule called apolipoprotein B (APOB), the main component in the "bad" cholesterol that builds up into dangerous plaques in the arteries. These T cells ramp up their attacks as atherosclerosis worsens, likely adding to inflammation in the arteries. The weird thing is that these T cells look a lot like the normally helpful Tregs. A new study reveals the true identities of these cells: they are exTregs. ExTregs are like zombie Tregs. They've gone through a genetic "deprogramming" and lost their ability to help regulate inflammation. Scientists don't know exactly why exTregs develop, but the phenomenon may happen when the body misses the mark in an attempt to adapt to chronic disease.

Researchers tagged both Tregs and harmful exTregs in a mouse model prone to atherosclerosis. These fluorescent red and green tags glowed when Tregs were functioning normally. A switch from green and red to only red revealed exTreg development in real time. The team then took organ samples from the mice and used a technique called flow cytometry to detect the green and red tags to sort the Tregs from the exTregs. The researchers used techniques called bulk RNA sequencing to learn more about these cells. The sequencing highlighted vast differences in gene expression and showed that exTregs make a distinct set of genes that sets them apart from Tregs.

Next, the researchers used the exTreg markers found in mice to transpose them to a single cell RNA sequencing performed on human blood samples. Through this process, they successfully identified biomarkers for human exTregs. The researchers found that the exTreg biomarkers they'd seen in mouse samples were also relevant for human exTregs. They discovered that exTregs from humans with atherosclerosis are potentially more potent. Going forward, the researchers hope to use exTreg biomarkers to detect and study the roles of these cells in other chronic health conditions, such as in patients with autoimmune diseases. Resesearchers also interested in studying samples from the same individual patients taken over time. How might exTreg biomarkers change as atherosclerosis changes? Would they see decreased signs of exTregs if a patient was put on an effective medication?