Fight Aging! Newsletter, September 4th 2023

Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients.

Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T cells and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD.

Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the central nervous system, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating central nervous system fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.

Multiple clinical conditions and pathophysiological processes have long been considered as inescapable and unmodifiable consequences of the aging process. However, these perceptions are changing. Over the past few decades, research focusing on the interplay between the fundamental processes of aging and the biology of co-morbidities has given rise to the concept of Geroscience, the goal of which is to develop new biologically-based therapeutic and preventive approaches that target fundamental aging processes; thus, to decrease age-related multi-morbidities as a group and improve healthspan.

The beneficial effect of using Gerotherapeutic drugs to modulate the fundamental molecular, cellular, and/or genetic mechanisms of aging has been demonstrated in animal models, and offers exciting preventive and even curative therapeutic translational opportunities in humans. However, Geroscience trials face numerous methodological challenges in their study design regarding the demonstration of clinical effectiveness successfully in humans. One critical challenge is that the usual design of therapeutic clinical trials is centered on disease-specific diagnosis and physiopathology, whereas Geroscience trials aim to target mechanisms of aging in order to delay or prevent the onset or reduce the progression of multiple age-related diseases, geriatric syndromes, and potentially alleviate or treat such conditions.

The European Medicine Agency (EMA) and the Food and Drug Agency (FDA) have high concordance (91-98%) in decisions on marketing approvals, but the arrival of gerotherapeutic drugs will challenge both agencies to define the terms of marketing approval in the context of Geroscience. Being an emergent discipline, Geroscience will challenge some of the established protocols for fast approval of new drugs and biomarkers needed to meet the challenges of an aging society. In general, FDA or EMA approve drugs for treating diseases; however, aging by itself is not currently considered as a "disease", but as the major risk factor for multiple morbidities.

Basic scientists, clinicians, and drug agency officials already interact so that the concept behind Geroscience is understood and shared. A scale for evaluating FDA-approved drugs for their Gerotherapeutic potential has been proposed. In this context, it is important to highlight that the design of the TAME (Targeting Aging with MEtformin) trial has been approved by the FDA; TAME aims to delay mortality and the onset of several age-related diseases (e.g., myocardial infarction, stroke, cancer, dementia) and conditions (e.g., major decline in mobility or cognitive function) rather than targeting a single disease. The TAME trial may serve as a proof of concept that proves to the medical agencies that aging can be a therapeutic indication in itself. This result would favor conditions for defining new marketing approval, type of approval, and approved indication for new or already approved drugs and will be incentive for pharmaceutical companies to invest in research on Geroscience.

Designing a disease-centric trial remains the only way to date to gain approval from the FDA or EMA, each of which still adheres to the "one disease, one drug" model. The regulatory constraints required for a new drug to be brought to patients and the extent to which the patients benefit from it must also be taken into consideration when designing a trial. However, targeting a single pathology in a clinical trial is not without risk either. Diagnostic criteria change over time, in particular with the emergence of biomarkers, not-withstanding that most diseases of ageing are of complex etiology, resulting from (still poorly understood) interactions between non-modifiable factors (including age, sex, and genetic predisposition) and modifiable factors, related to environmental and other exposures, lifestyle factors, etc. Moreover, it should be emphasized that some Gerotherapeutic drugs could have a very modest and difficult to demonstrate effect in organs evaluated separately, but have a clinically significant overall effect due to their action on the whole organism, and the alternative also exists that a study using a composite score might fail to capture substantial changes within just one domain if not statistically powered for that endpoint alone. A trial centered on only one function or disease is the current conventional approach but is probably not appropriate for certain molecules such as metformin, for which effects are pleiotropic, acting on multiple organs and through multiple biological mechanisms.

One of the hallmarks of Alzheimer's disease is disruption to the body's circadian rhythm, the internal biological clock that regulates many of our physiological processes. Nearly 80% of people with Alzheimer's experience these issues, including difficulty sleeping and worsening cognitive function at night. However, there are no existing treatments for Alzheimer's that target this aspect of the disease.

Boosting the circadian clock is an emerging approach to improving health outcomes, and one way to accomplish this is by controlling the daily cycle of feeding and fasting. The researchers tested this strategy in a mouse model of Alzheimer's disease, feeding the mice on a time-restricted schedule where they were only allowed to eat within a six-hour window each day. For humans, this would translate to about 14 hours of fasting each day.

Compared to control mice who were provided food at all hours, mice fed on the time-restricted schedule had better memory, were less hyperactive at night, followed a more regular sleep schedule and experienced fewer disruptions during sleep. The test mice also performed better on cognitive assessments than control mice, demonstrating that the time-restricted feeding schedule was able to help mitigate the behavioral symptoms of Alzheimer's disease.

The researchers also observed improvements in the mice on a molecular level. In mice fed on a restricted schedule, the researchers found that multiple genes associated with Alzheimer's and neuroinflammation were expressed differently. They also found that the feeding schedule helped reduce the amount of amyloid protein that accumulated in the brain. Amyloid deposits are one of the most well-known features of Alzheimer's disease.

Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic mouse models of AD.

We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.

DNA methylation-based age estimators (DNAm ageing clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between cardiorespiratory fitness (CRF), measured directly by expiratory gas analysis, and DNAm ageing clocks are largely unknown. We investigated the relationships between CRF and the age-adjusted value from the residuals of the regression of DNAm ageing clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of CRF to DNAmAgeAccel in the presence of other lifestyle factors.

DNA samples from 144 Japanese men aged 65-72 years were used to appraise first-generation (i.e., DNAmHorvath and DNAmHannum) and second-generation (i.e., DNAmPhenoAge, DNAmGrimAge, and DNAmFitAge) DNAm ageing clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrient intake, smoking, alcohol consumption, disease status, sleep status, and chronotype.

Both oxygen uptake at ventilatory threshold (VO2/kg at VT) and peak oxygen uptake (VO2/kg at Peak) showed a significant negative correlation with GrimAgeAccel, even after adjustments for chronological age and smoking and drinking status. Notably, VO2/kg at VT and VO2/kg at Peak above the reference value were also associated with delayed GrimAgeAccel. Multiple regression analysis showed that calf circumference, serum triglyceride, carbohydrate intake, and smoking status, rather than CRF, contributed more to GrimAgeAccel and FitAgeAccel. In conclusion, although the contribution of CRF to GrimAgeAccel and FitAgeAccel is relatively low compared to lifestyle-related factors such as smoking, the results suggest that the maintenance of CRF is associated with delayed biological ageing in older men.

Researchers estimate that the brain's hippocampus - which plays a key role in memory, learning, and emotion - makes about a thousand new neurons each day throughout adulthood. "Considering that the brain contains about 100 billion neurons, it's reasonable to question whether this level of neurogenesis could have any impact on brain function. But over the life of the animal, the effects of these new cells can add up as they make connections with other neurons and other parts of the brain."

To test whether adult neurogenesis is vital to brain health over the long term, the team stopped the process in adult mice by irradiating the birthplace of new neurons or with genetic engineering. Over time, the mice produced less and less of the neurotransmitter acetylcholine in the hippocampus, leading to a profound rewiring of a brain circuit critical for memory. The mice also experienced a slow but progressive decline in working memory (temporary "sticky notes" for carrying out mental tasks). Remarkably, while neurogenesis was suppressed immediately after treatment, the memory, anatomic, and biochemical changes took five months (about a quarter of the mouse life span) to emerge.

Even though the brain circuit changed in a way that impaired memory, the circuit did form new, but dysfunctional, connections that could be recruited to improve memory."It was as if existing neurons were trying, but failing, to compensate for the loss of neurogenesis and what started out as a subtle defect in acetylcholine, and they just needed a little nudge." The researchers suspected that the remodeled circuit had sufficient reserves of acetylcholine but couldn't release it when needed. Using a drug, the researchers nudged the circuit to release more acetylcholine and completely rescued the memory deficits even in aged mice.

"The results suggest that we have to revisit old notions about the aging brain. It seems to be more plastic than we've thought." Cholinesterase inhibitors have been used to treat patients with Alzheimer's disease, with little success. "We think this drug, and many others, have failed because they're focused on one type of cell or molecule. What our findings tell us is that we probably need to address the fact that the whole memory circuit is compromised in aging and dementia."

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis can sustain hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits.

These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro.

Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.

Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus, a retrospective cohort study was performed. Included patients were free of dementia during a 2-year look-back period and were ≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk and absolute risk reduction for developing AD.

For the Tdap/Td vaccine, 7.2% (n = 8,370) vaccinated patients and 10.2% (n = 11,857) unvaccinated patients developed AD during follow-up; the relative risk was 0.70 and absolute risk reduction was 0.03. For the HZ vaccine, 8.1% (n = 16,106) vaccinated patients and 10.7% (n = 21,273) unvaccinated patients developed AD during follow-up; the relative risk was 0.75 and absolute risk reduction was 0.02. For the pneumococcal vaccine, 7.92% (n = 20,583) vaccinated patients and 10.9% (n = 28,558) unvaccinated patients developed AD during follow-up; the relative risk was 0.73 and absolute risk reduction was 0.02. Thus several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

A new study assessed 15,450 individuals without atrial fibrillation who were referred for a treadmill test between 2003 and 2012. The average age was 55 years and 59% were men. Fitness was assessed using the Bruce protocol, where participants are asked to walk faster and at a steeper grade in successive three-minute stages. Fitness was calculated according to the rate of energy expenditure the participants achieved, which was expressed in metabolic equivalents (METs).

Participants were followed for new-onset atrial fibrillation, stroke, myocardial infarction, and death. The researchers analysed the associations between fitness and atrial fibrillation, stroke, and major adverse cardiovascular events (MACE; a composite of stroke, myocardial infarction and death) after adjusting for factors that could influence the relationships including age, sex, cholesterol level, kidney function, prior stroke, hypertension, and medications.

During a median of 137 months, 515 participants (3.3%) developed atrial fibrillation. Each one MET increase on the treadmill test was associated with an 8% lower risk of atrial fibrillation, 12% lower risk of stroke and 14% lower risk of MACE. Participants were divided into three fitness levels according to METs achieved during the treadmill test: low (less than 8.57 METs), medium (8.57 to 10.72) and high (more than 10.72). The probability of remaining free from atrial fibrillation over a five-year period was 97.1%, 98.4%, and 98.4% in the low, medium and high fitness groups, respectively.

In this prospective cohort study of 12,784 participants, based on a recently developed biological aging measure acquired at four-time points within an 8-year period, we identified three aging trajectories where participants in medium-degree or high-degree accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. We then found that adopting an overall plant-based dietary pattern was associated with lower odds of being in medium-degree or high-degree accelerated aging trajectories. Plant-based dietary patterns were assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) Our study demonstrated a differential impact of plant-based foods on accelerated aging trajectory, i.e., a healthful plant-based diet was more beneficial to aging than an unhealthful plant-based diet. Fresh fruits, fresh vegetables, and legumes were major contributors found in our healthful plant-based diet analysis, whereas refined grain, salt-preserved vegetable, dairy products, and pluck were major contributors from unhealthful plant-based diet analysis.

We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (odds ratio = 0.75 for PDI; odds ratio = 0.73 for hPDI) or high-degree (odds ratio = 0.63 for PDI; odds ratio = 0.62 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (odds ratio = 1.72) or high-degree (odds ratio = 1.70) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (hazard ratio = 1.56) or high-degree (hazard ratio = 3.72) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory.

Ageing is often accompanied with a decline in immune system function, resulting in immune ageing. Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence. The change in immune phenotype is a key indication of the diseased or healthy status. However, the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed. Here, we analysed T cell and natural killer (NK) cell subsets, the phenotype and cell differentiation states in 43,096 healthy Chinese individuals, aged 20-88 years, without known diseases. Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.

The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis. Our initial analysis and machine modelling prediction showed that naïve T cells decreased with ageing, whereas central memory T cells (Tcm) and effector memory T cells (Tem) increased CD28-associated T cells.

This is the largest study to investigate the correlation between age and immune cell function in a Chinese population, and provides insightful differences, suggesting that healthy adults might be considerably influenced by age and sex. The age of a person's immune system might be different from their chronological age. Our immune-ageing modelling study is one of the largest studies to provide insights into 'immune-age' rather than 'biological-age'. Through machine learning, we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.

Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4, a nuclear localization sequence attached to PGC1α4, and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus.

Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-mediated NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size, and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance, and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle.

Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.

Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia.

Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old) and old (22-25 monoth-old) ages. There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP.

This data suggests that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract diseases - including neurodegeneration, cardiovascular disease, arthritis, and cancer - as they age. Researchers previously discovered that high molecular weight hyaluronic acid (HMW-HA) is one mechanism responsible for naked mole rats' unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumors.

The team genetically modified a mouse model to produce the naked mole rat version of the hyaluronan synthase 2 gene, which is the gene responsible for making a protein that produces HMW-HA. While all mammals have the hyaluronan synthase 2 gene, the naked mole rat version seems to be enhanced to drive stronger gene expression. The researchers found that the mice that had the naked mole rat version of the gene had better protection against both spontaneous tumors and chemically induced skin cancer. The mice also had improved overall health and lived longer compared to regular mice. As the mice with the naked mole rat version of the gene aged, they had less inflammation in different parts of their bodies - inflammation being a hallmark of aging - and maintained a healthier gut. While more research is needed on exactly why HMW-HA has such beneficial effects, the researchers believe it is due to HMW-HA's ability to directly regulate the immune system.

The research examined data from electronic health records of 72,412 patients from a representative sample of the UK population, who had been diagnosed with atrial fibrillation (AF) between 2001 and 2017. The team assessed the health outcomes in patients in the first year after their AF diagnosis, and analysed changes in cause-specific mortality and hospitalisation over time and by sex, age, socioeconomic status, and diagnostic care setting. The average patient was aged 75.6. Some 48.2% of patients were women, and 61.8% had three or more comorbidities. Over the study period, coexisting health concerns became more common, with almost 70% of newly diagnosed AF patients also having at least three comorbidities. Mortality rates at one year post diagnosis were investigated, as well as the number of hospital admissions with an overnight stay within 1 year of diagnosis.

Over the study period, 20% of patients died from any cause within a year of being diagnosed with AF - but this declined over time. However the researchers found that deaths due to cardiovascular and cerebrovascular events (strokes) more than halved over the study period. Cardiovascular deaths declined from 7.3% in 2001/02 to 3% in 2016/2017, while cerebrovascular deaths declined from 2.6% to 1.1%. The researchers say that the lower rates of cardiovascular deaths among AF patients in the study may be partly explained by improvements in strategies to prevent heart disease, and by changes in clinical practice that could lead to people being diagnosed earlier.

By contrast, there was an increase in mortality rates from mental and neurological disorders, from 2.5% in 2001/02 to 10.1% in 2016/17. Of these deaths, 87.2% were caused by dementia, Alzheimer's disease, and Parkinson's disease. The research team say that while this could be partly due to greater awareness of dementia, it also strengthens the evidence that the relationship between AF and dementia is a pressing research priority.

The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established.

In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation.

Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.