In the course of Alzheimer's disease, two proteins called amyloid and tau accumulate in the brain. A study with more than 200 participants now provides insights into the interaction of these pathological phenomena. The data suggest that tau load in the brain impairs memory functions only when amyloid burden is also high. These findings therefore support therapeutic approaches aimed at removing amyloid from the brain in the early stages of Alzheimer's disease.

"It has long been known that deposits of tau proteins in the hippocampus and in neighboring brain areas impair memory. In the case of amyloid, on the other hand, no clear relationship to memory performance has been found to date. For this reason, among others, it is debated whether it makes sense at all to target amyloid therapeutically. Our current results suggest that this could indeed be helpful for memory function in the early stages of the disease. The crucial aspect is that you don't look at tau in isolation, but together with amyloid pathology. This is where a link becomes apparent when you study a larger number of individuals and accordingly have solid statistics."

We investigated whether the impact of tau-pathology on memory performance and on hippocampal and medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF.

We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction, and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment.

C/EBPβ is a transcription factor that promotes Alzheimer's disease pathologies via activating asparagine endopeptidase (AEP) in response to amyloid-β and inflammatory cytokines.

To explore C/EBPβ's role in aged nerve cells, researchers generated a mouse model that selectively overexpresses C/EBPβ in the brain to mimic aged animals. Researchers found that the mice's life span was shortened in a gene dose-dependent manner. Usually, normal life expectancy for a mouse is around 24-28 months. However, the life span for a mouse carrying one copy of overexpressed C/EBPβ is around 12-18 months and 5-9 months for mice carrying two copies. By contrast, deleting one copy of the C/EBPβ gene increases the life span with the most long-lived mice living more than 30 months.

The C/EBPβ gene is elevated in human brains during aging. It peaks in individuals 60 to 84 years old and declines in those more than 85 years old. Long-lived individuals usually show less expression of AEP genes in nerve cells, whereas short-lived individuals show greater AEP gene expression.

In worms, neural excitation increases with age and inhibition of excitation increases longevity. The scientists found that high levels of C/EBPβ or AEP in nerve cells shorten the worm's life span, whereas such gene expression in muscles has no effect on longevity. Similar to mice, deletion of these genes in worms increases the life span. Remarkably, inhibition of AEP using a drug increases the life expectancy of worms.

Life span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism and longevity. The researchers found that C/EBPβ/AEP signaling was inversely correlated with insulin signaling in the human brain. With the lowest insulin signaling in humans in their seventies and eighties, C/EBPβ/AEP activity peaks. However, in humans with extended longevity, C/EBPβ/AEP activity declines, while insulin signaling climbs in the brain.

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction.

Overexpression of CEBP-2 (ortholog of C/EBPβ) or LGMN-1 (orthology of AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.

Geroscience represents a novel paradigm whereby biological aging is recognized as the major modifiable driver of age-related diseases and other late-life conditions. Widespread clinical use of geroscience-guided interventions could transform the public health landscape because the ability to target biological aging as a risk factor could simultaneously delay the onset and progression of multiple conditions, thereby enhancing health, function, and independence in late-life. A corollary is that targeting this biology will affect human healthspan (the portion of lifespan free of major disease and disability) most profoundly, and with a better prognosis than the current model of addressing one disease at a time.

While aging is unequivocally the major risk factor for age-related diseases, regulatory bodies around the world, such as the FDA or EMA, do not yet recognize geroscience-guided clinical outcomes as a path to regulatory approval. This is in part because the processes for validating specific compounds or combinations of compounds for their ability to delay the onset and progression of multiple chronic diseases have not yet been delineated in humans. Without regulatory approval, insurers will not pay for such treatments, which disincentivizes pharmaceutical companies from developing geroscience-guided approaches, simply because there is no path for them to develop a viable business plan. Therefore, there is an urgent need to demonstrate, in a well-designed clinical trial, that a cluster of age-related diseases can be significantly delayed by repurposing existing or developing novel gerotherapeutics.

Targeting Aging with MEtformin (TAME) is such a study that has been under development for the last few years, and whose basic principles have been developed in consultation with the FDA. We believe that efforts to test and repurpose existing, safe gerotherapeutics should be extended beyond TAME, not only to increase the number of drugs potentially available to target aging in humans but also to mitigate the risks to the field, should any such trials fail to reach their desired outcome.

We sought to identify such FDA-approved drugs or classes of drugs that had at least one publication showing extension of lifespan in rodents and data in humans suggesting the highest chance of success if tested in a well-controlled TAME-like clinical trial. We developed a 12-point prioritization scale that assigns equal points for the preclinical and clinical evidence for each of these candidates. Points on the preclinical side were assigned for effects on the hallmarks of aging, improvement in healthspan and extension of lifespan in rodents as part of the NIA's Interventions Testing Program (ITP), a well-characterized, multicentered study to evaluate gerotherapeutics, as well as non-ITP rodent lifespan studies.

We were able to prioritize nine drug classes. SGLT2 inhibitors (SGLT2i), a relatively new drug class, was the only one to receive the maximum score, owing to not only its robust effects on improving rodent healthspan and lifespan (including ITP) but also strong evidence for the extension of healthspan and reduction of mortality in humans. Metformin was next on the list, and it received a submaximal score, due to negative findings for rodent lifespan extension in ITP. Acarbose, rapamycin/rapalogs, and methylene blue (MB) all had strong preclinical data and promising findings for human healthspan (the latter being the most robust for acarbose), but sparse clinical data for human mortality. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) were found to extend preclinical healthspan and lifespan (outside of ITP) and had robust effects on extending human healthspan, but the studies on human mortality, while abundant, were predominantly negative. The last three drugs on our list, senolytics Dasatinib + Quercetin (D + Q), aspirin, and N-acetyl cysteine (NAC), all had strong preclinical data, but their effects on human healthspan and mortality have not yet been assessed in clinical studies or appropriate doses/populations. Obviously, future studies may change the priority order for drugs that did not receive points due to the paucity of clinical data.

Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to identify circulating proteins that could predict subclinical atherosclerosis. Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study.

PIGR, IGHA2, APOA, HPT, and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA, and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS, and also in the subpopulation of individuals with low cardiovascular risk.

In conclusion, plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available.

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences.

Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.

Macrophages are large white blood cells that cruise through our body as a kind of clean-up crew, clearing hazardous debris. But in people with atherosclerosis - fatty deposits and inflammation in their blood vessels - macrophages can cause trouble. They eat excess fat inside artery walls, but that fat causes them to become foamy. And foamy macrophages tend to encourage inflammation in the arteries and sometimes bust apart plaques, freeing clots that can cause heart attack, stroke, or embolisms elsewhere in the body.

Changing how macrophages express a certain protein could prevent that kind of bad behavior. Researchers found that the protein, called TRPM2, is activated by inflammation. It signals macrophages to start eating fat. Since inflammation of the blood vessels is one of the primary causes of atherosclerosis, TRPM2 gets activated quite a bit. All that TRPM2 activation pushes macrophage activity, which leads to more foamy macrophages and potentially more inflamed arteries.

Researchers demonstrated one way to stop the cycle, at least in mice. They deleted TRPM2 from a type of lab mouse that tends to get atherosclerosis. Deleting that protein didn't seem to hurt the mice, and it prevented the macrophages from getting foamy. It also alleviated the animals' atherosclerosis. Researchers are now looking at whether increased TRPM2 expression in monocytes (circulating precursors of macrophages) in the blood correlates with severity of cardiovascular disease in humans.

A new study shows that a potential treatment for Alzheimer's disease may also improve cognitive function in people with Down syndrome. The drug sargramostim (recombinant GM-CSF, which stands for granulocyte-macrophage colony-stimulating factor) is the first to show memory improvement in Alzheimer's patients in a phase II clinical trial. GM-CSF is a normal human protein that is safe and well-tolerated with over 30 years of FDA-approved use for other disorders.

Researchers discovered that treatment with GM-CSF, which has pro-inflammatory, anti-inflammatory, and immune regulatory properties, reverses learning and memory deficits, the loss of certain nerve cells, and other abnormalities in the brain in a mouse model of Down syndrome and also improves cognition in normal aging mice.

The human version of GM-CSF/sargramostim has already been shown to be effective in improving cognition in people with mild-to-moderate Alzheimer's disease and in cancer patients. The findings support the hypothesis that GM-CSF/sargramostim may promote neuronal recovery from injury or from neurological disease through multiple mechanisms, some of which evidently enhance cognitive function.

Rapamycin is an mTOR inhibitor isolated from the Rapa Nui bacterium Streptomyces hygroscopicus. It is a well-established immune-modulating drug for use with transplant patients and has shown promising results on healthspan studies in laboratory animals. By collecting and disseminating data on several hundred people already taking low dose rapamycin for many months or years, this project will gather evidence for or against the use of rapamycin to improve health and prevent disease in people. At a minimum, this should largely resolve the current debate around safety of rapamycin use in this context.

Collected data will be analyzed primarily to assess common side effects experienced by patients (severity and frequency) in order to provide a true estimate of actual risk. Changes in medical or dental health from baseline will be assessed for each patient for whom that data is available. A summary of the overall cohort data will be published in a peer-reviewed journal.

Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation, and activation of retrotransposons are also often considered, given their strong association with aging.

In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases.

Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.

Exercise and weight control have been suggested as methods for mitigating the negative effects of chronic inflammation. Proper exercise has a dual effect in reducing chronic inflammation via weight reduction and lowering adipokines in cells. Resistance training (RT), a strength training exercise that involves progressive overload in which the muscles exert force against an external load, could be a safe and effective method of improving chronic low-grade inflammation in older individuals.

A previous study reported that RT was associated with anti-inflammatory effects by decreasing serum levels of IL-6 and CRP, in addition to inducing changes in TNF-α gene expression in elderly women. However, another study suggested that RT was not related to TNF-α, IL-6, IL-10, and CRP improvement. As a result, an integrated and clear conclusion on the effects of RT in the elderly is currently unavailable. The purpose of this review was to critically examine the effects of RT on chronic low-grade inflammation in elderly adults through a systematic review and meta-analysis of randomized controlled trials (RCTs).

We included studies that assessed the effect of RT on C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in those aged ≥60 years. The effect size was estimated using fixed or random-effects models. Subgroup analysis was performed regarding age, health status, training method, number of exercises, intensity, weekly frequency, and duration. In the 18 randomized controlled trials (539 patients) included, RT was effective in alleviating CRP, IL-10, and TNF-α in elderly adults and tended to reduce IL-6. Subgroup analyses showed CRP reduction regardless of age, training method, number of exercises, intensity, weekly frequency, and duration. RT can be used to ameliorate chronic low-grade inflammation in elderly adults.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against a potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration.

NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease.

One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging").

NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins.

Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin-proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging.

Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration.

Exosomes harvested from mesenchymal stem cells (MSCs-Exo), as a treatment for diseases, has better safety and convenience compared with stem cell therapy, and will certainly play a huge role in the future clinical treatment of diseases. Exosomes as the carrier of therapy can be applied to a variety of diseases, to achieve the effect that conventional therapy cannot achieve. As biologically active nano-vesicles, MSCs-Exo have shown many advantages in disease treatment, such as cardiovascular disease, neurodegenerative disease, tumors, and regenerative medicine.

Currently, an accumulating amount of evidence has been showing that MSCs-Exo has disease treating potential and can successfully apply for the therapy of several kinds of disease. A few clinical trials are currently on-going but there are still challenges to overcome for further clinical translation such as the scale-up of the production, the lack of standardization for isolation and characterization methods and the low encapsulation efficiency. In contrast with MSCs, evidence suggests that MSCs-Exo promotes angiogenesis, restrains inflammatory effects, decreases immunogenicity, and reduces tumor production.

As a therapeutic tool, compared with standard delivery methods, MSCs-Exo holds great therapeutic promise, but still faces many challenges. Due to the size and complexity of MSCs-Exo, there are challenges in clinical practice, such as large-scale pharmaceutical production and production costs. Previously, scientists used ultracentrifugation to purify exosomes, which was a labor-intensive and time-consuming process that could not be used for large-scale production. The focus of future research is to find new solutions in future research and develop a simple purification method with very low cost and safety.