Researchers have used transcriptomic and proteomic methods to investigate the chain of molecular events that lead to loss of protein homeostasis during brain aging. The researchers used Nothobranchius furzeri (killifish) as a model of aging to study mechanisms triggering protein homeostasis dysfunction. They have a life span of only 3-12 months, and thus age-dependent processes are exacerbated in this species, making it easier to detect changes in the concentration of RNAs and proteins, as compared to other model organisms.

"When comparing the data for the different age groups, we found that almost half of the approximately 9000 proteins that we managed to quantify are affected by aging." These age-related changes result in abnormal regulation of proteins (subunits) that compose macromolecular protein complexes, the types of machinery responsible for all cellular activities. Protein complexes are built by different proteins that need to be assembled in specific ratios. Our cells have mechanisms to guarantee the proper building of these complexes by regulating the precise (stoichiometric) number of specific subunits. This tightly regulated process, however, is impaired in aging.

There is a progressive loss of stoichiometry of protein complexes during aging, mainly affecting the ribosome, which is one of the most important protein complexes in the cell, responsible for producing all other proteins. The researchers demonstrated that ribosomes do not get adequately formed in old brains and aggregate, potentially influencing vital functions in the cell. Aggregation of ribosomes is not exclusive to killifish but also happens in mice, suggesting it is a conserved feature of brain aging.

Proteasomes are complexes of protein molecules that digest and recycle old or defective proteins and are an essential part of the protein homeostasis network ("garbage chipper" of the cell). The authors were able to show that proteasome activity is reduced early and progressively during the course of adult life and causes loss of protein complexes stoichiometry. They induced a reduction of proteasome activity during early adult life of the killifish using a specific drug for just four days and observed a premature aging signature including disrupted ratios of several protein complexes.  

The team also compared the gene expression data of more than 150 killifish with their lifespan. The analysis showed that the individuals' lifespan could be predicted based on changes in the expression of genes encoding for proteasomal proteins: fish that showed a greater decrease in proteasome transcripts at the beginning of life lived considerably shorter than fish able to maintain or increase proteasome expression. This finding supports the hypothesis that the reduction of proteasome activity is an early driver of aging in vertebrates.

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains.

Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

Mitochondrial dysfunction, generally characterized as a loss of efficiency in oxidative phosphorylation, is a hallmark of aging and a variety of chronic diseases. Mitochondrial dysfunction results in inefficient cellular energy production and in increased levels of reactive oxygen species (ROS) which may damage lipids, proteins, and nucleic acids. Mitochondrial dysfunction also affects the expression of nuclear genes involved in metabolism, growth, differentiation, and apoptosis. All these changes may explain the contribution of mitochondrial dysfunction to chronic and complex human diseases.

A major limitation to the routine evaluation of mitochondrial dysfunction in clinical practice is the lack of reliable measures of mitochondrial dysfunction available for clinical use. Mitochondrial DNA copy number (mtDNA-CN) is a promising biomarker of mitochondrial dysfunction that has the potential to become widely available in clinical practice. Other measures of mitochondrial dysfunction, including cell culture-based methods are optimized in vitro, do not make use of pre-existing datasets, and cannot be scaled-up for widespread use.

An emerging body of evidence supports roles for mtDNA in the complex underpinnings of a variety of diseases, including a number of cancers and aging-related disorders. A common link in these studies include anti-inflammatory pathways. These mechanisms will be further elucidated as our ability to measure mtDNA-CN from sequencing and microarray technologies expands. As studies increase in power and functional assessment of mechanisms underlying the effect of mtDNA on mitochondrial function and gene expression improve, our understanding of variation in mtDNA-CN as cause or consequence of disease development will rapidly improve.

mtDNA-CN is an especially attractive biomarker because its measurement in blood is both non-invasive and relatively cost-friendly to obtain. The proposed utility of mtDNA-CN as a biomarker for disease has been suggested by the observation that mtDNA content can differentiate healthy controls from patients with cancer and other diseases. In addition, mtDNA-CN has been shown to be relevant for risk reclassification for cardiovascular disease. Currently, these applications are limited by several analytical factors affecting the accurate and reproducible quantification of mtDNA-CN. The recent confirmation that human mtDNA is methylated adds yet another level of complexity to the crosstalk between the nucleus and mitochondrion and its control. We close by suggesting that improved detection techniques for mtDNA-CN as well as greater understanding of the mechanisms underlying individual, cell-type, and tissue-specific variation in mtDNA-CN are essential to determining the direct pathological, therapeutic and/or clinical relevance of this relatively cost-effective and easily measured biomarker.

Ageing of the immune system first manifests as a dramatic involution of the thymus. This is the primary lymphoid organ that generates and selects a stock of immunocompetent T cells. The thymus is composed of two morphological compartments that convey different functions: development of thymocytes and negative selection against self-reactive antigens are both initiated in the cortex before being completed in the medulla. Both compartments are composed of a specialized stromal microenvironment dominated by thymic epithelial cells (TECs).

Thymic size is already compromised in humans by the second year of life, decreases further during puberty, and continuously declines thereafter. With this reduced tissue mass, cell numbers for both lymphoid and epithelial cell compartments decline. This is paralleled by an altered cellular organization of the parenchyma, and the accumulation of fibrotic and fatty changes, culminating in the organ's transformation into adipose tissue. Over ageing, the output of naïve T cells is reduced and the peripheral lymphocyte pool displays progressively worsened T cell populations.

To resolve the progression of thymic structural and functional decline we studied TEC using single-cell transcriptomics across the first year of mouse life. Unexpectedly, we discovered that the loss and quiescence of TEC progenitors are major factors underlying thymus involution. The function of mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.

Pre-clinical and clinical evidence show that caloric restriction (CR) is an effective method to ameliorate cardiovascular pathologic remodeling and to improve cardiovascular function. For example, in a rat model for myocardial infarction and post-ischemic heart failure, 1-year long CR mitigated pathologic left ventricular remodeling and improved cardiac function and inotropic reserve. An average 11% CR for a 2-year period reduced cardiometabolic risk factors and increased predictors of health span and longevity in a healthy human clinical trial.

One of the underlying mechanisms for the anti-aging effect of CR is induction of autophagy, a process that removes senescent cells from tissues and thus prevent spreading of cellular senescence. It is now well established that autophagy is a converging point for the beneficial effects of longevity drugs such as rapamycin, other rapalogs, metformin, and resveratrol.

Optimal levels of autophagy is an evolutionarily-conserved intracellular catabolism process essential to preserve cellular homeostasis in response to the same or similar stressors that induce cellular senescence. Cellular senescence, an important hallmark of aging, is a critical factor that impairs repair and regeneration of damaged cells in cardiovascular tissues. Therefore, therapeutic targeting of autophagy can be an effective approach to mitigate cardiovascular diseases. In particular, cardiomyopathy caused by diabetes involves extensive deregulation of cardiac mitochondrial function and induction of mitochondrial autophagy (mitophagy) that may start as a survival mechanism, but can cause cell death when excessive.

Autophagy encompasses highly regulated cellular processes to maintain cellular homeostasis and proteostasis, and eliminates potentially harmful cellular stressors that induce cell death. The highly-conserved autophagy machinery forms double-membraned autophagosomes to sequester portions of the cytoplasm and organelles, and trafficks these autophagosomes to lysosomes for degradation. Various forms of autophagy including macroautophagy, microautophagy, and chaperone-mediated autophagy all lead to turnover of intracellular components.

While autophagy is a catabolic process that degrades damaged organelles, misfolded proteins, and other harmful stressors, it also generates new building blocks (for example amino acids), energy for anabolism in conditions of nutrient deprivation, and promotes self-renewal and differentiation of pluripotent stem cells which is essential for repair of damaged tissue. Autophagy dysregulation tilts the balance from autophagy being the protective mechanism to exerting detrimental effects on cells leading to apoptosis, to whole-organ dysfunction, and organismal demise. Therefore, better understanding of the underlying molecular mechanisms of therapeutic induction of autophagy is of utmost importance, and the levels of autophagy need to be carefully monitored.

Humankind has been plagued by infectious diseases throughout history, and the ongoing COVID-19 pandemic is a daunting reminder that this susceptibility persists in our modern society. After all, communicable diseases remain one of the leading causes of death worldwide. Unfortunately, some of these "microbial threats" have been underestimated and neglected by healthcare authorities, although they endanger millions of lives each year all over the world.

Fungal infections (FIs) represent an example of such overlooked emerging diseases, accounting for approximately 1.7 million deaths annually. To put these numbers in perspective, tuberculosis is reported to cause 1.5 million deaths/year and malaria around 405,000 deaths/year. The medical impact of FIs, however, goes far beyond these devastating death rates: FIs affect more than one billion people each year, of which more than 150 million cases account for severe and life-threatening FIs. Importantly, the number of cases continues to constantly rise. Thus, FIs are increasingly becoming a global health problem that is associated with high morbidity and mortality rates as well as with devastating socioeconomic consequences.

A crucial factor that contributes to the rising number of FIs is the drastic increase of the at-risk population that is specifically vulnerable to FIs, including elderly people, critically ill or immunocompromised patients. The overall lifespan increase due to the achievements of modern medicine and social advancements, the growing numbers of cancer, AIDS, and transplantation patients with the concomitant subscription of immune-modulating drugs as well as the excessive antibiotic use compose risk factors and niches for the development of FIs. Furthermore, the increasing usage of medical devices such as catheters or cardiac valves leads to a higher risk for the formation of biofilms. Biofilms represent an assembly of highly diverse, complex and eminently organized cells embedded in an extracellular matrix that conveys protection from physical and/or chemical insults. Thus, biofilms are often resistant to existing treatments and, in fact, are considered to essentially contribute to the high mortality rates associated with invasive FIs.

There is no doubt that the threat imposed by FIs will continue to increase worldwide with a number of obstacles (including resistance development) that need to be overcome. This demands rapid and innovative action at different levels. The search for therapeutic treatment options needs to be intensified. In sum, FIs are crucial contributors to the new old threat of infectious diseases, and upgrading our antifungal armamentarium by improving existing and/or devising novel antifungal strategies remains an urgent medical challenge.

Aging is undoubtedly one of the most important and yet unsolved problems of humanity. Many theories have been put forward, but none have yet been fully verified. Modern geroscience enumerates nine hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. The proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, this list is missing one particularly important hallmark: stochastic non-enzymatic modification of long-lived macromolecules.

First proposed in 1942, the cross-linking theory of aging postulates that aging results from the accumulation of intra-intermolecular covalent bonds (crosslinks) between molecules with slow turnovers, such as collagen and elastin of the extracellular matrix (ECM). These crosslinks affect the physical properties of the ECM (i. e. stiffness) which may cause cell dysfunction via mechanosensing. Additionally, there also exist adducts which may cause inflammation via activation of the receptor for advanced glycation endproducts (RAGE). We also think that ECM aging might be even more important than cellular aging since cells have effective mechanisms to repair or remove damaged proteins and organelles.

These modifications are a consequence of the biochemistry and the long turnover of some macromolecules and do not require any dysregulation of molecular pathways. Additionally, these modifications give rise to virtually all hallmarks of aging and age-related pathologies, which makes it an ideal candidate for the starting point of the vicious cycle of aging. Organisms with remarkably long lifespans like bowhead whale have exceptionally low rates of advanced glycation endproducts accumulation, which gives a hope that interventions that slow down the accumulation of non-enzymatic modifications should dramatically decrease the rate of aging and thus prolong both lifespan and healthspan.

Pathophysiological stress often damages mitochondria in myocytes which are vital for the heart's contractile activity. Therefore, continuous monitoring and repair of mitochondria are needed to maintain a healthy mitochondrial population in cells. Multiple levels of mitochondrial quality control exist both at the protein and organelle level.

First, because the majority of mitochondrial proteins are encoded in the nucleus, significant monitoring of mitochondrial precursor proteins is needed during their cytosolic translation and import. The ubiquitin-proteasome system shapes the mitochondrial proteome through steady-state turnover of mitochondrial precursors to ensure an appropriate stoichiometry between nuclear and mitochondrially encoded proteins and their proper localization. Second, mitochondria contain resident chaperones and proteases to ensure quality control within the mitochondria. Third, excessive levels of misfolded proteins in the mitochondrial matrix or a mito-nuclear protein imbalance activates a conserved mitochondrial ubuqiutin-proteasome system which functions to selectively induce a transcriptional response aimed at restoring mitochondrial proteostasis.

A closer examination into these processes reveals an inextricable link between mitochondrial quality control and cytosolic proteostasis. More recently, mitochondria themselves have been found to participate in general protein quality control through the import and degradation of misfolded cytosolic proteins.

In the event that the mitochondria cannot be repaired, myocytes have the option of either eliminating damaged mitochondrial components via mitochondrial-derived vesicles, or by removing the entire organelle through mitophagy. Elimination of the entire mitochondria is likely a last resort response because it requires the cell to replace the mitochondrion.

Continued investigations into the molecular drivers of mitochondrial quality have the potential to elucidate novel interventions for general the proteostatic stress seen during myocardial ischemia, pressure overload, and protein aggregation cardiomyopathies. Collectively, these mitochondrial quality control pathways represent an essential adaptive response in cardiac myocytes, and fruitful avenues for the development of novel therapies against cardiovascular diseases. Once a better understanding of the regulators and relationships between the various quality control pathways is gained, we will hopefully be able to translate this knowledge into improved treatments for disease.

In industrialized countries, lifespan averages 78 for males and 83 for females, but some exceptional individuals delay aging and live much longer than the rest of the population. Long Living Individuals (LLIs) represent a model of positive biology. We posit that the peripheral blood of LLIs may hold valuable biomarkers associated with an enduring performance of the immune system. Circulating factors unique to LLIs may also be directly involved in maintaining a proper balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage phenotypes.

The bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) is one of the most abundant proteins in respiratory secretions. BPIFB4 expression is highly responsive to airborne pathogens and participates in host protection. Of note, circulating BPIFB4 levels are constitutively increased in healthy LLIs as compared to frail ones and young controls. Moreover, carriers of the longevity-associated variant (LAV) have extremely prolonged life expectancy and show higher circulating BPIFB4 levels as compared with carrier of the wild-type haplotype.

We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55). If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state.

In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. This data indicates that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.

One important question in aging research is how differences in genomics and transcriptomics determine the maximum lifespan in various species. Despite recent progress, much is still unclear on the topic, partly due to the lack of samples in non-model organisms and due to challenges in direct comparisons of transcriptomes from different species. The novel ranking-based method that we employ here is used to analyze gene expression in the gray whale and compare its de novo assembled transcriptome with that of other long- and short-lived mammals.

Gray whales are among the top 1% longest-lived mammals. Despite the extreme environment, or maybe due to a remarkable adaptation to its habitat (intermittent hypoxia, Arctic water, and high pressure), gray whales reach at least the age of 77 years. In this work, we show that long-lived mammals share common gene expression patterns between themselves, including high expression of DNA maintenance and repair, ubiquitination, apoptosis, and immune responses. Additionally, the level of expression for gray whale orthologs of pro- and anti-longevity genes found in model organisms is in support of their alleged role and direction in lifespan determination.

Remarkably, among highly expressed pro-longevity genes many are stress-related, reflecting an adaptation to extreme environmental conditions. The conducted analysis suggests that the gray whale potentially possesses high resistance to cancer and stress, at least in part ensuring its longevity.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. Humanin is the first member of this new class of mitochondrial-derived signaling peptides that now includes MOTS-c and SHLP1-6. The humanin gene is found as a small open reading frame within the 16s rRNA gene of the mitochondrial genome. It is highly conserved in chordates but can also be found in species as distant as the nematode, suggesting that humanin is an ancient mitochondrial signal used to communicate to the rest of the organism.

Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence.

Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer's disease. Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine.

Multiple interventions that target primary aging processes are currently being explored. Senescent cell burden represents one fundamental aging process that has been carefully studied. Targeting it at the preclinical level by genetic and pharmacologic reduction has yielded compelling findings that support the geroscience hypothesis. Translation of promising pharmacologic interventions in the form of senotherapeutic agents has begun to assess safety and target engagement.

Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine. Clinically relevant primary endpoints for older adults will likely include aspects of both objective and subjective physical functioning, since these are predictive of morbidity and mortality, contribute to risks of cognitive decline and injury, are prominent components of geriatric syndromes, and are consistent with measurable improvements being made in the short term. Biomarker discovery will be facilitated by larger clinical trials, measurement of changes in multiple analytes in multiple target specimens, and replication of biomarker feasibility and utility across multiple sites within a single study and among different studies. In the longer term, it should be possible to assess the delays in onset of chronic diseases and geriatric syndromes with compression of morbidity, using interventions based on reduction of senescent cell burden and other interventions in the aging process.

Several years ago, a postdoctoral researcher was using a technique called siRNA to silence the PTB gene in connective tissue cells known as fibroblasts. It's a tedious process that needs to be performed over and over. He got tired of it and instead used a different technique to create a stable cell line that's permanently lacking PTB. At first, the postdoc complained about that too, because it made the cells grow so slowly. But then he noticed something odd after a couple of weeks - there were very few fibroblasts left. Almost the whole dish was instead filled with neurons. In this serendipitous way, the team discovered that inhibiting or deleting PTB transforms several types of mouse cells directly into neurons.

Recently, researchers applied this finding in what could one day be a new therapeutic approach for Parkinson's disease and other neurodegenerative diseases. Just a single treatment to inhibit PTB in mice converted native astrocytes, star-shaped support cells of the brain, into neurons that produce the neurotransmitter dopamine. As a result, Parkinson's disease symptoms disappeared. The treatment works like this: The researchers developed a noninfectious virus that carries an antisense oligonucleotide sequence - an artificial piece of DNA designed to specifically bind the RNA coding for PTB, thus degrading it, preventing it from being translated into a functional protein and stimulating neuron development.

The researchers administered the PTB antisense oligonucleotide treatment directly to the mouse's midbrain, which is responsible for regulating motor control and reward behaviors, and the part of the brain that typically loses dopamine-producing neurons in Parkinson's disease. A control group of mice received mock treatment with an empty virus or an irrelevant antisense sequence. In the treated mice, a small subset of astrocytes converted to neurons, increasing the number of neurons by approximately 30 percent. Dopamine levels were restored to a level comparable to that in normal mice. What's more, the neurons grew and sent their processes into other parts of brain. There was no change in the control mice. By two different measures of limb movement and response, the treated mice returned to normal within three months after a single treatment, and remained completely free from symptoms of Parkinson's disease for the rest of their lives. In contrast, the control mice showed no improvement.

Researchers collected data from 6,582 people in a nationally representative sample of the English population aged 50 years and over, from the English Longitudinal Study of Ageing. Three different sources were used to ascertain dementia: doctor diagnosis, informant reports and hospital episode statistics. It was found that people whose BMI was 30 or higher (at obese level) at the start of the study period had a 31% greater risk of dementia, at an average follow-up of 11 years, than those with BMIs from 18.5-24.9 (normal level).

There was also a significant gender difference in the risk of dementia associated with obesity. Women with abdominal obesity (based on waist circumference) had a 39% increased risk of dementia compared to those with a normal level. This was independent of their age, education, marital status, smoking behaviour, genetics (APOE ε4 gene), diabetes and hypertension - and yet this association was not found among the male participants. When BMI and waist circumference were viewed in combination, obese study participants of either gender showed a 28% greater risk of dementia compared to those in the normal range.

Prior evidence suggests that obesity might cause an increased risk of dementia via its direct influence on cytokines (cell signalling proteins) and hormones derived from fat cells, or indirectly through an adverse effect on vascular risk factors. Some researchers have also suggested that excess body fat may increase dementia risk through metabolic and vascular pathways that contribute to the accumulation of amyloid proteins or lesions in the brain. "It is possible that the association between obesity and dementia might be potentially mediated by other conditions, such as hypertension or anticholinergic treatments. While not explored in this study, the research question of whether there an interactive effect between obesity and other midlife risk factors, such as hypertension, diabetes, and APOE ε4 carrier status, in relation to dementia will be investigated in upcoming work."

"One of the things that we've learned in the last decade or so is that a lot of people that we think have dementia from Alzheimer's disease, actually don't. There are other brain diseases that cause the same kind of symptoms as Alzheimer's, including some that we only recently figured out existed." Researchers used brain autopsy data from 375 older adults. This work builds on the work last year to discover another form of dementia caused by TDP-43 proteinopathy now known as LATE.

Misfolded TDP-43 protein, which was discovered in 2006, is the "newest brain bad guy." Although TDP-43 exists normally in a non-disease causing form, it is seen in multiple debilitating diseases in addition to LATE, including ALS and frontotemporal dementia. As researchers reviewed clinical and brain autopsy data for research participants, they noticed there were significantly more people than expected that had not only Alzheimer's pathology but also pathology indicating Lewy bodies (alpha synuclein) and TDP-43. "They had every neurodegeneration causing pathology that we know about. There was not a name for this, so we came up with one: quadruple misfolded proteins, or QMP."

The group then obtained more data to conduct a study of how often QMP occurred and what that meant for the participant with QMP. The study found that about 20% of the participants with dementia had QMP, and their dementia was the most severe. "This is not great news, because it means that even if we could completely cure Alzheimer's disease, we still have to deal with TDP-43 and alpha synuclein, and they are common in old age. But, we have to understand exactly what we are up against as we try to stop dementia. We still have so much to learn."

A new analysis of 16 years of publicly accessible health data on 68.5 million Medicare enrollees provides broad evidence that long-term exposure to fine particles in the air - even at levels below current EPA standards - leads to increased mortality rates among the elderly. Based on the results of five complementary statistical models, including three causal inference methods, the researchers estimate that if the EPA had lowered the air quality standard for fine particle concentration from 12 μg/m3 down to the WHO guideline of 10 μg/m3, more than 140,000 lives might have been saved within one decade.

A number of studies have documented a strong correlation between long-term exposure to fine particulate and greater human mortality, but some concern has remained about the causal nature of the evidence, and whether it is sufficient to inform revisions to air quality standards. Some scientists argue that modern causal inference methods can provide such evidence, using the right data.

Analyzing a massive dataset through five distinct approaches, including two traditional statistical methods and three causal inference methods, researchers derived broad evidence consistent with a causal link between long-term particulate exposure and mortality. Modeling a 10 μg/m3 decrease of fine particle concentration between 2000 and 2016 resulted in a 6% to 7% decrease in mortality risk. Based on their model results, the researchers estimated that more than 140,000 lives might have been saved if the current U.S. standard for fine particle concentration had been lowered to 10 μg/m3 between 2007 and 2016.