Fine particulate matter (PM2.5) is an important air pollutant worldwide. Exposure to PM2.5 has been associated with adverse health effects, including cardiovascular disease, respiratory disease, lung cancer, and premature mortality. Several studies also suggest that long-term PM2.5 exposure is a risk factor for neurodegenerative diseases. Studies suggest that PM2.5 has the potential to induce dementia through biological mechanisms such as systemic inflammation, oxidative stress, and neuroinflammation. In addition, some evidence indicates that PM2.5 can exacerbate or accelerate existing diseases via these biological pathways.

A growing body of epidemiological evidence suggests that particulate air pollution contributes to dementia, including several longitudinal studies conducted in the United States and around the world. The majority of these studies found positive associations between PM2.5 and dementia. A systematic review and meta-analysis also concluded that exposure to PM2.5 is associated with a 16% higher risk of dementia per 10 μg/m3 increase in PM2.5 concentration.

However, previous studies have almost exclusively focused on the effects of PM2.5 mass concentrations. As a complex mixture, the toxic effects of PM2.5 may be determined primarily by its chemical components. PM2.5 components, such as organic matter (OM), inorganic nitrate (NO3-), inorganic sulfate (SO42-), black carbon (BC), soil particles (SOILs), and sea salt (SS), emitted from specific sources, have different physicochemical and toxicological characteristics, resulting in various health effects. To fill these knowledge gaps, we conducted a population-based cohort study of the Medicare dataset and a well-validated high-resolution (1 km × 1 km) PM2.5 components dataset from 2000-2017. The latter includes data on OM, NO3-, SO42-, BC, SOILs, and SS in the northeastern United States, where better exposure estimates exist.

We identified dementia diagnoses from patients' hospital and medical insurance records and carried out Cox proportional hazards regression to investigate their association with PM2.5 components. Among ∼2 million participants, 15.1% developed dementia. From the single-pollutant models, hazard ratios per interquartile range increase were 1.10 for black carbon, 1.08 for inorganic nitrate, 1.03 for organic matter, 1.13 for sulfate, 1.07 for soil particles, and 1.04 for sea salt. Increase in exposure to black carbon and sulfate per interquartile range had the strongest associations with dementia incidence.

Vascular aging is a multifaceted and complex process that ultimately renders the vessels prone to profound functional and structural disturbances that favor cardiovascular disease. One of the main mechanisms contributing to vascular aging is endothelial cell senescence. Senescent cells undergo functional and morphological changes that ultimately lead to growth arrest while remaining metabolically active. Importantly, these cells acquire a senescence-associated secretory phenotype (SASP), which results in the over-production and release of a wide array of cytokines and chemokines. The SASP favors leukocyte recruitment and is considered a main driver of sterile age-related inflammation or "inflammaging". Functionally, endothelial cell senescence is tightly associated with endothelial dysfunction and defective vasodilatation, considered as early markers of vascular disease and atherosclerosis.

In the present study, we have evaluated whether a positive feedback of IL-1β in the NLRP3 inflammasome via NF-κB could promote human endothelial senescence in vitro and murine endothelial dysfunction in vivo. Our results indicate that the NLRP3 inflammasome is pivotal in mediating the detrimental effects of IL-1β, showing that auto-activation is a crucial feature boosting endothelial cell senescence in vitro, which is paralleled by vascular dysfunction in vivo. Hence, the inhibitor of NLRP3 inflammasome assembly, MCC 950, was able to disrupt the aforementioned positive loop, thus alleviating inflammation, cell senescence and vascular dysfunction.

Besides, we explored alternative NLRP3 inflammasome inhibitory agents such as the RAS heptapeptide Ang-(1-7) and the anti-aging protein klotho, both of which demonstrated protective effects in vitro and in vivo. Altogether, our results highlight a fundamental role for the hereby described NLRP3 inflammasome/IL-1β positive feedback loop in stress-induced inflammaging and the associated vascular dysfunction, additionally providing evidence of a potential therapeutic use of MCC 950, Ang-(1-7) and recombinant klotho to block this loop and its deleterious effects.

The researchers used implantable "drug factories" the size of a pinhead to deliver continuous, high doses of interleukin-2, a natural compound that activates white blood cells to fight cancer. The drug-producing beads can be implanted with minimally invasive surgery. Each contains cells engineered to produce interleukin-2 that are encased in a protective shell.

Interleukin-2 is a cytokine, a protein the immune system uses to recognize and fight disease. It is an FDA-approved cancer treatment, but the drug factories provoke a stronger immune response than existing interleukin-2 treatment regimens because the beads deliver higher concentrations of the protein directly to tumors. "Once we determined the correct dose - how many factories we needed - we were able to eradicate tumors in 100% of animals with ovarian cancer and in seven of eight animals with colorectal cancer. If you gave the same concentration of the protein through an IV pump, it would be extremely toxic. With the drug factories, the concentration we see elsewhere in the body, away from the tumor site, is actually lower than what patients have to tolerate with IV treatments. The high concentration is only at the tumor site."

Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable delivery platform for cytokines that is composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines.

Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling was used to predict clinical translatability to humans. Notably, this platform elicited T cell responses in non-human primates, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and a major cause of dementia in the elderly. It is estimated that the incidence of AD doubles every 5 years after age 65, and 50% of the population aged 85 or older suffer from AD. Therefore, aging is considered the greatest risk factor for AD, although the mechanism underlying the aging-related susceptibility to AD is unknown. Evidence from both human and animal studies indicates that cellular senescence plays a critical role in the development of many aging-related diseases, including AD.

Senile plaques, which are extracellular deposits of β-amyloid (Aβ) peptides, and neurofibrillary tangles (NFTs), which are intracellular accumulation/deposition of hyperphosphorylated tau proteins, are two neuropathological features of AD. Although it is still debatable whether and how Aβ and hyperphosphorylated tau lead to neurodegeneration, a foundation of memory loss in AD, accumulating evidence indicates that both Aβ and tau pathologies are potent inducers of cellular senescence.

Senescent cells have been detected in the brain of AD patients and AD model mice that overexpress Aβ or tau protein. Removal of senescent cells pharmacologically and genetically reduced brain Aβ load and tauopathy and improved memory in these AD model mice. These data strongly suggest that cell senescence mediates Aβ- and tauopathy-induced neuropathophysiology in AD. These data also suggest that cell senescence promotes Aβ and tau pathologies. Elucidation of the mechanisms underlying brain cell senescence during aging and in AD, as well as the mechanism by which senescent cells contribute to neurodegeneration in AD, will be key to the development of strategies for the prevention and treatment of this devastating disease.

Vascular cognitive impairment (VCI) covers an entire spectrum of vascular pathologies that contribute to cognitive impairment, from pre-clinical subjective states to the manifestation of a severe state of cognitive decline such as vascular dementia (VaD). Even without the presence of risk factors, vascular aging leads to chronic cerebral hypoperfusion (CCH) that induces phenotypical changes in the brain and therefore makes the brain more vulnerable to disease. This emphasizes the importance of cerebral blood flow (CBF) regulation under physiological and pathological conditions. Cerebral blood vessels are responsible for the delivery of many important substances to the brain such as nutrients and oxygen, which is necessary for neuronal oxidative metabolism of energy substrates. Neurons have limited capacity for anaerobic metabolism, thus adequate CBF is critically important for function and viability of neurons.

CCH was reported to be a common feature in all subtypes of VCI. In fact, CCH was reported to begin at early stages of VCI and continue till the demented state of VaD. Furthermore, in a severe state of VaD, global CBF reduction in patients was reported to be more extensive than age-matched controls and Alzheimer's disease patients. VaD patient cohorts reportedly showed decreased CBF to all parts of the brain. A study reported a 31% decrease in CBF at the frontal cortex and a 39% decrease in CBF at the parietal cortex.

It is postulated that CCH is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation, and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration, and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain.

People who are more physically fit are less likely to develop Alzheimer's disease than people who are less physically fit, according to a preliminary study. The study involved 649,605 military veterans in the Veterans Health Administration database with an average age of 61 who were followed for an average of nine years. They did not have Alzheimer's disease at the start of the study. Researchers determined participants' cardiorespiratory fitness. Cardiorespiratory fitness is a measure of how well your body transports oxygen to your muscles, and how well your muscles are able to absorb oxygen during exercise.

The participants were divided into five groups, from least fit to most fit. Fitness levels were determined by how well participants did on a treadmill test. This test measures exercise capacity, the highest amount of physical exertion a person can sustain. For people who are middle-aged and older, the highest level of fitness can be achieved by walking briskly most days of the week, for two and a half hours or more per week.

The group with the lowest level of fitness developed Alzheimer's at a rate of 9.5 cases per 1,000 person-years, compared to 6.4 cases per 1,000 person-years for the most fit group. When researchers adjusted for other factors that could affect risk of Alzheimer's disease, they found that the people in the most fit group were 33% less likely to develop Alzheimer's disease than those in the least fit group.

We designed this study to determine whether stably elevated NAD+ levels in skeletal muscle would affect insulin sensitivity or mitochondrial function in mice fed a Western diet and whether pterostilbene (PT) would interact with nicotinamide riboside (NR) on these readouts. To accomplish this, mice received daily NR injections intravenously to bypass intestinal degradation and first-pass metabolism in the liver and make NR directly available to peripheral tissues such as skeletal muscle. PT was given through the diet, owing to its insolubility in water. We successfully increased NAD+ levels not only in skeletal muscle but also inguinal white adipose tissue (iWAT). This was not simply an acute effect around the time of the injection, but rather a sustained increase throughout the intervention period. In contrast, NAD+ levels in liver were unchanged by NR at this timepoint, which could be a result of the higher NAD+ turnover in this tissue.

In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. The metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.

Physical inactivity is a global public health problem. Regular engagement in muscle-strengthening activities (eg, resistance training) increases or preserves skeletal muscle strength, which has been shown to be inversely associated with mortality and the risk of non-communicable diseases (NCDs) such as cardiovascular disease (CVD) and cancer. Therefore, promoting muscle-strengthening activities may help in reducing the risk of premature death and NCDs.

Compared with aerobic activities, muscle-strengthening activities have been less frequently investigated in terms of their influence on the prevention of premature death and NCDs. Although these findings suggested a favourable influence of muscle-strengthening activities on the risk of NCDs and mortality, the dose-response association was not quantified. We therefore conducted a systematic review and meta-analysis of prospective cohort studies on muscle-strengthening activities and the risk of mortality and NCDs among adults aged ≥18 years. In addition to examining the health benefits of engaging in muscle-strengthening activities compared with the absence of muscle-strengthening activities independent of aerobic activities, we quantified the dose-response association between muscle-strengthening activities and health outcomes.

Sixteen studies met the eligibility criteria. Muscle-strengthening activities were associated with a 10-17% lower risk of all-cause mortality, cardiovascular disease (CVD), total cancer, diabetes, and lung cancer. No association was found between muscle-strengthening activities and the risk of some site-specific cancers (colon, kidney, bladder, and pancreatic cancers). J-shaped associations with the maximum risk reduction (approximately 10-20%) at approximately 30-60 min/week of muscle-strengthening activities were found for all-cause mortality, CVD, and total cancer, whereas an L-shaped association showing a large risk reduction at up to 60 min/week of muscle-strengthening activities was observed for diabetes. Combined muscle-strengthening and aerobic activities (versus none) were associated with a lower risk of all-cause, CVD, and total cancer mortality.

Many neurodegenerative disorders, including Alzheimer's disease (AD), are strongly associated with the accumulation of oxidative damage. Transgenic animal models are commonly used to elucidate the pathogenic mechanism of AD. Beta amyloid (Aβ) and tau hyperphosphorylation are very famous hallmarks of AD and well-studied, but the relationship between mitochondrial dysfunction and the onset and progression of AD requires further elucidation.

In this study we used transgenic mice (the strain name is 5xFAD) at three different ages (3, 6, and 20 months old) as an AD model. Cognitive impairment in AD mice occurred in an age-dependent manner. Aβ1-40 expression significantly increased in an age-dependent manner in all brain regions with or without AD, and Aβ1-42 expression in the hippocampus increased at a young age. In a Western blot analysis using isolated mitochondria from three brain regions (cerebral cortex, cerebellum, and hippocampus), NMNAT-3 expression in the hippocampi of aged AD mice was significantly lower than that of young AD mice. SOD-2 expression in the hippocampi of AD mice was lower than for the age-matched controls. However, 3-NT expression in the hippocampi of AD mice was higher than for the age-matched controls. NQO-1 expression in the cerebral cortex of AD mice was higher than for the age-matched controls at every age that we examined. However, hippocampal NQO-1 expression in 6-month-old AD mice was significantly lower than in 3-month-old AD mice.

These results indicate that oxidative stress in the hippocampi of AD mice is high compared to other brain regions and may induce mitochondrial dysfunction via oxidative damage. Protection of mitochondria from oxidative damage may be important to maintain cognitive function.

To examine the systemic effects of chloroquine (CQ) in vivo, we treated 24-month-old Sprague Dawley (SD) male rats with CQ twice a week for 5 months at a low dose of 0.1 mg/kg orally by water to avoid potential side effects. Low-dose CQ administration extended the lifespan of rats by approximately 6% in terms of median longevity and by about 13% in terms of maximum longevity. CQ-treated rats also tended to have decreased serum TNF-α levels and reduced the numbers of circulating white blood cells (WBC) and neutrophils (NEU) in old rats, suggestive of attenuated chronic inflammation.

In this study, we found that low concentrations of CQ alleviated stem cell senescence, repressed tissue fibrosis, and extended lifespan. Multi-tissue transcriptomic inspection demonstrated that CQ may have both beneficial and detrimental effects on aged animals in a tissue-specific manner. By surveying the transcriptomic landscape of CQ-treated tissues, we found that low-dose CQ treatment attenuated age-associated gene expression across tissues. The strongest effect was observed in the kidney where we found decreased levels of interferon-stimulated responsive element (ISRE)-containing genes and increased expression of transporter encoding genes. However, CQ also augmented pro-aging transcriptional signatures, which may elicit potential cardiac toxicity, without detectable functional impairment, during the duration of the experiment.

The role of CQ in counteracting aging may be linked to its ability to inhibit chronic inflammation systematically and alleviate fibrosis. Consistent with our observations, CQ reduces inflammation and effectively decreases the salivary and serum levels of IL-6, a key component of the senescence-associated secretory phenotype (SASP). In summary, our results demonstrate a geroprotective role of low-dose CQ on physiologically aged rats.

There is a vast body of literature where people claim that certain drugs, diets, or regimens extend the lives of model organisms such as ants, worms, flies, fish, or mice. People perform an intervention, measure how long the animals live, get an extension of median life of 10, 15, or 20 percent, and publish a paper. There are several problems with this approach. One problem is that papers - even those on the same species - often use different controls, making it impossible to compare results. We're lacking nice, standardized data about life span across laboratories and across organisms.

My colleagues and I realized that we need a standardized, scalable system we can use to test how drugs, diets, and other interventions affect behavior, reaction to stimuli, and additional measures of health span. We started developing a system using Daphnia magna, a species of water flea that has been used in toxicology and environmental research for decades, but hasn't been used to study aging.

What's so great about Daphnia? The species has a life span of one month, and even though it's an invertebrate, it is a complex organism. It is beautifully transparent, with a beating, two-chambered heart, an innate immune system, eyes, a brain, and muscle tissue. In fact, when we use electron microscopy to zoom in on the cells of Daphnia, we see that the neurons and muscle cells look very similar to human neurons and muscle cells. Daphnia is also extremely sensitive to small concentrations of drugs.

Our recent paper is establishing the baseline for Daphnia as a new model organism for studying aging. We describe the system in detail, including how we set up the tank, fed the animals, removed new offspring, and set the light cycles and temperature. These appear to be boring details, but the whole point is getting the boring details right. We are developing a set of routines that are needed to raise Daphnia in a standardized way that is also scalable.

Transposable elements, also called transposons, are genetic parasites found in all animal genomes. Normally, transposons are compacted away in silent chromatin in young animals. But, as animals age and transposon-silencing defense mechanisms break down, transposon RNAs accumulate to significant levels in old animals like fruit flies. An open question is whether the increased levels of transposon RNAs in older animals also correspond to increased genomic copies of transposons.

This study approached this question by sequencing the whole genomes of young and old wild-type and mutant flies lacking a functional RNA interference (RNAi) pathway, which naturally silences transposon RNAs. Although the wild-type flies with intact RNAi activity had little new accumulation of transposon copies, the sequencing approach was able to detect several transposon accumulation occurrences in some RNAi mutants. In addition, we found that some fly transposon families can also accumulate as extra-chromosomal circular DNA copies.

Lastly, we showed that genetically augmenting the expression of RNAi factors can counteract the rising transposon RNA levels in aging and promote longevity. We show that knocking down PAF1, a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that in addition to a possible influence by different genetic backgrounds, small RNA and RNAi mechanisms may mitigate genomic transposon expansion despite the increase in transposon RNA transcripts during aging.

Neurodegenerative proteinopathies are characterized by the deposition of filamentous protein aggregates in neurons and/or glia. The transactive response DNA-binding protein-43 (TDP-43), the microtubule-associated phosphoprotein tau, and α-synuclein protein can each misfold and accrue intracellularly into tangled filamentous inclusions manifesting in neurodegenerative diseases known collectively as TDP-43 proteinopathies, tauopathies, and synucleinopathies, respectively. The structures of TDP-43 and tau filaments in frontotemporal lobar degeneration (FTLD) and α-synuclein fibrils in multiple system atrophy (MSA) have recently been reported. What has emerged from these studies is that each disease has a homotypic molecular fold, or conformer, characteristic of the underlying neuropathology. The evidence for the "one conformer per disease" paradigm is growing, with the presence of unknown buried cofactors mediating the structural diversity of fibrillar polymorphs.

Here, using a combination of cryoelectron microscopy (cryo-EM) and mass spectrometry (MS), we show that a previously unsolved amyloid fibril found in cases representing a variety of neurodegenerative conditions is composed of a 135 amino acid C-terminal fragment of TMEM106B, a known risk gene for FTLD-TDP and aging. The fibrillization of TMEM106B into identical fibrillar structures in a wide range of sporadic or genetic TDP-43 proteinopathies (FTLD-TDP), a tauopathy (progressive supranuclear palsy), and a synucleinopathy (dementia with Lewy bodies) points toward a commonality between these diverse neurodegenerative diseases. This suggests that the formation of amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, may contribute to pathogenicity via a loss or gain of function.

Cellular aging is characterized by disruption of the nuclear lamina and its associated heterochromatin. How these structural changes within the nucleus contribute to age-related degeneration of the organism is unclear. Genes lacking CpG islands (CGI- genes) generally associate with heterochromatin when they are inactive. Here, we show that the expression of these genes is globally activated in aged cells and tissues.

We show that in humans and mouse models, global up-regulation of CGI- gene expression is a hallmark of normal and pathological aging. CGI- gene misexpression plays a central role in age-associated degenerative changes by penetrating and interconnecting previously established hallmarks of aging: disruption of nuclear architecture and epigenetic alterations in aged or senescent cells are tightly associated with CGI- gene up-regulation, which, in turn, disturbs intercellular communication. Moreover, CGI- gene misexpression provides insights into the underlying molecular mechanisms of various phenomena observed in aged cells, including global loss of functional identity and increased transcriptional noise.

In particular, a large fraction of the misexpressed CGI- genes encode secreted proteins, many of which are associated with the senescence-associated secretory phenotype (SASP); aged kidneys and hearts from diversity outbred mice, mouse models with disrupted nuclear architectures, and progeria and senescent cells express proinflammatory secretory CGI- genes, and most proteins whose levels increase in aged plasma are encoded by CGI- genes. Together, our findings suggest that disorganization of the nuclear periphery in aged cells results in misexpression of CGI- genes that are a direct source of systemic inflammatory mediators associated with aging.