Researchers tested a manufactured peptide called pUR4 to block the fibronectin protein in human heart cells donated by heart failure patients. The treatment prevented the human heart cells from failing and restored their function. The treatment also reduced fibrosis and improved heart function after a simulated heart attack in mice.

Fibronectin is normally a good actor in the body. It helps form a cell-supporting matrix for the body's connective tissues, aiding tissue repair after injury. But after a heart attack, fibronectin overreacts, it polymerizes and helps produce too much connective matrix. It also causes hyperactive production of clogged and dysfunctional cardiac myofibroblast cells that damage the heart. The pUR4 compound is designed so it will attach to surface points on fibronectin, effectively inhibiting its effects in injured heart cells.

The pUR4 molecular treatment used in the current study is one of several compounds that show promise in preliminary preclinical research data. A key question in the current study was verifying the results of pUR4 targeted molecular therapy in both the mouse models and human heart failure cells. In mice with simulated heart attack that as a control experiment received a placebo therapy, the animals developed significant fibrosis and heart failure. When researchers treated mice with pUR4 for just the first seven days after heart attack, or genetically deleted fibronectin activity from the heart cells of mice, these reduced fibrosis and improved cardiac function. Treatment of human failing heart cells with pUR4 also reduced their fibrotic behavior.

The researchers emphasize it's too early to know whether the experimental therapy in this study can one day be used to treat human heart patients clinically. Extensive additional research is needed first, including proving pUR4's safety in larger animal models and then moving on to establish proof-of-principal effectiveness treating heart failure in those models.

Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MF) following cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF, fibrosis, and improve cardiac function following ischemia/reperfusion (I/R)-injury.

Mouse and human MF were utilized to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathologic cellular features such as proliferation, migration, extracellular matrix (ECM) deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type (WT) mice received daily intraperitoneal injections of either pUR4 or control peptide immediately after cardiac surgery, for seven consecutive days.

pUR4 administration on activated MF reduced FN and collagen deposition into the ECM and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration. In vivo, daily administration of pUR4 for seven days post-I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathologic cardiac remodeling, and fibrosis up to 4 weeks post-I/R. Finally, inducible ablation of FN in fibroblasts post-I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis.

There are two distinctly different types of fat found in mammals: white adipose tissue (WAT), which is an essential site for triglyceride storage, and brown adipose tissue (BAT). The BAT is a protective mechanism of recent interest. BAT enhances energy metabolism and protects against cold exposure and obesity. A novel model to investigate the role of BAT in healthful aging and lifespan is the mouse model of the gene knockout (KO) of the regulator for G protein signaling 14 (RGS14), which has increased BAT.

Most prior work on RGS14 focused on its effects on embryonic development and on the visual cortex and central nervous system. The role of BAT in RGS14 KO and its ability to enhance lifespan and improve metabolism, the focus of the present investigation, have never been explored. To confirm the essential role of BAT in mediating the protection in the RGS14 KO, we transplanted BAT from RGS14 KO to wild type (WT) mice, a technique that is equivalent to a BAT KO, as it disrupts the salutary phenotype in the RGS14 KO and transplants these features to their WT, receiving the BAT.

Lifespan was monitored in the mice, and we observed significantly longer lifespan of RGS14 KO vs. WT mice. Median lifespan was increased by 4 months from 24 to 28 months. Median lifespan and maximum lifespan were increased to a similar extent in females and males. The older RGS14 KO mice were also protected from aging-induced atrophy of the thymus. It is also important that BAT protects against the aging phenotype, for example, graying and loss of hair, dermatitis, and hunched back, all of which were observed in old WT mice, but not observed in old RGS14 KO mice or in old WT mice, which received BAT transplants.

RGS14 KO mice had improved body composition compared to WT mice. RGS14 KO mice had lower body weight and WAT index (% of white fat to total body weight). The BAT index (% of brown fat to total body weight) was increased in RGS14 KO by 77% compared to their WT littermates. From RT-qPCR analysis to profile changes in BAT transcript levels, we found that BAT-specific markers were significantly upregulated. As healthful longevity and BAT are known to improve metabolic function, we assessed metabolism through indirect calorimetry and demonstrated greater oxygen consumption in RGS14 KO than WT mice.

In the RGS14 KO, SIRT1 was downregulated, while SIRT3 was upregulated. To confirm the role of the SIRT3 mechanism, a double KO (RGS14 KO X SIRT3 KO) was studied. The RGS14 X SIRT3 double KO mice lost their improved metabolism, pointing to SIRT3 as a mediator of the beneficial effects on metabolic regulation in the RGS14 KO animals. Therefore, RGS14 deficiency promotes increased SIRT3 activity, not only by increasing its expression levels, but also by increasing the availability of NAD+, an important cofactor required for sirtuin function. SIRT3 activation, in turn, leads to improved mitochondrial biogenesis, providing the molecular basis for healthful aging in the RGS14 KO animals.

The central principles of the mitochondrial theory of aging are that (i) mitochondrially produced reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), and (ii) ROS-induced lesions in mtDNA can lead to somatic mutations that accumulate, affect the integrity of respiratory chain, and cause mitochondria-dependent aging. More recent data seem to indicate that mtDNA might be more resistant to oxidative damage than previously thought. Instead, many have suggested that the origin of somatic mtDNA mutations is associated with the fidelity of the mtDNA polymerase γ (POLG). Additionally, there seems to be little experimental support for the vicious cycle theory, which attempts to explain the age-dependent accumulation of mutations by proposing a mutation-dependent increase of mitochondrial ROS production that, in turn, would result in elevated oxidative mtDNA damage.

Rather, the age-dependent increase in the somatic mutation load of mtDNA reported by many groups can be explained sufficiently by the replicative segregation of mitochondrial mutations. This theory has been supported by evidence that individual cells of aged persons accumulate high levels of only one specific mutation. Additionally, the effect of mtDNA mutations on mitochondrial ROS production has been reported to be strongly mutation dependent. Only certain mutations that affect the activity of Complex I and Complex V have been convincingly shown to increase mitochondrial ROS production, while random mtDNA point mutations do not seem to be associated with elevated oxidative stress.

One of the most important issues relating to the mitochondrial theory of aging is the very low frequency of somatic mutations detected in the mtDNA in tissue samples from older individuals. Obviously, the mitochondrial genome is present in multiple copies (approximately 10 copies per mitochondrium), and it is a well-established fact that intact mtDNA can complement for mutated genomes. Therefore, it is difficult to imagine how minor changes in the mitochondrial genome could lead to functional effects on the cellular level. Only a mosaic distribution of mutated genomes, resulting from preferential accumulation of mutants in certain cells, can explain the occurrence of such functional effects in these cells. To cause a functional effect within a cell, a pathogenic point mutation must typically exceed 85-90% heteroplasmy, while deletions appear to cause functional effects at heteroplasmy levels above only 60%.

This threshold concept has been validated in tissue samples from numerous patients with mitochondrial diseases harboring pathogenic point mutations or mtDNA deletions, which contain a mosaic of cells with defects in oxidative phosphorylation (OxPhos) that are usually detectable by testing for missing cytochrome c oxidase (COX). Similar mosaics of cells that do not have COX have been reported in postmitotic tissues, such as skeletal muscle, heart muscle, or the brain. However, the number of cells lacking COX in these cases is much lower than that reported in cases of mitochondrial diseases.

First attempts have been made to clarify the potential physiological impact of low amounts of cells lacking COX on intact tissues. In research studying such effects on mouse hearts, compelling evidence has been provided that if the frequency of deletions in a small number of individual heart cells exceeds the above-mentioned threshold, then arrhythmia - a typical symptom of age-related heart disease - may develop. Similarly, it is easy to imagine that individual neurons with impairment of OxPhos, which have been detected in many central nervous system disorders and in the aging brain, can affect the function of complex neuronal networks. However, this hypothesis remains to be investigated and further substantiated.

The longstanding question if old age is itself a disease has been addressed since ancient times, starting from the Roman playwright Terentius, who claimed "senectus ipsa est morbus" (old age itself is a disease), and Cicero who some decades later argued in De Senectute: "pugnandum, tamquam contra morbum sic contra senectutem" (we have to fight against aging, as we do against a disease). These quotations elegantly summarize a long-held view of aging and old age addressed by several scholars. Notwithstanding, with the birth of modern medicine in the nineteenth century, this old tenet has been somehow put apart, as the main interest at that time was to define precise medical entities (diseases and syndromes) and their causes (infections, genetics, degenerative processes, inflammation, etc.). This process ended up in considering aging and diseases as separate phenomena that could eventually interact but that are essentially different in nature.

In this review, we will reappraise and challenge the old tenet that aging and age-related diseases (ARDs) and geriatric syndromes (GSs) are separate entities, and we will suggest instead that both should be considered as parts of a continuum. To support this hypothesis, we will highlight that aging and ARDs/GSs share the same basic molecular and cellular mechanisms. Aging is the predominant risk factor for most diseases and conditions that limit healthspan. Accordingly, interventions in animal models that end up in an extension of lifespan prevent or delay many chronic diseases. Why? For many years the explanation was that aging per se is a physiological condition, which favors the onset of many diseases. However, their relationship is likely much more complex, and a major reason is because they share the basic mechanisms. Assuming that aging and ARDs/GSs share the same mechanisms, which are commonalities and differences?

We will argue that an integrated hypothesis, fitting most epidemiological and experimental data, is to consider ARDs/GSs as an acceleration of the aging process. The conceptualization of accelerated aging started from the observation of rare genetic disorders such as Hutchinson-Gilford progeria. Here, we extend the concept of acceleration of aging to those members of the general population undergoing ARDs and GSs, in comparison with a small minority of people, such as centenarians, who reach extreme age largely avoiding or postponing most ARDs/GSs. This consideration is reinforced by the observation that among centenarians there are few subjects who never suffered of any overt ARDs. These exceptional individuals can be taken as a proof of principle that "healthy" aging and diseases can occur separately, as phenotypes at the extreme of a continuum, which is fueled by a common set of molecular and cellular mechanisms.

Which are the basic mechanisms shared by aging and ARDs/GSs? A group of international experts identified "seven pillars" which actually include adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, epigenetic modifications, and inflammation. Following this idea, the very difference between aging and diseases would relay on the speed and intensity of aging cellular and molecular processes, combined with the genetic and lifestyle predisposition of specific organs and systems. Thus, on the long run, all the functional domains undergo a physiological decline that eventually can lead to overt clinical diseases, favored by system-specific genetic and environmental factors. This progressive path generates a continuum between the healthy juvenile status and the impaired unhealthy elderly one. Accordingly, all major ARDs/GSs are characterized by a long subclinical incubation period, where the diagnostic signs of diseases are largely unobservable due to the high operational redundancy of biological systems.

In conclusion, a debate exists on whether aging is a disease in itself. Some authors suggest that physiological aging (or senescence) is not really distinguishable from pathology, while others argue that aging is different from age-related diseases and other pathologies. It is interesting to stress that the answer to this question has important theoretical and practical consequences, taking into account that various strategies capable of setting back the aging clock are emerging. The most relevant consequence is that, if we agree that aging is equal to disease, all human beings have to be considered as patients to be treated, being an open question when this treatment should start. Many mechanisms proposed to cause aging are the same as those known to underlie ARDs/GSs, lending support to the hypothesis that the aging phenotype and ARDs/GSs are not separate entities but rather the visible consequences of the same processes which likely proceed at different rates.

A second conclusion is that medicine should combat aging to combat many ARDs at a time and not one by one. In this perspective, one could envisage following two possible strategies to attain this result: (A) Try to slow the aging rate through changes in life style, and possibly drugs or medical treatments that counteract the impairment of mechanisms such as those proposed in the "seven pillars." This strategy should help people to stay healthy and active as long as possible and pospone ARDs for decades, ideally until the apparently inevitable limit of human lifespan. (B) More radically, try to rejuvenate human tissues, organs, and whole body. In this case, also the limits of human lifespan could be likely overtaken.

We are relatively ready to the first strategy that appears more feasible and acceptable from an ethical and social point of view, as it would be very similar to what is already happening nowadays, i.e., an increase in life expectancy and in the number of people who attain 90 or 100 years of age and more in good health. We are not yet ready, in particular from a social and ethical point of view, for the second strategy, which opens uncanny scenarios of rejuvenating bodies and very long life for the bulk of the population, a topic addressed in utopian, dystopian, and science fiction novels. Taking into account the fantastic, unprecedented rate of scientific discoveries in the field of aging and rejuvenation, it is timely and urgent to open a large debate.

ArunA Biomedical today announced the publication of data demonstrating that neural stem cell-derived extracellular vesicles (NSC EVs) improved tissue and functional recovery in pigs following ischemic stroke. This is the first ever study to evaluate the therapeutic potential of human NSC EVs in a large animal model representative of the human brain. The neural-derived exosomes, a form of EVs, are a new class of cell-free biologics and cell-mediated drug delivery systems to treat central nervous system and neurodegenerative disorders.

"This study, coupled with our previously published studies focused on a mouse model, represents the first time that a company demonstrated proof-of-concept of the therapeutic potential of extracellular vesicles in two divergent animal species and two stroke types - embolic and ischemic." This is the third study recently completed by ArunA, the first two of which demonstrated improved outcomes in middle-aged and aged mice following embolic stroke.

Study results showed NSC EV treatment: was neuroprotective; eliminated intracranial hemorrhage in ischemic lesions; improved behavior and mobility; decreased cerebral infarct volume and brain swelling; and led to significant improvements at the tissue and functional levels.

Research on the biology of ageing has been conducted for centuries. Survival curves showing the surviving proportion of a population versus time are an intuitive means of illustrating the whole lifespan of a group of organisms and remain a key component of ageing research. Various anti-ageing interventions have been demonstrated to extend the lifespan of model organisms ranging from nematodes to fruit flies to rodents, with contradictory reports in rhesus monkeys. These interventions have mainly included calorie restriction (CR), genetic manipulations, and pharmaceutical administration.

However, whether these interventions extend the lifespan via universal or distinct patterns remains unclear. Traditionally, in ageing research, survival data from lifespan experiments are mainly analysed in the original study, and data are not collected and stored together. Meta-analyses are mainly limited to either sufficiently large subsets of survival data acquired under identical conditions or the application of methods accounting for varying additional factors. The published meta-analyses of survival data have mostly assessed CR. For example, reportedly, CR significantly extends lifespan, and the proportion of protein intake is more important for lifespan extension than the degree of CR. No study has demonstrated whether CR, genetic manipulation, or pharmaceutical administration is superior at extending lifespan and delaying ageing.

Here, we attempted to resolve this question by conducting a comprehensive and comparative meta-analysis of the effect patterns of these different interventions and their corresponding mechanisms via survival curves. We have focused our analyses on Caenorhabditis elegans and Drosophila, powerful model systems that are widely used in ageing research. We developed an algorithm that enabled us to combine multiple strains of these species from a large number of studies and to extract general trends from relevant results.

Our study indicated that CR and genetic manipulations are effective ways in delaying senescence. The effect pattern of CR is superior to that of genetic manipulation in Caenorhabditis elegans but similar to that of genetic manipulation in Drosophila. Genetic manipulation in mammals faces many problems and risks, and CR, including changes in diet composition, time-restricted feeding, or CR mimetics, could be a more feasible approach for humans. These considerations and our results support CR as a feasible and effective anti-ageing intervention.

To me, efforts to counteract biological aging and fighting chronological ageism are two sides of the same coin. But for many this is probably not the case. For one, this is just not an issue at all people in general think about. And yet, all the people reaching adulthood and more are taking hits both from biological aging and from ageism during their lifetime. If you work on counteracting biological aging, you are working on fighting one form of ageism already. And am also hoping that if you think yourself as one who fights ageism you will recognize that understanding biological aging and support scientific efforts to extend healthy lifespan might be the most effective way to support the life of older people in the long term.

The World Health Organization defines ageism as the stereotyping, prejudice, and discrimination towards people on the basis of age. The claim I would like to make is there are two forms of discriminatory ageism, but only one of them has a connection to biological age. The first type is intergenerational ageism, and the main machinery involved here is chronological age. If you think that the deleterious effects of biological aging is the main or only cause for prejudice against older people then imagine a world where biological aging doesn't exist, yet kids are still born and new generations develop their own culture and references. It seems clear that in a world like that ageism and tensions between generations would still be an issue. Biological aging is not needed in order for ageism to happen.

For the second type: does the existence of biological aging and the visible signs of biological aging trigger ageism all by themselves? Yes, this is classical ageism, rooted in a positive bias for the young, and it has a long, long history in human culture. This type of biologically triggered ageism goes one way though, as it affects only older people by definition.

By now you might have guessed the argument I'm going to construct: people working on interventions to counteract processes of biological aging are at the same time working on removing the physiological, cognitive differences between the biologically old and biologically young. So they fight not just biological aging but biologically driven ageism too. Minimizing the differences between biological ages and maximizing the differences between chronological ages, they will make it hard for decision-makers to build ageism into the very fabric of companies and other institutions.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Tremendous efforts have been made to develop novel therapeutics to potentially reverse disease progression. Substantial neuronal loss is observed even in mild AD patients. Intuitively, increasing the number of neurons or replacing lost neurons are potential therapeutic strategies for AD. Stem cells are capable of renewing themselves continuously and differentiating into specialized cells, including neurons.

The process of generating new fate-specified, functional neurons from neural progenitor cells, which are functionally incorporated into a neural circuit, is defined as neurogenesis. Across different species, neural regeneration mainly takes place at the dentate gyrus of the hippocampus and the subventricular zone along the lateral ventricle. Notably, the dentate gyrus, which plays a crucial role in memory formation processes, is related to early memory loss in AD. Neurogenesis decline accompanies normal aging. For AD, accumulating evidence suggests that impaired neurogenesis plays a role in its pathogenesis. Multiple molecules involved in AD pathogenesis, such as ApoE, PS1, and APP were recognized to take part in neurogenesis modulation. Therefore, understanding the mechanism of neurogenesis dysfunction and intervening with neurogenesis represents an alternative AD therapeutic strategy.

Generally, neurogenesis can be modulated by multiple factors that are related to lifestyle, including learning, exercise, social interaction, caloric restriction, blood oxygen level, and even microbial colonization. In this regard, advocating a healthy lifestyle exerts at least a mild effect on preventing or controlling AD in the long run. Apart from lifestyle modification, which exerts mild effects, several pioneering studies identified key molecules or drugs that rescue or reverse NSC dysfunction in elderly animal models, such as via plasma exchange.

Transplanting stem cells to substitute for lost neurons is another intuitively feasible strategy. However, studies have confirmed that the main benefit of stem cell transplantation is a neurosecretory effect. Various neurotrophic factors involved in modulating multiple cellular functions that promote the amelioration of pathological features and cognition in animal models have been recognized. There has been increasing commercial interest to transform current advances in transplantation into clinical practice on human patients.

A hallmark of aging is the reduction in cellular renewal and proliferation across different tissues and organs. The insulin producing beta cells, which reside in the islets of Langerhans, provide a good model to study regulators of cellular aging. Whereas young beta-cell are highly proliferative and increase rapidly in number from the prenatal phase until early stages of development in mammals, beta-cell proliferation becomes dramatically reduced in adults.

Previous studies have indicated that both extrinsic factors, such as the vasculature, and intrinsic factors, such as chromatin modifications, may influence the age-related changes in beta-cells. For example, rejuvenating the beta-cell environment by implanting old islets in younger animals is sufficient to restore the proliferative potential of the aged beta-cells. In addition, transcriptome and methylome studies revealed age-dependent DNA methylation changes at cell-cycle regulators, which may contribute to the quiescence of aging beta-cell.

To identify signals that change in beta-cells during organismal aging, we used the zebrafish as a model. We first characterized the rate of beta-cell proliferation in juvenile, younger, and older adults, and found that proliferation declines with advancing age. We performed transcriptomics of beta-cells from younger and older animals, which identified an upregulation of genes involved in inflammation, including NF-kB signaling. The analysis of inflammatory signaling with single-cell resolution confirmed that NF-kB signaling was activated in a heterogeneous manner at the level of individual beta-cells. Notably, beta-cells with higher levels of NF-kB signaling exhibit a more pronounced proliferative decline compared to their neighbors with lower activity.

It seems like the field of aging science has grown remarkably. Are you optimistic that we're on the verge of real breakthroughs in longevity improvements?

I'm not as optimistic as I was a few years ago. The Next Big Thing in the field is likely to be senolytic drugs. These are able to selectively remove the body's worn-out cells that have become toxic, without poisoning our healthy cells. I think they'll add a decade or more to the human lifespan. Calorie restriction mimetic and exercise mimetic drugs will be another boost if they can be made safe. After that, I think the big challenge will require taking control of our epigenetics (heritable changes that don't require changes to the genome itself). Epigenetics, I believe, is in control of aging at a deep level. Epigenetics is so complicated that 20 years into the age of epigenetics, we're still just beginning to understand how it works.

Why are you less optimistic about the potential for major breakthroughs in aging science now in 2018 than you were previously?

Originally, my thinking went like this: The conventional view has been that aging exists despite evolution's best efforts over hundreds of millions of years to eradicate it. Evolution is already trying to make us live as long as possible, and for humans to extend our lifespan, we'll have to do some pretty fancy thinking to come up with something that evolution hasn't already tried. However, this conventional view is wrong. In fact, evolution has preferred defined lifespans to indefinite lifespans. So, we might hope that we can eliminate aging entirely by understanding the mechanisms of self-destruction that evolution has built into our life history and biochemically disabling them. I had thought that this could probably be done by blocking the signals, jamming the works. Pharmaceutical companies are generally quite good at turning off a hormone or a whole biochemical pathway once it's been identified.

The reason I'm less optimistic now is that I believe that the evolved mechanism of self-destruction involves gene expression, which is to say epigenetics. Different genes are turned on at different stages of life (this is a big part of what epigenetics is), and the genes turned on late in life turn the body against itself. Mechanisms like apoptosis (cell death), autoimmunity, and inflammation are all dialed up. The reason my expectations are scaled back now is that epigenetics has turned out to be enormously complicated. We once thought that a few transcription factors controlled a large number of genes, turning them on and off en masse. We now know that there are thousands of different transcription factors, almost as many as there are genes. And there is wide overlap between genes that have transcriptional functions and genes that have metabolic functions.

Could you flesh out a little your contributions to aging science, in terms of the evolutionary theory of programmed death in humans and most other species?

In the modern understanding of evolutionary fitness, evolution is highly motivated to make you live as long as possible, so long as you are still churning out babies. So, where does aging come from? The standard answer is that there are genes that tie fertility directly to deterioration late in life, and evolution has not found a way around this; it has not found a way to have lots of fertility early in life without incurring damage later on, despite hundreds of millions of years of trying to overcome this limitation.

I have described a great mass of evidence against this picture. Much of it is common sense, but there is a lot of technical, genomic evidence as well. The evidence strongly points to the inference that natural selection has preferred shorter lifespans to indefinite (or very long) lifespans. Why might this be? My theory is that it is about ecosystem stability. It's not possible to construct a stable ecosystem out of selfish individuals that are each trying to live as long as possible and produce as many offspring as possible. In order to have stable ecosystems, nature has had to accept limits to fertility and to lifespan.

The reason that the evolutionary community is so resistant to this idea is that it requires natural selection to occur within entire ecosystems. In other words, this ecosystem persisted because it was stable, while that one collapsed because it was way out of balance. For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene. Most evolutionary biologists today believe that the selfish gene is the only mode by which evolution operates, though they could not articulate a reason why, if challenged.

Uncovering the shared genetic architecture across neurodegenerative diseases may elucidate underlying common disease mechanisms and promote early disease detection and intervention strategies. Progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD) are age-associated neurodegenerative disorders placing a large emotional and financial impact on patients and society. Despite variable clinical presentation, PSP, AD, and FTD are characterized by abnormal deposition of tau protein in neurons and/or glia. While PD is classically characterized by alpha-synuclein deposits, recent studies support the role of tau and neurofibrillary tangles in modifying PD clinical symptoms and disease risk.

Genome-wide association studies (GWAS) and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in MAPT (which encodes tau) that increase risk for PSP, FTD, AD, and PD. However, beyond MAPT, the extent of genetic overlap across these diseases and its relationship with common pathogenic processes observed in PSP, FTD, AD, and PD remain poorly understood. Here, using previously validated methods, we assessed shared genetic risk across PSP, PD, FTD, and AD. We then applied molecular and bioinformatic tools to elucidate the role of these shared risk genes in neurodegenerative diseases.

We identified CXCR4 as a novel locus associated with increased risk for both PSP and PD. We found that CXCR4 and functionally associated genes exhibit altered expression across a number of neurodegenerative diseases. In a mouse model of tauopathy, CXCR4 and functionally associated genes were altered in the presence of tau pathology. Together, our findings suggest that alterations in expression of CXCR4 and associated microglial genes may contribute to age-associated neurodegeneration. Despite the lack of strong genetic association across these three neurodegenerative diseases, we found that CXCR4 expression was altered in brains that are pathologically confirmed for PSP, PD, and FTD. Thus, these findings support our hypothesis that these three neurodegenerative disorders share common pathobiological pathways.

CXCR4 is a chemokine receptor protein with broad regulatory functions in the immune system and neurodevelopment. CXCR4 has been shown to regulate neuronal guidance and apoptosis through astroglial signaling and microglial activation. Furthermore, it has been shown that CXCR4 is involved in cell cycle regulation through p53 and Rb. Our results provide additional evidence that immune and microglial dysfunction contribute to the pathophysiology in PSP, PD, and FTD. These findings have important implications for future work focused on monitoring microglial activation as a marker of disease progression and on developing anti-inflammatory therapies to modify disease outcomes in patients with neurodegenerative diseases.

Atherosclerotic plaques form over a long time by a focal accumulation of lipids, immune cells, and smooth muscle cells in the arterial wall and plaques that rupture can cause acute cardiovascular events, such as myocardial infarction and stroke. Rupture-prone, high-risk plaques are associated with clinical symptoms and characterized by histological evidence of vulnerability and a high inflammatory burden. While this knowledge has advanced considerably over the past few years, our understanding of the metabolic processes within plaques in this inherently metabolic disorder has been lagging behind.

Emerging research has shown that cell metabolism and the inflammatory response are tightly intertwined. Macrophages, abundantly found in atherosclerotic plaques, and other leucocytes, change their metabolism according to their tasks in the immune response. Activated leucocytes change to a predominantly anabolic metabolism by upregulating pathways, such as glycolysis, the pentose-phosphate pathway (PPP), and glutaminolysis, to provide the necessary energy to enable their activation and proliferation. In contrast, catabolic pathways, such as fatty acid oxidation (FAO), are downregulated in these cells. Recently, it has been shown that overutilization of glucose is crucial for blood monocytes and in vitro differentiated macrophages from patients with coronary artery disease (CAD) to mount a destructive inflammatory response. Yet, it remains to be determined whether such an interconnection between cellular metabolism and the inflammatory response is present in human atherosclerotic plaques.

Recent studies have challenged the established concept of the vulnerable atherosclerotic plaque and call for improved methods for identification of the high-risk plaque. Plaque metabolomics might be able to provide a largely unexplored layer of functional characterization of high-risk lesions and thus add value to future risk stratification strategies and novel therapeutic approaches. Metabolic profiling of atherosclerotic tissues has so far focused on comparing lipid metabolite levels in different parts of the same plaque or to plaque adjacent intimal thickenings without being able to produce clear biological insights of clinical significance.

A more clinically relevant approach is to distinguish high- from low-risk plaques according to their metabolic profile. Therefore, we assessed metabolite profiles of 159 highly stenotic carotid atherosclerotic plaques isolated from patients with or without symptoms. We show that high-risk plaques, characterized as being symptomatic, vulnerable by histology, and inflamed with elevated inflammatory mediators, had a specific metabolite signature, distinct from the metabolite profile of low-risk plaques. These data highlight a previously unappreciated role of cellular metabolism in the high-risk plaque and as a discriminating feature from low-risk plaques, indicating that metabolic pathways could be targeted to treat and identify high-risk atherosclerotic plaques.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in developed societies. Advancing age is the primary risk factor for CVD, which is largely mediated by adverse changes to arteries. Two features of vascular aging that are key antecedents to CVD are the development of endothelial dysfunction, as assessed by reduced endothelium-dependent dilation (EDD), and stiffening of the large elastic arteries. Vascular dysfunction with age is a consequence of excessive superoxide-related oxidative stress, much of which is of mitochondrial origin. Given the projected increase in CVD prevalence in the coming decades, driven mainly by increases in the number of middle-aged and older (MA/O) adults, identifying novel strategies that reduce excess mitochondrial reactive oxygen species (mtROS) to improve vascular function and reduce CVD risk in this population is a biomedical priority.

MitoQ is a mitochondria-targeted antioxidant consisting of the naturally occurring antioxidant ubiquinol attached to a lipophilic cation; the lipophilicity and positive charge of this compound enable it to cross cell membranes and accumulate in the matrix facing the surface of the mitochondrial inner membrane where it is optimally positioned to reduce mtROS. MitoQ is now available as a dietary supplement and recently was administered chronically (3 weeks) to healthy young adults without adverse effects. However, presently, the efficacy of chronic MitoQ supplementation for improving vascular function in healthy MA/O adults is unknown. Accordingly, we sought to translate our preclinical findings to humans by conducting the first randomized, double-blind, placebo-controlled clinical trial with MitoQ in healthy late MA/O humans.

MitoQ was well tolerated, and plasma MitoQ was higher after the treatment versus placebo period. Brachial artery flow-mediated dilation was 42% higher after MitoQ versus placebo; the improvement was associated with amelioration of mitochondrial reactive oxygen species-related suppression of endothelial function. Aortic stiffness (measured via carotid-femoral pulse wave velocity) was lower after MitoQ versus placebo in participants with elevated baseline levels. Plasma oxidized LDL (low-density lipoprotein), a marker of oxidative stress, also was lower after MitoQ versus placebo. These findings in humans extend earlier preclinical observations and suggest that MitoQ and other therapeutic strategies targeting mitochondrial reactive oxygen species may hold promise for treating age-related vascular dysfunction.

Expansion of gene families with the concomitant acquisition of new functions can be a driving force for the evolutionary differentiation of species. Compared to other mammals, primate and human genomes include many interspersed segmental duplications, which may have been of special relevance for the evolution of the primate lineage. About 430 blocks of the human genome have been identified as having been subject to multiple duplications during hominoid evolution. Clustering analysis of these segmentally duplicated regions in the human genome suggests that a part of the duplication blocks have formed around a "core" or "seed" duplicon.

The SPATA31 gene family belongs to the core duplicon gene families and it has been shown to be one of the fastest evolving gene families in the human lineage. It has expanded from a single copy in mouse to at least nine copies in humans, located at seven different sites on both arms of chromosome 9. Compared to the mouse gene, we found that the human SPATA31 genes are broadly expressed and have acquired new functional domains, among them a cryptochrome/photolyase domain, suggesting the acquisition of a function in UV damage repair.

Antibody staining showed that the protein is re-localized from the nucleolus to the whole nucleus upon UV irradiation, a pattern known for proteins involved in UV damage sensing and repair. Based on CRISPR/Cas mediated knockouts of members of the gene family in fibroblast cell cultures, we found that the reduction of copy number in cells leads to enhanced sensitivity towards UV-irradiation. Given that increased UV-light resistance of the skin may have played a major role in human evolution, we proposed that the acquisition of an involvement in UV damage sensing or repair has lead to the adaptive evolution of SPATA31.

An interesting side effect of the SPATA31 gene knockouts was that the respective cells survived somewhat longer than normal primary fibroblast cell lines, although this was difficult to quantify. We have therefore used here the alternative approach, namely to over-express a representative member of the SPATA31 gene family, SPATA31A1, and study its effect on cell survival. We find that this over-expression results indeed in premature senescence of the cells, through interference with known aging related pathways. Based on these results, we asked whether natural copy number variation in humans correlates with senescence, in the sense that fewer SPATA31 copies should correlate with longer life span. We can indeed show this effect in a cohort of long-lived individuals. Humans that have reached an age of 95 or higher have on average fewer SPATA31 gene copies than a younger control population.

It has generally been suggested that there is a complex interaction between cellular senescence, tumor incidence due to somatic mutations, and aging. Our data imply that SPATA31 genes are part of this process and that their variation in copy number contributes via this effect to longevity in humans. Having more copies may lead to more somatic mutations, including some that cause cancer, while having fewer copies reduces this effect, thus allowing longer life spans.

The SPATA31 copy number effect on aging can be seen as an example for antagonistic pleiotropy. Higher copy numbers provide a benefit early in life, due to better protection of the skin against sunlight, allowing to spend more time during the day for foraging, social life, mate seeking and child care, all factors that should increase reproductive fitness. Hence, there would be positive selection for higher copy numbers. But more copies would also lead to a higher expression of SPATA31 and our cell-culture results show that such a higher expression induces DNA repair pathways. This could lead to a higher incidence of repair-induced damage in the cells and thus to cancer. If this becomes a problem during reproductive age, one would have a potential negative selection against high copy number. Hence, a balance in copy number should be maintained in the population, but with a certain variance. This variance has the effect that total lifetime beyond reproductive age is affected, with individuals with fewer copies having a higher probability to live longer.