Fight Aging! Newsletter, February 26th 2024

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To What Degree is Alzheimer's Disease a Modern Phenomenon?

Here find an interesting commentary on what might be gleaned of the prevalence of Alzheimer's disease in antiquity from the body of ancient writings on the topic of aging, memory, and health. The consensus is that Alzheimer's disease is a creation of modernity, some combination of a longer life expectancy for a greater fraction of the population coupled with increased calorie intake and less active lives. Yet unlike type 2 diabetes, risk of Alzheimer's risk doesn't correlate well with the usual suspect lifestyle choices that raise the risk of age-related disease and lower life expectancy.

This line of thinking has led to many hypotheses on the contributing factors leading to Alzheimer's disease. Some are unsupported by anything other than coincidence, comparing the introduction of a new factor in modern lives with the rising incidence of Alzheimer's disease, such as the thought that paracetamol use is causing this form of neurodegeneration. Better supported by the evidence is the view that persistent viral infection is involved in the pathogenesis of Alzheimer's disease. Since viruses evolve rapidly over time, it is tempting to speculate on the role of this viral evolution in an increased burden of Alzheimer's in the aged population today - but this is indeed only speculation. It is also hard to reconcile this hypothesis with the relative lack of Alzheimer's disease in modern hunter-gatherer populations.

Did the ancient Greeks and Romans experience Alzheimer's?

You might think age-related dementia has been with us all along, stretching back to the ancient world. But a new analysis of classical Greek and Roman medical texts suggests that severe memory loss - occurring at epidemic levels today - was extremely rare 2,000 to 2,500 years ago, in the time of Aristotle, Galen, and Pliny the Elder. Ancient Greeks recognized that aging commonly brought memory issues we would recognize as mild cognitive impairment, or MCI, but nothing approaching a major loss of memory, speech and reasoning as caused by Alzheimer's and other types of dementia. Centuries later in ancient Rome, a few mentions crop up. Galen remarks that at the age of 80, some elderly begin to have difficulty learning new things. Pliny the Elder notes that the senator and famous orator Valerius Messalla Corvinus forgot his own name. Cicero prudently observed that "elderly silliness ... is characteristic of irresponsible old men, but not of all old men."

Dementia in the Ancient Greco-Roman World Was Minimally Mentioned

The possibility that Alzheimer's disease and related dementias (ADRD) is a modern disease arises from the minimal mention of advanced cognitive decline by ancient Greeks and Romans, who were mainly concerned with the physical frailties of older ages. Because standard medical histories of elderly health lacked mention of cognitive decline, we examined texts by Greek and Roman authors that mentioned memory loss and dementia. Primary texts of Greco-Roman authors, 8th century BCE into the 3rd century CE, that mentioned cognitive decline were identified and critically evaluated. Secondary sources were excluded.

No ancient account of cognitive loss is equivalent to modern clinical data. The term dementia was occasionally used in antiquity, but not invariably linked to old age. Ancient Greeks and Romans expected intellectual competence beyond age 60. While some memory loss was acknowledged, we found only four accounts of severe cognitive loss that might represent ADRD. The possibility of modest ADRD prevalence in ancient Greece and Rome is consistent with its low prevalence in the Tsimane of Bolivia. These contemporary Amerindians live under conditions of high mortality from frequent infections and minimal cardiovascular disease with physically demanding lives. Tsimane after age 60 had increased mild cognitive impairment; the few cases of dementia were not clinically consistent with AD.

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Astrocyte Reactivity in the Development of Alzheimer's Disease

Glial fibrillary acidic protein (GFAP) consistently shows up in proteomic analyses of age-related neurodegenerative processes, particularly now that more research groups are engaged in building early warning biomarker profiles for the later development of Alzheimer's disease. Such studies are usually focused on Alzheimer's disease because that is where most neuroscience funding is directed, but the presence of GFAP as a marker is more generally applicable to the aging of the brain and its supporting cell populations.

Astrocyte cells exhibit increased expression of GFAP when they become reactive, it is a well-known marker of this state. Reactivity occurs in response to damage and altered signaling in the tissue environment characteristic of blood-brain barrier disruption, injury, and neurodegenerative disease. The reactivity of astrocytes is straightforward to describe, in terms of changed expression of markers and changed morphology, but the consequences of reactivity are far from fully mapped at the detail level. Reactivity may overlap with cellular senescence, but not all reactive astrocytes are senescent. The presence of reactive astrocytes is clearly associated with the progression of neurodegenerative conditions, however.

Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer's disease

Defining the progression of blood biomarkers of Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD.

In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD).

Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic mouse model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.

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A Popular Science View of Recent Thinking on DNA Damage as a Cause of Aging

There are presently two views of the way in which stochastic DNA damage can contribute to aging. Most DNA damage occurs in inactive genes in cells that will not replicate many more times, and thus cannot possibly produce systemic consequences throughout large regions of the body. The first argument for a way in which random DNA damage can produce a broader effect is via somatic mosaicism, in which mutational damage occurs in stem cells, allowing those mutations to spread throughout tissue over time. It is unclear as to how to measure the contribution of this process to age-related loss of function, however, and its contribution to aspects of aging other than cancer risk remains debated.

The second view focuses on changes in gene expression that can result from the complex processes of DNA damage and DNA repair. The actions of DNA repair in particular can alter the balance of various factors in the cell nucleus, leading to altered epigenetic marks on the genome, altered nuclear genome structure, and consequently altered transcription of DNA to RNA. This can link DNA damage even in inactive genes to broad consequences for cell behavior. Today's popular science article provides a readable overview of one such issue noted in older animals, dysfunction in the RNA polymerase II that moves along the genome to read DNA and assemble molecules to form RNA. With age, this production of RNA becomes slower and more prone to failure, changing the landscape of gene expression and thus also changing cell behavior.

Why Do We Age? DNA Damage A Likely Cause

Researchers discovered that, in older mice, RNA polymerase II often begins to stall while transcribing DNA into RNA. By analyzing the liver of two-year-old mice - ancient, by mice standards - they noticed that up to 40% of all RNA polymerase II complexes had stalled. To add to this, each stalled complex is likely to block the next three complexes behind it, quickly leading to queuing and gunking up the DNA strand until the obstruction can be cleared. The researchers found that larger genes are especially prone to these issues, leading to a bias towards expression of small genes.

With transcription interrupted, gene expression is also interrupted. As a result, many cellular pathways begin to go haywire; they are deprived of the proteins they need for problem-free functioning. These include all of the same pathways that begin to malfunction as we age. In other words, the genetic fingerprint produced by interrupted transcription is the same as that produced by aging, suggesting that the two are intimately connected. Affected pathways include those involved in nutrient sensing, clearing of cellular debris, energy metabolism, immune function, and the ability of cells to handle damage. All of these play vital roles in shaping life span.

The researchers next set out to understand what caused the RNA polymerase II to stall in older mice. Their suspicions fell on spontaneous, internal DNA damage. Gene expression patterns in cells that have been exposed to DNA-damaging agents are very similar to those seen during normal aging. Premature aging disorders, such as Cockayne syndrome, are also characterized by DNA damage; the usual DNA repair mechanisms malfunction, leading to stalled RNA polymerases at sites of damage, known as lesions. Given these similarities, the scientists speculated that DNA damage could also be involved in normal aging.

To test their hunch, the researchers monitored genetically altered mice that lacked the usual DNA repair machinery, leaving them prone to accumulated DNA damage. These mice exhibit many features of premature aging, including a significantly shortened lifespan. As expected, the rate of transcription was noticeably lower in these mice compared to healthy controls.

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Attempting to Determine Harmful versus Adaptive Changes Using Epigenetic Clock Techniques

The largest of the present challenges facing the use of epigenetic clocks to measure biological age is that there is no established causal connection between what the clock measures, meaning the methylation status of specific CpG sites on the genome, and specific aspects of the burden of age-related damage and dysfunction; e.g. which changes are due to chronic inflammation, which due to mitochondrial dysfunction, etc. Thus the results obtained from an epigenetic clock assay, the raw methylation data or the resulting epigenetic age, are not actionable. There is nothing one can do with that information to guide health practices or choice of intervention.

Various approaches are under development to attempt to connect DNA methylation of CpG sites to underlying mechanisms of aging. The slow and painful method is to investigate each CpG site in isolation, and this has the look of decades of work at the very least. There are other ways forward, however. The one noted here is a clever use of Mendelian randomization to try to link CpG sites to observable traits, followed by splitting up clocks into (probably) harmful methylation changes versus (probably) adaptive methylation changes. Given that as a tool, then one can try to validate whether this assignment of harmful versus adaptive methylation changes is any good using independent data sets and animal studies.

New epigenetic clocks reinvent how we measure age

Existing epigenetic clocks predict biological age (the actual age of our cells rather than chronological) using DNA methylation patterns. However, until now, no existing clocks have distinguished between methylation differences that cause biological aging and those simply correlated with the aging process.

Using a large genetic data set, researchers performed an epigenome-wide Mendelian Randomization (EWMR), a technique used to randomize data and establish causation between DNA structure and observable traits, on 20,509 CpG sites causal to eight aging-related characteristics. The eight aging-related traits included lifespan, extreme longevity (defined as survival beyond the 90th percentile), health span (age at first incidence of major age-related disease), frailty index (a measure of one's frailty based on the accumulation of health deficits during their lifespan), self-rated health, and three broad aging-related measurements incorporating family history, socioeconomic status, and other health factors.

With these traits and their associated DNA sites in mind, researchers created three models, termed CausAge, a general clock that predicts biological age based on causal DNA factors, and DamAge and AdaptAge, which include only damaging or protective changes. Investigators then analyzed blood samples from 7,036 individuals ages 18 to 93 years old from the "Generation Scotland Cohort" and ultimately trained their model on data from 2,664 individuals in the cohort. With this data, researchers developed a map pinpointing human CpG sites that cause biological aging. This map allows researchers to identify biomarkers causative to aging and evaluate how different interventions promote longevity or accelerate aging.

Causality-enriched epigenetic age uncouples damage and adaptation

Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits.

We established a new framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge-clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed landscape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

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An Update on Kimer Med, Improving on the DRACO Antiviral Technology and Moving Towards the Clinic

The state of anti-viral therapies isn't that great, all things considered. Technology has not yet advanced to the point at which a viral infection can be simply shut down, as is the case for near all bacterial infections. The present anti-viral drugs are either vaccines (useful!) or merely shift the odds somewhat by interfering in some part of the viral life cycle, but nowhere near as effectively as desired. Many persistent viral infections are thought to contribute meaningfully to forms of age-related dysfunction, and there is too little that can be done about that at the present time.

This landscape is one of the reasons why there was so much interest in our community in the double-stranded RNA activated caspase oligomerizer (DRACO) technology, an approach to selectively killing cells in which viral replication is taking place. DRACO offered the promise of being broadly and rapidly effective for ending infection by many different viruses, and doing so with little adaptation of the core technology from virus to virus, a big improvement over the present state of the art. Initial results in animal studies looked good.

As is all too often the case for promising technologies, however, the DRACO research program faltered in funding and ultimately halted. It took some time, and a number of failed fundraising efforts, for another group to emerge to pick up the flag and run with it. That group is Kimer Med, a New Zealand biotech startup. It seems they have made considerable strides in the last few years, building their own version of DRACO without the assistance of the original researchers, and improving on the technology to the point at which clinical trials are foreseeable.

What happened to DRACO?

When Dr Todd Rider announced his breakthrough DRACO discovery in 2011, the world sat up and took notice. Headlines read: "Experimental drug could defeat any virus", and "A kill switch for all viruses". Rider's discovery was called "visionary" by the White House and named one of the best inventions of the year by Time magazine. But then, nothing happened. Rider lost his funding. He tried crowdfunding and failed, and very little has been heard of him and his revolutionary discovery since.

Enter Kimer Med

Kimer Med was founded in March 2020 during the height of the COVID-19 pandemic. The founders both knew of Rider's work and understood its potential, but were surprised to find that it had not progressed further, especially given the obvious need. With decades of scientific and entrepreneurial experience between them, they founded Kimer Med to pursue the life-saving promise of broad-spectrum antivirals. However, the journey has not been easy. Both Rider's DRACO paper and the associated patents omitted key information, probably intentionally. It took Kimer Med two years and millions in funding to unpack Rider's results and fill in the gaps.

But as a result of this research, Kimer Med has been able to refine and build on the foundational science, surpassing Rider's results against human viruses. Recently, the company announced success against a total of 10 different viruses, including all four serotypes of Dengue, Zika, Rhinovirus, Influenza, and HSV-2. Going one step further, Kimer Med has now designed a platform for the rapid development of modular, broad-spectrum antivirals. Using the platform, the company has been able to produce and test a wide range of antiviral compounds. The good news is, based on their antiviral's mechanism of action and the ability to customise antivirals to bypass viral defences, Kimer Med believes that efficacy is likely against many more viruses, as well as new, as-yet-unknown viruses ("disease X").

Does this mean we can cure just about any viral infection?

The initial promise of DRACO was "kryptonite for viruses" - one miracle therapy that could wipe out all viral infection. "Based on our research over the past three years, we don't think that's probable. What is possible, and very much within our reach, is a family of broad-spectrum antivirals, each one capable of treating a group of viruses. For example, our lead candidate works against Dengue and Zika virus, both members of the flavivirus family, and we expect that we'll see results against some other flaviviruses as well."

The implications for human health and longevity

There are currently about 220 viruses known to infect humans, resulting all manner of disease, as well as causing or contributing to many other conditions such as Alzheimer's Disease, multiple sclerosis, and multiple forms of cancer. Numerous latent viruses infect vast numbers of the human population, and are linked to deterioration and dysfunction of the immune system - immunosenescence - which results in increased vulnerability to infection and sickness as we age. Right now, there are approved antiviral treatments for only 11 of these 220 viruses.

Most current antiviral therapies merely suppress or inhibit viral replication. Curative antivirals are scarce, and there's no existing treatment that can eradicate latent infection. One of the potential advantages of Kimer Med's antivirals is that they bolster the innate immune system, helping it eliminate virally infected cells. Instead of bursting open and spreading the virus throughout the body, infected cells are disposed of by triggering a natural process known as apoptosis - the orderly breakdown and disposal of damaged, infected or unwanted cells.

"Despite decades of antiviral development, we really haven't seen anywhere near the same success against viruses as we saw with early antibiotics, such as penicillin and sulfa. Rider's great insight was to target the dsRNA common to virtually all viruses, instead of something highly specific, which is what most conventional antivirals do. This has opened the door to genuinely broad-spectrum antivirals, and paved the way for us to create therapies for a whole range of currently unmet medical needs. Our goal now is to complete our pre-clinical studies and progress our first antiviral through to phase one clinical trials. Ultimately, this is where Rider failed and where we must now succeed."

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Age-Related Changes in mTORC1-Related Nutrient Sensing Degrade Intestinal Stem Cell Function

Dysregulation of nutrient sensing is one of the hallmarks of aging, and the work here illustrates that this dysregulation has downstream consequences to stem cell function in at least intestinal tissues. That said, it seems unlikely that this disruption of nutrient sensing in later life, in part caused by increased levels of the mTORC1 complex, is close to the root causes of aging. One might expect rejuvenation therapies targeting forms of damage and dysfunction that are closer to the causes of aging to result in restoration of more youthful nutrient sensing.

The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation.

We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.

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Reviewing the Development of Senotherapeutics to Treat Aging

Senescent cells accumulate with age and contribute meaningfully to chronic inflammation and degenerative aging. Destroying these cells produces rapid and sizable reversal of age-related diseases in mice, demonstrating that the presence of senescence cells acts to maintain a more dysfunctional, inflamed metabolism. This is well known by now, and numerous biotech companies in the first wave of development of senolytic treatments to selectively destroy senescent cells are in varying stages of preclinical and clinical development. Meanwhile, the off-label use of dasatinib and quercetin, a low-cost senolytic therapy that is neither developed nor promoted by any company, continues to look promising based on the slow progression of clinical trials.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflammageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals.

Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity.

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Circulating Protein Biomarkers Correlate with Future Risk of Dementia

Researchers here demonstrate a predictive biomarker panel for Alzheimer's disease risk based on protein levels assessed in a blood sample. This is a one of a number of similar tests developed in recent years. The question is what one might do given a measurement that suggests high risk of Alzheimer's disease. At present, the only option is to generally improve lifestyle choices, but Alzheimer's is not as correlated with lifestyle factors as is the case for, say, type 2 diabetes. Based on the suggestion that senescent cells are important to neurodegeneration, one might take senolytic drugs intermittently, a few times a year at most. Based on the evidence for persistent viral infection to be important to the development of Alzheimer's disease, one might choose to take antiviral drugs. Other options are thin on the ground at present.

Scientists used the largest cohort of blood proteomics and dementia to date, including blood samples from 52,645 healthy participants recruited from UK Biobank - a population-based study cohort. Blood samples collected between 2006 and 2010 were frozen and then analysed 10-15 years later by the research team who analysed them between April 2021 and February 2022. Until March 2023, a total of 1,417 participants went on to develop dementia - and these people's blood showed dysregulation of protein biomarkers.

Of 1,463 proteins analysed, aided by with a type of artificial intelligence known as machine learning, 11 proteins were identified and combined as a protein panel, which the researchers have shown to be highly accurate at predicting future dementia. Further incorporation of conventional risk factors of age, sex, education level and genetics, showed for the first time the high accuracy of the predictive model, indicating its potential future use in community-based dementia screening programs.

Proteins (for example Glial Fibrillary acidic protein, GFAP) had previously been identified as potential biomarkers for dementia in smaller studies, but this new research was much larger and conducted over several years. Known as a longitudinal analysis (a study conducted on a sample of participants over a number of years), the researchers were able to show the differences and trajectories between those with dementia and controls across 15 years.

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More Visceral Fat, Greater Cognitive Decline in Later Life

Modern studies of the effects of excess body weight on long term health use measures, such as waist circumference or weight-adjusted waist index, that are more sensitive to visceral fat than subcutaneous fat. Excess visceral fat in the abdomen is actively harmful, in large part via causing an increased level of chronic inflammation via a variety of distinct mechanisms. Chronic inflammation accelerates the onset and drives the progression of neurodegenerative conditions, and thus might be expected to correlate with cognitive decline.

Some studies suggest that excessive obesity can lead to cognitive decline and dementia. In the relation between obesity and low cognitive performance, the area of distribution of obesity (e.g., central or overall) may be important. However, some common obesity measurement indices, like body mass index (BMI), lack sensitivity in identifying body fat distribution. Based on this, a new index for assessing obesity called the WWI (weight-adjusted waist index), has been proposed to evaluate obesity by weight-standardized waist circumference. The WWI can reflect weight-independent central obesity and has better accuracy than BMI.

A cross-sectional research study was carried out with information from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. This research looked at the connection between the WWI and three tests of low cognitive function in US civilians. In this cross-sectional study which recruited 2,762 individuals aged 60 years and over, the authors found a marked correlation between the WWI and low cognition, and this correlation was not significantly dependent on age, sex, race, education, BMI, smoke, drink, hypertension, or diabetes. In a model with all adjustments, a positive relationship was found between the WWI and poor cognitive function.

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A Gene Therapy to Promote Cardiomyocyte Proliferation Improves Late Stage Heart Failure in Rats

Researchers have developed a gene therapy that upregulates of Cdk1 and Cdk4 in heart muscle. These genes provoke cardiomyocytes into replication, and this has been shown to improve function in the context of heart failure. Here, researchers show that this can help to improve heart function even comparatively late into the development of progressive heart failure, broadening the number of patients who can potentially benefit once this reaches the clinic.

Heart failure remains the leading cause of mortality in the U.S. During a heart attack blood stops flowing into the heart. Without oxygen, part of the heart muscle dies. The heart muscle does not regenerate, instead it replaces dead tissue with a scar made of cells called fibroblasts that do not help the heart pump. If there is too much scarring, the heart progressively enlarges, or dilates, weakens and eventually stops working.

In a previous study, researchers successfully used gene therapy to improve acute cardiac dysfunction in animals. Their method effectively and specifically delivered genes that promote proliferation to heart cells, generating new heart muscle. This approach not only strengthened the heart improving its ability to keep the blood flowing, but also prevented typical subsequent congestion in the liver, kidneys, and lungs in rats and pigs. "In this study, we did something that had not been done before. We intervened with the same gene therapy but not during acute heart failure or early in the disease as in our previous experiments, but late in the disease during the chronic phase four weeks after cardiac injury had severely damaged the heart."

Four months after treating the animals, the researchers checked cardiac function and heart structure. "We were surprised to see evidence of significant heart cell proliferation, a marked reduction in scar size and a significant improvement in cardiac function. Although heart dilation and lung congestion associated with chronic heart failure were not improved, the treatment partially improved liver and kidney functionality."

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Circulating Claudin-5 Correlates with Age and Alzheimer's Disease

Researchers here demonstrate an association between increased claudin-5 levels in the bloodstream and age-related neurodegeneration. This is distinct from an underlying age-related decline in claudin-5 levels. The scientists do not speculate too deeply as to why this relationship might exist, but others have done so in the past. In short, claudin-5 is an important tight junction protein in the blood-brain barrier wrapping blood vessels that pass through the central nervous system. The blood-brain barrier prevents unwanted molecules and cells from passing to and from the brain. Dysfunction and leakage of the blood-brain barrier is characteristic of later life and neurodegenerative conditions, encouraging inflammation in brain tissue in response.

While claudin-5 is clearly necessary for blood-brain barrier function, it is an open question as to why exactly there is more of it in the bloodstream in the context of outright neurodegenerative disease versus the context of aging. Is some other form of disarray preventing it from integrating into the barrier when expressed, or is upregulation of expression a response to dysfunction in the blood-brain barrier, or is some other process at work under the hood?

The blood-brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). Claudin-5 (CLDN-5) is a protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL).

The BBB functions as a selective gate for the uptake of essential molecules from blood into the brain and the excretion of harmful molecules from the brain into blood via transporters and receptors on cellular membranes. In addition, the BBB prevents the influx of blood-borne neurotoxins, cells, and pathogens into the brain because of the formation of tight junctions (TJs) in the intercellular space between adjacent macrovascular endothelial cells. Loss of BBB integrity has been observed in neuroinflammatory disorders, and patients with early AD demonstrate BBB leakage. In addition, patients with early cognitive dysfunction show BBB breakdown in the hippocampus, which occurs independently of brain accumulation of amyloid and tau. These several findings indicate that BBB TJ-sealing components might be impaired in MCI- and AD-related pathology.

Breakdown of the BBB, which is associated with CNS diseases, is accompanied by the invasion of leukocytes and activation of astrocytes. The matrix metalloproteinases (MMPs) secreted by these invading leukocytes have been shown to lead to the degradation of CLDN-5 in the BBB of mice. In a rat ischemic model, MMPs secreted from astrocytes likewise degraded CLDN-5 in the BBB. In addition, the number of pericytes in the BBB was greater in patients with AD compared with cognitively healthy peers, perhaps reflecting a response to endothelial breakdown. As is similar to our findings for patients with MCI or AD, circulating CLDN-5 levels are elevated in other CNS diseases, including ischemic stroke, bipolar disorder, and obsessive-compulsive disorder. The CLDN-5 circulating in blood might be derived from the endothelial cells in the BBB.

Interestingly, we found a significant negative association of plasma CLDN-5 level with age in MCI and AD. Ultrastructural analysis of TJ seals in the BBB did not reveal normal age-associated changes. In the current study, CLDN-5 levels were higher in younger than in older patients in both the MCI and AD groups. This is consistent with an analysis of autopsied brains which reported that the CLDN-5 level decreases with AD progression. Because reactive astrocytes and endothelial cells in the BBB in AD produce MMPs, prolonged activation of MMPs might lead to the degradation of CLDN-5 and, thus, lower plasma CLDN-5 levels in older compared with younger patients with cognitive deficits.

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Signaling Between Cell Types is Vital to Heart Regeneration

A fair amount of the research and development work aimed at spurring greater regeneration of an injured heart is focused on cardiomyocytes, either by delivering new cells, or by encouraging existing cells to replicate or otherwise better resist the hostile environment following injury. As researchers here point out, regeneration is known to be an intricate dance between multiple different cell populations. Thus the signaling that facilitates coordination between those cell types may prove to be a better target for intervention than any single cell population, and single cell population approaches that have shown promise in the past may be promising because they indirectly stimulate the right sort of signaling in the injured heart.

Intensive investigations utilizing single-cell genomics and genetic experiments were conducted by a team of scientists to shed light on the potential of the human heart to achieve self-repair and regeneration. Heart disease remains a leading cause of death worldwide, with myocardial infarction, also known as a heart attack, causing irreparable damage to cardiac muscle cells. While current treatments focus on alleviating symptoms and improving blood flow, they fall short in addressing the crucial issue of lost cardiomyocytes (CMs), leading to further complications such as heart failure.

Contrary to longstanding beliefs, the study reveals that regeneration of CMs requires a complex microenvironment, where a dynamic synergy between CMs, resident immune cells, and cardiac fibroblasts is the driving force behind cardiac renewal. Through intricate signaling mechanisms, these cell types coordinately instruct and support each other, facilitating CM proliferation and effectively repairing damaged heart tissue. "Understanding heart regeneration on a molecular level is an important step towards developing innovative therapeutics that can facilitate CM regeneration. Our study challenges the existing paradigm, suggesting that targeting the microenvironment rather than a specific cell type is instrumental in healing the injured heart."

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MTTP as a Mediator of the Benefits of Exercise

MTTP is a longevity-associated gene involved in lipid metabolism and correlated with cardiovascular function. Here, researchers use flies to demonstrate that the fly version of MTTP, called mtp, is involved in the mechanisms by which exercise improves long-term cardiac health. It isn't clear as to how exactly MTTP or mtp is involved in the known set of mechanisms important to the pace of aging and cardiovascular health. That sort of deep dive into establishing connections between cellular processes occurs only after numerous studies have demonstrated an interesting correlation, and even then it is a slow and incremental process.

Microsomal triglyceride transfer protein (mtp) in Drosophila is a direct homolog of human MTTP (microsomal triglyceride transfer protein), a lipid transfer protein found in the liver and intestine. Given its role as a rate-limiting enzyme in lipid metabolism, MTP has been associated with human longevity, coronary artery disease, and other vascular diseases caused by adverse lipid profiles (peripheral vascular disease, renal vascular disease, and stroke), which account for a significant portion of human mortality.

Diastolic dysfunction is a major cardiac dysfunction, and an important predisposing factor is age. Although exercise training is often used for the prevention and treatment of cardiovascular disease nowadays, little is currently known about whether exercise interventions associated with the slowing of cardiac aging are related to mtp-related pathways.

In the present study, after establishing a Drosophila exercise model, we found that cardiac systolic function and mtp expression levels decline with aging in Drosophila. Besides, there is a strong association between age-related diastolic dysfunction and mtp expression levels. Importantly, endurance exercise improves age-related diastolic dysfunction and prolongs lifespan, possibly related to the upregulation of mtp expression, thereby enhancing lipid metabolism in aged Drosophila.

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RNA Transfer Between Cells is Tightly Regulated, and Disruption Shortens Life Span

It is not always the case that genetic alterations that shorten life span are interesting: there are many ways to break a complex system, and only some of those breakages are relevant to the dysfunction of aging. Researchers here explore the transfer of RNA between cells in nematode worms, showing that too much RNA uptake causes reduced life span. Is this relevant to aging, however? Most likely only if this set of regulatory processes become changed in maladaptive ways in later life. Otherwise, this is just another one of the countless different ways to break the complex regulatory systems of a living organism.

Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans, a similar mechanism is conferred by the systemic RNAi pathway. Members of the Systemic RNA Interference Defective (SID) family act at different steps of cellular RNA uptake and export.

The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded RNA (dsRNA)-gated channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1, sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan.

Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan.

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Correlations with Mortality in Levels of Proteins Secreted by Senescent Cells

Here, researchers investigate correlations between late life mortality and levels of specific proteins produced by senescent cells as a part of the senescence-associated secretory phenotype (SASP). While looking over the paper, it is worth bearing in mind that circulating levels of many of the molecules thought to be important components of the SASP do not appear to correlate well with senescent cell burden. Why this is the case remains to be understood on a molecule by molecule basis, but note that many of the SASP molecules are widely used for signaling by other cell types and in other circumstances.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults.

We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1,923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79) than the covariates alone (0.70). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

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