Fight Aging! Newsletter, June 17th 2024

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Transplantation of Young Bone Marrow Improves Symptoms in a Mouse Model of Alzheimer's Disease

To what degree is Alzheimer's disease driven by immune system aging and consequent dysfunction? The evidence is compelling for increased inflammatory behavior in microglia, innate immune cells of the brain, to be important in neurodegenerative conditions. The state of inflammation in the brain can be driven by inflammatory signaling from the body as well as by mechanisms local to the brain. For example, senescent cells in the aged body produce inflammatory signals that circulate to affect every tissue. It is the overall burden that matters, not just local excesses.

Many issues in the aged immune system arise in the bone marrow, due to changes in the production of immune cells, or damage to the systems of production. In today's open access paper, researchers show that transplanting bone marrow from young donors mice into aged Alzheimer's model mice, in order to restore a more youthful production of immune cells, acts to reduce pathology in the brain. Inflammation is reduced and circulating monocytes in the bloodstream outside the brain become more efficient at clearance of the amyloid-β associated with Alzheimer's disease and this mouse model. The burden of amyloid-β in the brain is also reduced.

While inflammation is important to Alzheimer's disease pathology, this data suggests that the effect noted here is associated with the dynamic equilibrium between amyloid-β in the brain versus the body. Other groups have demonstrated, in human trials even, that reducing amyloid-β outside the brain leads to a reduction within the brain, validating the peripheral sink hypothesis.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model

The aged immune system experiences a decline in the production of immune cells, a reduction in immune repertoire diversity, and an increase in dysfunctional immune cells. These changes are collectively referred to as immunosenescence, which not only plays a causal role in driving systemic aging, including brain aging, but also contributes to an increased susceptibility to age-related diseases such as Alzheimer's disease (AD). Therefore, rejuvenating aged immune cells represents a potential therapeutic strategy for AD.

Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells.

The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral amyloid-β (Aβ) plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

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Short Reprogramming of Vascular Endothelium Reduces Blood Pressure in Hypertensive Mice

Reprogramming occurs in the early embryo, a conversion of adult germ cells into embryonic stem cells mediated by expression of the Yamanaka factors - canonically Oct3/4, Sox2, Klf4, and c-Myc. This is accompanied by a reset of age-related changes in gene expression, and a clearing out of cell damage and dysfunction. This process cannot fix everything, but in conjunction with the ability to selectively sacrifice embryonic cells with too great a burden of molecular damage, it does effectively ensure that the embryo is young even though its parents are old.

Partial reprogramming involves a short period of exposure to one or more of the Yamanaka factors or other reprogramming agents that can indirectly induce expression in one or more of the Yamanaka factors. The goal is to provoke the rejuvenation of gene expression observed in embryonic development without causing a loss of cell state and function. Researchers continue to work towards the most optimal way to achieve this outcome, but a number of approaches are presently in preclinical development. Along the way, researchers are producing proof of concept demonstrations for novel applications of reprogramming technologies, such as the one noted in today's open access preprint.

A Single-Short Partial Reprogramming of the Endothelial Cells decreases Blood Pressure via attenuation of EndMT in Hypertensive Mice

Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Growing evidence supports a likely causal association between cardiovascular diseases and the presence of endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially acquire mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases.

Using a partial reprogramming of ECs, via overexpression of Oct-3/4, Sox-2, and Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertensive mice. OSK overexpression induced partial EC reprogramming in vitro, and these cells showed endothelial progenitor cell (EPC)-like features with lower migratory capability. OSK treatment of hypertensive BPH/2J mice normalized blood pressure and resistance arteries hypercontractility, via the attenuation of EndMT and elastin breaks. OSK-treated human ECs from hypertensive patients showed high eNOS activation and NO production, with low ROS formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and EndMT, restoring their phenotypes in human ECs from hypertensive patients.

Overall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension-induced vascular damage.

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Correlating Regional Blood-Brain Barrier Dysfunction with Alzheimer's Disease Biomarkers

The blood-brain barrier is a layer of specialized cells that only very selectively allow passage of molecules and cells to and from blood vessels that pass through the brain. The barrier separates the biochemistry of the brain from that of the rest of the body. Unfortunately, the blood-brain barrier becomes dysfunctional with age, allowing leakage of unwanted molecules and cells into the brain, where they can, for example, provoke chronic inflammatory behavior in innate immune cells and other supporting cell populations responsible for maintaining brain tissue. It is presently thought that blood-brain barrier dysfunction is important in the development of neurodegenerative conditions, and may be an early contributing cause, preceding many of the other biomarkers and pathological mechanisms.

In today's open access paper, researchers report on their use of MRI to produce regional maps of blood-brain barrier leakage in the brains of old and young volunteers. The researchers then compared these maps with PET imaging of amyloid-β and tau protein, both of which misfold and aggregate in old age, and particularly in the context of Alzheimer's disease, in search of correlations. The researchers found a tendency for blood-brain barrier dysfunction to follow the regional pattern of neurodegenerative pathology that is associated with Alzheimer's disease. This is another data point to add to the evidence for the importance of the blood-brain barrier in neurodegenerative conditions. More effort should be directed towards approaches that might reverse age-related blood-brain barrier dysfunction.

Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults

Brain aging is accompanied by the aggregation of pathological proteins and the increasing prevalence of cerebrovascular disease. Recent research has shown that blood-brain barrier dysfunction is an important feature of both brain aging and Alzheimer's disease (AD). Blood-brain barrier permeability (BBBp) alteration in human aging and Alzheimer's disease (AD) has been documented through the detection of blood-derived proteins in the hippocampus (HC) and cortex of AD patients and increases in the cerebrospinal fluid (CSF) of the plasma albumin protein ratio (Qalb) in both aging and AD. More recent evidence of BBBp in humans comes from studies using the high spatial and temporal resolution imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows measurement of subtle BBB changes. A number of studies using DCE MRI have shown increased BBBp in both aging and AD with particular vulnerability of the hippocampus to this process. Major questions remain, however, regarding the overall spatial distribution of BBBp, whether abnormalities are limited to the medial temporal lobe (MTL) and most importantly, whether or how BBBp is related to the development of AD.

In this study, we investigated the relationship between BBBp and AD through two lines of evidence. First, we examined the full spatial distribution of BBBp which offers an ability to draw inferences about causal mechanisms and to help establish the role of BBBp in dementia. To do this, we compared BBB function in a group of cognitively normal older adults (OA) to young adults (YA) and mapped the whole brain distribution of BBBp. Second, we investigated whether BBBp in OA was associated with APOE4 genotype and regional Aβ and tau, measured using PET imaging.

Using DCE-MRI in cognitively normal OA and YA, we showed that increased BBBp in aging does not occur globally, but rather occurred predominately in the temporal lobe, with involvement of the parietal, and less involvement of occipital and frontal lobes. In these regions we also found that APOE4 carriers had greater BBBp than non-carriers. The regional BBBp we found strikingly reflects the pattern of brain vulnerability to AD pathology, particularly in regions that are affected early. Tau accumulation in normal aging begins in the medial temporal lobe and spreads to neighboring regions in the inferolateral temporal and medial parietal lobes in the presence of Aβ. The pattern of brain Aβ accumulation overlaps with the spatial location of tau best in later disease stages, covering regions in prefrontal, parietal, lateral temporal, and cingulate cortices.

In line with previous studies, we saw greater BBBp in the MTL, particularly regions which accumulate tau pathology and undergo atrophy in normal aging, but do not typically accumulate Aβ at early stages of AD. We also saw that in our sample the frontal lobe is relatively spared from increased BBBp, which is interesting because this brain region is associated with early Aβ accumulation but late tau accumulation. These differences suggest that increased BBBp follows a distribution pattern more like tau accumulation than Ab, with involvement of the MTL, temporal, parietal, and occipital lobes. The degree of BBBp alteration varied considerably in older individuals and increases were also seen in young adults, so it is difficult to say with certainty that these changes are pathological from these data alone. However, their associations with brain regions affected by AD and the possibility of relationships with abnormal protein accumulation, raise concerns.

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Replication Stress as an Underappreciated Contribution to Cellular Senescence and Aging

Replication stress is the name given to disruptions to the process of DNA replication that takes place when a cell divides. The double stranded genome splits, unzipping into two single strands that are each provided with the complementary nucleotides in order to reform as two complete double-stranded copies. The rapidly moving point at which this unzipping takes place, where the two strands actually separate, is called the replication fork. It is a busy area of complex protein machinery, prone to failure and ongoing correction of failures. Unresolved failures lead to DNA damage, and DNA damage during this replication process can lead to cellular senescence.

Today's open access paper reviews what is known of the contribution of replication stress to the age-related burden of cellular senescence. Replication stress is a major culprit in at least one of the progeria conditions that give patients some of the appearance of accelerated aging, but to what degree is this the right place to look in order to measure the progression of normal aging? This is an open question, as replication stress is not so often measured versus markers of one of its outcomes, increased cellular senescence.

What other outcomes can replication stress produce in addition, however? Researchers here note an interesting connection to repair of double strand DNA breaks, that, as you may recall, has been implicated in driving the epigenetic changes that are characteristic of aging. If replication stress provokes greater double strand breaks and thus greater efforts to repair those breaks, it may well be a useful marker of aging.

Replication stress as a driver of cellular senescence and aging

Replication stress can be caused by an endogenous or environmental condition that disrupts the faithful copying of the genome. Replication stress is defined as stalling or slowing of replication fork progression which may lead to replication collapse and DNA damage. Stalled forks need to be protected and recovered to resume DNA synthesis and prevent genomic instability, a hallmark of aging.

A direct link between compromised stalled fork recovery and aging has been established by characterizing the molecular phenotypes of cells isolated from individuals with Werner Syndrome (WS), an autosomal recessive premature aging disease resulting from loss-of-function mutations in the WRN gene. Over the years, experimental evidence has demonstrated critical functions of the RECQ helicase WRN in stability and recovery of stalled replication forks under conditions of replication stress. Consistent with the roles of WRN in processing and stabilizing stalled forks, WS fibroblasts show reduced DNA replication capacity, fork asymmetry, heightened genomic instability, and premature replicative senescence. These phenotypes are likely attributed to failure to resolve complex replication intermediates resulting from stalled replication forks upon functional loss of WRN.

Cellular senescence driven by replication defects is considered a hallmark of aging. This prompts one to consider replicative stress as a potentially useful biomarker for aging. Although cell metabolism markers such as β-galactosidase staining have been a popular marker for senescent cells, markers of replication stress have not been as extensively studied. Rather, DNA damage emanating from replication stress or by other avenues (e.g., oxidative stress) has been postulated as a key biomarker for cellular senescence and even organismal aging. One of the most prominent DNA lesions associated with changes to the genome that is implicated in (and perhaps a driving force of) aging is the double strand break (DSB), one of the most lethal forms of DNA damage and a source of great genomic instability due to its recombinogenic nature.

Recently, the researchers developed an inducible DNA break mouse model that enabled them to investigate the importance of epigenetic changes induced by chromosome breaks for aging. Alterations in epigenetic landscape in regions surrounding the DSBs were associated with aging phenotypes at the cellular and organismal levels. However, whether the aging phenotypes associated with epigenetic changes are reversible at the organismal level remains to be seen. Nonetheless, the described model system will be useful for future work to study in vitro and in vivo aging. It remains to be determined if DSBs deriving from replication stress drive aging in replicative tissues by a mechanism that is different from the one described above, in which DSBs introduced frankly by the in vivo inducible restriction endonuclease system in both non-replicative and replicative tissues cause aging in a manner that is heavily dependent on epigenetic changes.

Although one could argue that DSBs represent only one of multiple DNA lesions to induce accelerated aging, the probability that they occur at the fork in replicative tissues in vivo is high. Replication fork stalling followed by blockage leads to single-stranded and ultimately DSBs, i.e., broken replication forks that cells must deal with using fork reconstruction pathways to preserve genomic stability. Typically, these repair mechanisms to heal DSBs at broken replication forks involve HR repair or the less faithful nonhomologous end-joining (NHEJ). Although stalled forks can be restarted by non-recombinogenic mechanisms, the transient single-stranded DNA that arises is susceptible to breakage. Thus, it is difficult to tease out if a structural feature of the stalled or arrested replication fork, the fork-associated DSB itself, or both represent a key signaling event in cellular senescence and aging. Either way, in proliferating cells of rapidly turning over tissues, replication stress is a driving force for age-associated signaling pathways associated with delayed fork progression.

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Reversible Cryopreservation Continues to be the Point of Focus to Expand Cryonics

The cryonics industry has remained non-profit and small for fifty years. Only a few hundred people have been cryopreserved on death, a tragedy that receives to little attention. A cryopreserved individual has, in principle, some unknown odds of a restored life at some point in a more technologically capable future. Higher odds than the present end of life alternatives, of course. This is provided that the fine structure of the brain is sufficiently preserved, and there remains debate over the degree to which this can be achieved using the technologies and protocols of today. Cryonics organizations and researchers lack the resources needed to conduct the sort of research and development needed to firmly answer questions of this nature, and to effectively react to the answers by developing new approaches.

Expanding the cryonics industry has proven to be challenging, ever stuck in the earliest stages of bootstrapping small gains in reach and capabilities to obtain small increases in funding. The best of the present options for expansion involves a focus on achieving robust, reliable forms of reversible cryopreservation, initially of small tissues and then organs, as there is a strong demand for this capability. Small tissue preservation is need to improve research tools, while the ability to store organs indefinitely would dramatically improve the logistics and reduce the costs of the organ donor industry. Demand leads to funding and commercial development, and as the first applications of reversible cryopreservation spread into the market, this is expected to in turn change the perception of the feasibility of whole body cryopreservation.

All of that said, it is good to see progress on this front in the form of a well funded company. Laura Deming has been leading an effort to work on reversible cryopreservation for a few years now, and it seems that it is is now time to announce the progress achieved to date. Research into reversible cryopreservation has been at the point of making the leap to for-profit development for a decade or so, and hopefully this will encourage other groups to move more rapidly towards commercial applications of their approaches. The wheels turn slowly, but at least they are turning.

Cradle emerges with $48m to build reversible cryonics technology

Cryonics startup Cradle was unveiled this week, boasting $48 million in funding and a mission to develop and prove the feasibility of whole-body reversible cryopreservation. Co-founded by venture capitalist and longevity pioneer Laura Deming and chief scientist Hunter C Davis, the company is built on the belief that pausing and restarting biological functions on demand is a solvable problem. "We're building reversible cryo technologies. Think the hibernation pods you see in space movies for long-term travel - we want to build that."

Cradle's approach to cryopreservation focuses on pausing molecular motion through cooling, thus preventing tissue damage that typically occurs during freezing. This concept leverages technologies like those used in in vitro fertilization (IVF), where embryos can be stored at cryogenic temperatures for extended periods. By adapting and scaling these principles, Cradle seeks to achieve cryopreservation of larger biological systems, including human organs and potentially whole bodies. The company's web site states "We are optimistic that human whole-body reversible cryopreservation is solvable."

Cradle has identified three areas of medicine that it believes its technology can potentially benefit. First, by cryopreserving neural tissue, the company aims to improve the accessibility of human brain tissue samples for research, potentially accelerating drug development and neuroscience research. Second, Cradle believes that cryopreservation could extend the viability window for donor organs, allowing more time for testing and matching, thereby reducing rejection rates and improving transplant outcomes. And finally, the company suggests its technology could allow patients with terminal illnesses to pause their biological time, giving them the opportunity to survive until effective treatments become available.

Cradle said its first major milestone, achieved in February 2024, involved recovering electrical activity in a cryopreserved and rewarmed slice of rodent neural tissue. The company claims this breakthrough serves as a foundational proof of concept, paving the way for its more ambitious goals. Next steps for Cradle include demonstrating preserved synaptic function and long-term potentiation in cryopreserved neural tissue, and eventually, achieving functional preservation of whole organs and even entire organisms.

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Mapping Lipid Changes with Age in Mice Points to the Gut Microbiome

Researchers here note some interesting findings when mapping age-related changes in the levels of lipid metabolites present in tissues in mice. This is a starting point on the road to finding novel aspects of aging that might be addressed. The researchers focus down on changes related to lipids produced in the gut microbiome. It is presently known that the gut microbiome is influential in health and pace of aging, and that the relative population sizes of microbial species undergo harmful changes with age. While some inroads have been made, a complete map of specific problematic changes has yet to be produced; here researchers have found another point of entry to that mapping process.

Lipids, often in the form of fats or oils, are essential molecules for storing energy in our bodies, among other things. In addition, lipids act as signaling molecules and as components of cell membranes. Metabolism - the breakdown of biomolecules such as lipids and sugars into their component parts - slows down as we age, which helps explain why it's easier to gain weight, and more difficult to lose it, as we get older. Although this has been known for over 50 years, how changes in lipid metabolism in particular affects lifespan and health remain unclear. Before this question can be fully answered, we need to know what the actual changes are, in great detail. Only then can scientists begin looking for links between aging lipid metabolism and human health. Toward this end, researchers used mice to develop an atlas of age-related changes in lipid metabolites.

By using a cutting-edge technique to take multiple snapshots of the mouse lipidome - all lipid metabolites present in a biological sample - the researchers found that bis (monoacylglycero) phosphate (BMP) type lipids increased with age in the kidneys, liver, lungs, muscles, spleen, and small intestine of the mice. These lipids play key roles in cholesterol transport and the breakdown of biomolecules within cellular recycling centers called lysosomes. Age-related lysosomal damage might result in cells making more BMPs, which could lead to further metabolic changes, such as increasing cholesterol derivatives in the kidney.

The researchers also investigated the impact of gut bacteria on the lipidome, discovering that while gut bacteria produced many structurally unique lipids, only sulfonolipids increased with age in the liver, kidney, and spleen. In fact, no other group of lipid metabolites from gut bacteria were even detected in these peripheral tissues. "As this kind of lipid is known to be involved in regulating immune responses, the next phase of our research will involve testing the gut bacteria-derived sulfonolipids to determine their structure and physiological functions."

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Low Dose Naltrexone Produces a Small Extension of Life in Nematodes

Over the past decade, researchers have put a great deal of effort into automating and otherwise reducing the costs of studies of aging in nematode worms. A properly equipped team can now screen thousands of compounds in a year in nematodes, while obtaining good data on life span and pace of decline with age via a range of metrics. Sadly, short-lived species such as nematodes have life spans that are far more plastic in response to interventions than is the case for longer-lived species such as our own. A 10-20% increase in nematode life span is likely irrelevant to humans; some interventions that probably do little in humans have increased nematode life span by 100% or more. It is worth bearing this in mind when reading papers such as the one noted here.

There is increasing interest in the concept of aging as a druggable target to prevent age-related diseases. However, developing new drugs to address human aging presents challenges in conducting clinical trials. In the absence of validated risk biomarkers, a large and initially healthy population would need to be treated over an extended period, making it difficult to conduct trials. Therefore, repurposing existing drugs with a good safety profile is a more practical short-term solution than developing new drugs.

Naltrexone is a prescription medication approved by the US Food and Drug Administration (FDA) in 1984 for the treatment of alcohol use disorder and opioid use disorder. It belongs to a class of drugs called opioid antagonists. In recent years, there have been several significant findings regarding a specific dosage of naltrexone called low-dose naltrexone (LDN). LDN has been shown to have immune-modulating properties that could reduce various oncogenic and inflammatory autoimmune processes and alleviate symptoms of certain mental ailments.

Here, we studied the potential benefits of low-dose naltrexone (LDN) in promoting healthy aging using Caenorhabditis elegans as a model organism. We found that LDN treatment extended both healthspan and lifespan in worms, while high-dose naltrexone did not produce the same effects. Further metabolomics analysis revealed that LDN treatment induced metabolic changes that led to increased activity of both amino acid and glucose metabolism, but the longevity effect was independent of the DAF-16/FOXO3 signaling.

We then tested various mutant strains and found that the lifespan extension induced by LDN treatment was dependent on the SKN-1/NRF2 transcription factor. We also observed that LDN treatment not only increased the expression of innate immune genes but also upregulated the oxidative stress response, in line with a role for SKN-1/NRF2 in LDN's lifespan promoting effects. Inhibiting the nuclear translocation of SKN-1 from the cytosol could attenuate the LDN-mediated innate immune gene expression and oxidative stress response. Overall, our study highlights the potential of LDN as a therapeutic agent for promoting healthy aging and identifies its mechanism of action.

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A Small Molecule Approach to Provoke Growth of Synapses

This popular science article notes the progress of a small molecule treatment that provokes growth of dendritic spines in neurons, helping to restore lost synaptic connections. The company plans to treat amyotrophic lateral sclerosis (ALS) patients, but it is an interesting question as to whether it is would be desirable to undergo this sort of boosted formation of synapses in the broader context of aging and dysfunction of neuromuscular junctions. Since the therapy has passed an initial test of safety in volunteers, we will no doubt find out in time.

Amyotrophic lateral sclerosis (ALS) affects nerve cells in the brain and spinal cord, called motor neurons, that control voluntary muscle movements like walking, talking, and breathing. As the neurons die and can't send messages to the muscles, loss of muscle control worsens over time and is eventually fatal. Spinogenix, a clinical-stage biopharmaceutical company, has developed SPG302, a unique once-a-day pill that regenerates the gaps, called synapses, between neurons to restore communication. Following promising results from clinical trials to evaluate the drug's safety, the FDA has approved the company's Investigational New Drug (IND) application, paving the way for further trials.

SPG302's early-stage clinical trials in Australia with healthy adults demonstrated that it's well-tolerated and produces therapeutic levels that match the results seen in preclinical animal models. Spinogenix started dosing ALS patients in April 2024 and has received significant interest from people wanting to enroll in the trial.

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An Approach to Reduce Mitochondrial Function in the Heart Promotes Regeneration

In an interesting reversal of the usual goals in aged tissue, researchers here demonstrate an approach that reduces mitochondrial function in heart muscle to provoke replication of cardiomyocyte cells and consequent regeneration. Since this is achieved via downregulation of a single gene, it is a possible basis for future therapies aimed at improving function in the aged heart, or, the more usual focus in the research community, provoking greater regeneration following the injury and scarring of a heart attack.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling, during which the ardiomyocyte number doubled, but without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident.

In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways.

We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

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Mechanisms for Amyloid Fibrils to Accelerate Calcification of Heart Valves

Amyloids are formed from a few varieties of protein that can misfold or otherwise become altered in ways that encourage other molecules of the same protein to also misfold or become altered in the same way. They spread and gather to form solid aggregates, disruptive to normal cell tissue function. Forms of amyloid relevant to the heart and vasculature include amyloid-β, transthyretin, and medin. Researchers here note that amyloid fibrils may act to encourage and accelerate unwanted calcification of tissue. They focus on the heart, but one might argue for the same processes to operate throughout the cardiovascular system.

Calcific aortic valve disease (CAVD) is the major heart valve disease that afflicts nearly 10 million patients globally with an annual mortality exceeding 100,000, and the numbers continue to rise. In CAVD, microcrystals of hydroxyapatite (a calcium phosphate mineral) deposit onto the heart valve leaflets and impair cardiac function. The disease has a dismal prognosis with most untreated patients dying two years after diagnosis. Currently, the only available treatment is surgical aortic valve replacement, which is not appropriate for all patients. While previous studies of the histology samples from explanted calcified aortic valves have found amyloid deposits in or near calcified areas, the causal relationship between amyloid deposition and calcification is unclear.

Researchers have now proposed a molecular mechanism that links amyloid deposition in the aortic valve with degenerative calcification. They also theorize that other risk factors for CAVD, such as high blood levels of lipoprotein, can contribute to calcification both directly and indirectly through the mechanisms that involve amyloid accumulation.

Harnessing the "resolution revolution" in cryogenic electron microscopy, groups of researchers around the world were able to determine hundreds of structures of patient-derived protein aggregates called amyloid fibrils. Such fibrils are associated with major human diseases including Alzheimer's and Parkinson's diseases, diabetes, and heart diseases such as atherosclerosis and calcific aortic valve disease. "We noticed that the unique geometry of amyloid fibrils, with their periodic arrays of acidic residues on the surface, provides a perfect match for the precursors of calcium phosphate crystals that deposit in the heart valve and impair its normal function."

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IRAK-M Upregulation as an Approach to Slow the Progression of Macular Degeneration

Researchers here report that the IRAK-M protein is protective of retinal cell health, but the amount of IRAK-M expressed in the retina declines with age. This may be due to the increased oxidative stress that is characteristic of aged tissues. Gene therapy to increase IRAK-M expression appears to slow the progression of damage and loss of function in the retina in mice, at least in the models tested. It remains to be seen as to whether this will hold up in the condition itself.

Progression of age-related macular degeneration (AMD) affects around 200-million people worldwide. Patients suffering from AMD often start with blurred vision or seeing a black dot in their central vision, which can ultimately expand to the point where there is no useful central vision. The exact cause of AMD is complex and thought to involve a combination of aging, genetics, environment, and lifestyle factors. Primarily affecting people over the age of 50, the risk of developing AMD significantly increases with age​ and makes tasks like reading and driving​ difficult.

Scientists believe that chronic inflammation, which is typical with aging, is associated with the reduction of a key immune regulatory protein called IRAK-M. This protein is crucial for protecting the retinal pigment epithelium (RPE), a layer of cells essential for maintaining a healthy retina. When RPE cells are damaged, it can result in serious eye conditions and vision loss.

In this study, researchers investigated the role of IRAK-M in AMD by examining genetic variations and their link to AMD risk. By studying IRAK-M levels in patient samples and mouse models of retinal degeneration, the team observed changes in retinal function in mice lacking the IRAK3 gene, which expresses the IRAK-M protein. They found that IRAK-M decreases with age, especially in the retinal pigment epithelium (RPE), and this decline is more pronounced in those with age-related macular degeneration (AMD).

The team then sought to explore whether increasing IRAK-M could protect retinal cells from degeneration in mouse models and whether it is a potential therapeutic target for macular degeneration. They show that increasing IRAK-M levels through RPE-specific gene delivery helps protect against the effects of aging and oxidative stress and reduces retinal degeneration. The researchers aim to help develop the therapies further through a new spin-out company called Cirrus Therapeutics.

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DDX5 Can Form Prion-Like Aggregates in the Aging Brain

A prion is a protein that can misfold in a way that encourages other molecules of the same protein to misfold in the same way. It can thus spread like a pathogen through cells and tissues, producing pathological changes in its wake. "Prion" is a term used inconsistently in the research community, as the very well researched amyloid-β and α-synuclein, drivers of neurodegenerative conditions, have prion-like properties but are rarely referred to as prions. So in one sense, yes, there are indeed prions in the aging brain, spreading and causing harm. Here, researchers look into the protein DDX5 in short-lived killifish, and report that it, too, can exhibit prion-like behavior and thus may be causing harm in the aging brain. As they note, the human version of this gene is very similar, similar enough that the observations may hold up in our species.

Prion-like properties have been proposed to drive the progression of several neurodegenerative pathologies by facilitating the transmission of protein aggregates from affected to unaffected areas of the brain. Long viewed as a rare biological oddity, prions have recently been discovered throughout evolution, from yeast to humans. Prions and prion-like self-assembly have been implicated in normal physiological functions, such as metabolism, cell fate determination, antiviral responses, and inflammation.

Here, we leverage the killifish as a powerful model to unbiasedly identify proteins that aggregate during normal brain aging. Using quantitative proteomics, we identify many proteins with an increased propensity to aggregate in the aging brain. One of these proteins, the RNA helicase DDX5, forms aggregate-like puncta in old brains of both killifish and mice and has prion-like seeding properties in cells. DDX5 rapidly undergoes phase separation in vitro, and these condensates mature into solid aggregates that are inactive and potentially infectious. The aggregation of key proteins during normal vertebrate brain aging could contribute to the age dependency of cognitive decline.

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More on PI3K Inhibitors as Senolytic Drugs

Senolytic drugs selectively clear senescent cells from aged tissues. They are variably effective in different stages of cellular senescence, origins of cellular senescence, and tissue types, as senescent cells vary widely in the details of their biochemistry. We might expect a near future clinical marketplace to feature a dozen or more senolytic therapies, each of which is tailored to specific circumstances and age-related conditions. One of the interesting use cases is to destroy the senescent cancer cells that remain in the body after chemotherapy and other forms of cancer treatment. This will likely require somewhat different senolytics from those used to clear cells that become senescent in other contexts. As an example of this sort of research, scientists here explore the senolytic abilities of PI3K inhibitor drugs in cancer cells.

The targeted elimination of radiotherapy-induced or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells.

Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib)) and PI3K class delta (with CAL-101 (Idelalisib)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.

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Increased mTORC1 Nutrient Sensing Shortens Life Span in Mice

The mTOR protein forms complexes, of which mTORC1 is involved in nutrient sensing. Inhibiting mTORC1 mimics some of the effects of a low calorie diet, meaning cells will undertake greater maintenance and repair while also reducing activities that tend to produce molecular damage. The result of either low calorie intake or mTORC1 inhibition is a modestly slowed pace of aging, lesser degrees of dysfunction, lower chronic inflammation in later life, and so forth. Researchers here demonstrate that this can work in the other direction as well. They stimulate the activity of mTORC1 via RagC, producing the same downstream signaling that would occur with in response to a high calorie diet. This intervention reduces life span in mice via inflammatory mechanisms, one more piece of evidence pointing to the importance of inflammation in the processes of aging.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan.

Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

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An Artificial Lymph Node to Guide T Cells to Attack Specific Targets, Such as Cancers

Lymph nodes are points of coordination for the immune system, where T cells of the adaptive immune system are presented with antibodies that match target molecules, in effect given instructions as to what to attack next. Calling a structure made of biomaterials and decorated with antibodies an "artificial lymph node" does get the point across, but this is a far cry from, say, a lymph node organoid that shares a similar structure and set of cell populations with a natural lymph node. Still, the artificial structure does serve this one purpose, to instruct T cells. Researchers here envisage implanting a lymph node substitute as a part of a T cell therapy for cancer, using appropriate antibodies to ensure that the T cells will aggressively attack cancerous cells.

Lymph nodes - tiny glands throughout the body, mainly in the neck, armpits and groin - are part of the immune systems of mammals, including mice and people. They number in the hundreds so that immune cells in one area of the body don't have to travel far to alert the immune system to impending danger. "They are a landing spot where T-cells, the immune system's fighting cells, lay dormant, waiting to be activated to fight infections or other abnormal cells. Because cancers can trick T-cells into staying dormant, the artificial lymph node was designed to inform and activate T-cells that are injected alongside the lymph node."

To create the artificial lymph node, the scientists used hyaluronic acid, a substance found naturally in the body's skin and joints. Because of its properties, hyaluronic acid is often used in biodegradable materials such as wound healing patches meant to be implanted or applied to the body. Among those properties, hyaluronic acid can connect with T-cells via a cell surface receptor. Researchers used hyaluronic acid as the scaffolding, or base, for their new lymph node, and added MHC (major histocompatibility complex) or HLA (human histocompatibility antigen) molecules, which rev up T-cells and other immune system components. Then, they also added molecules and antigens common to cancer cells to "teach" T-cells what to look for.

"By adding different antibodies to the artificial lymph node, we have the ability to control what the T-cells are being activated to search for. An advantage to this approach over other cell-based therapies such as CAR-T is fewer manufacturing steps. Current cell-based therapies require extracting T-cells from a patient, manipulating them outside of the body to recognize a particular type of cancer, and injecting them back into the patient. In our approach, we inject T-cells along with an artificial lymph node, and the T-cells get primed and educated by the artificial lymph node inside of the body. Then, the T-cells can travel anywhere to destroy cancer cells."

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