Fight Aging!

The balance of microbial populations making up the gut microbiome shifts with age. The research community has developed a good list of contributing causes, ranging from lifestyle changes to aspects of degenerative aging that affect immune function and the state of the intestinal lining, but the degree to which any given contribution is important relative to the others remains a question mark. The immune system is responsible for gardening the gut microbiome, suppressing the population growth of problem microbes, but immune aging likely reduces this activity. In turn, growing populations of problem microbes can help to provoke chronic inflammation that further harms immune function, and beyond that tissue function throughout the body.

With an increased attention given to the aging of the gut microbiome, researchers are beginning to identify specific mechanisms by which it can provoke inflammation and tissue dysfunction. Today's open access paper is an example of this sort of work, in which the authors identify valeric acid as a problem metabolite, produced in greater amounts by the aged gut microbiome, and which stimulates harmful inflammatory signaling. This is one of many reasons for a greater focus on ways to rejuvenate the gut microbiome, restoring the youthful balance of populations. Practical approaches do exist, including fecal microbiota transplantation, flagellin immunization, and others. Making these approaches more available to the public would likely provide meaningful benefits to late life health.

Gut microbiota of old mice worsens neurological outcome after brain ischemia via increased valeric acid and IL-17 in the blood

Studies have shown that gut microbiota can modulate inflammatory responses in the brain after brain ischemia. Antibiotics-induced changes in the gut flora provide neuroprotection against brain ischemia in mice. A recent study has shown that aging-related changes in gut microbiota may influence the outcome of experimental stroke in mice. However, the mechanisms for this effect are not defined. Consistent with these experimental stroke findings, stroke patients with significant gut dysbiosis may have a worsened neurological outcome, suggesting a potential role of gut microbiota in determining stroke outcome in humans.

Gut microbiota can produce multiple metabolites. Among them, short-chain fatty acids (SCFA) are one of the major types of metabolites and can regulate inflammatory responses, a process that affects neurological outcome after brain ischemia. Previous studies have shown that SCFAs are decreased with aging in the feces. A recent study has shown that stroke patients have changes in SCFA concentrations in their feces. However, whether SCFAs are involved in aging-related changes in brain ischemic tolerance and how SCFAs affect stroke outcome is not known.

Interleukin (IL)-17 is a proinflammatory cytokine. It is produced from a group of T helper cells and can induce the production of chemokines that recruit immune cells to the site of inflammation and facilitate the production of other proinflammatory cytokines, such as IL-6 and IL-1β. A previous study has shown that the decrease of IL-17-positive T helper cells may contribute to the neuroprotection induced by antibiotics-caused gut floral changes.

Old C57BL/6J male mice (18 to 20 months old) had a poorer neurological outcome and more severe inflammation after transient focal brain ischemia than 8-week-old C57BL/6J male mice (young mice). Young mice with transplantation of old mouse gut microbiota had a worse neurological outcome, poorer survival curve, and more severe inflammation than young mice receiving young mouse gut microbiota transplantation.

Old mice and young mice transplanted with old mouse gut microbiota had an increased level of blood valeric acid. Valeric acid worsened neurological outcome and heightened inflammatory response including blood interleukin-17 levels after brain ischemia. The increase of interleukin-17 caused by valeric acid was inhibited by a free fatty acid receptor 2 (FFAR-2) antagonist. Neutralizing interleukin-17 in the blood by its antibody improved neurological outcome and attenuated inflammatory response in mice with brain ischemia and receiving valeric acid. Old mice transplanted with young mouse feces had less body weight loss and better survival curve after brain ischemia than old mice transplanted with old mouse feces or old mice without fecal transplantation.

Our results suggest that a novel pathway linking gut microbiota, valeric acid, FFAR 2, and IL-17 mediates increased inflammatory response to brain ischemia and worsened neurological outcome after ischemic stroke in old mice.

The growing focus on cellular senescence as a contributing cause of aging has identified senescent cells as important agents in a range of conditions, age-related and otherwise. Interestingly, the pathology of both type 1 and type 2 diabetes appears to be mediated by senescent beta cells in the pancreas. Clearing senescent cells has been shown to be beneficial in animal models of these conditions, but it remains to be seen as to whether human patients will benefit. There are many conditions that might be treated with senolytic therapies to selectively destroy senescent cells, and only so many research groups and companies working in the space. Only a small number of age-related conditions are presently targeted by trials and programs of development, and forms of diabetes are not even close to the top of the much longer list awaiting attention.

Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes.

Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans.

Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.

Link: https://doi.org/10.3389/fendo.2023.1212716

Changes in the gut microbiome take place with advancing age, an increase in populations that provoke chronic inflammation, a reduction in the populations producing beneficial metabolites. Even only considering rising levels of inflammation in the aging body, it is clear that the gut microbiome can contribute to many age-related conditions. As researchers investigate the details, they also find other ways in which specific manifestations of aging may be in part caused by changes in the gut microbiome. Given that there are practical approaches demonstrated to restore a more youthful balance of intestinal microbial populations, such as flagellin immunization and fecal microbiota transplantation, one would imagine that we'll see greater adoption of these interventions in the near future.

The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the human gut microbiome and high resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia in two large cohorts; Framingham Heart Study (FHS, n=1,227, age range 32-89), and the Osteoporosis in Men Study (MrOS, n=836, age range 78-98).

Stool samples from study participants underwent amplification and sequencing of the 16S rRNA gene. The resulting 16S rRNA sequencing data was processed separately for each cohort. Resulting amplicon sequence variants were assigned taxonomies using the SILVA reference database. Controlling for multiple covariates, we tested for associations between microbial taxa abundances and HR-pQCT measures using general linear models. Abundance of 37 microbial genera in FHS, and 4 genera in MrOS, were associated with various skeletal measures including the association of DTU089 with bone measures, which was independently replicated in the two cohorts.

A meta-analysis of the taxa-bone associations further revealed that greater abundances of the genera; Akkermansia and DTU089, were associated with lower radius total volumetric bone mineral density (vBDM), and tibia cortical vBMD respectively. Conversely, higher abundances of the genera; Lachnospiraceae NK4A136 group, and Faecalibacterium were associated with greater tibia cortical vBMD. We also investigated functional capabilities of microbial taxa by testing for associations between predicted (based on 16S rRNA amplicon sequence data) metabolic pathways abundance and bone phenotypes in each cohort. While there were no concordant functional associations observed in both cohorts, a meta-analysis revealed 8 pathways including the super-pathway of histidine, purine, and pyrimidine biosynthesis, associated with bone measures of the tibia cortical compartment.

Link: https://doi.org/10.3389/fendo.2023.1237727

It is not too far from the truth to say that everyone in the field of aging research has their own theory of aging. Enormous amounts of data exists, measurements of near every aspect of cellular biochemistry, to note the ways in which these aspects change with age, yet we lack the framework to link all of the data together, to firmly state what is important and what is not, what is cause, what is consequence, and how exactly the network of age-related changes are linked to one another. Aging is a dark forest in which the boundaries are well mapped, but only a few of the interior features have been well explored.

So why not a view of aging centered around hormesis? That is the topic covered by today's open access commentary. It is similar in many ways to views of aging centered around the capacity for resilience in the face of stress. If a biological system cannot right itself after experiencing some form of perturbation, then the odds of catastrophic failure might be expected to be higher. This, at the core of it, is aging: an increased risk of catastrophic failure resulting from loss of functional capacity. Unfortunately, when it comes to treating aging as a medical condition one can't stop there, and the fine details of the biochemistry involved are in fact of great importance.

Hormesis defines the limits of lifespan

This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of numerous degenerative diseases and debilitating effects of aging. It proposes that the most fundamental, evolutionary-based integrative strategy to sustain and protect health is based on the concept of hormesis. This concept integrates anti-oxidant, anti-inflammatory, and cellular repair responses at all levels of biological organization (i.e., cell, organ and organism) within the framework of biphasic dose responses that describe the quantitative limits of biological plasticity in all cells and organisms from bacteria and plants to humans.

A major feature of the hormetic concept is that low levels of biological, chemical, physical and psychological stress upregulate adaptive responses that not only precondition, repair and restore normal functions to damaged tissues/organs but modestly overcompensate, reducing ongoing background damage, thereby enhancing health beyond that in control groups, lacking the low level "beneficial" stress. Higher doses of such stress often become counterproductive and eventually harmful. Hormesis is active throughout the life-cycle and can be diminished by aging processes affecting the onset and severity of debilitating conditions/diseases, especially in elderly subjects.

The most significant feature of the hormetic dose response is that the limits of biological plasticity for adaptive processes are less than twice that of control group responses, with most, at maximum, being 30-60 % greater than control group values. Yet, these modest increases can make the difference between health or disease and living or dying. The quantitative features of these adaptive hormetic dose responses are also independent of mechanism. These features of the hormetic dose response determine the capacity to which systems can adapt/be protected, the extent to which biological performance (e.g., memory, resistance to injury/disease, wound healing, hair growth, or lifespan) can be enhanced/extended and the extent to which synergistic interactions may occur.

Hormesis defines the quantitative rules within which adaptive processes operate and is central to evolution and biology and should become transformational for experimental concepts and study design strategies, public health practices, and a vast range of therapeutic strategies and interventions.

Large mammals must evolve efficient ways to suppress cancer in order to become large. Being large means having more cells, any of which could undergo potentially cancerous mutations. In order for cetaceans such as the large whales to exist at all, they must employ much more effective anti-cancer strategies than those found in humans. If we can identify those strategies, then perhaps they might form the basis for novel cancer therapies. Given the state of this research, it is still too early to say whether this is a plausible near future opportunity, or whether it will turn out to require to great a degree of biological engineering to accomplish over the next few decades.

Despite the generally increased cancer risk in large, long-lived organisms, cetaceans, among the largest and longest-living mammals, appear to possess a counteracting mechanism. Nevertheless, the genetic basis underlying this mechanism remains poorly understood. The p53 pathway serves as an ideal target for studying the mechanisms behind cancer resistance, as most cancer types have evolved strategies to circumvent its suppressive functions. Here, comparative genetic analysis of 73 genes involved in the p53 pathway in cetaceans was undertaken to explore the potential anticancer mechanisms behind natural longevity.

Results showed that long-lived species contained three positively selected genes (APAF1, CASP8, and TP73) and three duplicated genes (IGFBP3, PERP, and CASP3) related to apoptosis regulation. Additionally, the evolutionary rates of three genes associated with angiogenesis (SERPINE1, CD82, and TSC2) showed a significant relationship with longevity quotient (LQ) and maximum lifespan (MLS), suggesting angiogenesis inhibition as another potential strategy protecting cetaceans from cancer. Interestingly, several positively selected tumor suppressor genes with high copy numbers were correlated with body size in the large-bodied and long-lived cetacean lineages, corroborating Peto's paradox, which posits no link between cancer incidence and body size or longevity across species.

In conclusion, we identified several candidate genes that may confer cancer resistance in cetaceans, providing a new avenue for further research into the mechanisms of lifespan extension.

Link: https://doi.org/10.24272/j.issn.2095-8137.2023.058

Comparing this paper with a recent examination of CD44 in species life span differences is a good illustration of the complexity of cellular biochemistry. CD44 expression seems arguably bad in the context of vascular aging, but arguably good in the context of central nervous system aging. It is quite common for genes to have very different positive or negative influences in different tissues, different circumstances, different levels of expression. Evolution tends to produce molecular machinery that is promiscuously reused in different ways in different circumstances. Nothing is simple! Thus CD44 can upregulate cell maintenance of one type in central nervous system cells, while impairing another form of cell maintenance in the vasculature, and this is just one example of many similar circumstances.

The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes.

Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.

Link: https://doi.org/10.1038/s41467-023-41346-y

A sizable body of evidence supports a role for inflammatory microglia in the aging of the brain. Microglia are innate immune cells resident in the central nervous system, analogous to macrophages elsewhere in the body, but with an additional portfolio of duties relating to maintenance of the synapses that connect neurons. Most of the inflammatory microglia present in the aged brain are merely overactive, a maladaptive response to signs of damage and dysfunction characteristic of aging. This can include the presence of protein aggregates, unwanted molecules, cells, and bacteria passing through a leaking blood-brain barrier, or issues internal to the microglia themselves such as mislocalization of mitochondrial DNA into parts of the cell where it is inappropriately recognized as foreign.

Some inflammatory microglia are senescent, however. Cells become senescent constantly throughout life, but the immune system destroys them, or they undergo programmed cell death, and in youth this happens efficiently enough to prevent any accumulation. With advancing age, clearance of senescent cells falters, and their numbers steadily increase. While the proportion of cells that are senescent at any given time is never very large, even in late life, senescent cells energetically secrete a potent mix of inflammatory signals. They are very disruptive to normal tissue function, even through comparatively few in number. Today's open access paper examines one of the many specific ways in which the metabolites produced by senescent microglia may be disruptive to brain tissue.

H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear.

Compelling evidence suggests that abnormal histone modifications influences the translation of cellular metabolic intermediates into changes in gene transcription and expression. This is mediated by cellular intermediary metabolites which serve as cofactors that either add or remove chromatin modifications, induced by chromatin modifying enzymes. Concentration changes in these cellular metabolic intermediates may up- or down-regulate gene expression by altering chromatin states. A recent study found that lactate, a product of glycolysis and a significant energy source, can regulates gene transcription via lactylation of histones through fluctuations in lactate content in cells, representing a new post-translational modification contributor to the epigenetic landscape.

Several lines of evidence suggest that senescent cells are still metabolically active, and can induce changes in their environment through secreted molecules or by switching energy metabolism fashion. Senescent cells are associated with a shift towards glycolysis. In this work, we found that lactate levels are significantly increased in senescent microglia, indicating that senescent microglia switch their metabolism from OXPHOS to aerobic glycolysis, which produces ATP rapidly but also generates massive lactate. Moreover, senescent microglia-trigged accumulation of lactate caused enhanced histone lysine lactylation (Kla) levels, contributing to the development and progression of brain aging and Alzheimer's disease pathogenesis. These preliminary results suggest that the metabolic transition to aerobic glycolysis of senescent microglia may also affect itself and its local environment by affecting neuroinflammation through histone Kla-mediated epigenetics.

One of the areas of research that seems constantly on the verge of producing an impressive advance is the use of nanoscale scaffold materials to encourage regrowth of tissue, such as bone and cartilage. The space of possible combinations of techniques is vast, and there only so many researchers, and only so much funding. Advances such as the one noted here are published by research groups several times a year, and this has been the case for more than a decade now. This part of the field seems eternally in a state of progress and exploration, with promising leads, yet it remains the case that clinical options for regenerative medicine are far more limited than the space of the possible demonstrated in animal studies.

Osteochondral defects pose a great challenge and a satisfactory strategy for their repair has yet to be identified. In particular, poor repair could result in the generation of fibrous cartilage and subchondral bone, causing the degeneration of osteochondral tissue and eventually leading to repair failure. Herein, taking inspiration from the chemical elements inherent in the natural extracellular matrix (ECM), we proposed a novel ECM-mimicking scaffold composed of natural polysaccharides and polypeptides for osteochondral repair. By meticulously modifying natural biopolymers to form reversible guest-host and rigid covalent networks, the scaffold not only exhibited outstanding biocompatibility, cell adaptability, and biodegradability, but also had excellent mechanical properties that can cater to the environment of osteochondral tissue.

Additionally, benefiting from the drug-loading group, chondrogenic and osteogenic drugs could be precisely integrated into the specific zone of the scaffold, providing a tissue-specific microenvironment to facilitate bone and cartilage differentiation. In rabbit osteochondral defects, the ECM-inspired scaffold not only showed a strong capacity to promote hyaline cartilage formation with typical lacuna structure, sufficient mechanical strength, good elasticity, and cartilage-specific ECM deposition, but also accelerated the regeneration of quality subchondral bone with high bone mineralization density. Furthermore, the new cartilage and subchondral bone were heterogeneous, a trait that is typical of the natural landscape, reflecting the gradual progression from cartilage to subchondral bone. These results suggest the potential value of this bioinspired osteochondral scaffold for clinical applications.

Link: https://doi.org/10.1016/j.scib.2023.07.050

While cholesterol is essential to health, localized excesses of cholesterol produce toxicity and cell dysfunction. Normal cholesterol will achieve this outcome in the levels found in atherosclerotic plaque, but some varieties of altered cholesterol are individually more toxic and disruptive. 7-ketocholesterol, for example, is a only a small fraction of all cholesterol, but it is suspected to produce a meaningful contribution to dysfunction leading to the development of atherosclerotic plaque.

Cyclarity Therapeutics takes the approach of tailoring cyclodextrin molecules to bind 7-ketocholesterol specifically. While some cyclodrextrins can bind and sequester ordinary cholesterol, any sort of non-specific attack on cholesterol will cause considerable harm, given that it is an essential molecule, found in cell membranes. One must find ways to target only the unwanted cholesterol in specific locations, or, as Cyclarity does, pick out an altered form of cholesterol that can be indiscriminately removed. 7-ketocholesterol has no useful function, and the body would be better off without it.

A class of cyclodextrin (CD) dimers has emerged as a potential new treatment for atherosclerosis; they work by forming strong, soluble inclusion complexes with oxysterols, allowing the body to reduce and heal arterial plaques. However, characterizing the interactions between CD dimers and oxysterols presents formidable challenges due to low sterol solubility, the synthesis of modified CDs resulting in varying number and position of molecular substitutions, and the diversity of interaction mechanisms.

To address these challenges and illuminate the nuances of CD-sterol interactions, we have used multiple orthogonal approaches for a comprehensive characterization. Results obtained from three independent techniques - metadynamics simulations, competitive isothermal titration calorimetry, and circular dichroism - to quantify CD-sterol binding are presented. The objective of this study is to obtain the binding constants and gain insights into the intricate nature of the system, while accounting for the advantages and limitations of each method.

Notably, our findings demonstrate ~1000× stronger affinity of the CD dimer for 7-ketocholesterol in comparison to cholesterol for the 1:1 complex in direct binding assays. These methodologies and findings not only enhance our understanding of CD dimer-sterol interactions, but could also be generally applicable to prediction and quantification of other challenging host-guest complex systems.

Link: https://doi.org/10.1016/j.carbpol.2023.121360

Epigenetic marks on the genome, such as DNA methylation at CpG sites, determine its structure. That in turn determines which regions of DNA are exposed to transcriptional machinery, which proteins are manufactured, and thus the behavior of the cell. Epigenetic marks and the structure of the genome change constantly in response to circumstances, but some of these changes have been found to be characteristic of aging, leading to the development of epigenetic clocks to measure biological age.

In today's open access paper, the authors report on a novel approach to the development of a clock that measures the burden of aging. Rather than using unbiased machine learning across as many DNA methylation sites on the genome as can be usefully measured, the researchers consider only DNA methylation sites that show little tendency to change with age, under the assumption that these are functionally important to normal cell function and tissue health. Should any of these sites in fact change methylation status, which does appear to occur to a growing degree with advancing age, then something is going wrong as a consequence. The results are interesting, and seem worthy of further exploration.

Fail-tests of DNA methylation clocks, and development of a noise barometer for measuring epigenetic pressure of aging and disease

This study shows that Elastic Net (EN) DNA methylation (DNAme) clocks have low accuracy of predictions for individuals of the same age and a low resolution between healthy and disease cohorts; caveats inherent in applying linear models to non-linear processes. We found that change in methylation of cytosines with age is, interestingly, not the determinant for their selection into the clocks. Moreover, an EN clock's selected cytosines change when non-clock cytosines are removed from the training data; as expected from optimization in a machine learning (ML) context, but inconsistently with the identification of health markers in a biological context.

To address these limitations, we moved from predictions to measurement of biological age, focusing on the cytosines that on average remain invariable in their methylation through lifespan, postulated to be homeostatically vital. We established that dysregulation of such cytosines, measured as the sums of standard deviations of their methylation values, quantifies biological noise, which in our hypothesis is a biomarker of aging and disease. We term this approach a "noise barometer" - the pressure of aging and disease on an organism.

We describe a new quantification of biological age from DNAme, based on the noise of the most-regulated, age invariable cytosines. This approach fits well with the importance of age-specific increase in biological noise and it is the quantification of primary data without numerical adjustments, which improves on ML predictions. The points of increased DNAme noise turned out to be 49-52 and 64-67 years of age, and it would be very interesting to probe global omics at these transitional ages. Our noise barometer distinguishes health from disease and can potentially distinguish one pathology from another completely different pathology. The different time-shapes of different diseases might enable epidemiology of a specific disease in a population, based on the curve of epigenetic noise.

The biological significance of noise-detector cytosines is clear and the effects of their deregulation with time and disease are expected to be many and deleterious. Namely, the likely reason for the noise-detectors cytosines to be on average invariable in their methylation with age is that they are in the regulatory regions of genes that are vital at constant levels.

The study of large differences in longevity between otherwise similar species has produced interesting insights into how biochemical and genetic differences might contribute to species life span. As of yet, the field has failed to produce much in the way of actionable insights, however. The recent transfer of a gene from naked mole rats to mice was notable for being one of only a few such exercises conducted with increased life span as a goal. Still, the wheel turns, and we may expect to see an increasing application of what is known of the genetics of species longevity in the decades ahead.

The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals.

Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues.

We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. This HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.

Link: https://doi.org/10.1016/j.celrep.2023.113130

Researchers here illustrate the point that one can produce mortality-associated profiles from just about any sufficiently complex set of medical data. The focus here is on metabolites measured in a blood sample. Given the many thousands of different small molecules found in the bloodstream, this is far from the only group to have produced profiles and clocks from the metabolome. The body changes in characteristic ways with age and disease, and those who are worse off, laboring under a greater burden of damage and dysfunction, will see that status reflected at every level of measurement.

Experimental studies reported biochemical actions underpinning aging processes and mortality, but the relevant metabolic alterations in humans are not well understood. Here we examine the associations of 243 plasma metabolites with mortality and longevity (attaining age 85 years) in 11,634 US (median follow-up of 22.6 years, with 4288 deaths) and 1,878 Spanish participants (median follow-up of 14.5 years, with 525 deaths).

We find that, higher levels of N2,N2-dimethylguanosine, pseudouridine, N4-acetylcytidine, 4-acetamidobutanoic acid, N1-acetylspermidine, and lipids with fewer double bonds are associated with increased risk of all-cause mortality and reduced odds of longevity; whereas L-serine and lipids with more double bonds are associated with lower mortality risk and a higher likelihood of longevity. We further develop a multi-metabolite profile score that is associated with higher mortality risk. Our findings suggest that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality. The underlying mechanisms remain to be determined.

Link: https://doi.org/10.1038/s41467-023-41515-z

There is a certain type of media entity and journalist that really only cares about name dropping the wealthy and the famous, and has absolutely no interest in accuracy, education, understanding, factual conveyance of information, all of those pleasant things that make the world turn. Thus there will continue to be articles about ongoing intitiatives relating to aging, such as the one I'll reluctantly point out today, that are abysmal. This sort of article is abysmal because it actively, willfully conflates a whole set of very different activities with very different merits under one heading, while appealing to lowest common denominator sentiments such as mocking the wealthy, class envy, and so forth. It is lazy, it is writing that makes the space of information about the topic worse, it is a harmful influence on the world.

Of the projects mentioned, research into epigenetic reprogramming such as that conducted by Altos Labs has the greatest merit. It may plausibly lead to forms of rejuvenation therapy. It is likely that the smaller companies in the industry will make faster progress towards first generation reprogramming therapies in the clinic than the larger groups such as Altos Labs, because sizable funding tends to come attached to sizable risk-aversion, but the larger groups will fill in the gaps, sustain ongoing efforts through the inevitable missteps and failures, and enable a much improved second generation of therapies. This is just one class of therapy. There are many others, each with their own segment of the industry, and which could sustain a book-length treatment of what it is they do, why they do it, and what their prospects are.

Research and development of therapies is very different activity to that of motivated self-experimenters such as Bryan Johnson. Carrying out single participant studies on oneself can have merit, in the sense of attracting attention to possible interventions that should be given more attention by academia and industry. The results generated by a single individual form an anecdote, not data, but if it can inspire funding for a larger trial that produces actionable data, then the single person effort was useful. Bryan Johnson appears to want to answer the question of just how far one could go to optimize the state of aging in a 40-something individual. We know that physically active hunter-gatherer populations do very well in comparison to sedentary first world populations as one progresses into the 40s and beyond. But can one use presently available techniques to go beyond that, and by how much? To the degree that Johnson inspires clinical trials and greater investment into some of the interventions that has has used, then good for him. Everything else is just a high profile hobby.

The challenge inherent in being 40-something or 50-something and in good shape is that there are many questions one can't answer in any reasonable amount of time regarding the usefulness of specific approaches to the treatment of aging. A person of this age and health status just doesn't exhibit a large enough burden of damage and change, and it is presently poorly understood as to exactly what aging processes are dominant in determining those changes that do occur between 25 and 45. So, for example, Bryan Johnson won't be able to add his data to the discussion of whether first generation senolytics are a great idea or not, or at least not for another 20 years or so. He simply doesn't have enough senescent cells at the present time to obtain meaningful results.

Inside the very strange, very expensive race to "de-age"

Whether it's taking a shuttle to the edge of space, buying the biggest yacht, or challenging one another to a cage fight, with great wealth and power seems to come a voracious desire to engage in games of one-upmanship. The Rejuvenation Olympics, an online leaderboard launched by tech millionaire Bryan Johnson earlier this year, takes the rivalry of the rich to the next level. The game? "Reversing" your age. Participants compete not on physical abilities but on how quickly and by how much they can slow their "biological age." It's almost who can be the best Benjamin Button. Competitors do this mostly by adjusting their diets (like which macronutrients and supplements they consume), being physically active, and retesting their "age" regularly. They're not actually reverting to a more youthful version of themselves - that's not biologically possible. Rather, these competitors are racing to see who can age the slowest; as the Rejuvenation Olympics website quips, "You win by never crossing the finish line."

Among various health and wellness fads, longevity is the pursuit receiving much of the attention - and money - from the ultrarich. Last year, according to a report from the news and market analysis site Longevity.Technology, more than $5 billion in investments poured into longevity-related companies worldwide, including from some big-name tech founders and investors. Many of these companies are aiming to prolong life by focusing on organ regeneration and gene editing. The buzzy life extension company Altos Labs, which researches biological reprogramming - a way to reset cells to pliable "pluripotent stem cells" - launched last year with a whopping $3 billion investment, and counts internet billionaire Yuri Milner and, reportedly, Amazon founder Jeff Bezos among its patrons. Bezos was also an investor in the anti-aging startup Unity Biotechnology.

OpenAI founder Sam Altman, meanwhile, recently invested $180 million in Retro Biosciences, a company vying to add a decade to the human lifespan. Some of the most famous names in the death-defying sector are old: Calico Labs, a longevity-research subsidiary of Alphabet, was launched by then-Google CEO Larry Page in 2013. Nor is it just Silicon Valley that's excited about the prospect of living longer. Tally Health, a new biotech company co-founded by Harvard scientist David Sinclair - who is something of a celebrity in the longevity community - boasts some Hollywood A-list investors: John Legend, Gwyneth Paltrow, Ashton Kutcher, Pedro Pascal, and Zac Efron. Basically, if you're anyone with any kind of serious money, chances are you've thrown some of it into the life-extension industry.

Is maladaptive loss of autophagy a meaningful contributing factor in Alzheimer's disease? The results of a recent clinical trial suggest so. Autophagy is the name given to a collection of cellular maintenance processes responsible for recycling unwanted proteins, molecular waste, and damaged cell components. Improving autophagy should in turn improve cell function. The drug development program noted here has reached the stage of later human trials to assess efficacy, and is focused on correcting one specific mechanism that appears to negatively affect autophagy in the Alzheimer's brain, and that in turn helps to clear out damaging protein aggregates associated with Alzheimer's disease pathology.

Blarcamesine works by selectively binding to the sigma-1 receptor (SIGMAR1), which is expressed at consistently high - if not increasing - levels in the brain of healthy aging adults. In Alzheimer's disease, however, SIGMAR1 expression drops. SIGMAR1 activation has also recently been linked with autophagy, the cellular process by which damaged organelles and faulty proteins are cleared. Treatment with blarcamesine leads to the upregulation of SIGMAR1 in the brain, which could potentially activate autophagy in the brain and help in the clearance of amyloid and tau deposits.

At 48 weeks of treatment, the change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13) scores in blarcamesine-treated patients was significantly better than placebo comparators. Blarcamesine was likewise significantly better than placebo when cognition was evaluated using the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scale. Biomarker data showed that blarcamesine treatment resulted in a significant drop in pathological amyloid beta levels and a corresponding improvement in Aβ42/40 ratio, pointing to the molecule's strong anti-amyloid potential. The drug candidate also resulted in lower brain volume loss versus placebo.

Link: https://www.biospace.com/article/anavex-s-blarcamesine-slows-cognitive-decline-in-alzheimer-s-patients

Relevant to the goal of slowing or reversing aging, a broad panoply of evidence points to the need to control the chronic inflammation that is characteristic of aged tissues. Constant, unresolved inflammatory signaling actively disrupts tissue structure and function, changing cell behavior for the worse. It is likely the largest part of the way in which lingering senescent cells provide their contribution to the aging process, and many other forms of cellular dysfunction observed in aging can also generate inflammatory reactions. The contribution of senescent cells to the chronic inflammation of aging will likely be the easiest to control: simply destroy these errant cells. Other processes occurring inside the cells in aged tissues may be more challenging to rein in, such as the mislocalization of nuclear DNA and mitochondrial DNA, triggering innate immune mechanisms that evolved to react to the presence of bacteria and viruses.

Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues.

A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.

Link: https://doi.org/10.1007/s11357-023-00915-1

The Longevity Escape Velocity (LEV) Foundation was founded by Aubrey de Grey to address an important missing aspect of the ongoing work to produce treatments that target the underlying mechanisms of aging. While the research and development community has made sizable strides in the past decade, and the first rejuvenation therapies now exist in at least prototype form, it remains the case that next to no-one is conducting combination studies that use two or more of these interventions. When considering therapies that can repair forms of the cell and tissue damage that cause aging, it seems plausible that two different therapies will be additive, producing larger results than either alone.

The LEV Foundation is presently conducting the Robust Mouse Rejuvenation 1 Study, and is raising funds for the next study in line, Robust Mouse Rejuvenation 2, testing other promising interventions to prove that there is synergy between very different forms of repair therapy. These studies, and the many more like them that should be running throughout the research community and industry, but are not, will form the first foundation for the next few decades of medical practice. It has always been apparent that there would be a toolkit of many rejuvenation therapies, each addressing some aspect of aging, and that these therapies would be used in combination. But that conjecture still requires concrete proof to convince the industry and the medical community.

Many of the Fight Aging! audience have in the past supported the SENS Research Foundation annual fundraisers, some of you by offering matching donations to encourage others to donate. It worked well, and collectively our community has raised a great deal of funding over the past decade to support the growth of rejuvenation biotechnology research under the SENS umbrella, helping to fund many promising research programs that went on to spawn biotech startups. All those who have done so in the past, I encourage you to reach out and offer your support again to the LEV Foundation in their present important work, and help make the Robust Mouse Rejuvenation 2 study a reality.

Below, see Aubrey de Grey's comments on current efforts at the LEV Foundation, and a call for matching donors to help with the soon to be launched fundraiser:

A decade ago, five indisputably mainstream luminaries of geroscience published a paper that remains, by far, the most highly-cited publication in the entire field this century: "The Hallmarks of Aging". It had its roots in a paper that I and my collaborators published more than a decade earlier: "Time to talk SENS: Critiquing the Immutability of Human Aging", and laid to rest the debate as to whether the divide-and-conquer, damage-repair approach that the earlier paper introduced was feasible. What remained was to implement it.

Inevitably, some of the component interventions in the SENS rejuvenation biotechnology program are much more challenging to implement than others. That is why, while the field has mostly focused on the lower-hanging fruit, SENS Research Foundation has focused on filling that vacuum by targeting the hardest types of damage to repair, since no divide-and-conquer approach can succeed otherwise.

Now, however, the field has reached a new phase of implementing the SENS program. While the themes that SRF have pursued remain relevant, and are now much better funded as a result of Richard Heart's admirable initiative of 2021 that added $27 million to SRF coffers, it has also become possible to move to the final phase of the implementation of divide-and-conquer, namely the combining - in mice, for now - of interventions that individually show considerable promise.

That is why my new organisation, LEV Foundation, is focusing on combination studies as its flagship research program. I continue to provide regular updates on social media regarding the first such study, which we at LEVF are terming "Robust Mouse Rejuvenation 1", as the study progresses towards the point at which interesting differences emerge in the mortality of the cohorts.

Importantly, there is a long list of promising interventions not included in our current study, and which I and the LEVF team are eager to incorporate into a second study: Robust Mouse Rejuvenation 2. We are now focused on raising the funds for this new project, which like our first study will continue to identify the best combinations, antagonistic interactions, and sex and age differences in the degree to which each intervention can impact aging.

The specifics of the second study are being finalized, and we have conducted extensive work to narrow the options down, as I outlined in my presentation at LEVF's Dublin conference. Many of the remaining decisions, both between these options and concerning their details, come down to cost. Thus it continues to be the nature of our work that every offer of financial support counts. We are immensely grateful to those who have made our past work possible, and those who continue to make our future plans possible. Please reach out if you can help to make a difference!

While a great deal is known about the ways in which old tissues differ from young tissues, there remains considerable room to theorize on how exactly aging is caused and progresses. Which manifestations are causative, and which downstream consequences, which mechanisms are important, which are side-effects or diversions. Theories of aging abound, alongside frameworks intended to steer thinking about aging. We stand in the opening years of a new era of medicine, in which the first rejuvenation therapies exist or are under development, senolytics that can clear senescent cells, alongside reprogramming strategies and potentially a few others. The growing attention only encourages more theorizing, but the practical development of therapies targeting specific mechanisms of aging will be the path to greater knowledge. Only by addressing a specific mechanism of aging and observing the results can we rapidly determine whether or not it is important.

The adaptation-maladaptation framework of aging posits that a cornerstone of aging is a decrease in the ratio of beneficial adaptation (Ab) to harmful adaptation (Ah) at several organizational levels of the organism, from cells to cell networks to the whole body. Decreases in Ab lead to lowered capacities in physiological adaptation functions such as learning and memory, immune system plasticity, and muscle anabolism, whereas increases in Ah promote dysfunctional metabolic remodeling, cancer, autoimmunity, and pathological cardiovascular remodeling, among others.

Certain adaptation mechanisms such as adaptive transcription can be involved in protection against aging as well as driving aging-related pathologies. Thus, aging-related decline might be inevitable but not necessarily due to random accumulation of damage over time but because adaptive mechanisms will, one way or the other, lead to progressive dysfunction (e.g., either through "directed" damage as part of adaptation or through maladaptation). Because aging is at least partly an active process, it might be possible to counteract it if we understand how biological goal states can be influenced and how adaptation mechanisms can be directed. To do so, we need to study the underlying molecular signaling dynamics in greater detail beyond mere upregulation or downregulation and beyond simple association studies.

Studying aging from the perspective of the adaptation-maladaptation dilemma with the central phenotype of a reduction in Ab/Ah opens up new experimental and theoretical approaches to study longevity mechanisms.

Link: https://doi.org/10.3389/fragi.2023.1256844

Atherosclerosis is the growth of fatty lesions in blood vessel walls, leading eventually to a rupture and blockage to cause a heart attack or stroke, and along the way causing narrowing of blood vessels sufficient to lead to heart failure and dysfunction elsewhere in the body as the supply of blood to tissues is reduced. Today's paper on this topic is a little disorganized, something of a random assembly of thoughts on mechanisms relevant to the development of atherosclerosis. Atherosclerosis is the single largest cause of human mortality, and attempts to treat contributing mechanisms have so far not stopped it from being the single largest cause of human mortality. So perhaps it is something that we should all be putting more thought into, and broadening the range of development programs in an attempt to produce more meaningful therapies.

Atherosclerosis is chronic arterial inflammation caused by both conventional and unconventional risk factors that result in plaque development in the vascular intima. Inflammation starts with the activation of NLRP3 inflammasomes, which results in the production of proinflammatory cytokines IL-1 and IL-18, acting via the autocrine, paracrine, or endocrine pathways. IL-1 has been demonstrated to promote its own gene expression in a variety of cell types through an amplification loop known as autoinduction. IL-1 increases endothelial dysfunction, leukocyte-endothelial cell adhesion, procoagulant activity, and neutrophil recruitment, all of which contribute to atherogenesis and plaque ruptures.

Aging is one of the strongest risk factors for atherosclerosis which increases the morbidity and mortality of patients. Understanding the mechanisms of the age-related increase in atherosclerotic diseases can better guide prevention and therapy in this risk group, since it is unclear whether aging itself increases the susceptibility to atherosclerotic diseases and their severity. In this review, we present two main areas in which aging promotes atherosclerosis. The first group of factors is those outside of the vascular system, such as the impact of age on the clonal hematopoiesis of indeterminate potential (CHIP) differentiation of hematopoietic cells in the myeloid cell lineages. The second group of factors is the vascular intrinsic ones, such as the effect of aging on vascular bioenergetics due to impairment of mitochondrial function, mitophagy (removal of damaged mitochondria), and an impact on inflammation in vessels. In addition, mitochondrial DNA damage, which is an early event of atherogenesis in apolipoprotein deficient (ApoE) mice, can result in mitochondrial dysfunction, leading to proatherogenic processes such as inflammation and apoptosis.

The vascular endothelium, as an integral component of the cardiovascular system intimately interfacing with the blood, plays a crucial role in maintaining systemic homeostasis. It acts as a lining of the cardiovascular system, forming a particular barrier to various molecules. It assumes multifaceted functions within the human body, being intricately responsive to a myriad of external stimuli present in the surrounding environment. The vascular endothelium plays a regulatory role in vascular muscle contraction, relaxation, smooth muscle proliferation, and the expression of adhesion molecules or chemotactic factors. These factors are responsible for the adhesion, activation, or migration of inflammatory cells, as well as platelet adhesion and aggregation. Additionally, the vascular endothelium influences the coagulation and fibrinolysis processes. Disruption of these processes underpins the mechanism of atherosclerosis of the blood vessels.

Link: https://doi.org/10.3390/ijms241713434

The SENS Research Foundation staff have carried out the public service of extensively discussing and dismantling the evidence commonly cited in support of metformin as a way to modestly slow aging, showing that said evidence is problematic, to say the least. Metformin might make life modestly better for diabetics, but it doesn't slow aging. This view of the human data matches the poor quality of the animal model data, in which metformin makes a poor showing in comparison to the robust data for a modest slowing of aging that is produced by the use of, say, mTOR inhibitors, or the practice of calorie restriction.

Regardless of what you, I, the SENS Research Foundation staff, or just about anyone else thinks of the merits of metformin and the problems with human studies of metformin, the TAME trial to assess the use of metformin to treat aging will forge ahead. Regardless of whether it succeeds or (as I expect) fails, the point of the TAME trial is to pave the way, to have browbeaten the FDA into accepting a trial design in which the target is aging, not any specific disease of aging. That has essentially taken place. The next well-funded group will try that same trial design with mTOR inhibitors, or plasma dilution, or senolytics, or small molecule reprogramming agents. Sooner or later, it will become commonplace to run trials that target aging, rather than development programs sidetracking into the treatment of specific age-related disease while hoping for off-label use to take off.

More Studies on Metformin and Survival

In an earlier five-part series, I laid out the reasons to be skeptical that metformin would pan out as a longevity therapeutic. The centerpiece of the second post in the metformin series was a 2014 observational study, which is the one study that is most often cited as evidence that metformin slows aging in humans. A press release that accompanied the Bannister paper wrongly stated that it showed that "Type 2 diabetics can live longer than people without the disease" if they take metformin.

But as other scientists had pointed out before me, the study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients whose blood sugar was harder to get under control (those on second-line diabetes medications) as well as to a random assortment of the nondiabetic population. Their study design then unwittingly but systematically pushed subjects who were taking metformin "off the books" as soon as their diabetes got worse. This methodological artifact created the illusion that metformin users lived longer lives than nondiabetics, because it meant that the study would only count metformin users as metformin users if they managed to stay healthy.

In the months since I wrote the original blog post explaining this, I've become aware of two other studies asking the same core question but using different methods - and they both find that, as you would expect, people on metformin for diabetes are shorter-lived than people without diabetes. Because these studies address this question more directly than any of the studies discussed in that blog post, we'll review them here. In summary, the metformin users were clearly dying more often than the nondiabetic population. The long-term effect on metformin was better than going untreated as a diabetic, but its benefits were clearly not even enough to get them back on the miserable course of "normal" aging, let alone to have a real anti-aging effect.

We shouldn't stop looking for hidden benefits in common medications - and if we find good evidence that such a drug might slow something as terrible as degenerative aging, it may be worth it to follow that signal up with clinical trials. But with metformin, a story that emerged in cell culture and some poorly-designed animal and human observational studies have led many smart people astray. And even if metformin had turned out to be as effective as it seemed to be in some of the early studies of metformin in abnormally short-lived animals, the implied potential benefits for aging humans would have been pretty modest. It would garner an aging humanity a far greater gain if the media, many advocates, and scientists would redirect the resources and attention that have gone into metformin into developing therapies that directly repair the damage in aging tissues.

The typical path for any program in biomedical research and development is to first demonstrate interesting results in animal studies using forms of genetic engineering or gene therapy, and then find small molecules that adjust the same mechanism. Small molecules are never as good as genetic manipulations, the size of the effect is always smaller, usually much smaller, and there are inevitably side-effects. Small molecule development is much easier to conduct, however, more familiar to investors and regulators and program managers, a well-trodden path. Thus while the future of medicine is gene therapy, in search of large effect sizes and no side-effects, the present industry remains near entirely focused on small molecules. Given the popularity of reprogramming as an approach to treat aging, an increasing number of research groups and companies are working to find small molecules that induce reprogramming to some degree, an alternative to gene therapies that induce expression of the Yamanaka factors. Based on the discoveries to date, it seems plausible that they will succeed.

Two weeks ago, longevity biotech startup Clock.bio emerged from stealth with $4 million in funding, and setting itself an ambitious goal to be in a Phase 3 trial for a healthspan-extending intervention by the end of the decade. With the clock ticking, the company is already working to map rejuvenation biology across the entire human genome over the next 12 months. Having completed an initial screen of around 1,000 genes, Clock.bio says it has already identified several new potential rejuvenation targets.

The company is based on the idea of triggering the self-rejuvenation mechanism of pluripotent stem cells to gain insight into the cellular drivers of aging and rejuvenation. Crucially, Clock.bio has found a way to shortcut the screening process required to identify rejuvenation drivers across the entire human genome. "We have been able to create a paradigm in the lab, where we override the repair programs, and force-age the stem cells, so that their rejuvenation capabilities kick in again." The company uses unbiased CRISPR screens on large samples of stem cells to identify gene candidates that are causally relevant for cell rejuvenation.

Clock.bio then identified some existing, approved drugs that could potentially be used against the targets identified in the first screen. "We looked at whether these drugs could beneficially modulate aged neurons - we found that they did, and if we combined them the results got even better. So, now we have this end-to-end validation in vitro - from being able to identify rejuvenation genes, which are essentially controlling repair processes, through to activating those repair processes in aged cells. It's a completely unbiased way to understand every process that's involved in restoring the aging hallmarks."

Link: https://longevity.technology/news/the-quest-for-rejuvenation-without-reprogramming/

Parkinson's disease is characterized by the loss of dopamine-generating neurons, with the inflammatory pathology leading up to that issue thought to be driven by the spread of misfolded α-synuclein. Dysfunctional mitochondrial quality control can make these dopamine-generating neurons more vulnerable to the underlying pathology, however, and thus a fraction of Parkinson's disease arises in people with mutations that cause this sort of dysfunction. That has directed researchers towards mitochondrial function as an important factor in the progression of the condition, but it will probably turn out to be more useful to focus on the deeper causes, such as inflammation and cell dysfunction driven by α-synuclein aggregation.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson's. But the new study suggests that a dysfunction in the neuron's synapses - the tiny gap across which a neuron can send an impulse to another neuron - leads to deficits in dopamine and precedes the neurodegeneration. The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans.

Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy.

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson's disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48. The reason for the disparity led to an important new discovery. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson's.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal - unrelated to its recycling work - where it controls dopamine release. With this new understanding of what went wrong for the sister, scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons. "We discovered a new mechanism to activate Parkin in patient neurons. Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."

Link: https://www.eurekalert.org/news-releases/1001506

The increased blood pressure of hypertension is very damaging. So much so that blunt therapies that override regulatory systems controlling blood pressure, reducing blood pressure without in any way addressing the underlying causes of hypertension, can reduce mortality and incidence of age-related disease. Hypertension is a downstream consequence of forms of age-related cell and tissue damage that also cause many other forms of dysfunction. But a sizable fraction of their contribution to degenerative aging is mediated by increased blood pressure.

Hypertension turns biochemical issues in aging into physical trauma to tissues. It causes pressure damage such as rupture of capillaries to delicate structures necessary to tissue function in the kidney, brain, and elsewhere. It accelerates the progression of atherosclerosis, in which fatty lesions form in blood vessel walls. It contributes to destructive remodeling of heart muscle. Further, hypertension speeds the progression of neurodegenerative conditions leading to dementia, the subject of today's open access meta-analysis. The data demonstrates the point made above, that controlling hypertension makes a sizable difference to the risk of suffering dementia, a measure of just how much damage raised blood pressure does to the brain when sustained over time.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. This study assessed the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (older than 60 years) with dementia. Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries. Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables.

The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group.

The analysis included 17 studies with 34,519 community dwelling older adults (58.4% female) with a mean age of 72.5 ± 7.5 years and a mean follow-up of 4.3 ± 4.3 years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio 1.42) and 26% increased risk compared with individuals with treated hypertension (hazard ratio 1.26). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls. The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses.

In conclusion, this individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Is it possible to measure the pace of aging at any given moment? Are there biomarkers that reveal not the biological age of the individual, but rather how fast that biological age is changing? The field is presently focused on developing measures of biological age, such as the extensive work on epigenetic clocks. Some information about pace of aging might be inferred from whether biological age is higher or lower than chronological age, assuming a biological age measurement that is actually accurate, something that still a topic for contention. But that doesn't say anything about the momentary pace of aging at any given time. That information would certainly prove useful in the context of testing interventions that adjust the pace at which aging proceeds. It isn't all that interesting in the context of interventions that reverse aging, such as by repairing the underlying cell and tissue damage that causes aging. In that case, pace of aging becomes irrelevant. The desire to measure the pace of aging reflects a bias towards merely slowing aging rather than achieving rejuvenation, and that is certainly the character of much of the field, sad to say.

Researchers interested in the biology of aging, and its potential modification by antiaging drugs, have devoted a substantial amount of community effort to the search for possible biomarkers of aging, conceived as quantifiable traits that can reveal the biological age of an individual animal. The central framework here is that such biomarkers might change monotonically through some relevant portion of adult life, might discriminate younger from older adults, might predict mortality risk at some useful distance from ultimate date of death, and, crucially, might serve, individually or collectively, as surrogate endpoints for studies of putative antiaging diets, drugs, or polymorphic alleles. Like an odometer in a car, biomarkers or weighted combinations of biomarkers might in principle reveal how far along the aging trajectory an individual organism has already proceeded. Odometers do not reveal the speed at which a car is currently traveling. A low-mileage or high-mileage car might be going quickly or slowly. Speed and distance traveled are independent and unconnected measures of a vehicle's state.

This essay presents the concept of aging rate indicators (ARIs) as speedometers for aging research. In principle, an ARI is a quantitative trait or measurement, an endpoint, which discriminates slow-aging mice from normal mice; it measures how quickly the aging process is proceeding in an individual organism. (The definition carefully takes no position on whether ARIs might also discriminate fast-aging animals from normal ones, a topic that will be deferred for another occasion). An ideal ARI would make this discrimination regardless of the age at which it is measured, at least within the portion of adult life where serious diseases are rare and mortality risk is minimal. The critical feature of an idealized ARI, the critical test of a candidate ARI, is that it should be modulated, in the same direction, by antiaging perturbations, whether the slowed aging and extended lifespan are caused by genetic factors, by dietary intervention, or by lifespan-increasing drugs.

It is helpful to consider the differences between ARIs and the more familiar biomarkers of aging. If a measurement - an estimate of collagen cross-linking, a score of visual acuity, or reflex speed, an index combining levels of DNA methylation at several sites, a T cell subset ratio, and so on - is proposed as a biomarker of aging, it is expected to show age-related change in adults, that is, to distinguish young, middle-aged, and older adults. Evaluation of an endpoint as a candidate ARI involves an entirely different set of criteria. Evidence that a candidate ARI changes with age is quite beside the point, because ARIs are taken to be measures of the pace or speed at which aging is currently occurring, and not as indices of how much a given subject has already aged, in the past. In such a framework, estimates of ARIs made in young adults are expected to be highly informative, because these individuals may actually be aging at different rates; for example, one might be on a calorie-restricted (CR) diet, or carry a mutant growth hormone receptor (GHR) allele, or be in a rapamycin treatment cohort. The key criterion for a putative ARI is that it should be modified, in a consistent direction, by most or all genes, diets, and drugs that are known, on independent evidence, to slow the signs of aging, postpone late-life illnesses, and increase lifespan.

Link: https://doi.org/10.59368/agingbio.20230003

Research into the effects of the human microbiome on health and aging has progressed quite rapidly in recent years. It now costs little to sequence a sample to determine the which bacterial species are present and in what proportions. With age, the intestinal barrier, blood vessels, and blood-brain barrier begin to leak, allowing greater passage of microbes into the body. Additionally, the immune system declines in function, reducing the ability to clear these microbes from tissues.

In the case of patients with Alzheimer's disease, researchers are finding that the gut microbiome exhibits characteristic differences when compared with old people without this condition. The work here shows that this difference extends to the microbes leaking into the brain. This may indicate that specific immune dysfunction is present in Alzheimer's disease, favoring certain microbial species, or more likely, that changes in the microbiome provide an important contribution to the onset and progression of this form of dementia. The precise details as to why this is the case, over and above merely considering increased inflammation, remain to be determined.

When biomes turn unhealthy, either by invasion of outside pathogens, or a major change in the relative numbers of the microbial species present, a dysbiosis, or imbalance in the microbiota, occurs. This dysbiosis can alter human metabolism and cause inflammation, which has been linked to the tissue damage seen in ulcerative colitis, rheumatoid arthritis, and many other chronic inflammatory diseases. Studying 130 samples from the donated brains of 32 people - 16 with Alzheimer's and 16 age-matched controls without the disease, researchers found bacterial flora in all the brains- but the Alzheimer's brains showed profoundly different bacterial profiles compared to their age-matched controls.

The group used full-length 16s ribosomal RNA gene sequencing, a technique that can detect any and all bacterial species present in a sample. In this process, the researchers pinpointed disease-specific sets of bacteria in almost all of the Alzheimer's-affected brains, suggesting these groups of bacteria are strong predictors of the disease. The authors detected five brain microbiomes, four that are hypothesized to be present at different times in the evolution of the Alzheimer's-afflicted brains. The authors said it is likely that the observed Alzheimer's microbiomes evolve to become more pathogenic as the disease progresses with the later stages characterized as a pathobiome. The authors hypothesize that the brain begins with a healthy biome, but as the disease develops, the healthy biome is supplanted as a new set of microbes replace the original healthy ones with the eventual emergence of the Alzheimer's pathobiome.

Samples from both sets of brain samples were drawn from the frontal and temporal lobes and entorhinal cortex. Based on the random distribution of microbiomes requiring delivery all over the brain, the results were consistent with failure in one or more of the brain's networks; however it too soon to tell if the observed distribution patterns result from a leaky blood-brain barrier, the brain's glymphatic system, or synaptonemal transmission that allowed bacteria, including Cutibacterium acnes (formerly called Proprionibacterium acnes), Methylobacterium, Bacillus, Caulobacter, Delftia, and Variovora to enter the brain. In Alzheimer's brain samples, the researchers noted, these pathogenic bacteria appeared to have overpowered and replaced Comamonas sp. bacteria, which are associated with a dementia-free brain.

Link: https://drexel.edu/news/archive/2023/September/Could-a-Breakdown-in-the-Brains-Networks-Contribute-to-Alzheimers-Disease

It can be argued that the largest challenge facing the development of means to treat aging as a medical condition is that there is, as of yet, no useful consensus position on how to measure aging, how to define aging, or which of the countless measurable aspects of biochemistry that change with age are the most appropriate targets for therapy. This means that any given research group or biotech startup has a lot of leeway to argue that their approach is the right one - and it might take twenty years to establish the effects of their therapies on long-term health and life span, even given a successful development program. There is a shotgun approach underway, in which the research and development communities try many different things and see how it goes, only limited by their ability to persuade sources of funding to support the work. I imagine that this will continue for the foreseeable future, given just how long it takes to assess the efficacy of a given approach to therapy.

From a funding perspective, should the first generation of therapies to slow and reverse aspects of aging start to produce very promising data on long-term health by the end of the 2030s, there will be thereafter be funding for just about every option on the table to treat aging. The hype cycles will come and go, and it may well be the case that enough funding to try all of the available options will in fact be needed. It seems to me that the most straightforward way to reverse engineer the biology of aging, to decide on which of the many identified mechanisms are the most important, the closest to being root causes, is to produce prototype and first generation therapies for all of the plausible approaches to rejuvenation, the various means of repair of cell and tissue damage, and compare the resulting benefits in human trials. It won't be a fast process, but likely faster than the other options on the table.

We need to shift the focus of aging research to aging itself

The field of aging is at a precipice. Attention and funding are increasingly focused on this area, and exciting, fundamentally important findings are being reported literally every day. As the great promise of targeting aging comes into sharper focus, we are rapidly approaching the point where we must face the elephant in the room: We lack any semblance of a consensus on the nature of aging or, more fundamentally, on the essence of this process. Taking steps to resolve these foundational issues in aging biology will enable us to advance this field to the next level.

As a field, we claim to study aging - but what, in essence, do we study? What is that most basic, fundamental feature of the process that we call aging? Is it functional decline, damage accumulation, increased mortality rate, continuation of development, increased biological age, decrease in the strength of natural selection, the totality of age-related changes, loss of homeostasis, loss of information, their combination, or something else? After organisms reach adulthood, all of these features seemingly go hand in hand, but their coordination is not perfect, and there must be one underlying, explanatory feature that leads to the others. What is it, and can we truly advance the field without identifying it?

Aging biology is exponentially growing as a field, and talented scientists are designing and carrying out many elegant studies. However, in many ways, we are attempting to construct a building without a foundation. One can see this by the lack of clear answers to some of the most basic questions: When does aging begin? To what extent, if any, is biological age dynamic and potentially reversible? Which biomarkers are most appropriate to measure biological age, and do any of them actually measure aging directly?

To begin answering these questions and ensuring the future success of this field, we propose two critical concepts on which aging biologists can actively focus their collective attention: the essence of aging and the nature of aging. To be clear, we are not suggesting that either a formal definition or a unified theory of aging is an immediate need for the field. The essence and nature of aging represent more fundamental concepts, from which we envision that a consensus definition and theory of aging may proceed in the future. In the immediate term, these concepts may serve as building blocks to form the basis of our understanding of aging biology.

We define the "essence of aging" as the most basic, essential, explanatory, and causative feature of biological aging. It is the underlying driving force of the manifestations of advanced age, such as frailty, loss of function, and age-related diseases. Identifying the essence of aging is critical if we wish to study and target aging itself, rather than its later-stage manifestations. Many aging biologists invoke the hallmarks or pillars of aging as a basic starting point for conceptually framing aging biology. However, the essence of aging, in our minds, represents a more fundamental concept underlying these and other characteristics of aging. In the same way that the Hallmarks of Cancer can be reduced to a single essence - mutations - we should be able to, and should strive to, distill a single essence of aging that drives all of the hallmarks/pillars and higher-level manifestations of aging.

We define the "nature of aging" as the inherent properties and dynamics that characterize aging as a biological phenomenon. The nature of aging is conceptually related to critical outstanding questions in the field, such as the behavior of biological age over the life course; the point at which aging begins; and the extent to which aging of a subset of cells or tissues impacts the aging of surrounding or distant cells/tissues. The nature of aging is a much broader concept than the essence of aging, but understanding the nature of aging is no less critical to our ability to target this process.

What are the mechanisms that allow long-lived mammals to be long-lived? It remains to be seen as to whether it will be cost-effective and of sizable benefit to isolate specific genetic differences that can be used as a basis for therapies in humans, but it isn't a terrible idea to conduct the search. Clearly cancer suppression is an interesting topic, and one it might well be possible to build novel therapies based on the study of whales and elephants. Another good place to start is the operation of the immune system. The age-related decline of immune function is clearly important to the onset and progression of age-related disease. We might well ask how long-lived mammals maintain functional immune systems for a much longer period of time than shorter-lived but otherwise quite similar species.

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution.

A close relationship between B-cell:T-cell ratio and immunosenescence was detected, as B-cell:T-cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of reactive oxygen species (ROS)-induced damage in mouse.

PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.

Link: https://doi.org/10.1111/acel.13982

Chronic pain conditions are poorly understood, often incorrectly diagnosed or dismissed by medical practitioners, and, generally, have only poor and unreliable options for treatment. Given that aging degrades the function of all bodily systems, it is no surprise to find a significant incidence of chronic pain in older adults. It is an open question as to the degree to which similar mechanisms are at play to those causing chronic pain in younger adults, and whether useful information can be obtained by comparing the biochemistry of similar conditions in old and young individuals. Unfortunately there remains a lack of understanding as to what is actually going on under the hood in these diverse conditions, leading to a great deal of suffering in a large patient population.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding $600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact.

This review article examines and summarizes pre-clinical research and clinical data on chronic pain among older adults to identify knowledge gaps and provide the base for future research and clinical practice. We provide evidence to suggest that neurodegenerative conditions engender a loss of neural plasticity involved in pain response, whereas low-grade inflammation in aging increases central nervous system sensitization but decreases peripheral nervous system sensitivity. Insights from preclinical studies are needed to answer mechanistic questions. However, the selection of appropriate aging models presents a challenge that has resulted in conflicting data regarding pain processing and behavioral outcomes that is difficult to translate to humans.

Link: https://doi.org/10.1177/17448069231203090

In today's open access paper, researchers attempt to throw a big tent over three distinct issues in the aging of the body and brain. Firstly, the intestinal barrier fails, allowing bacteria and bacterial metabolites into tissue and the circulation, where they can provoke dysfunction and inflammation. Secondly, blood vessels become leaky, harming surrounding tissues by allowing excessive fluid, inappropriate molecules and cells to escape. Lastly, the blood-brain barrier leaks; this is a more specialized barrier layer surrounding blood vessels in the brain, and when it leaks, the passage of unwanted cells and molecules into the brain again produces dysfunction and inflammation.

Can one really draw a circle around these three quite different phenomenon and talk about a unified "leaky syndrome", as the authors of today's paper do? Perhaps so if these issues largely begin with intestinal barrier dysfunction, allowing gut microbes and their inflammatory metabolites into the bloodstream to cause increased dysfunction in blood vessel walls. That this is the primary issue has yet to be determined, but given that we are entering an era in which the aged gut microbiome is both accurately measurable and can be rejuvenated via techniques such as fecal microbiota transplant, flagellin immunization, and so forth, I'd imagine much more will be known a decade from now.

Treating Leaky Syndrome in the Over 65s: Progress and Challenges

Aging is a natural process associated with decreased physiologic function in all organs, i.e. it not only affects our immune system, but also affects all tissues and cells, resulting in increased risk of several chronic diseases and vulnerability to death. The gut microbiome is now recognized as one of the key elements to maintaining host health1 and contributing to disease progressions such as high abundance of pathogenic bacteria (such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile) and low abundance of short-chain fatty acid producing bacteria such as Bifidobacterium, Faecalibacterium, Roseburia. Several studies over the past few years revealed that the gut microbiome and its composition changes with age which could have significant implications on overall health during aging, however, the mechanisms by which it impacts the biology of aging remain largely unknown.

The microbiome is composed of diverse microbes i.e., bacteria, archaea, viruses, eukaryotic microbes, and fungi, that have lived in and around our body since birth. The gut and skin are the most extensively colonized regions of our body, while other areas including the mouth, eyes, ears, and reproductive organs also harbor dense populations of specific microbes. These microbes establish a symbiotic relationship with the host, playing a crucial role in regulating essential functions such as protection against pathogens, immunomodulation, and maintaining the structural integrity of the gut mucosal barrier, indicating a strong association between abnormalities in gut microbiota and the development of a wide range of diseases including autoimmune disorders, depression, and neurodegenerative diseases such as Alzheimer's disease and metabolic disorders.

However, the mechanisms by which the microbiome contributes to the development of these diseases are unclear. There can be several mechanisms but inflammation is a key suspect. Low-grade inflammation is often higher in older adults but the source of inflammation remains largely elusive. Growing evidence indicates that gut dysbiosis, characterized by an imbalance in gut microbial composition, tends to escalate with age. This dysbiosis, in turn, contributes to increased gut permeability, often referred to as "leaky gut". This heightened permeability facilitates the passage of pro-inflammatory substances such as bacterial toxins and lipopolysaccharide (LPS) from the gut lumen into the bloodstream or mucosal immune system, thereby triggering inflammation. Elevated inflammation is also known to increase the permeability of other epithelial and endothelial barriers such as intestinal epithelia (leaky gut), blood vessel endothelia (leaky vessels), blood-brain barrier (BBB) (leaky brain), and others, and collectively called "leaky syndrome". The link between leaky syndrome with chronic inflammation and microbiome dysbiosis in aging biology remains poorly understood.

With age, the immune system becomes simultaneously less capable (immunosenescence) and more active and inflammatory (inflammaging). This constant, low-grade, unresolved inflammatory activity is driven by a range of different mechanisms. For example, senescent cells energetically secrete pro-inflammatory signals, and their numbers grow with age in tissues throughout the body. Further, age-related issues in cell function can lead to fragments of DNA from mitochondria and the nucleus leaking into the cytoplasm, where they trigger innate immune mechanisms intended to detect pathogens. Constant, unresolved inflammation is harmful to cell and tissue function, as illustrated by this paper, focused on the kidney. Control of inflammation much be a part of any comprehensive toolkit of approaches to slowing and reversing degenerative aging.

Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive. Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining, and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments.

During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures.

Together, these data suggest that during normal renal aging tubular cells activate a program of 'tubuloinflammaging', which might contribute to age-related phenotypical changes and to increased disease susceptibility.

Link: https://doi.org/10.3389/fimmu.2023.1222339

Researchers here note the phenomenon in which blood pressure declines in very late life, in the last few years. In studying a Chinese population, they find that the greatest mortality risk attends those whose blood pressure is initially high and then begins to decline while still remaining above the normal range. The consensus of recent years is that lower is better, as the raised blood pressure of hypertension causes pressure damage and disruption of normal tissue maintenance throughout the body. Study data appears to support this hypothesis. Nothing is ever simple, of course, and two different individuals can exhibit quite different degrees and manifestations of cardiovascular aging in late life.

Optimal blood pressure (BP) management strategy among the elderly remains controversial, with insufficient consideration of long-term BP trajectory. In this study, we included 11,181 participants older than 60 at baseline (mean age, 80.98 ± 10.71) with 42,871 routine BP measurements from the Chinese Longitudinal Healthy Longevity Survey. Latent class trajectory analysis and Cox proportional hazard model were conducted to identify trajectory patterns and their associations with mortality. Furthermore, we also applied mixed-effects model to identify terminal BP trajectories among the elderly.

Compared with stable at normal high level trajectory, excess systolic BP (SBP) trajectory with decreasing trend was associated with a 34% (hazard ratio, HR = 1.34) higher risk of all-cause mortality. Considering the competing risk of non-CVD death, excess BP trajectory with decreasing trend had a more pronounced effect on cardiovascular disease (CVD) mortality, in which HR was 1.67. Similar results were also found in diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) trajectories. We further conducted a mixed-effects model and observed that SBP and PP trajectories first increased and began to decline slightly six years before death. In contrast, DBP and MAP showed continuous decline 15 years before death.

In conclusion, long-term BP trajectory was associated with all-cause mortality, especially CVD mortality. Keeping a stable BP over time may be an important way for CVD prevention among the elderly.

Link: https://doi.org/10.3389/fcvm.2023.1157327

The hundreds of mitochondria present in every cell in the body undertake the essential duty of producing chemical energy store molecules, adenosine triphosphate (ATP), used to power the cell. With age, mitochondria become less efficient and more damaged, generating oxidative stress and triggering inflammation while producing less ATP than is optimal. This is thought to be a major contribution to degenerative aging, though as for all contributions to aging, it requires a highly targeted way to improve mitochondrial function in order to determine just how important it is. That highly targeted therapy doesn't yet exist in a useful form. The most plausible near future candidate is transplantation of young, functional mitochondria.

Mitochondria are descended from ancient bacteria that became symbiotic with early cells. As such, they retain a small remnant circular genome, the mitochondrial DNA. In today's open access paper, researchers note that while the mitochondrial transcription machinery producing proteins from DNA sequences is different from that of the nucleus, mitochondrial DNA is still subject to epigenetic marks that can change protein output. Epigenetic patterns on the genome are known to change with age, producing changes in protein levels that are some mix of harmful and adaptive. It is reasonable to think that epigenetic regulation of protein production can be just as involved in age-related declines in the mitochondria as it is in the nucleus.

Mitochondrial epigenetics in aging and cardiovascular diseases

Mitochondria are cellular organelles which generate adenosine triphosphate (ATP) molecules for the maintenance of cellular energy through oxidative phosphorylation. They also regulate a variety of cellular processes including apoptosis and metabolism. Of interest, the inner part of mitochondria - the mitochondrial matrix - contains a circular molecule of DNA (mtDNA) characterised by its own transcriptional machinery. As with nuclear DNA, mtDNA may also undergo nucleotide mutations that have been shown to be responsible for mitochondrial dysfunction.

During physiological aging, the mitochondrial membrane potential declines and associates with enhanced mitophagy to avoid the accumulation of damaged organelles. Moreover, if the dysfunctional mitochondria are not properly cleared, this could lead to cellular dysfunction and subsequent development of several comorbidities such as cardiovascular diseases (CVDs), diabetes, respiratory diseases, as well as inflammatory disorders and psychiatric diseases.

As reported for genomic DNA, mtDNA is also amenable to chemical modifications, namely DNA methylation. Changes in mtDNA methylation have shown to be associated with altered transcriptional programs and mitochondrial dysfunction during aging. In addition, other epigenetic signals have been observed in mitochondria, in particular the interaction between mtDNA methylation and non-coding RNAs. Mitoepigenetic modifications are also involved in the pathogenesis of CVDs where oxygen chain disruption, mitochondrial fission, and reactive oxygen species (ROS) formation alter cardiac energy metabolism leading to hypertrophy, hypertension, heart failure, and ischemia/reperfusion injury.

In the present review, we summarize current evidence on the growing importance of epigenetic changes as modulator of mitochondrial function in aging. A better understanding of the mitochondrial epigenetic landscape may pave the way for personalized therapies to prevent age-related diseases.

The Open Genes database provides summaries of the information available on longevity-associated genes, from well-established and well-replicated effects such as that associated with klotho expression, to much less well supported data. Thousands of genes have at least a study or two suggesting an effect on longevity in studies of lower animals, and many of those may turn out to be experimental error. Yet since every fundamental cellular process can be influenced by dozens or hundreds of genes, even though there are comparatively few important processes of aging, one might well expect there be to be thousands of related genes. Looking at the practical outcome of all of this study, at the end of the day, the large human epidemiological databases and genetic studies suggest that common gene variants have very little effect on longevity when compared to the impact of lifestyle choices. Genetics, I suspect, is not the road to human rejuvenation. Instead, therapies that repair specific forms of damage will be needed.

The Open Genes database was created to enhance and simplify the search for potential aging therapy targets. We collected data on 2402 genes associated with aging and developed convenient tools for searching and comparing gene features. A comprehensive description of genes has been provided, including lifespan-extending interventions, age-related changes, longevity associations, gene evolution, associations with diseases and hallmarks of aging, and functions of gene products.

For each experiment, we presented the necessary structured data for evaluating the experiment's quality and interpreting the study's findings. Our goal was to stay objective and precise while connecting a particular gene to human aging. We distinguished six types of studies and 12 criteria for adding genes to our database. Genes were classified according to the confidence level of the link between the gene and aging. All the data collected in a database are provided both by an API and a user interface. The database is publicly available on a website at https://open-genes.org/.

Link: https://doi.org/10.1093/nar/gkad712

Chronic inflammation is a feature of many age-related conditions, including neurodegenerative diseases such as Alzheimer's disease. Is inflammation secondary to protein aggregation and other features of aging that drive the development of neurodegenerative conditions, or is inflammation of primary importance in the onset of cognitive impairment and Alzheimer's disease? These are complex conditions in which many forms of pathology and damage interact, and only now are there means to selectively reduce age-related chronic inflammation via the selective destruction of senescent cells. The results of clinical trials of therapies that clear senescent cells should provide some insight into the importance of inflammation in neurogenerative conditions.

Mild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD.

In the present study, we assessed a set of various serum and cerebrospinal fluid (CSF) biomarkers, including AD hallmarks and central nervous system and peripheral system inflammatory mediators, in a cohort of 30 healthy control, 45 non-impaired control, and 30 mild cognitively impaired patients. Our results confirmed specific activation of inflammatory processes in the brain of the MCI cohort. Additionally, the presence of systemic biomarkers in the CSF of the MCI population could give an indication of blood-brain barrier (BBB) permeability. Finally, IL-1β was upregulated in MCI serum and correlated with NLRP3 activation biomarkers.

AD has been described as a cascade of several biochemical mechanisms. First, the amyloid plaques start to accumulate abnormally in the brain, triggering an inflammatory response that will chronically exacerbate amyloid deposition and neurotoxicity. This will be followed by the production and hyperphosphorylation of tau proteins generating neurofibrillary tangles. All three mechanisms together are then responsible for altering neuronal transmission in the brain, which results in cognitive decline. Consequently, it is the combination of amyloids, inflammation, and tau proteins together that is responsible for cognitive impairment. As our patients have MCI based on cognitive tests and potentially early AD onset, the stage of the disease could correspond to the transition between amyloid aggregation and inflammatory response activation.

Link: https://doi.org/10.3390/ijms241310523

A single course of treatment with the combination of dasatinib and quercetin clears meaningful numbers of senescent cells from aged human tissues, and to much the same degree as it does in mice. In mice this treatment dramatically, rapidly reverses signs of age-related disease. The research community has known this for the better part of a decade, with ever more studies added over this time. Near every age-related condition is reversed to some degree via the use of senolytic therapies that can selectively clear senescent cells, with dasatinib and quercertin continuing to be one of the better treatments, comparing those with published data.

One might think that there would be a rush to demonstrate that this cheap drug and supplement combination works in humans, and could therefore be used widely to improve late-life health by reducing the burden of senescent cells in near every older person. But no. Only a few studies have been conducted, tentatively. Today's research materials report on another of these efforts, a small phase 1 clinical trial that tells us nothing about efficacy, and only what we already knew about safety, that dasatinib and quercetin are safe for older people to use at senolytic doses and dosage schedules. The incentives operating in the clinical development community are such that any cheap, existing drug is unlikely to receive much attention, no matter how good it is. Vast sums are devoted to making new senolytic drugs, while a drug that might achieve a great deal of good in the world is left on the shelf.

That situation won't change any time soon, but there is a role for philanthropy here. It would not require all that much in funding to run a half dozen informal, hundred-participant clinical trials, on the scale of the PEARL trial for rapamycin, to demonstrate that, yes, dasatinib and quercertin is as good as we suspect it to be. The purpose would not be to demonstrate this point to the FDA, as dasatinib is already approved and quercetin is a supplement, and so these could be very lean trials, absent all the regulatory overhead and its costs. The goal is rather to demonstrate the merits and safety of this senolytic therapy to the physicians who can choose to prescribe off-label.

Phase I Clinical Trial Shows Treatment Designed to Clear Senescent Cells in Alzheimer's Disease is Safe

Senescent cells are old, sick cells that cannot properly repair themselves and don't die off when they should. Instead, they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.

For the current study, the research team enrolled five participants aged 65 and older with symptoms of early-stage Alzheimer's disease. Participants received oral dasatinib plus quercetin over two consecutive days, followed by two weeks of no drugs. The cycle repeated six times for a total of 12 weeks. The research team also collected data on the safety and efficacy of the two drugs by monitoring side effects. They assessed biomarkers of senescence in cerebrospinal fluid (CSF) and blood, and also evaluated patients' cognition and brain images before treatment and after they completed the 12-week study. They found that both dasatinib and quercetin levels increased in the blood, and dasatinib was detected in the CSF in four subjects. Quercetin was not detected in the CSF of any participant. "We also determined that the treatment was safe, feasible and well-tolerated. There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further." Researchers also saw evidence to suggest that the combination therapy cleared amyloid from the brain and lowered inflammation in the blood. "However, we shouldn't over-interpret these results. There was a small number of people enrolled, there was no placebo arm to compare results."

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility, and efficacy. Five participants (mean age = 76 years) completed the 12-week pilot study.

D and Q levels in blood increased in all participants. In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile.

CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels. In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability, and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies.

Mitochondria are the power plants of the cell, responsible for generating chemical energy store molecules to power cell processes. Urolithin A is one of a number of supplements shown to improve mitochondrial function, though as for the others it isn't all that impressive when compared to the effects of regular exercise. Nonetheless, this and other approaches to modestly attenuate age-related declines in mitochondrial function are under active development. They are not solutions to the problem of mitochondrial aging, however. For that we must look to more radical approaches to therapy, such as mitochondrial transplantation, allotopic expression of mitochondrial DNA in the cell nucleus, and partial reprogramming to reset expression of genes essential to mitochondrial function.

The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action.

The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.

Link: https://doi.org/10.7759/cureus.42550

Researchers have studied calorie restriction as a means to slow aging quite extensively, but organisms are highly complex and there is always more that can be investigated. Here, researchers look in detail at the effects of calorie restriction in mice on the beta cells of the pancreas, necessary for the normal function of insulin metabolism. It is interesting to see mitophagy reduction as a means of increased mitochondrial function, though this could indicate that calorie restriction adjusts mitochondrial activity in ways that extend the functional life span of an individual mitochondrion, thereby less need for mitophagy. The big question regarding research into the mechanisms of calorie restriction is whether this is a useful way to find a basis for drug development aimed at slowing aging, given that long-lived species exhibit a much smaller effect on life span resulting from the practice of calorie restriction, and studies in mice almost certainly overstate benefits that might be obtained in humans.

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. We investigated these questions by exposing adult mice to mild CR (i.e., 20% restriction) for up to 12 months and applied in vivo and in vitro metabolic phenotyping of beta cell function followed by single cell multiomics and multi-modal high resolution microscopy pipelines (electron, light, mass spectrometry, and isotope microscopy) to investigate how CR modulates beta cell heterogeneity and longevity.

Gene regulatory network analysis links this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.

Link: https://doi.org/10.1101/2023.08.23.554369

A number of supplement-based approaches have been demonstrated to modestly improve mitochondrial function with age. This includes the various ways to increase NAD levels using vitamin B3 derivatives, mitochondrially targeted antioxidants such as SkQ1, MitoQ, and SS-31, and other compounds such as urolithin A for which the mechanism causing improved mitochondrial function is not as well determined. There is an argument to be made that all of these compounds work because they in some way improve the operation of mitophagy, a mitochondrial quality control mechanism that senses worn and damaged mitochondria, before directing them to a lysosome for recycling. That sensing is complicated and incompletely understood, which makes it challenging to determine what exactly is going on under the hood.

We do know that mitochondrial function and mitochondrial quality control are improved by the practice of calorie restriction, as well as by the exercise needed to maintain physical fitness. This might lead us to suspect that these approaches to improving mitochondrial function will have smaller effects on life span in long-lived humans than in short-lived mice, as that is exactly what happens in the case of calorie restriction. Meanwhile, we have no intuition as to the size of the outcomes that might be achieved via complete replacement of mitochondria, which is to my eyes the most promising approach to mitochondrial rejuvenation, or via allotopic expression, producing backup copies of mitochondrial DNA, or via partial reprogramming, which resets problematic gene expression changes that occur with age and impair aspects of mitochondrial function.

New study: reversing aging in the blood stem cells and the immune system

The aging process is often accompanied by a decline in the proper functioning of the hematopoietic and immune systems, making older adults more susceptible to infections, blood disorders, and even tumor development. A new study focused on a key player in the blood system - hematopoietic stem cells (HSCs). These cells are responsible for generating various types of blood cells, playing a critical role in maintaining a healthy immune system. As we age, HSCs experience a decline in their ability to regenerate blood and show a preference for a specific type of cell lineage, which contributes to immune system dysfunction.

By introducing a natural compound called Urolithin A, which targets mitochondria - the energy powerhouses of cells - researchers were able to reverse the decline in HSC function. Mitochondria abnormalities were identified as a contributing factor to the aging of HSCs. Urolithin A acted as a mitochondrial modulator, effectively restoring the mitochondrial function within HSCs. Urolithins are not found in food; however, their precursors are. Urolithin A is the result of transformation of ellagic acids and ellagitannins by the gut microflora in humans.

The most interesting finding of this preclinical study was that this intervention not only rejuvenated the blood reconstitution capability of older HSCs but also improved immune system function in aged mice. When Urolithin A was incorporated as a dietary supplement, it not only revitalized the immune system's lymphoid compartments but also enhanced overall HSC performance. This translated to an improved immune response against viral infections, showcasing the potential of Urolithin A to combat age-related immune system decline.

Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs.

The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.

To say that there is a lack of standardization in aging research is understating the matter. Pity the authors of reviews and meta-reviews, as they struggle to compare outcomes of animal studies between completely different, incompatible methodologies. Inconsistency in results is something of a feature even when different research groups attempt replication. The authors of this paper-length complaint focus down on one specific issue, the lack of standarization in the scientific control arm of a life span study, which is enough in and of itself to make comparison and replication challenging.

The search for interventions to slow down and even reverse aging is a burgeoning field. The literature cites hundreds of supposedly beneficial pharmacological and genetic interventions in model organisms: mice, rats, flies and worms, where research into physiology is routinely accompanied by lifespan data. Naturally the negative results are more frequent, yet scientifically quite valuable if analyzed systematically. Yet, there is a strong "discovery bias", i.e. results of interventions which turn out not to be beneficial remain unpublished.

Theoretically, all lifespan data is ripe for re-analysis: we could contrast the molecular targets and pathways across studies and help focus the further search for interventions. Alas, the results of most longevity studies are difficult to compare. This is in part because there are no clear, universally accepted standards for conducting such experiments or even for reporting such data. The situation is worsened by the fact that the authors often do not describe experimental conditions completely. As a result, works on longevity make up a set of precedents, each of which might be interesting in its own right, yet incoherent and incomparable. Here we point out specific issues and propose solutions for quality control by checking both inter-study and intra-study consistency of lifespan data.

Link: https://doi.org/10.1101/2023.08.17.552381

Interestingly, telomerase upregulation to lengthen telomere length may turn out to be a decent match for the capabilities of lipid nanoparticle (LNP) delivery of messenger RNA (mRNA) as an implementation of gene therapy. This produces one to two days of expression which, by the sound of things, is enough to give telomeres enough of a boost in length to be worth the exercise, can be repeated as needed, is familiar to regulators, and the LNP field is energetically working towards variant LNPs that can target specific tissues and cell types.

The question is whether or not lengthening of telomeres via telomerase gene therapy is a good idea in humans. There is a lot of hype over telomere length, but given that telomeres shorten with each cell division, average telomere length in a tissue is a fuzzy measure of the pace of cell replication versus pace of production of new cells by the stem cells that support that tissue. Stem cell activity declines with age, ergo so does average telomere length. The hypothesized risk lies in extending the life span of cells that are potentially cancerous. In mice, telomerase gene therapy is quite beneficial, both extending life and reducing cancer risk. Humans and other large mammals exhibit very different telomere dynamics, however, so one can't assume that the mouse data is a clear green signal. Given a company working towards this goal, we might hope that questions will be answered in the years ahead.

Longevity biotech Rejuvenation Technologies has emerged from stealth with seed financing to develop mRNA-based therapeutics to address mechanisms of aging. The company says it has developed an mRNA approach "capable of rewinding 10 years of telomere shortening with a single dose." Rejuvenation's products are optimized telomerase mRNA encapsulated in a custom tissue targeted lipid nanoparticle. The company says it plans to expand its operations and bring on additional team members to oversee scale-up manufacturing, clinical operations, and R&D efforts to expand mRNA delivery capabilities to additional organ systems.

"A single dose of our telomerase mRNA reverses years of telomere shortening in hours. Rejuvenation's LNP technology can also deliver mRNA to the lung and liver, and we've shown remarkable efficacy in preclinical models in both liver fibrosis and liver failure."

Link: https://longevity.technology/news/rejuvenation-technologies-exits-stealth-with-10-6m-for-age-reversing-mrna-therapeutics/

Neural stem cells residing within a few regions of the mammalian brain divide to generate new daughter neurons throughout adult life, the process of neurogenesis. Neurogenesis is particularly associated with functions such as memory, which requires changes in brain state driven by the creation of new neurons and neural connections. Additionally, however, researchers have identified a population of dormant progenitor cells that can mature into neurons, more broadly distributed throughout the brain. This population can be diminished and eventually exhausted by that activity, but researchers hypothesize that it could nonetheless be a source of regenerative capacity for the aging brain if the remaining pool of dormant progenitor cells could be awakened.

More speculatively, this type of progenitor cell might be a good candidate for cell therapies aimed at improving function in the aging brain. If the mechanism of awakening is understood and production of the cell type possible, continual rounds of therapy might be undertakn. Still, such efforts to restore the brain are future concerns: it remains quite challenging to deliver any therapy to the brain, never mind very challenging forms of therapy such as those involving the production and quality control of cells.

The awakening of dormant neuronal precursors in the adult and aged brain

The mammalian brain is traditionally described as a network of neurons and glia, in which maturation and establishment of connectivity occur shortly after birth, followed by circuit refinement throughout the early part of life. Yet, there are exceptions concerning the timing of maturation because specific types of neurons are added progressively to the brain circuits during the adulthood. Some well-known neuronal "latecomers" are those originating from the brain areas designated as adult neurogenic niches.

Recent studies and new technology allowed researchers to update the current concepts of adult neurogenesis by revealing the existence of other types of neuronal precursors, which reside outside the neurogenic niches. Although generated during the embryonic development, these cell types retain post-mitotic immaturity until adulthood. During adulthood, such neuronal precursors, herewith referred to as "dormant precursors," eventually awaken and become adult-matured neurons (AM). Much about the awakening and maturation of dormant precursors is yet to be revealed. So far, several works in different mammalian species suggested that dormant precursors occupy numerous brain regions.

We previously demonstrated that, after awakening, dormant precursors undergo axonal sprouting, formation of synapses, and the progressive acquisition of functional input and output during the transition from precursor to AM. At the same time, we were puzzled to note that while many dormant precursors undertook the course of maturation during early adulthood, some cells remained immature throughout adulthood. Similar observation was also common in other mammalian species, including primates and humans.

Consequently, we questioned whether the precursors remaining dormant for most of a lifetime can actually eventually awake and follow a course of late maturation or whether they fail to awaken altogether. On the one hand, we speculated that the aging of the brain may hinder or completely impair the awakening. On the other hand, if late awakening and maturation were possible, this would imply that the old brain in mammalians is equipped with an unexplored source of young neurons.

Hematopoietic stem cells in the bone marrow give rise to red blood cells and immune cells. Like all stem cell populations, they become increasingly dysfunctional with age, however. In part this is damage to the stem cells themselves, but a sizable portion of the problem results from age-related damage and change in the niche of supporting cells that is needed to maintain a stem cell population. It is hoped that restoring stem cell function in older individuals will go a long way towards producing slowed aging and improved health. At present the research community is progressing towards this goal one stem cell population at a time, but it seems plausible that some discoveries will be broadly applicable to all stem cells in the adult body.

Aging of the hematopoietic system promotes various blood, immune, and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction. Autophagy is central for the benefits associated with activation of longevity signaling programs, and for HSC function and response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional. However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown.

Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche. We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment.

Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.

Link: https://doi.org/10.1101/2023.08.17.553736

A number of lines of research suggest that forms of calorie restriction and fasting can improve the function of the immune system. It is also noted that fasting can reduce the number of immune cells found in the circulation. The complement system is a part of the innate immune system, reacting to invading pathogens in order to rouse immune cells to action. Red blood cells play a part in the complement system, and researchers here show that fasting can improve the immune response despite a lower number of circulating white blood cells by improving the ability of red blood cells to trigger a response.

Fasting is known to influence the immune functions of leukocytes primarily by regulating their mobilization and redistribution between the bone marrow and the peripheral tissues or circulation, in particular via relocalization of leukocytes back in the bone marrow. However, how the immune system responds to the increased risk of invasion by infectious pathogens with fewer leukocytes in the peripheral blood during fasting intervention remains an open question.

We used proteomic, biochemical and flow cytometric tools to evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria, and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability.

Link: https://doi.org/10.1186/s12979-023-00359-3

I attended the 10th Aging Research and Drug Discovery (ARDD) conference in Copenhagen recently, alongside my Chief Scientific Officer at Repair Biotechnologies, Mourad Topors. If one wanted to take in all of the presentations and take notes, as I've done in the past, ARDD would be much more of a test of endurance than other longevity industry conferences. It is five 12 hour days, starting with networking at 8am, the last presentations going on past 8pm, and then socializing at nearby bars afterwards for the truly dedicated. This on top of jet lag for those coming in from the US in direction and Asia in the other. The intent of the organizers is for participants, and those following the livestream, to drop in for the topics that interest them, and take the time for other activities in between.

The mix of attendees was, as always, some combination of academics, the founders of biotech startups, visitors from Big Pharma, and investors, those being a mix of interested individuals and venture capitalists. Judging from discussions held in the corridors, the present view of the investment market for biotech startups is that while some people are raising funds with apparent ease, it is still not a great environment. Better than the start of the year, but not great. There were fewer institutional investors at ARDD than in past years, and the consensus appears to be to expect fiscal gloom until later in 2024. Expenditures are cut, timelines extended, and bridge rounds are raised, business as usual for lean times.

The Big Pharma interest in the conference varied from "to be honest, my boss told me an hour ago to come in and represent the company, I'm really not familiar with this," to department heads with interesting experience and well-considered positions on the field. As some of you may know, one of my areas of interest is the path to better gene therapies, and I had a lengthy conversation with the director of a gene therapy program in which our views aligned on many of the details. Viral vectors are going to be amazing in 2050, but are very much not amazing now; there would be a mass exodus from the development of mRNA therapies if only someone could find a way to deliver plasmids to the nucleus; the development of tissue-targeted delivery systems seems on the verge of becoming impressive, but still has a long way to go if your targets are small areas of the body; and so forth.

This year, I confess, I attended only a fraction of the many presentations in the program. Most of my time was taken up with networking. For those who didn't attend, I recommend looking through the program and waiting for the videos to be posted. There were some interesting talks. The role and details of cellular senescence in aging was a frequent topic. Both the academic and industry communities are rapidly digging in to the biochemistry of senescence, with new discoveries emerging and the debates shifting on a regular basis. The Deciduous Therapeutics program is becoming one of the most interesting in the industry, given that their approach to rousing the immune system to destroy senescent cells lasts for a considerable time following a single dose. At the same time, they are far enough along in their work that the supply of new details shared in public is drying up, as often happens.

We at Repair Biotechnologies shared that our LNP-mRNA therapy can rapidly reverse both atherosclerosis and nonalcoholic steatohepatitis (NASH) in animal models. We plan to submit our first pre-IND package later in the year. Maxwell Biosciences is making an appearance at most conferences these days as they ramp up their program; they produce a small molecule mimetic of the LL-37 antimicrobial peptide, a sort of too-good-to-be-true part of the innate immune system that improves just about every process the immune system touches when upregulated. It attacks bacteria, viruses, cancers, and even appears to improve aspects of tissue maintenance. Their program is focused on delivery as needed. It did occur to me that one could learn from the Minicircle approach to follistatin upregulation and use some form of long-lasting vector to turn a small volume of subcutaneous fat cells into a factory for LL-37, permanently upregulating it and its effects on immune defenses, but apparently this doesn't have the desired effect - hence the need for a mimetic rather than the original peptide.

Other fellow travelers on the conference circuit showing off their progress included some of the growing number of reprogramming ventures: Retro Biosciences, rapidly expanding their research footprint and likely to become a behemoth in the industry the next time they go out to seek investment; Life Biosciences, about which much the same might be said; the actual behemoth of Altos Labs; and smaller ventures such as Turn Bio. Epigenetic reprogramming to reset the biochemistry of aged cells is, as one might expect, another frequent topic at conferences these days. Arguably the majority of funding for research and development in the field of longevity is currently focused on forms of partial reprogramming, which at least offers the hope that a decade from now we'll have answers to all of the most important questions about this approach.

We do live in a barnstorming age for biotechnology, and so very much more can be accomplished than regulators would approve for widespread use. There are a lot of high-flying technical discussions going on behind the scenes. Anything that starts with "why can't we just..." usually ends with "well, we could, but it would be very hard to obtain approval." Passing through the regulatory process is, meanwhile, so very expensive than only the most conservative, safe, incremental programs have an easy road to finding the necessary funding. Biotech investors are, if anything, even more conservative than the regulators, very ready to anticipate difficulties and avoid investing in those programs.

To conclude, if you'd like a crash course on the state of the scientific field and the industry focused on treating aging as a medical condition, attending ARDD is one of the better options on the table.

Thymocytes created in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. The thymus, unfortunately, loses active tissue with age, and this progressively reduces the pace at which new T cells are created. Lacking replacements, the adaptive immune system becomes increasingly made of up senescent, exhausted, and malfunctioning cells. This is an important component of immune aging.

Researchers here note that the presence of excess fat tissue correlates with greater atrophy of the thymus. Given that chronic inflammation is hypothesized to be important in driving this thymic involution, this result is not all that surprising. Excess visceral fat is metabolically active and generates inflammatory signaling through a range of mechanisms. Thus better lifestyle choices improve the odds of having more active thymic tissue in later life, and a less aged immune system.

Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation, and increased morbidity. Other factors, aside from chronological age, have been proposed to affect the involution rate. In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. The major aims were to establish the prevalence of fatty degeneration of thymus and to determine its associations with demographic, lifestyle, and clinical factors, as well as inflammation, T cell differentiation, and thymic output.

In total, 1,048 randomly invited individuals (aged 50-64 years, 49% females) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size and a 4-point scoring system, with scale 0-3 based on the ratio of fat and soft tissue. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation. Age, male sex, high BMI, abdominal obesity, and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels.

Link: https://doi.org/10.1186/s12979-023-00371-7

Mammals have a very wide range in life spans, and the study of mammals might be thought to be more relevant to efforts to extend human longevity than the study of other taxonomic classes. It is quite unclear at this time whether moving genes and mechanisms between mammalian species is likely to produce meaningful gains cost-effectively in the near future, but we certainly won't know if we don't try. Meanwhile, bivalves are another class with a large range in species life span. There is much to be said for undertaking the same sort of search for the determinants of species life span in bivalves as is presently ongoing in mammals. Having results for two quite different classes is likely to be more illuminating of the mechanisms of aging than the results for mammals alone.

Among Metazoa, bivalves have the highest lifespan disparity, ranging from 1 to 500+ years, making them an exceptional testing ground to understand mechanisms underlying aging and the evolution of extended longevity. Nevertheless, comparative molecular evolution has been an overlooked approach in this instance. Here we leveraged transcriptomic resources spanning thirty bivalve species to unravel the signatures of convergent molecular evolution in four long-lived species: Margaritifera margaritifera, Elliptio complanata, Lampsilis siliquoidea, and Arctica islandica (the latter represents the longest-lived non-colonial metazoan known so far). We applied a comprehensive approach - which included inference of convergent dN/dS, convergent positive selection, and convergent amino acid substitution - with a strong focus on the reduction of false positives.

Genes with convergent evolution in long-lived bivalves show more physical and functional interactions to each other than expected, suggesting that they are biologically connected; this interaction network is enriched in genes for which a role in longevity has been experimentally supported in other species. This suggests that genes in the network are involved in extended longevity in bivalves and, consequently, that the mechanisms underlying extended longevity are - at least partially - shared across Metazoa. Although we believe that an integration of different genes and pathways is required for the extended longevity phenotype, we highlight the potential central roles of genes involved in cell proliferation control, translational machinery, and response to hypoxia, in lifespan extension.

Link: https://doi.org/10.1093/gbe/evad159

One of the ways in which cell damage characteristic of aging can provoke inflammation is via the mislocalization of DNA. Either nuclear DNA or mitochondrial DNA can find its way to the cytosol, where it can trigger responses evolved to detect bacterial or viral infection, or severe cell damage. This creates a cascade of downstream signaling leading to an inflammatory response. In youth these events occur comparatively rarely, and in circumstances wherein immune response and potentially even cell death are beneficial. With age, however, there is a continued mild but growing level of dysfunction and consequent sustained inflammation that is never fully resolved. Such continual inflammatory signaling is disruptive to cell and tissue function, and is thought to be an important contributing factor in degenerative aging.

In today's open access paper, researchers examine the contribution of nuclear DNA mislocalization to one specific form of heart failures://en.wikipedia.org/wiki/Heart_failure">heart failure, dilated cardiomyopathy, in which the heart becomes enlarged and weakened in response to poorly understood causes. The researchers examine human tissues with an eye to validating data obtained in animal models. The overall picture is that stress on cells in the heart leads to an excessive pace of DNA double strand breaks, which in turn enables DNA fragments to escape from the nucleus into the cytosol. There, the inflammatory reaction takes over. Sustained inflammation in turns drives the dysfunctional regulation leading enlargement and weakening of heart muscle. The degree to which this mechanism is important in humans might be determined via inhibition of specific parts of the cytosolic DNA detection mechanism, a test that might be readily carried out given funding and the will to try.

Cytosolic DNA sensing protein pathway is activated in human hearts with dilated cardiomyopathy

The genome is constantly exposed to numerous stressors, which induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates NFκB and IRF3, which induce the expression of the pro-inflammatory genes. There is scant data on the activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM).

To our knowledge, our study results are the first documentation of increased expression levels of the protein components of the CDSP pathway, namely CGAS, TBK1, RELB, P52, and P50 in the human heart samples from patients with heart failure due to DCM. These findings by showing the upregulation of expression of the CDSPs, including the components of the NFκB pathway, complement the previous data on the activation of the nuclear DDR pathway in human heart tissues from patients with DCM. The findings in the human heart samples, being devoid of the genetic manipulations, also give credence to the findings in the model organisms.

Collectively, the data implicate increased DSBs and activation of the DDR and CDSP pathways in the pathogenesis of the DCM and set the stage for further delineation of the pathogenic role of these pathways in human primary DCM. Given the salubrious effects of targeting the CDSP pathway in mouse models of DCM, the findings raise the prospects for targeting the activated CDSP pathways for the prevention and attenuation of the phenotype in human primary DCM. Given that cell stress, including transcriptional stress, is common to various forms of cardiovascular pathology, one may speculate that increased DSBs and activation of DDR and the CDSP pathways are pervasive and ubiquitous features of cardiovascular diseases.

There is a growing interest in the role of transposable elements in aging. These are sections of the genome, remnants of ancient viral infections, that are capable of copying themselves when active, causing mutational damage in the process. Transposable elements are suppressed in youth, their portions of the genome folded away and hidden from transcriptional machinery, but this suppression fails with age as epigenetic markers that determine the structure of the genome change. Any mechanism that increases mutational damage in large numbers of cells might be suspected to contribute to degenerative aging, but definitive proof is always a challenge, given the difficulty of adjusting just one feature of cellular biochemistry in isolation of all other features. Nonetheless, researchers make the attempt here in nematode worms, and the results are interesting.

Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability.

Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in somatic cells also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.

Link: https://doi.org/10.1038/s41467-023-40957-9

The vitamin B3 derivative nicotinamide riboside is one of the more studied ways to increase nicotinamide adenine dinucleotide (NAD) levels in aged tissues. NAD is important in mitochondrial function, but for incompletely understood reasons becomes less available with advancing age. Delivering precursors to NAD synthesis such as nicotinamide riboside can help to boost NAD levels, but researchers have failed to show that the increase in NAD levels and resulting health benefits of this sort of approach are any better than those produced by regular exercise. Clinical trials of various means of increasing NAD levels have produced mixed to uninspiring results. The open access paper here is in part a review of this history, and in part a pitch for using a different, more stable form of nicotinamide riboside to improve the effect size.

Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage.

Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.

Link: https://doi.org/10.3390/molecules28166078

Chronic inflammation remains an important contributing process in the development of age-related dysfunction and disease, one that is presently difficult to address. This unresolved inflammation is a direct consequence of a number of different causes of aging. They include mitochondrial dysfunction leading to mislocalization of mitochondrial DNA into the cytoplasm, where it triggers responses evolved to detect bacterial infection, as well as the now well-studied burden of senescent cells found in aged tissues and the pro-inflammatory secretions that these errant cells produce.

A great many research groups and development programs are aimed at suppression of excessive inflammation. Unfortunately, near all present approaches suppress both excessive and necessary inflammation, reducing harms, but at the cost of also impairing vital immune responses to infection and cancer. Approaches to date that definitively only reduce harmful chronic inflammation while preserving the response to infection and cancer include some stem cell therapies and the clearance of senescent cells via senolytic drugs, but these are not as widely used as they might be. The more established approaches to reducing inflammation involve the blockade of specific signal molecules such as TNF or interference in the response to those signals, but these signals and their responses are involved in essential as well as unwanted inflammation.

It is hoped that an improved understanding of the complex mechanisms that regulate the inflammatory response and its resolution will lead to ways to distinguish excessive inflammation from necessary inflammation, and thus interventions that only suppress the harmful, unwanted inflammation. To that end, one can find a great deal of research similar to that summarized in today's open access review paper, digging into the regulation of inflammation in search of novel targets for anti-inflammatory treatments.

MicroRNA-7: A New Intervention Target for Inflammation and Related Diseases

MicroRNAs (miRNAs) are a class of small noncoding RNA that can regulate physiological and pathological processes through post-transcriptional regulation of gene expression. As an important member of the miRNAs family, microRNA-7 (miR-7) was first discovered in 2001 to play an important regulatory role in tissue and organ development. Studies have shown that miR-7 participates in various tissue and organ development processes, tumorigenesis, aging, and other processes by regulating different target molecules. Notably, a series of recent studies have determined that miR-7 plays a key regulatory role in the occurrence of inflammation and related diseases. In particular, miR-7 can affect the immune response of the body by influencing T cell activation, macrophage function, dendritic cell (DC) maturation, inflammatory body activation, and other mechanisms, which has important potential application value in the intervention of related diseases.

Under normal circumstances, inflammation is a physiological defense response of the body to stimulation, involving a complex and fine-tuned regulatory process that is conducive to eliminating pathogens and promoting tissue repair. It is now known that the inflammatory process is closely related to the body's innate and adaptive immune responses, involving the activation and function of innate immune cells, such as macrophages and DCs, and adaptive immune cells, such as T cells and B cells. However, if the immune response process is abnormal, the continuous development of inflammation can lead to autoimmune or inflammatory diseases, neurodegenerative diseases, and even cancer. The inflammatory response involves innate and adaptive immune response processes mediated by immune cells with the participation of histiocytes and molecules. Therefore, the regulatory mechanisms involved in the development of inflammation and related diseases are very complex. The analysis of these mechanisms is of great significance for understanding the mechanisms of related diseases and clinical treatment.

This article reviews the current regulatory role of miR-7 in inflammation and related diseases, including viral infection, autoimmune hepatitis, inflammatory bowel disease, and encephalitis. It expounds on the molecular mechanism by which miR-7 regulates the occurrence of inflammatory diseases. Finally, the existing problems and future development directions of miR-7-based intervention on inflammation and related diseases are discussed to provide new references and help strengthen the understanding of the pathogenesis of inflammation and related diseases, as well as the development of new strategies for clinical intervention.

It is well known that the aging of the vasculature contributes to the aging of the brain. The brain requires a great deal of energy to operate, and the nutrients and oxygen needed for optimal brain metabolism are supplied in the bloodstream. With age, capillary density declines, the heart becomes weaker, and blood vessels are narrowed by the development of atherosclerotic lesions. All of this combines to reduce the delivery of nutrients to the brain, and its metabolism suffers as a result. Here, researchers present additional evidence to support this view of the impact of cardiovascular aging on brain aging.

Cardiovascular disease and dementia frequently occur together in elderly people. Nevertheless, few longitudinal studies have examined how atherosclerosis and its associated risk factors affect brain health from middle age. Now, a new study provides data on this relationship; the results confirm the importance of controlling traditional cardiovascular risk factors, such as hypertension, cholesterol, diabetes, smoking, and a sedentary lifestyle, not only to preserve cardiovascular health, but also to prevent Alzheimer's disease and other dementias.

In 2021,scientists discovered that the presence of cardiovascular risk factors and subclinical (presymptomatic) atherosclerosis in the carotid arteries (the arteries that supply the brain) was associated with lower glucose metabolism in the brains of apparently healthy 50-year-old participants in the PESA-CNIC-Santander study. Glucose metabolism in the brain is considered an indicator of brain health. Glucose is the main energy source for neurons and other brain cells. The PESA-CNIC-Santander study is a prospective study that includes more than 4,000 asymptomatic middle-aged participants who have been exhaustively assessed for the presence and progression of subclinical atherosclerosis since 2010.

Researchers have continued to monitor the cerebral health of these participants over 5 years. Their research shows that individuals who maintained a high cardiovascular risk throughout this period had a more pronounced reduction in cerebral glucose metabolism, detected using imaging techniques such as positron emission tomography (PET). "In participants with a sustained high cardiovascular risk, the decline in cerebral metabolism was three times greater than in participants who maintained a low cardiovascular risk. The individuals showing this metabolic decline already show signs of neuronal injury."

Link: https://www.cnic.es/en/noticias/lancet-healthy-longevity-early-action-control-cardiovascular-risk-factors-preserves-brain

Researchers here report on the characterization of a stem cell population in the adult thymus that gives rise to the thymic epithelial cells that allow the thymus to host the development of T cells of the adaptive immune system. This is of interest because the thymus atrophies with age, losing active thymic epithelial tissue. The supply of new T cells provided to the immune system diminishes greatly as a consequence, and this is a major contributing factor in the age-related decline of immune function. It is the case that cell therapy approaches are one of the potential ways in which an aged thymus might be regenerated, and the discovery of a stem cell population associated with this tissue can only help these efforts.

The thymus is necessary for lifelong immunological tolerance and immunity. It displays a distinctive epithelial complexity and undergoes age-dependent atrophy. Nonetheless, it also retains regenerative capacity, which, if harnessed appropriately, might permit rejuvenation of adaptive immunity. By characterizing cortical and medullary compartments in the human thymus at single-cell resolution, in this study we have defined specific epithelial populations, including those that share properties with bona fide stem cells (SCs) of lifelong regenerating epidermis.

Thymic epithelial SCs display a distinctive transcriptional profile and phenotypic traits, including pleiotropic multilineage potency, to give rise to several cell types that were not previously considered to have shared origin. Using here identified SC markers, we have defined their cortical and medullary niches and shown that, in vitro, the cells display long-term clonal expansion and self-organizing capacity. These data substantively broaden our knowledge of SC biology and set a stage for tackling thymic atrophy and related disorders.

Link: https://doi.org/10.1016/j.devcel.2023.08.017

Not all tissues are equal in their energy needs. The brain and more consistently active muscles, such as the heart, are at the top of the list. Energy for cell and tissue processes is provided by the chemical energy store molecule adenosine triphosphate (ATP), which is produced by mitochondria. Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now evolved to become fully integrated cell components. Mitochondria still replicate much like bacteria, each containing a small remnant circular genome. When damaged or dysfunctional, mitochondria are cleared by the complex process of mitophagy, a mitochondrially targeted form of autophagy that recognizes impaired mitochondria and ensures that they are transported to a lysosome for disassembly.

Unfortunately, mitochondria become dysfunctional with age in ways that can (a) promote inflammation, such as via escape of mitochondrial DNA into the cytoplasm where it can trigger defenses that evolved to identify bacterial DNA, and (b) reduce ATP production. Epigenetic changes affect the dynamics of mitochondrial fusion and fission in ways that impair mitophapy. Similarly, epigenetic change leads to a decline in autophagy in general with age. Worn and damaged mitochondria accumulate as a result. Further, mitochondrial DNA is less well protected and repaired than is the case for nuclear DNA. Damage to mitochondrial DNA can disrupt ATP production and in extreme cases produce broken mitochondria that can outcompete their undamaged peers, replicating to overtake a cell. All of this arguably produces the worst outcomes in tissues like the heart and brain, where the demand for ATP is the highest.

Cardiovascular aging: the mitochondrial influence

The beating heart is a highly energy-consuming organ and the cellular energy needed to sustain contraction is primarily generated by mitochondrial oxidative phosphorylation (OXPHOS). Mitochondria are also involved in supporting various metabolic processes, as well as activation of the innate immune response and cell death pathways. Thus, the heart is highly susceptible to the effects of mitochondrial dysfunction. Mitochondria have been directly implicated as underlying drivers of cardiac aging. Studies have reported that the age-related decline in cardiac function is partly attributed to dysregulation of mitochondrial function and a decline in mitochondrial quality control. The aged heart accumulates dysfunctional mitochondria that are deficient in ATP generation and become major sources of reactive oxygen species (ROS) and oxidative stress. Interestingly, various interventions or treatments that directly or indirectly target mitochondria to reduce ROS generation, promote oxidative metabolism or enhance quality control have all been demonstrated to delay cardiac aging and alleviate disease development.

Currently, effective treatments to prevent age-related cardiovascular dysfunction are lacking, but there is a strong interest in developing therapeutics that are aimed at preserving or improving mitochondrial health in cells. Many interventions that protect against cardiac aging, including caloric restriction, exercise, and nicotinamide riboside, spermidine or rapamycin treatments, are mediated at least in part through the preservation of mitochondria. Pre-clinical studies clearly suggest that directly targeting mitochondrial ROS production or enhancing repair and turnover may have promising therapeutic benefits in the aging heart. For example, administration of the mitochondria-targeted antioxidant MitoTEMPO to aged mice reduces oxidative stress and improves systolic and diastolic function, while MitoQ administration ameliorates vascular endothelial dysfunction in aged mice. Treatment of aged mice with the mitochondrially-targeted tetrapeptide SS-31 (elamipretide) for 8 weeks leads to reduced oxidative stress in hearts with improvements in cardiac function and reversal of cardiac hypertrophy.

There is also great interest in developing small molecules that can directly activate mitophagy in cells. VL-004 is a small molecule that increases mitophagy and longevity in C.elegans via dct-1, the worm homolog of mammalian mitophagy receptors Bnip3 and BNIP3L/NIX. VL-004 failed to extend lifespan in dct-1 mutant worms, confirming that the effect on lifespan extension is dependent on mitophagy. Although these studies targeting mitophagy are promising, whether the beneficial effects are preserved in larger organisms remains to be investigated.

Due to the longer lifespan in the population, treatments that prevent late-life morbidities and increase healthspan are urgently needed. Dysfunctional mitochondrial are clearly major contributors to cardiac aging. Although rejuvenating mitochondria to reverse or prevent aging by directly targeting mitochondrial ROS or activating mitophagy seems to have anti-aging benefits, these interventions are not without risks. ROS also function as signaling molecules in cells and complete suppression of mitochondrial ROS has adverse effects on heart function. Similarly, too much activation of mitophagy can lead to excessive clearance of mitochondria. If the clearance exceeds the cells' capacity to generate new mitochondria, it can lead to a catastrophic energy deficiency. Thus, the therapeutic window of these interventions needs to be clearly defined.

Perhaps the most important challenge in the field of regenerative medicine is to enable engraftment and survival of transplanted cells, allowing new cell populations to replace those made damaged or dysfunctional due to age, injury, or other causes. Despite some advances, survival of transplanted cells remains a significant challenge. Here is one example of signs of progress on this front, however. Judging by the recent past, solutions discovered by researchers are likely to continue to be tissue specific. This implies that a great deal more work lies ahead in order to build a usefully broad toolkit to allow creation and transplantation of suitable cells for all of the major tissues of interest, such as heart, lung, kidneys, liver, and so forth.

Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells.

After months in vivo, donor-derived cells retain their mature phenotypes, as characterized by single-cell RNA sequencing (scRNA-seq), histologic profiling, and functional assessment that demonstrates continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung's facultative progenitor and differentiated epithelial cell compartments with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy that can be utilized to better understand the mechanisms and utility of engraftment.

Link: https://doi.org/10.1016/j.stem.2023.07.016

Researchers here report on a drug discovery effort targeting PU.1, a gene implicated in increased inflammation of microglia in the brain. Microglia are innate immune cells of the central nervous system. Like macrophages in the rest of the body, they react to the damage and dysfunction of aging with increased inflammatory behavior, a maladaptive response that worsens pathology. Chronic, unresolved inflammation is clearly disruptive to tissue function wherever it occurs in the body. In the brain, chronic inflammation is a well-studied feature of conditions such as Alzheimer's disease. A greater population of inflammatory microglia is characteristic of aging and neurodegenerative conditions, and the research community is increasingly interested in finding ways to address this issue.

A 2015 study implicated PU.1 as a regulator of errant microglia inflammation in a mouse model of Alzheimer's disease. Genetically knocking down PU.1 in the body is not a viable therapeutic strategy given its importance in normal healthy function. Researchers therefore screened more than 58,000 small molecules from libraries of FDA-approved drugs and novel chemicals to see if any could safely and significantly reduce key inflammation and Alzheimer's related genes regulated by by PU.1 in cell cultures. After several rounds of increasingly stringent screening, they narrowed the field down to six chemicals. A11 was by far the most potent among them.

Researchers tested the effects of A11 doses on the function of human microglia-like cells cultured from patient stem cells. When they exposed the microglia-like cells to immune molecules that typically trigger inflammation, cells dosed with A11 exhibited reduced expression and secretion of inflammatory cytokines and less of the cell body shape changes associated with microglia inflammatory responses. The cells also showed less accumulation of lipid molecules, another sign of inflammatory activation. Looking at gene expression patterns, the scientists observed that A11-treated cells exposed to inflammatory triggers behaved much like unperturbed microglia, suggesting that A11 helps prevent microglia from overreacting to inflammatory cues.

In a new paper, researchers started with experiments to further validate that PU.1 would be a therapeutically meaningful target. To do that the scientists compared gene expression in immune cells of postmortem brain samples from Alzheimer's patients and mouse models and matching non-Alzheimer's controls. The comparisons showed that Alzheimer's effects major changes in microglial gene expression and that an increase in PU.1 binding to inflammatory gene targets was a significant component of that change. Moreover, they showed that reducing PU.1 activity in a mouse model of Alzheimer's reduced inflammation and neurodegeneration, the death of neurons.

Two more lab tests aimed at understanding how A11 exerts its effects revealed that it doesn't change PU.1 levels. Instead it counteracts PU.1 activity by recruiting several proteins including MECP2, HDAC1, SIN3A and DMNT3A, known to repress expression of its targets. Essentially amid Alzheimer's disease, A11 tamps down what PU.1 amps up.

Link: https://picower.mit.edu/news/molecule-reduces-inflammation-alzheimers-models

The article I'll point out today is an entirely unremarkable, high level tour of the most discussed, most notable portions of the longevity industry and related research efforts. Twenty years ago, we'd all have been delighted to see the media both noticing translational aging research at all, and then actually taking seriously the prospect of treating aging as a medical condition. We've come a long way to now see summary discussions of work on the treatment of aging as business as usual, not really worth mentioning. Still, articles like this miss near all of the really interesting projects, and that is the way of high level overviews. What is most talked about today is only rarely what is most important tomorrow, or at least given a few years to see how and where the dust settles.

Articles of this sort also tend to feature people who believe that only marginal progress towards greater longevity is possible in the foreseeable future; that may or may not be true, but to even answer that question a great deal more support for clinical trials of presently available options is required. The first viable senolytic drugs have been known for going on a decade, low-cost and readily available for anyone who wants to try them. Yet there is no rush to run clinical trials that would answer whether or not they are as impressive in human aging as they are for mice, and the vast majority of older people have no idea that this option is even on the table.

Interested in living healthier longer? Longevity science explained

After age 65, most people have two or more chronic diseases. U.S. adults in their 60s and 70s take up to five different prescription medications at a time. And what helps one condition may worsen another. At about 76, the U.S. life expectancy, the adult will probably die from one of these diseases. All of these chronic conditions share a risk factor: age. It may be the process of aging itself that makes us vulnerable to these diseases, which affects our health span (how long we stay healthy) and life span (how long we live.) As we get older, we lose strength and mobility as our bodies undergo molecular changes that eventually undermine their integrity and resiliency. Scientists refer to these changes as hallmarks. These include chronic inflammation and the accumulation of senescent cells that stop multiplying because of damage or stress but don't die as they are supposed to.

Some researchers believe that through addressing aging itself, diseases related to aging can be pushed back and possibly prevented. This would mean living healthier, longer. "The important implication is that we can study the biology of aging, start to learn about it and we have a potential to intervene in that biology to have a positive impact on disease outcomes and health." The field is known by many names: longevity, geroscience, anti-aging. Regardless of the name, it's still in the early stages. Several drugs may have the ability to postpone or prevent the onset of debilitating diseases. Animal studies have demonstrated their potential, and now clinical trials are beginning to assess whether their promise holds true in humans. "I think it's certainly legitimate to ask why we haven't done that previously. And in part it's because we really haven't had the knowledge base to be able to do that."

One promising drug is rapamycin. It's an antifungal approved by the FDA as an immune suppressor to prevent organ recipients from rejecting a new organ. Rapamycin inhibits a protein called mechanistic target of rapamycin (mTOR). The protein senses nutrients and then controls cell outputs regulating many processes in the cell. Giving rapamycin to yeast, worms, flies and mice prolonged their lives, studies have shown. Scientists began exploring rapamycin's anti-aging effects in people, and studies suggest this immune-suppressing compound can actually improve immune function in older adults boosting their response to flu shots and lowering their odds of getting severely ill during cold and flu season.

As we age, immune function both declines and increases. Though the ability of our immune system to respond to pathogens declines, it can also overreact by striking in the absence of any threat. This can result in healthy tissues and organs being attacked, which can lead to chronic inflammation linked with various kinds of diseases. So, what is causing the inflammation itself? One possible culprit is senescent cells that stop dividing but don't die. They accumulate as we get older and give off inflammatory signals, which contribute to some age-related diseases.

If a drug is ever to be used as an anti-aging therapy, it'll need to be tested in healthy people who are aging naturally the way that new drugs for a certain illness are tested on people who have that disease. However, aging isn't officially defined as a disease. One clinical trial aims to prove that aging is something that can be targeted and treated. It involves metformin, long used to treat Type 2 diabetes. In a trial called Targeting Aging With Metformin (TAME), researchers will track 3,000 adults 65 to 80, who will take the drug for six years. The goal is to see if metformin can prevent or delay three age-related diseases: dementia, heart disease, and cancer. This will show if metformin can increase health span. If the trial succeeds, it may show that drugs to target aging don't need to be expensive and can be available to more people, not just the rich.

An interesting question is posed here by some of the researchers responsible for creating plastoquinone mitochondrially-targeted antioxidants. To what degree do mitochondrially-targeted antioxidants improve mitochondrial function and modestly slow aging by preventing cardiolipin oxidation? Past a certain level of detail, less is known of mitochondrial biochemistry than one might think. This organelle is very well studied, but it is still the case that many approaches known to improve mitochondrial function are incompletely understood, or only understood in outline. It is clear that the mitochondrial generation of reactive oxygen species is a problem that increases alongside mitochondrial dysfunction with age, but down in the depths of the interaction of many different molecules there is room for argument and opinion regarding how it all actually works in practice.

Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function (6), which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation.

Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.

Link: https://doi.org/10.3390/ijms241612540

Neural stem cells produce the new neurons necessary for memory function and maintenance of brain tissue throughout adult life. This process of neurogenesis declines with age, however. Neural stem cell activity is reduced with age, in much the same way as all stem cell populations (and their niche structures) appear to become damaged and impaired as a result of the mechanisms of aging. Do we know enough about the way in which neural stem cells age in order to attempt prevention? As researchers point out here, some strategies may make the situation worse by exhausting rather than renewing stem cell pools. A few inroads are being made, however.

Extensive research in recent years has significantly advanced our knowledge of the mechanisms underlying neural stem cell (NSC) aging and age-related decline in neurogenesis, although much remains obscure. Central to this decline is an escalating impairment of the NSC pool, characterized by increased quiescence, altered lineage specification, and progressive depletion of NSCs. The mechanisms underlying NSC aging in the dentate gyrus (DG) are complex and multifactorial. Over the course of their life, NSCs accumulate several defects, including a failure to maintain a healthy proteome, metabolic alterations, DNA damage, and epigenetic drift. It is now recognized that, in addition to intrinsic mechanisms, extrinsic changes in the NSC niche and systemic environment are the primary contributors to NSC aging, and that these mechanisms are not mutually exclusive, but rather interrelated and interacting with each other.

To safeguard the NSC pool from depletion, it is vital to gain a comprehensive understanding of the cellular and molecular mechanisms regulating NSCs and their aging. The advent of innovative new techniques such as single-cell RNA sequencing and spatial transcriptomics holds immense potential for unravelling the full complexity of the mechanisms involved in the declining capacities of NSCs during aging. Other technologies, such as CRISPR-Cas or adenovirus-mediated gene transfer, enable diverse types of gene function screens, facilitating the exploration of molecular interdependencies and their impact on NSC aging. Understanding the mechanisms that control NSC functions and their aging holds potential for the identification of novel therapeutic targets to either slow the aging process or rejuvenate aged NSCs, thereby enhancing the regenerative and cognitive capacities of the aging hippocampus.

Preventively, simple interventions with few side effects, such as diet or exercise, are particularly promising. Curatively, it becomes more difficult, as the interventional activation of NSCs usually leads to premature exhaustion and accelerated depletion of the pool. However, recent findings that have been able to identify targets whose manipulation increases the self-renewal of NSCs in the aged DG without accelerating their depletion (VEGF, combination of Plagl2 with anti-Dyrk1a) give cause for optimism.

Link: https://doi.org/10.3390/cells12162086

Are beneficial effects of transfusion of blood fractions from young individuals to old individuals observed in animal studies the result of transferring the contents of extracellular vesicles rather than any signal molecules not packaged into a vesicle? While considering this question, it is worth noting that transfusion of plasma has quite mixed outcomes in both mice and humans. It doesn't appear to be a good approach to therapy, based on the results to date.

This is unlike the robust benefits produced in old animals by heterochronic parabiosis, linking the circulatory system of an old and a young mouse. In a parabiosis study, the old mouse is getting a great deal more of everything that might be found in young blood than is the case in even repeated transfusions employed as therapy. At the same point in time potentially harmful components of old blood are being (a) diluted, and (b) passed through young kidneys, liver, and other organs that might remove them. These latter aspects of parabiosis do not occur in transfusion, and at present there is some debate as to whether there are any meaningfully beneficial factors to be found in young blood fractions.

In today's open access paper, researchers describe transfusion of serum rather plasma from young animals to old animals, and provide data to suggest that it is the contents of the extracellular vesicles in serum that mediate beneficial effects. It is worth noting that extracellular vesicles will be present in all blood fractions unless deliberately filtered out. Blood fractionation is accomplished via centrifugation, so it is possible that there is some biasing of vesicles to one fraction or another based on size. Otherwise, the same arguments might be applied to serum transfusions as to plasma transfusions; despite the existence of some studies in which benefits were shown, the data in aggregate doesn't make this appear to be a good basis for therapy.

Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice

The conventional wisdom is that a better understanding of the myriad roles of extracellular vesicles (EVs) in central nervous system (CNS) homeostasis is essential for developing novel therapeutics to alleviate and reverse the neurological disturbances of aging. Thus far, an increasing number of studies have revealed the complexities of EV-mediated cell-cell communications in the brain, predominantly emphasizing the role of EV released by brain cells under physiological conditions. It has been well established that EVs can cross brain barriers such as the blood-brain barrier (BBB) and brain-cerebrospinal fluid (CSF) barrier (BCsfB).

If isolated from CSF and plasma, brain EVs provide an array of options with which to learn about normal brain functions and monitor changes in the brain associated with aging or neurodegenerative pathology. Since humoral factors can enter the brain at the BBB and BCsfB, in vivo models, for example, heterochronic parabiosis (HB), heterochronic blood exchange (HBE), and infusions of small volumes of plasma or serum, have been used to uncover and better understand the role of those factors in aging and age-related diseases. Recently, using infusions of small volumes of serum, we evaluated the contribution of circulating EVs to the beneficial effect of young serum on aged muscle stem cell (MuSC) function and the skeletal muscle regenerative cascade. We demonstrated that young serum restored a youthful bioenergetic and myogenic profile to old muscle cell progeny and that this effect was dependent on circulating EVs. Yet, the full spectrum of effects of circulating young EVs on aged organs and tissues, including the brain, remains poorly understood.

In this study, we examined the effect of young serum on the cognitive performance of aged mice. We show that repeated infusions with small volumes of young serum significantly improved age-associated memory deficits and this effect was abrogated after the serum was depleted of circulating EVs. RNA-seq analysis of choroid plexus demonstrated effects on genes involved in barrier function and trans-barrier transport. Interestingly, the hippocampal transcriptome demonstrated a significant upregulation of Klotho (Kl) gene, which codes for the longevity protein Klotho, following young serum treatment. Notably this effect was abrogated after serum EV depletion, suggesting that EVs may serve as vehicles for Klotho messages from the periphery to the brain. Given the well-established role of Klotho in cognitive functioning, we performed transcriptional profiling of Klotho knockout (Klko) and Klotho heterozygous (Klhet) mice and found an association with downregulated categories such as transport, exocytosis, and lipid transport, while upregulated genes were associated with microglia.

To test if changes in transcriptomes represent transcriptomic rejuvenation, we correlated the transcriptomes of the treated mice to the most recently published chronological aging clocks, which revealed a reversal of transcriptomic aging in the choroid plexus. The results of our study indicate that further evaluation of EVs as vehicles for delivering signals from the periphery to the brain and coordinating the responses of different brain regions will open new avenues with which to expand the research and to better understand aging and rejuvenation.

This open access paper tours a number of the present approaches under development to the treatment of aging as a medical condition, dwelling the most on therapies targeting senescent cells, either for destruction or to suppress the harmful senescence-associated secretory phenotype. We live in an exciting time of great potential, an age of accelerating progress in the capabilities of medical biotechnology, though it remains the case that too few people realize just how close we are to the widespread use of the first practical rejuvenation therapies.

Aging poses one of the greatest challenges for modern medicine, as it is a major risk factor for chronic diseases such as cancer, cardiovascular and neurodegenerative diseases. As the global population continues to age, there is an urgent need to develop effective interventions and diagnostic tools to prevent illness and extend a healthy lifespan, thereby reducing the burden of age-related diseases on healthcare systems.

Most basic research on aging is focused on identifying mechanisms contributing to this trait. Several hallmarks/pillars of aging have been defined and summarize the main processes underlying aging. Although these definitions are still suboptimal, they provide a nice framework used by many groups in the field to define which aspects of aging their research is focused on. One approach is to target the driving mechanisms of aging, like impaired autophagy and senescence. Inactivation of the mTOR pathway by interventions such as dietary restriction or with small molecule inhibitors like rapamycin, results in autophagy de-repression and lifespan extension (in fruit flies, worms, and mice). Extensive data suggest that rapamycin and rapalogs may have positive effects on age-related conditions and possibly on human longevity.

Cellular senescence is another potentially druggable mechanism that has been much 'in focus' to try to prevent or treat many age-associated pathologies, including cardiovascular, cerebrovascular, neurodegenerative, metabolic, and malignant diseases. Accumulated senescent cells (SenC) have deleterious effects due to the induced proinflammatory microenvironment that supports chronic low-grade inflammation ('inflammaging') and possible tumor development, and accelerate other aging mechanisms which will progress concomitantly. The depletion of SenC in aged organisms, either via genetic ablation or pharmacologically with senolytics, may have therapeutic benefits by alleviating a series of age-associated comorbidities and thus improving healthspan and even lifespan, as shown in lower organisms.

By now, research and development in the biology of aging have moved to the mainstream with initiatives by large pharmaceutical companies and funds, highlighting the growing interest in geroscience and the development of interventional gerotherapeutics. On the financing side, players like Altos Labs and Hevolution have entered the field, looking to deploy massive amounts of capital to accelerate research and commercial product development. These initiatives reflect the increasing recognition of the potential commercial impact of anti-aging therapies on healthcare and society.

Link: https://doi.org/10.1111/jcmm.17912

Age-related disease places a huge financial burden on individuals and their caregivers; even the need for caregivers arises only because aging produces disability. Even only considering cardiovascular disease, the largest contribution to human mortality, the costs are enormous. This is a point often made by advocates arguing for greater institutional funding of ways to treat aging. Present levels of funding for research and development of means to reduce age-related disease are very low in comparison to the massive ongoing costs that result from age-related disease. It makes little sense for this to be the case in an age of rapid progress in biotechnology, but nonetheless it is the case that vastly more funding is devoted to novel approaches in war, sports, and video games than towards improving medical technology.

Cardiovascular disease (CVD) cost the EU an estimated €282 billion in 2021, according to late breaking research presented at ESC Congress 2023. Health and long-term care accounted for €155 billion (55%) of these costs, equalling 11% of EU health expenditure. "CVD had a significant impact on the EU27 economy, costing a total of €282 billion in 2021. That's equivalent to 2% of Europe's GDP and is significantly more than the entire EU budget itself, used to fund research, agriculture, infrastructure and energy across the Union. By choosing not to invest in cardiovascular disease we are simply deferring the cost. This data forces us to ask the question: do we invest in cardiovascular health today or be forced to pay more at a later stage?"

This was the most comprehensive and up-to-date analysis of the economic costs of CVD to society in the EU since 2006. It is the first study to use Europe-wide patient registries and surveys rather than relying on assumptions and, unlike previous reports, includes the costs of long-term social care. The current analysis provides estimates of the societal economic costs of CVD for the 27 members states of the EU in 2021, including 1) health and social care; 2) informal care; and 3) productivity losses. The breakdown includes: €130 billion for healthcare (46%); €25 billion for social care (9%); €79 billion for informal care (28%); €15 billion in productivity losses due to illness/disability (5%); €32 billion in productivity losses due to premature death (12%). The total cost equated to €630 per EU citizen, ranging from €381 in Cyprus to €903 in Germany.

Healthcare included primary care, emergency care, hospital care, outpatient care and medications, while social care included long-term institutionalised care, and care at home. The main contributor was hospital care, which cost €79 billion, representing 51% of CVD-related care costs. CVD medications accounted for €31 billion (20%) of care costs, followed by residential nursing care homes at €15 billion (9%). Informal care costs included the work or leisure time, valued in monetary terms, that relatives and friends gave up to provide unpaid care. Relatives and friends provided 7.5 billion hours of unpaid care for patients with CVD, amounting to €79 billion across the EU.

Link: https://www.eurekalert.org/news-releases/999753

Neurogenesis is the process by which new neurons are created by neural stem cells, thereafter maturing and integrating into existing neural circuits. This is most studied in the hippocampus, where continual change in the circuits of the brain is essential to memory. With age, the pace of neurogenesis declines, as one might expect given what is known of the progressive loss of stem cell activity in later life. This is thought to contribute to cognitive decline in general, and to loss of memory function specifically.

In today's open access paper, researchers report on a study in which they disabled neurogenesis in mice to observe the resulting loss of memory function. Along the way they found evidence for a compensatory process that operates when neurogenesis falters, but operates poorly. The process can be dramatically improved by provoking a greater secretion of stored acetylcholine. This prevents loss of memory function, despite the continued lack of neurogenesis. As the researchers point out, success in restoring memory in mice via this approach is unexpected, given that efforts to increase levels of acetylcholine, via acetylcholinesterase inhibitor drugs that block the degradation of acetylcholine, failed to produce meaningful gains in memory function. Clearly the underlying biochemistry is complex.

Baby Neurons in Adult Brains Are Needed to Maintain Memory

Researchers estimate that the brain's hippocampus - which plays a key role in memory, learning, and emotion - makes about a thousand new neurons each day throughout adulthood. "Considering that the brain contains about 100 billion neurons, it's reasonable to question whether this level of neurogenesis could have any impact on brain function. But over the life of the animal, the effects of these new cells can add up as they make connections with other neurons and other parts of the brain."

To test whether adult neurogenesis is vital to brain health over the long term, the team stopped the process in adult mice by irradiating the birthplace of new neurons or with genetic engineering. Over time, the mice produced less and less of the neurotransmitter acetylcholine in the hippocampus, leading to a profound rewiring of a brain circuit critical for memory. The mice also experienced a slow but progressive decline in working memory (temporary "sticky notes" for carrying out mental tasks). Remarkably, while neurogenesis was suppressed immediately after treatment, the memory, anatomic, and biochemical changes took five months (about a quarter of the mouse life span) to emerge.

Even though the brain circuit changed in a way that impaired memory, the circuit did form new, but dysfunctional, connections that could be recruited to improve memory."It was as if existing neurons were trying, but failing, to compensate for the loss of neurogenesis and what started out as a subtle defect in acetylcholine, and they just needed a little nudge." The researchers suspected that the remodeled circuit had sufficient reserves of acetylcholine but couldn't release it when needed. Using a drug, the researchers nudged the circuit to release more acetylcholine and completely rescued the memory deficits even in aged mice.

"The results suggest that we have to revisit old notions about the aging brain. It seems to be more plastic than we've thought." Cholinesterase inhibitors have been used to treat patients with Alzheimer's disease, with little success. "We think this drug, and many others, have failed because they're focused on one type of cell or molecule. What our findings tell us is that we probably need to address the fact that the whole memory circuit is compromised in aging and dementia."

Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits.

These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

Macrophages of the innate immune system can adopt a variety of behavior packages in response to circumstances. The most commonly studied are M1 (aggressive and inflammatory) versus M2 (anti-inflammatory and regenerative), as these capture two of the most interesting aspects of these immune cells. Macrophages hunt and destroy pathogens and rogue cells in their M1 form, but also participate in tissue maintenance and repair in their M2 form. A sizable number of research and development programs are based on ways to persuade M1 macrophages in injured tissues to switch into the M2 phenotype, resulting in improved regeneration and reduced harmful inflammation. Here, researchers show that their approach to this switching of phenotype can improve outcomes in a rat model of heart attack.

The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established.

In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation.

Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.

Link: https://doi.org/10.1002/adfm.202210864

A downward trend in cardiovascular mortality has prevailed for some time now, and we might take the data here as an example of ways in which improved options for detection and treatment produce results in specific portions of the patient population. Also worthy of note is the point that these older patients have many issues, and while slowing the pace of cardiovascular decline with age should have beneficial effects throughout the body, reduced cardiovascular mortality due to improved treatment that specifically focuses on cardiovascular disease allows other age-related conditions to claim a greater proportion of the population.

The research examined data from electronic health records of 72,412 patients from a representative sample of the UK population, who had been diagnosed with atrial fibrillation (AF) between 2001 and 2017. The team assessed the health outcomes in patients in the first year after their AF diagnosis, and analysed changes in cause-specific mortality and hospitalisation over time and by sex, age, socioeconomic status, and diagnostic care setting. The average patient was aged 75.6. Some 48.2% of patients were women, and 61.8% had three or more comorbidities. Over the study period, coexisting health concerns became more common, with almost 70% of newly diagnosed AF patients also having at least three comorbidities. Mortality rates at one year post diagnosis were investigated, as well as the number of hospital admissions with an overnight stay within 1 year of diagnosis.

Over the study period, 20% of patients died from any cause within a year of being diagnosed with AF - but this declined over time. However the researchers found that deaths due to cardiovascular and cerebrovascular events (strokes) more than halved over the study period. Cardiovascular deaths declined from 7.3% in 2001/02 to 3% in 2016/2017, while cerebrovascular deaths declined from 2.6% to 1.1%. The researchers say that the lower rates of cardiovascular deaths among AF patients in the study may be partly explained by improvements in strategies to prevent heart disease, and by changes in clinical practice that could lead to people being diagnosed earlier.

By contrast, there was an increase in mortality rates from mental and neurological disorders, from 2.5% in 2001/02 to 10.1% in 2016/17. Of these deaths, 87.2% were caused by dementia, Alzheimer's disease, and Parkinson's disease. The research team say that while this could be partly due to greater awareness of dementia, it also strengthens the evidence that the relationship between AF and dementia is a pressing research priority.

Link: https://medicinehealth.leeds.ac.uk/medicine/news/article/636/half-as-many-atrial-fibrillation-patients-dying-of-heart-attacks-and-strokes