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