Fight Aging!

Why are long-lived individuals long-lived? While some evidence suggests that cultural transmission of beneficial lifestyle choices across generations might explain much or all of the phenomenon of long-lived families, and continued examination of large databases of genetic information has tended to reduce the estimated contribution of genetic variants to life expectancy, there continue to be studies demonstrating that older cohorts exhibit fewer of the long list of mutations and variants known to be disadvantageous. The implication here is that small reductions in mortality add up over time and over large populations. The older the population, the greater the odds that any given member will have more beneficial gene variants and fewer harmful gene variants. The effect size for any given variant when it comes to mortality risk does not have to be large for this to be the case.

Given that the effect size for a given gene variant is typically small, and indeed the discovery of a variant that moves average life expectancy by a year or more is big news, is there really much to be gained from the exploration of the genetics of extremely long-lived people? So far the results seem to bear out the pessimistic viewpoint: that this is probably helpful to those working on the long, long road ahead to a complete map of metabolism, how it changes with age, and how that all maps to health outcomes, but that we should not expect useful therapies to slow aging to emerge from this part of the field.

Depletion of loss-of-function germline mutations in centenarians reveals longevity genes

While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data.

In this study, we have discovered that centenarians, within the large cohort we examined, possess a significantly lower burden of predicted deleterious LOF variants compared to controls. This finding suggests that a protective genetic background, characterized by the depletion of damaging coding mutations, contributes to the exceptional longevity of centenarians. Notably, we also observed a lower mutation burden in centenarian offspring, although the effect was less pronounced. These findings support the notion of a heritable component to longevity outside of protective and common variants and suggest that the combined genetic background, including protective variants and depletion of damaging variants, may be transmitted across generations to support exceptional longevity.

Our pathway analysis revealed that centenarian exomes are depleted of LOF variants in several pathways related to aging and disease, including Class A/1 (Rhodopsin-like receptors), hyaluronan metabolism, post-translational protein modification, and mitochondrial translation. Class A/1 (Rhodopsin-like) receptors are involved in various physiological processes and have been implicated in age-related diseases, suggesting their potential role in longevity. Hyaluronan is a key component of the extracellular matrix that has been shown to decline with age, and its increase contributes to the extension of lifespan. Variants that maintain hyaluronan homeostasis may, therefore, promote healthy aging in humans. Post-translational protein modifications play crucial roles in protein function and stability, and their dysregulation has been associated with various age-related diseases. Mitochondrial translation has also been linked to lifespan extension in model organisms.

To complement our analysis of rare LOF variants, we also investigated the causal role of identified longevity genes in aging-related traits using Mendelian randomization (MR) analyzes. This approach allows us to infer potential causal relationships between gene expression and phenotypes of interest by using expression quantitative trait loci, eQTLs (common variants that are associated with gene expression) as instrumental variables. Our MR analyzes provided evidence for the causal effects of several longevity-associated genes, including RGP1, PCNX2, and ANO9, on multiple aging-related traits. PCNX2 was identified to be associated with longevity in an independent genome-wide association study, while ANO9 was associated with various cancers. These findings suggest that these genes may directly influence the aging process and contribute to the extended healthspan and lifespan. The consistent causal effect estimates across different aging-related traits further support the robustness of these associations.

Inadvertent and deliberate breeding programs in domesticated animals have engineered great diversity into single species. Different breeds of dogs exhibit radically different life spans, for example, and this natural experiment may allow some insight into the relative importance of various mechanisms of aging. Research suggests that transposon activity is an important factor in determining the longevity of a dog breed, as outlined here. Transposons are relics of ancient viral infections, DNA sequences capable of hijacking cell machinery to copy themselves across the genome. In youth, transposon activity is suppressed, but with advancing age their activity increases as a consequence of epigenetic changes, acting as a source of mutational damage and disruption of cell activities.

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project.

Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age. This LINE1 pattern differed in magnitude across breeds of different sizes - the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species.

Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of inter-species, demographic-dependent aging variation.

Link: https://doi.org/10.1101/2024.10.08.617286

Near all patients exhibiting type 2 diabetes have the condition as a result of being overweight. Losing weight will improve the diabetic metabolism; studies have shown that type 2 diabetes is reversible even into fairly late stages. The primary outcome of taking GLP-1 receptor agonists such as semaglutide is weight loss. Excess visceral fat in individuals who are overweight or obese contributes to chronic inflammation and a variety of other mechanisms that are known to accelerate the onset and progression of age-related disease. The brace of recent papers lauding GLP-1 receptor agonists as treatments for age-related disease, focusing heavily on changes in cellular biochemistry in their discussions of the topic, are really just a new way of advocating for the evident benefits of weight loss in those who are overweight.

Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior Alzheimer's disease (AD) diagnosis by comparing semaglutide with seven other antidiabetic medications.

Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33) and most weakly compared with other GLP-1RAs (HR, 0.59). Similar results were seen across obesity status, gender, and age groups. Semaglutide was associated with significantly lower AD-related medication prescriptions. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM.

Link: https://doi.org/10.1002/alz.14313

Why is degenerative aging near universal in species, when the few (probably) actually immortal species such as hydra show that aging isn't an inevitability, while negligibly senescent species such as naked mole-rats show that youthful health can be maintained throughout much more of life and old age than in our own species. There are two big tent camps when it comes to views on the evolution of aging. The first is a fairly static camp, in which aging is a seen as a side-effect of selection pressure falling most heavily on the performance of young individuals; evolution selects changes that support early reproductive success, regardless of the consequences to later health. Aging is a side-effect of what is called antagonistic pleiotropy, negative consequences of selected changes.

The second camp sees aging as an evolutionarily selected program, rather than a side-effect of evolutionary processes, is far from unified in what that actually means, and for the past twenty years has been undergoing change and ideation at a fair pace. The most discussed ideas in programmed aging in the 2020s are quite different from those of the 2010s. There is even a faction between the two camps that blends together concepts of antagonistic pleiotropy and programmed aging into variants of what is presently called the hyperfunction theory of aging. It is sometimes hard to keep track of who is presently in favor of what on this side of the fence, but the papers usually make for interesting reading.

Does this all have practical consequences? For a while back in the day it was possible to say yes, because it looked like epigenetic changes were a far downstream consequence of the actual causes of aging, the underlying cell and tissue damage, and programmed aging advocates usually argued for therapies to focus on changing gene expression from aged to youthful patterns. From the aging-as-damage perspective, that was exactly the wrong thing to do if large gains in health were the intended goal. Now the waters are much less clear. Epigenetic changes may in fact be much closer to the root causes of aging, as research into the consequences of stochastic mutational damage illustrate, and the sorts of therapy proposed by researchers who favor programmed aging versus the antagonistic pleiotropy viewpoint are no longer all that different. Other factors, largely economic, are now arguably more important in determining which approaches make the leap from laboratory to industry.

Epigenetic clocks and programmatic aging

Recent years have witnessed exciting advances relating to methylation clocks and programmatic aging theory. We have highlighted here the convergence of these two paths of progress, and described several new ideas arising from this convergence. Understanding of the biological processes of aging that methylation clocks correspond to has lagged behind the recent rapid progress in clock characterization. Several features of clocks suggest that this hidden biology involves developmental processes.

Recently developed programmatic theories offer a framework of ideas within which such developmental aging mechanisms can potentially be understood. Such a framework includes explanations for how such clocks evolve, the programmatic mechanisms in which they act, and how those mechanism contribute to late-life disease. Central to this framework is the hypothesis that epigenetic and developmental changes occurring throughout life history are part and parcel of the same process. According to evolutionary theory, genes exhibiting antagonistic pleiotropy, that are beneficial early in life yet detrimental later on, may be favored by natural selection, causing aging. In the context of programmatic theories, the basic hypothesis is that developmental gene action and processes that are beneficial earlier in life continue later in life, in a futile fashion, becoming detrimental and pathogenic.

Here we explore how recent discoveries about methylation clocks cohere with the developmental theory of aging. We present several new perspectives, questions, and speculations arising from the cross-referencing of these two subjects, and argue for the timeliness of interdisciplinary integration of biogerontology with developmental biology. Central to these ideas is the hypothesis that epigenetic changes occurring throughout life history (including ontogenesis and senescence) are part of wider developmental changes. We have elaborated upon this explanatory framework, introducing new terminology (including the distinction between onto-developmental and maturo-developmental processes). Hypotheses proposed include the regulation by polycomb proteins of a trade-off between developmental fidelity and plasticity, and the presence of a conserved developmental sequence as a major, previously unseen element in the aging process. These suggestions provide examples of the sort of thinking that is possible by combining ideas from evolutionary biology, biogerontology, and developmental biology, in what we have described as a developmental gerontology or devo-gero approach.

Cardiometabolic aging is focused on heart and the liver, and the interactions that take place as loss of function and dysregulation occurs in one, other, or both. Everything in the body is connected, structurally and chemically. The liver is the center of cholesterol metabolism, and cholesterol is at the center of the development of atherosclerosis, for example. This isn't the only way that the liver can affect vascular health, and in return many aspects of vascular health can also affect the function of the liver.

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage.

Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging.

Link: https://doi.org/10.3389/fphar.2024.1447890

Development of the ability to usefully measure biological age will progress in lockstep with the development of treatments to reverse biological age. It must. There is no good way to rapidly assess the ability of a therapy to treat aging without an assay to measure of the state of aging. Equally, there is no good way to validate a proposed measure of biological age without the existence of therapies capable of reversing aspects of aging, by repairing some of the cell and tissue damage that causes the various manifestations of degenerative aging. Nothing comes into being fully formed, and piecemeal advances on each side of this fence will support further progress on the other side, step by step.

Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials.

Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.

Link: https://doi.org/10.3390/ijms25126793

Over time, ever increasing funding and interest has been devoted to the development of epigenetic clocks based on age-related changes in the DNA methylation status of various CpG sites on the genome. This is one of the epignetic mechanisms shaping the packaging of nuclear DNA, and thus which sections are exposed to transcription machinery, which proteins are manufactured, and consequent cell behavior. DNA methylation patterns can produce a fair estimate of chronological age, and are thought to reflect biological age, the burden of damage and dysfunction that gives rise of age-related disease and mortality. Given a wealth of data from many species, one can start to look beyond the individual at how DNA methylation patterns and their changes over time relate to species characteristics such as maximum life span. Interestingly, it appears that the relationships are quite different between (a) pace of aging for an individual and DNA methylation versus (b) species maximum life span and DNA methylation.

Today's open access paper is a lengthy discussion of this point, a review of some years of work focused on processing DNA methylation data in search of insights and correlations. When it comes to answers to the most interesting questions, this is only the starting point, however. It remains to be seen as to how the details of DNA methylation can map to a better understanding of the mechanisms that drive differences in species longevity. There is the hope that, given the sizable difference in life span between a mouse, a human, and a whale, somewhere in all of this data are the seeds of practical enhancement biotechnologies that will produce significant gains in healthy life span. It is far too early to say whether or not that is the case, and I would wager that this will be a slower, harder path than repair-based biotechnologies described in the Strategies for Engineered Negligible Senescence vision, but nonetheless, there you have it.

Fundamental equations linking methylation dynamics to maximum lifespan in mammals

We established the Mammalian Methylation Consortium with two primary objectives. The first objective was to develop DNA methylation-based measures to track the passage of time, culminating in the creation of the pan-mammalian methylation clock. The second objective aimed to understand the epigenetic correlates of maximum mammalian lifespan, a goal explored through a trilogy of papers. In the first paper, we developed multivariate predictors of maximum lifespan based on cytosine methylation. This predictor can estimate species-specific characteristics, such as maximum lifespan, from a DNA sample, even if the species is unknown. The second paper characterized individual CpGs and clusters of CpGs (modules) that correlate with maximum lifespan, providing insights into the methylation landscape of long-lived species. Interestingly, this study found only a weak overlap between CpGs that correlate with maximum lifespan and those associated with chronological age. While we understand that a species characteristic like maximum lifespan is genetically hardwired and does not change with the individual's age, this finding challenges the intuitive hypothesis that individual aging (the passage of time) must relate to maximum lifespan (a species characteristic).

Prior studies have linked the rate of change in methylation to maximum lifespan in smaller samples of mammalian species, and have suggested a strong position correlation between slower average rate of change in methylation and increased species maximum lifespan. But this is not always the case. By leveraging the large dataset from our Mammalian Methylation Consortium and a careful mathematical framework we demonstrate that the strong correlation between slower average rate of change in methylation and increased species maximum lifespan is only found in certain chromatin states such as bivalent promoters. In other chromatin states, the correlation is either not present or even reversed. Future studies might delve deeper into which chromatin regions result in the opposite interpretation, where a rapid rate of change correlates with an increased maximum lifespan.

Epidemiologists here note that there is no interaction between the correlations of physical activity and diet with mortality risk, at least in the measures used for this study. Additionally the researchers quantify the size of the survival benefit produced by increased exercise or improved diet. While analysis of human data can only demonstrate correlations, animal studies have comprehensively demonstrated causation in these matters. It is quite reasonable at this point to assume causation when observing a correlation between these lifestyle choices and mortality risk.

A prospective cohort study was performed on 9,349 adults aged 40 to 79 years from the population-based European Prospective Investigation into Cancer in Norfolk Study, with repeated measurements of physical activity (PA) and diet (from 1993 till 2004) and subsequent follow-up till 2022 (median follow-up 18.8 years). Validated questionnaires were used to derive physical activity energy expenditure (PAEE) as a proxy of total PA and adherence to the Mediterranean diet score (MDS, range 0-15 points) as an indicator of overall diet quality, and their changes over time (∆PAEE and ∆MDS).

Over 149,681 person-years of follow-up, there were 3,534 deaths. In adjusted models, for each 1 standard deviation difference in baseline PAEE (4.64 kJ/kg/day), ∆PAEE (0.65 kJ/kg/day per year), baseline MDS (1.30 points) and ∆MDS (0.32 points per year), hazard ratios (HRs) for all-cause mortality were 0.90, 0.89, 0.95, and 0.93, respectively. Compared with participants with sustained low PAEE (under 5 kJ/kg/day) and low MDS (less than 8.5 points), those with sustained high PAEE and high MDS had lower all-cause mortality (HR 0.78), as did those who improved both PAEE and MDS (HR 0.60). There was no evidence of interaction between PA and diet quality exposures on mortality risk. Population impact estimates suggested that if all participants had maintained high levels of PA and diet quality consistently, cumulative adjusted mortality rate would have been 8.8% lower.

These findings suggest that adopting and maintaining higher levels of PA and diet quality are associated with lower mortality. Significant public health benefits could be realised by enabling active living and healthy eating through adulthood.

Link: https://doi.org/10.1186/s12916-024-03668-6

Organoid tissues generated by 3D printing are limited in size because it remains challenging to print capillary networks. Without capillaries, nutrients and oxygen can only perfuse a few millimeters into a tissue. Cells will perform some self-assembly, so printed tissue doesn't have to be perfect, but it does need a complex and extensive blood vessel network. This is at present the biggest roadblock on the way to printing entire replacement organs, and has been for more than a decade. It is why considerable effort still goes into the development of alternatives that focus on improving logistics and capabilities for the transplantation industry, such as recellularization of donor organs with patient-matched cells, and xenotransplantation of organs grown in genetically engineered pigs.

"In prior work, we developed a new 3D bioprinting method, known as "sacrificial writing in functional tissue" (SWIFT), for patterning hollow channels within a living cellular matrix. Here, building on this method, we introduce coaxial SWIFT (co-SWIFT) that recapitulates the multilayer architecture found in native blood vessels, making it easier to form an interconnected endothelium and more robust to withstand the internal pressure of blood flow." The key innovation developed by the team was a unique core-shell nozzle with two independently controllable fluid channels for the "inks" that make up the printed vessels: a collagen-based shell ink and a gelatin-based core ink. The interior core chamber of the nozzle extends slightly beyond the shell chamber so that the nozzle can fully puncture a previously printed vessel to create interconnected branching networks for sufficient oxygenation of human tissues and organs via perfusion. The size of the vessels can be varied during printing by changing either the printing speed or the ink flow rates.

The team used a shell ink that was infused with smooth muscle cells (SMCs), which comprise the outer layer of human blood vessels. After melting out the gelatin core ink, they then perfused endothelial cells (ECs), which form the inner layer of human blood vessels, into their vasculature. After seven days of perfusion, both the SMCs and the ECs were alive and functioning as vessel walls - there was a three-fold decrease in the permeability of the vessels compared to those without ECs.

Finally, they were ready to test their method inside living human tissue. They constructed hundreds of thousands of cardiac organ building blocks (OBBs) - tiny spheres of beating human heart cells, which are compressed into a dense cellular matrix. Next, using co-SWIFT, they printed a biomimetic vessel network into the cardiac tissue. Finally, they removed the sacrificial core ink and seeded the inner surface of their SMC-laden vessels with ECs via perfusion and evaluated their performance. Not only did these printed biomimetic vessels display the characteristic double-layer structure of human blood vessels, but after five days of perfusion with a blood-mimicking fluid, the cardiac OBBs started to beat synchronously - indicative of healthy and functional heart tissue.

Link: https://wyss.harvard.edu/news/3d-printed-blood-vessels-bring-artificial-organs-closer-to-reality/

With few exceptions, first generation stem cell therapies appear to produce their positive results, such as months-long suppression of chronic inflammation, via signaling generated by transplanted cells in the short time before they die. A sizable fraction of the signaling that passes between cells is carried within extracellular vesicles, small membrane-wrapped packages of molecules generated by one cell and taken up by another. There are many forms of extracellular vesicle, largely classified by size at the present time in absence of a better understanding of function. Research has shown that harvesting vesicles from stem cells in culture and then transplanting those vesicles can produce similar benefits to transplanting the cells themselves, while being a much easier proposition from the point of view of the cost and logistics of storage, delivery, and quality control.

Nonetheless, the use of extracellular vesicles in therapy retains many of the challenges of the use of cells in therapy. Standardization is very hard. Too little is known of how to constrain cells to produce specific vesicles and vesicle content. One still needs to source and manage the cells that generate the vesicles in the first place. Outcomes vary widely from patient to patient and clinic to clinic. This is why the pace of progress towards widespread use in the clinic outside the medical tourism field remains slow. Today's open access paper considers extracellular vesicle therapy specifically in the case of brain injury and neurodegenerative conditions, but the points made are broadly applicable to all forms of therapy that make use of vesicles harvested from cells.

Extracellular vesicle therapy in neurological disorders

Extracellular vesicles (EVs) are vital for cell-to-cell communication, transferring proteins, lipids, and nucleic acids in various physiological and pathological processes. They play crucial roles in immune modulation and tissue regeneration but are also involved in pathogenic conditions like inflammation and degenerative disorders. EVs have heterogeneous populations and cargo, with numerous subpopulations currently under investigations. EV therapy shows promise in stimulating tissue repair and serving as a drug delivery vehicle, offering advantages over cell therapy, such as ease of engineering and minimal risk of tumorigenesis.

Despite the rapid growth in the EV field, much remains to be studied. There are numerous EV classes and subclasses yet to be fully characterized. The heterogeneity within EV classes leads to variability in their effects. Studies isolating EVs from the same cell line report different cargo and mechanisms of action. The effects of EV subpopulations are also not fully understood, with research predominantly focused on exosomes. The roles of microvesicles (MVs) are still controversial, as they can be either therapeutic or pathogenic depending on their source. MVs and other large EVs may be worth exploring further since they can deliver more cargo.

Characterization and purification of EVs are crucial for clinical application. To control the effects of EVs, production methods need to be strictly replicable to avoid heterogeneity, with specific culture and modulation techniques. EVs are involved in multiple pathological processes, such as inflammation, tumorigenesis, and toxic protein spreading. Blocking these pathological EVs is challenging due to a lack of specificity, necessitating more precise techniques for targeting them. Multiple sources of EVs have been studied, but not thoroughly across all domains of treatment. Some cell sources may be better suited for certain roles; for example, stem cells for neuroregeneration, glia for immunomodulation, and endothelial cells for angiogenesis. The targeting ability of EVs is another area that has not been extensively explored. Optimal EV preconditioning, administration regimens, and safety profiles also require further investigation.

A better understanding of EV subtypes and their specific roles will mark a significant milestone in medicine, leading to safer, more effective and disease-tailored EV therapy for a variety of neurological disorders.

A range of evidence suggests that persistent infection, particularly some herpesviruses, raises the risk of Alzheimer's disease and other neurodegenerative conditions. It may be that Alzheimer's is strongly dependent on the dysfunction of immune cells in the brain, and infection hastens this dysfunction in later life. Equally, other less well understood mechanisms may be involved. Here, researchers demonstrate that it is possible to distinguish a protein expression signature of past infection in blood samples, and some of these differentially expressed proteins also correlate to measures of brain aging.

Infections have been associated with the incidence of Alzheimer's disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin, and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe.

We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

Link: https://doi.org/10.1038/s43587-024-00682-4

As a general rule in life science research, proposed novel mechanisms almost always actually exist, but their relative importance in determining outcomes is almost always unclear. Just because a mechanism of aging looks plausible and appears to operate doesn't mean it is creating a significant amount of age-related dysfunction at the end of the day. Here, researchers propose that a leakage of digestive enzymes into the body, a result of age-related dysfunction in intestinal barrier function, contributes meaningfully to degenerative aging. It is an interesting idea, but more work is needed to determine how important this is in driving outcomes in aging.

The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract.

Using immunohistochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage.

These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.

Link: https://doi.org/10.1371/journal.pone.0312149

Senescent cells accumulate with age in tissues throughout the body, an important contribution to age-related dysfunction and disease. On entering the senescent state, a cell ceases to replicate and begins to energetically secrete a pro-inflammatory mix of signals, rousing the immune system to action. In youth, cellular senescence serves useful purposes, such as coordination of regeneration from injury and removal of potentially cancerous cells. In the young, senescent cells are removed rapidly by the immune system, preventing their accumulation. With advancing age, the balance between creation and destruction shifts and a population of lingering senescent cells grows over the years. The inflammatory signals that are useful in the short term become harmful when sustained over the long term, a major contribution to the characteristic chronic inflammation of old age.

While most efforts targeting cellular senescence are focused on ways to selectively destroy these errant cells in aged tissues, a smaller faction of the research community is more interested in finding ways to reduce the secretion of inflammatory signals. In principle, the presence of senescent cells would cause comparatively little harm provided their inflammatory signaling was greatly reduced. One can look at cellular senescence in the long-lived naked mole-rats as a model for this desired goal, as senescent cells in that species do not produce anything like the same degree of inflammatory signaling. There is no way as yet to produce a similar degree of reduced inflammatory signaling in mice, but researchers continue to look for a viable approach.

Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers

In response to various stimuli, senescent cells (SnCs) accumulate in aging tissues, and this occurs in parallel with chronic inflammation and age-related functional decline. SnCs are normally rare in most tissues, suggesting that the ripple effect of the senescence-associated secretory phenotype (SASP) amplifies pro-inflammatory signaling in the senescent microenvironment. Because the processes of de novo protein production and secretion consume a lot of cellular energy, unique strategies must exist to collaboratively regulate gene expression, the epigenome, and metabolism.

During the senescent transition of the cells, senescence-associated phenotypes are shaped entirely through epigenomic and metabolic coregulation. The expression of cyclin-dependent kinase inhibitor p16, one of the biomarkers for SnCs, is induced. Activation of the p16-retinoblastoma protein (RB) pathway not only causes cell-cycle arrest but also triggers metabolic reprogramming of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) by upregulating glycolytic enzymes and the pyruvate dehydrogenase phosphatase 2 that augments the active form of pyruvate dehydrogenase. Since the resulting metabolites, such as S-adenosylmethionine, α-ketoglutarate (αKG), and acetyl-coenzyme A (CoA), are used for adjusting the activities of epigenome modifiers, they further affect the epigenomic state that defines the transcriptional program of SnCs. However, molecular specificity for SASP-related pro-inflammatory gene regulation has not been convincingly established.

Citrate plays important roles in energy production, macromolecular biosynthesis, and protein modification. Within the mitochondria, citrate is generated from acetyl-CoA and oxaloacetate by the citrate synthetase and serves as a substrate in the tricarboxylic acid (TCA) cycle that produces essential metabolites for OXPHOS. In addition, citrate is exported from mitochondria to the cytoplasm and subsequently cleaved by ATP-citrate lyase (ACLY), which generates acetyl-CoA and oxaloacetate. Acetyl-CoA derived from this unique reaction, so called the non-canonical TCA cycle pathway, acts as a source for various metabolic functions, including fatty acid synthesis and the mevalonate pathway, and protein acetylation. Although recent studies have shown that ACLY inhibition improves metabolic health and physical strength in obese mice the role of the non-canonical TCA cycle pathway mediated by ACLY in SnCs remains totally unknown.

Here, we show that ACLY is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.

Senescent cells are poised for self-destruction, but held back by a range of mechanisms that are amenable to sabotage, given suitable small molecules. Much of the first wave of senolytic drug development, treatments that can selectively destroy some fraction of the harmful burden of senescent cells found in aged tissues, exploited ways to force senescent cells into apoptosis. New ways to provoke forms of programmed cell death in senescent cells are being found all the time, and it is interesting to keep an eye on this part of the field. The illustrative work noted here is only conducted in cell culture, so should be taken with a grain of salt until animal data arrives, but is novel for employing ferroptosis as the chosen path to destruction, and in the use of lipids rather than the usual small molecules.

Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice.

Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic polyunsaturated fatty acids (PUFAs) and reactive oxygen species (ROS) levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.

Link: https://doi.org/10.1101/2024.10.14.618023

Mitochondria are the powerplants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) used to power cell activities. With age, mitochondria become less effective in this task, producing less ATP and increased amounts of oxidative byproducts, adding to cell stress. This is the result of damage to mitochondrial DNA, less well protected and repaired than the DNA in the cell nucleus, combined with maladaptive changes in the expression of genes important to mitochondrial function and quality control. A reduced supply of ATP contributes to dysfunction in tissues and organs, particularly energy-hungry tissues such as muscle and brain.

The mitochondrial electron transport chain (ETC) contributes 80%-90% of ATP in most mammalian tissues, making mitochondrial dysfunction detrimental due to reduced ATP production, indispensable for biological functions. Aging leads to alterations in ETC components, contributing to a number of age-related conditions. Hence, one of the consequences of the aging process is the drop in the efficiency of this energy production mechanism, leading to a decline in ATP production and subsequent cellular energy deficits. Dysfunctional mitochondria are increasingly associated with aged cardiovascular tissues.

Proper substrate utilization is imperative for the myocardium to fulfill its function, primarily relying on ATP (re-)synthesis through fatty acid oxidation within mitochondria. The myocyte employs additional pathways, such as glycolysis, creatine kinase, and adenylate kinase, in response to high ATP demand. During increased work, glycogen, glucose, and phosphocreatine are utilized to meet ATP demand, maintaining constant ATP levels. The efficiency of ATP production varies depending on substrate oxidation, with fatty acid oxidation producing more ATP. This metabolic plasticity diminishes in chronic pathologies like congestive heart failure, impacting myocardial oxygen efficiency and causing intracellular ATP depletion.

Spare respiratory capacity, the ability to increase ATP production during heightened demand or reduced fuel supply, is crucial for cellular function and survival. Mitochondrial plasticity involves the efficiency of mitochondrial coupling and provides increased respiratory capacity under stress conditions. This phenomenon is particularly significant in ischemic injury and situations of augmented energy demand such as sepsis, endurance exercise, trauma, or heart failure. In the heart, aging leads to a decline in mitochondrial oxidative phosphorylation function. Increased electron leakage and mitochondrial ROS production contribute to oxidative damage, particularly affecting intrafibrillar mitochondria. Deficient mitochondrial energetics, altered Ca2+ homeostasis, and excessive reactive oxygen species (ROS) generation contribute to reduced stress adaptability and augmented vulnerability to disease in the aged myocardium.

Link: https://doi.org/10.20517/jca.2023.50

Modern omics technologies make it possible to generate enormous amounts of data from biological samples at low cost. All of the stages and influences on gene expression in cells, segmented by tissue and cell type, or even in single cells, are open to inspection in detail. The same is true of circulating molecules outside cells. Aging produces changes in cells and circulating molecules, some of which are individual, but many of which are much the same from person to person, and thus any sufficiently large set of biological data can be mined for signatures of aging. Machine learning has developed to the point at which this development of signatures can be accomplished as cost-effectively as the generation of the data in the first place.

In today's open access paper, researchers report on the development of signatures of aging based on senescence-associated secretory phenotype (SASP) molecules secreted by senescent monocytes. Monocytes are innate immune cells resident in the spleen, but also circulating in the bloodstream before entering tissue to transform into macrophages. Researchers first evaluated monocyte SASP in vitro to determine which molecules to look for in blood samples, and from there found signatures that correlate with mortality in large epidemiological data sets. We will probably see a lot more of this sort of segmentation of data of interest, ever finer slices, as researchers continue to explore what can be accomplished in the construction of biomarkers of aging.

A plasma proteomic signature links secretome of senescent monocytes to aging- and obesity-related clinical outcomes in humans

In recent years, senescence of immune cells, including monocytes, have been implicated as a potentially key driver of age-related pathologies. Senescence of immune cells increases with age and is thought to contribute to an age-related increase of sterile inflammation - "inflammaging" - and higher susceptibility to infectious diseases. Additionally, higher levels of senescence in the immune system drive systemic aging and propagate senescence in solid organs, such as the liver, kidney, and lung. There is emerging evidence that senescent monocytes accumulate in vivo in humans. These circulating immune cells form up to 10% of the total white blood cells and are involved in pathogen recognition via Toll-like receptors (TLRs) and regulation of inflammation. A proinflammatory phenotype of monocytes has been attributed to senescence in the elderly. Moreover, monocytes are promising sources of biomarkers due to their abundance in blood. Despite their potential involvement in inflammaging and biomarker potential, the role of monocyte senescence-associated proteins in aging and their potential as clinical biomarkers are poorly characterized.

In recent years, high-throughput proteomic studies have quantitatively profiled senescence-associated proteins in circulation and demonstrated their associations with diverse aging-related outcomes in humans, including mortality, multimorbidity, strength, and mobility. These studies leveraged human cohorts, such as InCHIANTI (Invecchiare in Chianti), BLSA (Baltimore Longitudinal Study of Aging), GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing), Lifestyle Interventions for Elders (LIFE), and others. However, no biomarker studies to date have comprehensively characterized the monocyte-specific SASP and evaluated its clinical utility as circulating biomarkers in humans.

We identified circulating biomarkers of senescence associated with diverse clinical traits in humans to facilitate future non-invasive assessment of individual senescence burden and efficacy testing of novel senotherapeutics. Using a novel nanoparticle-based proteomic workflow, we profiled the senescence-associated secretory phenotype (SASP) in monocytes and examined these proteins in plasma samples (N = 1,060) from the BLSA. Machine learning models trained on monocyte SASP associated with several age-related phenotypes in a test cohort, including body fat composition, blood lipids, inflammation, and mobility-related traits, among others. Notably, a subset of SASP-based predictions, including a 'high impact' SASP panel that predicts age- and obesity-related clinical traits, were validated in InCHIANTI, an independent aging cohort. These results demonstrate the clinical relevance of the circulating SASP and identify relevant biomarkers of senescence that could inform future clinical studies.

The chronic inflammation of aging is harmful to health, the result of accumulating senescent cells, maladaptive reactions to molecular damage characteristic of aging, and other similar problems. While short-term inflammation is useful and necessary to defense against pathogens, elimination of potentially cancerous damaged cells, and regeneration from injury, unresolved, constant inflammatory signaling is disruptive to tissue structure and function. It changes cell behavior for the worse throughout the body. The immune system is complex, and so is inflammatory signaling. There are many possible ways to measure inflammation, and most have some dependency on the broader context of the state of the body, specific medical condition, and so forth. As researchers demonstrate here, it is quite possible to depart from the usual measures to produce novel and potentially better assessments of the contribution of inflammation to mortality based on omics data.

Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (Polygenic-Risk-Score; PRS), metabolomics (Metabolomic-Risk-Score; MRS), and epigenetics (Epigenetic-Risk-Score; ERS) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFa).

We found that multi-omics risk-scores generally outperformed single-omics risk scores in prediction of all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher hazard ratio (HR) per standard deviation (SD) increase for all cause-mortality when including both score and circulating IL6 in the same model (1-SD IL6 MRS-ERS: HR=1.77 vs. 1-SD circulating IL6 HR=1.11; 1-SD IL6 PRS-MRS: HR=1.32 vs. 1-SD circulating IL6 HR=1.31; 1-SD PRS-MRS-ERS: HR=1.62 vs. 1-SD circulating IL6: HR=1.16).

In the Nurses' Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1-SD of IL6 PRS and 1-SD IL6 PRS-MRS had HR=1.13 and HR=1.13, among individuals older than 65years without mutual adjustment of the score and circulating IL6. Our study demonstrated that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for aging process and lifespan.

Link: https://doi.org/10.1101/2024.09.24.24313672

The thymus plays host to thymocyte cells originally generated in the bone marrow, guiding their maturation into T cells of the adaptive immune system. The aged thymus steadily loses active tissue, however, and the supply of new T cells dwindles as a result. Most people in their 50s have very little thymic function, and without a supply of reinforcements the adaptive immune system becomes ever more dysfunctional over time. Back in the 2010s there was considerable academic interest in approaches to the regeneration of the thymus based on upregulation of FOXN1 expression, but that proved challenging enough for those efforts to die out (aside from one persistent academic group that may have recently found a solution). Absence of a suitable delivery system for FOXN1 gene therapy targeted to the thymus was one major issue. That FOXN1, like many transcription factors, downregulates its own expression was another. Now, however, there are a fair number of companies in the growing longevity industry working on various possible approaches to the problem.

Tolerance Bio is developing an allogeneic cell therapy platform based on induced pluripotent stem cells (iPSCs) as well as pharmacological treatments aimed at immune diseases. Thymic dysfunction is linked to various immune diseases due to age-related decline, congenital defects, or damage from medical interventions like surgery, chemotherapy, and infection. Tolerance Bio aims to reverse these effects by developing artificial thymuses from stem cells, targeting disease-specific treatments such as thymic organoids. The company also seeks to delay thymic involution with drugs to prevent both natural and accelerated thymic decline. Restoring thymic function could not only combat immune diseases but also extend healthy lifespan by improving the body's immune response.

Tolerance Bio joins a number of companies seeking to harness the power of the thymus against aging and disease, including ARPA-backed Thymmune, Vidaregen and Thymox. In 2015, Dr Greg Fahy, renowned aging researcher and CSO of Intervene Immune, commenced the first clinical trial to explore if thymus regeneration could reverse aspects of human aging, with results showing participants' epigenetic age was "significantly decreased" by the treatment.

Link: https://longevity.technology/news/tolerance-bio-launches-to-boost-human-healthspan-via-the-thymus/

The axons that connect neurons are sheathed in myelin, an insulator necessary to maintain normal electrochemical transmission through the nervous system. Demyelinating conditions such as multiple sclerosis produce profound dysfunction leading to death precisely because myelin is so fundamental to the correct operation of nerves and brain. With normal aging, a lesser degree of damage to myelin sheathing occurs, however, and this is thought to contribute to cognitive decline. As is the case for many aspects of aging, there are many possible interconnected mechanisms involved, and it isn't clear as to which are more or less important, or whether the list is complete.

Myelination is an active, ongoing process conducted by oligodendrocyte cells. Many of the possible mechanisms driving loss of myelin involve a reduced oligodendrocyte population size or activity, but in today's open access paper, researchers discuss how proteins that encourage or prevent phagocytosis, the engulfment and destruction of cells or debris in tissue by immune cells, might be involved in age-related demyelination. The researchers argue for the importance of a maladaptive increase in pro-phagocytosis decoration ("eat me" signals) near myelin structures combined with a maladaptive reduction in anti-phagocytosis decoration ("don't eat me" signals) near myelin structures and on oligodendrocytes. The result is damaged myelin and too little remyelination activity.

Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline

Although the cause of myelin pathology is not known, microglia are likely contributors as they play an important role in removing myelin debris that inhibits remyelination, a process which becomes dysregulated with age. Microglia become overburdened with degenerating myelin, and failure to clear the debris results in accumulation of damaged myelin that blocks remyelination and proper myelin maintenance. Moreover, the aging brain is characterized by chronic inflammation, which is especially elevated in white matter regions. This neuroinflammation puts microglia into a cycle of contributing to inflammation while also responding to proinflammatory signaling. Chronic neuroinflammation heightens microglia-mediated elimination of cellular components, which may become misdirected with excess pro-inflammatory signaling.

The timing and precision of microglia-mediated debris removal is regulated by immunologic proteins that either initiate or inhibit phagocytosis. Two such proteins are the "eat me" classical complement initiator, C1q, and the "don't eat me" immune-regulatory protein, CD47. Dysregulation in both C1q and CD47 have been implicated in age-related diseases such as multiple sclerosis (MS), a chronic demyelinating disease, synapse removal, and normal aging. Our previous study showed that C1q and CD47 expression are dysregulated in aging gray matter, likely contributing to age-related synapse loss.

Changes in C1q and CD47 in aging white matter may direct microglia towards chronic phagocytosis and inflammation and hinder efficient debris clearance and myelin maintenance. However, studies in white matter have mainly focused on either "eat me" or "don't eat me" proteins and not both, so the interaction between the two in white matter remains unknown even though both C1q and CD47 bind to myelin and proper balance between the two molecules is critical for phagocytosis. Since these signals have not been studied in aging white matter tracts in relation to myelin damage and related cognitive impairment, the present study aimed to assess changes in the balance of C1q and CD47 in the white matter of the aging cingulum bundle in cognitively assessed nonhuman primates.

Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.

Alzheimer's disease is characterized by a long, slow buildup of amyloid-β aggregates in the brain, and in this period symptoms are minor to non-existent. The amyloid cascade hypothesis of Alzheimer's disease suggests that this aggregation sets the stage for a later feedback loop between tau protein aggregation and chronic inflammation in the brain, which produces a more rapid, sizable increase in pathology and loss of function. Researchers here use omics technologies to produce a map of postmortem diseased brains that supports this two phase view of the development of Alzheimer's disease, adding more detail to the existing picture.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics, and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years.

We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.

Link: https://doi.org/10.1038/s41593-024-01774-5

The balance of microbial populations making up the gut microbiome changes with age, in ways that negatively affect health. Pro-inflammatory microbes increase in number while populations producing beneficial metabolites decrease in size. Researchers here discuss the evidence for an aged gut microbiome to contribute to various aspects of cardiovascular disease, and show that in mice an aged gut microbiome increases risk of arrhythmia. The researchers suggest that the mechanism of interest is increased oxidative stress resulting from the activities of microbial populations, which is then disruptive to the normal metabolism of the heart. There may be other mechanisms.

The prevalence of arrhythmias and incidence of sudden cardiac death (SCD) increases markedly with age, leading to higher morbidity and mortality in the elderly. The frequency of arrhythmias, particularly atrial fibrillation (AF) and ventricular tachyarrhythmias (VT), is expected to increase with aging. Gut microbiota has been recognized as an important factor in the development of cardiovascular diseases, such as AF, heart failure (HF), ischemia, and reperfusion. It is also considered to be an endocrine organ that plays a role in the manipulation of host immunity and metabolic homeostasis. It has been shown to play both beneficial and adverse roles in AF rats and patients, which could be related to the heterogeneity of the microbiota.

Research indicates that in patients with AF, the relative abundance of Ruminococcus, Streptococcus, and Enterococcus increase, while that of Faecalibacterium, Oscillospira, and Bilophila decreases. From the perspective of intestinal content metabolism, the bacteria producing trimethylamine oxide (TMAO) in gut microbiota of AF patients increase. Moreover, local injection of TMAO in canine can activate atrial autonomic nerve plexus, shorten effective refractory period (ERP) value, and then promote arrhythmia, which because of the activation of p65/NF-κB signaling and inflammatory cytokines.

Here, we demonstrated that arrhythmia susceptibility in aged mice could be transmitted to young mice using fecal microbiota transplantation (FMT). Mechanistically, increased intestinal reactive oxygen species (ROS) in aged mice reduced ion channel protein expression and promoted arrhythmias. Gut microbiota depletion by an antibiotic cocktail reduced ROS and arrhythmia in aged mice. Interestingly, oxidative stress in heart induced by hydrogen peroxide (H2O2) increased arrhythmia. Moreover, aged gut microbiota could induce oxidative stress in young mice colon by gut microbiota metabolites transplantation. Vitexin could reduce aging and arrhythmia through OLA1-Nrf2 signaling pathway.

Overall, our study demonstrated that the gut microbiota of aged mice reduced cardiac ion channel protein expression through systemic oxidative stress, thereby increased the risk of arrhythmias.

Link: https://doi.org/10.1016/j.isci.2024.110888

Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the single largest cause of human mortality. More novel approaches to treatment are welcome, as the present standard of care, involving reduction of circulating LDL-cholesterol in the bloodstream, is nowhere near effective enough. It only modestly reduces plaque growth, and cannot regress existing plaque. Atherosclerotic plaques are fat-laden cell graveyards, regions of disrupted metabolism and inflammation. The innate immune cells called macrophages are drawn there or created locally to attempt to repair the lesion, but are overwhelmed by the toxic environment and become dysfunctional and die, adding their mass to the plaque. Eventually a plaque ruptures, to cause a heart attack or stroke.

Some years back, researchers reported that CD47 is abundant in atherosclerotic plaque, decorating the surface of dying and dead cells. CD47 is a "don't eat me" marker that prevents cells from being destroyed by local immune cells as they interact with tissue. Normally this and other other protective markers are lost when a cell approaches death, but for yet to be fully explored reasons this is not the case in the toxic environment of an atherosclerotic plaque. This unwanted overabundance of CD47 prevents some of the clearance of cell debris in the plaque that would otherwise happen. Using techniques developed in cancer research, where anti-CD47 therapies are now well established to try to prevent cancerous cells from abusing CD47 to protect themselves from immune cells, researchers have shown that delivering CD47 to atherosclerotic plaque can slow its progression in mouse models of atherosclerosis.

This research, starting a decade ago or so, led to the formation of Bitterroot Bio, a company now starting an initial phase 1 safety trial of a CD47 inhibitor targeted to macrophages. Today's open access paper reports on earlier tests of their drug in pigs, one of the many steps along the way to the regulatory approval needed to test in human volunteers. Reading through the various published papers on this approach, it seems the case that this therapy only slows progression of plaque, but it hopefully turns out to be better at doing that than the present approach of lowering LDL cholesterol in the bloodstream.

Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis

Among the many emerging translational targets in the field of cardiovascular medicine, a phenomenon known as efferocytosis has recently been prioritized for study. Efferocytosis refers to the engulfment and clearance of pathological cells by professional phagocytes such as macrophages. Within the atherosclerotic plaque, enlargement of the necrotic core is, in part, a consequence of impaired removal of apoptotic vascular cells, which have upregulated the key anti-phagocytic 'don't-eat-me' molecule CD47 on their surface. The growth of a necrotic core contributes to plaque instability and eventual rupture, which serves as a nidus for subsequent acute thrombosis.

Antibodies (Ab) which block the binding of CD47 to its receptor SIRPα potently reduce plaque vulnerability and lesion size by preventing the accumulation of apoptotic debris in murine models of atherosclerosis. These pre-clinical observations were recently extended in a phase I trial of the first humanized anti-CD47 Ab. Subjects receiving 'macrophage checkpoint inhibitors' experienced a dramatic reduction in vascular inflammation of the carotid artery scans. Unfortunately, anti-CD47 Ab treatment in both mouse models and humans has been shown to induce anemia due to the non-specific erythrophagocytosis of aged red blood cells (RBCs) in the spleen.

Studies demonstrating toxicity of anti-CD47 antibody-mediated blockade therefore prompted a search for methods which could reactivate efferocytosis in a precision-targeted manner. To do this, we generated a macrophage-specific nanotherapy loaded with a chemical inhibitor of Src homology 2 domain-containing phosphatase-1 (SHP-1), a small molecule downstream of the CD47-SIRPα signaling axis. This 'Trojan horse' nanoparticle selectively delivered drug to inflammatory monocytes and macrophages within the atherosclerotic plaque, potently augmented phagocytosis, and reduced atherosclerosis as effectively as gold-standard Ab therapies in mouse models. Most notably, this therapy did not cause any hematological toxicity.

Accordingly, the aim of this study was to test our targeted nanoparticles in a large animal model of cardiovascular disease (CVD) to determine if additional translation of our nanotherapy toward human clinical trials is justified.

The body has evolved to balance the levels of many different molecules across different tissues. Multiple systems of signaling, transport, motivation, intake, and excretion interact in order to achieve homeostasis, constantly shifting in response to deficiency or excess. Water is one of the more important molecules managed by this sort of complicated, dynamic balance. As a general rule, all complex systems in the body run awry with aging; the more complex, the more vulnerable it is to damage and dysfunction. The molecular damage of aging changes cell behavior, homeostatic systems stop working as well as they did in youth, and ultimately the failure to achieve homeostasis in the face of stresses that push the system out of normal bounds can prove fatal.

Tight control of fluid balance is essential for life. This is achieved by a physiologic system that monitors the osmolality and volume of the blood and, in response to dehydration, triggers two counterregulatory responses: water consumption, which is motivated by the sensation of thirst, and water reabsorption by the kidney, which is triggered by the hormone vasopressin (AVP). These two responses are controlled by dedicated neural circuits in the forebrain that directly sense changes in fluid balance.

Dysregulation of fluid homeostasis is a common feature of aging. For example, older adults report a reduced perception of thirst and consume less water after many thirst-evoking (dipsogenic) stimuli. In addition, the ability of the kidney to concentrate urine declines with age, leading to greater loss of fluid in older adults. As a result, aging is associated with increased prevalence of chronic dehydration, which is a significant risk factor for morbidity and mortality.

The specific alterations in the fluid homeostasis system that are caused by aging are not well understood. One challenge is that fluid balance involves multiple interacting systems, including a neuroendocrine system that controls water resorption (the AVP-kidney axis); a sensory system that monitors fluid balance and ingestion, which includes subfornical organ (SFO) glutamatergic neurons and their sensory afferents arising from the mouth, throat, and viscera; and a motivational system which drives water seeking and consumption, which includes SFO glutamatergic neurons as well as their downstream targets such as the dopamine system.

It has only recently become possible to monitor and manipulate these fluid homeostasis neurons in behaving animals. Here we have performed a comprehensive analysis of how the fluid homeostasis system is altered by aging in mice. We investigated animals of both sexes, across a range of ages from young to very old, and subjected them to batter of analyses at different levels, including: (1) physiologic measurements of fluid balance, kidney function, and AVP release and sensitivity; (2) behavioral analyses of drinking and motivation in response to diverse thirst stimuli (food, dehydration, hyperosmolality, and hypovolemia); (3) neural recordings from circuit nodes that control drinking, AVP release, and motivation, and (4) optogenetic manipulations to test the sufficiency of circuit nodes. These experiments revealed that a subset of these functions is impaired during aging, whereas others are unexpectedly enhanced.

Link: https://doi.org/10.1101/2024.09.26.615271

People age at different rates, and any give population will distribute across a range of late life health status and mortality risk. As a concept, biological age is clearly useful, a way to talk about this variance in pace of aging. The output of an attempt to measure biological age is not biological age, however. It is a measure that may or may not reflect biological age. Some researchers feel that current use of the term "biological age" is lax, often applied without qualification to the output of epigenetic clocks and other assessments.

Usage of the phrase "biological age" has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric.

We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO2 max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole-body biological aging.

To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.

Link: https://doi.org/10.1111/acel.14377

Autophagy is a collection of processes responsible for recycling protein structures in the cell. There are numerous moving parts, not all of which are fully understood or characterized. Firstly, there is the question of how structures are identified for recycling, a process that is quite different on a structure by structure basis. Mitophagy, autophagy targeted to mitochondria, is very different in its opening stages to ribophagy, autophagy targeted to ribosomes, to pick one comparison of many. Secondly, there is the engulfment of the structure to be recycled into an autophagosome, a membrane assembled specifically for this purpose. Thirdly, there is the transport of that autophagosome to a lysosome where it merges to deliver its cargo to the lysosome interior. Lastly, there is the internal lysosomal activity in which enzymes break down the delivered structure into amino acids for reuse.

Autophagy is clearly important to aging, in that interventions known to modestly slow aging tend to upregulate autophagic activity. Autophagy is difficult to measure, however, and there is some debate over whether and how it slows with advancing age. One can pick any given molecular aspect of autophagy to measure, but it will not be clear as to whether an increase or decrease of that measure reflects an overall enhancement or decine of autophagy. A decreased measure could mean that efficiency has increased, while an increased measure could mean that some dysfunction is leading to futile overactivity in one part of the process. Further, aging could affect autophagy very differently in different tissues or even different cell populations in the same tissue. Average measures may blur out useful information, or a measure obtained in one place may provide misleading data. Most studies of autophagy make only one measure, and are thus subject to this sort of criticism.

Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging

Once thought to be an acute stress response, our previous work established that mitophagy is a basal, homeostatic process that operates during normal physiology to clear damaged mitochondria through the autophagic pathway. This steady-state mitochondrial turnover occurs independently of mitochondrial stress-induced PINK1-Parkin signaling in a cell- and tissue-specific fashion with a complex regulatory network. In short-lived model organisms such as yeast and nematodes, mitophagy levels decrease with age, leading to the widely held hypothesis that mitophagic capacity may also decline in aged mammalian tissues and could contribute to age-related neurodegeneration. Significant translational efforts are underway to enhance or restore mitophagy levels in these pathological contexts. However, because short-lived and long-lived species have distinct evolutionary pressures, it remains unclear whether lessons learned from short-lived organisms and cell lines actually translate to mammalian physiology - a question that has great translational significance. Mammalian postmitotic neurons survive for decades, have high energy demands and are particularly sensitive to homeostatic impairments. Understanding organelle homeostasis in long-lived mammals is crucial, given how aging accelerates cognitive decline and disease.

How natural aging modifies mammalian mitophagy in distinct brain regions and cellular subtypes remains to be examined, because profiling mitophagy within intact tissues and brain circuits is not straightforward using conventional techniques. Thus, while major insights have been possible from tractable short-lived model organisms, the question of how autophagy pathways are modulated in natural mammalian aging has remained an intractable question. Overcoming these limitations, genetically encoded optical reporter mouse models have recently emerged as powerful tools to monitor specific stages of physiological autophagy and mitophagy in intact tissues at high resolution with cell-specific precision.

Here, using two genetically encoded reporter mouse strains, we tracked mitophagy and autophagy longitudinally throughout the mouse lifespan in several pathophysiologically important brain regions, with cell types including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia, and interneurons. We defined aging-related dynamics in mitophagy and autophagy, providing strong evidence that decreased mitophagy and autophagy are not general features of healthy mammalian brain aging. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.

Readily available epidemiological data sets have grown considerably in size over the past few decades, with the UK Biobank as an example of the type. Here, researchers use this data on correlations between lifestyle and mortality to make an assessment of the optimal choices. It is somewhat taken as read that better choices in the matter of weight, exercise, and so forth do in fact reduce mortality - that the correlation does in this case imply causation. That is the consensus, and well supported by animal studies of the effects of lifestyle factors on long term health, in which causation can be demonstrated. It is reasonable to expect that most of the lifestyle effects on mortality are similar across mammals, although one should probably also expect differences in the size of effect for any given relationship.

A prospective cohort study was conducted using data from over half a million UK Biobank participants. Two datasets were created by subjective and objective measurements of physical activity: the Subjective Physical Activity (SPA) and Objective Physical Activity (OPA) datasets. Lifestyle patterns, including diet habits, exercise levels, and sleep quality, were assessed within these datasets. Biological aging was quantified using validated methods, including Homeostatic Dysregulation, Klemera-Doubal Method Biological Age, Phenotypic Age, and Telomere Length. All-cause mortality data were obtained from the National Health Service.

The findings indicate that, in most cases, maintaining an anti-inflammatory diet, engaging in at least moderate physical activity, and ensuring healthy sleep conditions are associated with delayed physiological aging (Cohen's d ranging from 0.274 to 0.633) and significantly reduced risk of all-cause mortality (hazard ratio for SPA: 0.690; hazard ratio for OPA: 0.493). These effects are particularly pronounced in individuals under 60 years of age and in women. However, it was observed that the level of physical activity recommended by the World Health Organization (600 MET-minutes/week) does not achieve the optimal effect in delaying biological aging. The best effect in decelerating biological aging was seen in the high-level physical activity group (≥ 3000 MET-minutes/week). The study also highlights the potential of biological age acceleration and telomere length as biomarkers for predicting the risk of mortality.

Link: https://doi.org/10.1186/s11556-024-00362-7

Chronic, unresolved inflammation is a feature of aging. Constant inflammatory signaling is disruptive to tissue structure and function, and contributes to the onset and progression of all of the common, ultimately fatal age-related conditions. Inflammatory signal molecules generated in one organ will circulate throughout the body to provoke inflammation in other organs. This is the one of the many ways in which any one localized point of failure or excessive amount of age-related cell and tissue damage will tend to drag down the rest of the body.

As people age, the liver is among several organs that experience chronic, low-grade inflammation, a state that keeps the immune system activated even though there is no threat. Cells that die through necroptosis burst and release substances that lead to inflammation. Using an aging mouse model, researchers demonstrated the damaging effects of necroptosis in the liver, as well as the reduction of those effects when necroptosis was blocked. They also found that activating necroptosis in the liver increased liver inflammation and, surprisingly, increased brain inflammation, which affected the ability of mice to build nests, a possible sign of cognitive impairment.

"We hypothesize that when liver necroptosis is activated, the liver secretes toxic or inflammatory molecules that enter the bloodstream and cross the blood-brain barrier, where they cause inflammation in the brain. This type of organ crosstalk is becoming very important in research. Usually, when we study a disease condition, we focus on one organ, but when we do that, we miss the systemic effect. What we have found in our mice studies so far matches what is reported for patients - that people with liver diseases have high inflammation in the liver and also have cognitive issues. Our key question is what is causing this increase in inflammation in aging? It is important that we advance our knowledge in this area because it is critical that we develop new ways to treat these diseases."

Link: https://www.ouhsc.edu/News/details/organ-crosstalk-extends-harms-of-inflammation-from-liver-to-brain

The 16S rRNA gene is a component of the ribosome in bacteria. It conveniently contains (a) highly conserved sections, allowing this gene sequence to be reliably found in DNA samples from any bacterial species, but also (b) regions that vary widely by species, allowing for the identification of the bacterial species of origin. Thus the 16S rRNA region of bacterial genomes can cost-effectively sequenced in bulk from any sample, and the data analyzed to produce an assessment of which bacterial species are present, and in what relative proportions. In the case of the gut microbiome, fecal samples lead to a map of the bacterial populations of the intestine.

The composition of the gut microbiome is presently thought to be influential on long term health. The relative proportions of bacterial species making up the gut microbiome change with age, for reasons that include diet and immune system dysfunction, but which are far from fully explored in detail. Nonetheless, in a world in which it costs little to gather this data, greater understanding will come in time. In recent years, the research community has demonstrated correlations between gut microbiome composition and chronological age, as well as the presence of specific age-related conditions. It seems likely based on animal studies that ways to produce lasting, calibrated restoration of a youthful balance of microbial populations can be produced from the starting point of fecal microbiota transplantation, and that this class of therapy will provide to be beneficial for all older people.

Identification of age-associated microbial changes via long-read 16S sequencing

In this study, we investigated the association between age and gut microbial composition in individuals residing in Singapore. To the best of our knowledge, this is the first full-length 16S rRNA gene assessment of the gut microbiota in a multi-ethnic country. Previous studies evaluating the effect of age on the gut microbiome primarily used a short-read 16S rRNA gene sequencing approach. The limited resolution of short-read sequencing often fails to detect bacterial changes at the species/strain level, which can affect data interpretation. In our work, we utilized the long-read sequencing approach to explore age-related gut microbiome alterations for the first time. In addition to replicating previous findings, our study unveiled several novel differentially abundant taxa and predicted functional pathways associated with age.

Despite the insignificant differences in alpha diversity and beta diversity, several differentially abundant bacterial taxa were detected among the age groups. For instance, a notable decrease in Bacteroides uniformis was observed in the gut microbiome of middle-aged individuals, while Bacteroides plebeius was significantly elevated in the old group. These findings align with multiple earlier studies, which reported contrasting findings on the abundances of Bacteroides in the gut microbiome of individuals from different age groups. Some studies documented increased levels in younger adults, while others reported higher abundances in the elderly group. Interestingly, recent investigations have also linked the differential abundance of Bacteroides to the overall health status of the study group. Collectively, these findings underscore the importance of employing sequencing techniques that provide precise taxonomic assignments down to the species/strain level, thereby facilitating a more comprehensive delineation of the gut microbiome and permitting a more accurate understanding of the microbial ecology associated with specific conditions.

In the pairwise comparison between middle-aged and old groups, we found that elderly individuals exhibited a significantly higher abundance of Klebsiella pneumoniae (as well as the Klebsiella genus) in their gut microbiome. The elevated level of K. pneumoniae in older individuals is believed to be associated with factors such as increased use of medication or inflammation linked to interleukin-6, both of which are common in older individuals. This bacterium, which is known to be a pathogen, may contribute to health issues frequently observed in this age group.

Besides replicating previous research findings, our study revealed several novel differentially abundant bacterial species that have not been previously reported. These include increased abundances of Eggerthella lenta in middle-aged participants and reduced levels of Catenibacterium mitsuokai in elderly individuals. E. lenta, a bacterium belonging to the Coriobacteriaceae family, is known as an opportunistic pathogen implicated in various conditions and infections. C. mitsuokai, on the other hand, is generally considered part of the normal human gut microbiome. Previous studies have linked C. mitsuokai with dyslipidemia and insulin resistance, and a higher abundance of the Catenibacterium genus has been associated with a potentially lower risk of frailty. Altogether, these findings suggest potential health implications related to changes in the levels of C. mitsuokai in the gut microbiome. The observed reduction of C. mitsuokai in elderly individuals of our cohort could either reflect age-related alterations in gut microbiome composition or represent a compensatory response to the health changes commonly seen in old individuals.

Researchers here work towards developing a better characterization of the age-related burden of senescent cells in skin tissue. As for all tissues in the body, the number of senescent cells in skin grows with age. This is the result of an imbalance between pace of creation and pace of clearance by the immune system; with age, cell stress increases while the capabilities of the immune system decline. Lingering senescent cells constantly secrete pro-inflammatory signals, and this contributes to body-wide inflammation. Skin is a large organ, and provides a meaningful fraction of this contribution of senescent cells to the whole body chronic inflammation of aging.

Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and cell-extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging.

A skin-specific cellular senescence gene set, termed SenSkin, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.

Link: https://doi.org/10.1111/acel.14358

Researchers here report on the discovery of a long non-coding RNA that in flies reduces the pace of creation of ribosomes, and thus the pace of protein synthesis in ribosomes, by inhibiting production of a specific ribosomal protein. The result is extended lifespan. This is intriguing, as improving ribosomal function has been shown to extend life in short-lived species, and this does not have the look of an improvement. But equally, there are signs that long-lived individuals may exhibit reduced creation of ribosomes. Protein synthesis in ribosomes is also reduced in a number of life extending interventions, such as calorie restriction and its mimetics. As for all matters of cellular biochemistry in the context of aging, the influence of ribsosomal activity is complex and the fine details matter.

Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterize aal1 (ageing-associated lncRNA), which is induced in quiescent fission yeast cells. Deletion of aal1 shortens the chronological lifespan of non-dividing cells, while ectopic overexpression prolongs their lifespan, indicating that aal1 acts in trans. Overexpression of aal1 represses ribosomal-protein gene expression and inhibits cell growth, and aal1 genetically interacts with coding genes functioning in protein translation. The aal1 lncRNA localizes to the cytoplasm and associates with ribosomes. Notably, aal1 overexpression decreases the cellular ribosome content and inhibits protein translation.

The aal1 lncRNA binds to the rpl1901 mRNA, encoding a ribosomal protein. The rpl1901 levels are reduced ~2-fold by aal1, which is sufficient to extend lifespan. Remarkably, the expression of the aal1 lncRNA in Drosophila boosts fly lifespan. We propose that aal1 reduces the ribosome content by decreasing Rpl1901 levels, thus attenuating the translational capacity and promoting longevity. Although aal1 is not conserved, its effect in flies suggests that animals feature related mechanisms that modulate ageing, based on the conserved translational machinery.

Link: https://doi.org/10.1038/s44319-024-00265-9

Cells become senescent at some pace throughout the body and throughout life, largely by reaching the Hayflick limit on replication, but also under other circumstances, such as when a cell sustains potentially cancerous mutational damage. A senescent cell ceases replication and actively secretes pro-inflammatory signals that (a) encourage senescence in bystander cells and (b) attract the attention of the immune system to destroy the senescent cell. This is all find so long as the immune system can destroy senescent cells rapidly enough to prevent their accumulation, but this stops being the case in later life as the immune system declines in effectiveness. Senescent cells accumulate and become disruptive to tissue structure and function.

Researchers have in the past shown that introducing senescent cells into joint tissue in mice is enough to induce or accelerate osteoarthritis. In today's open access paper, researchers report on the introduction of senescent cells into the skin of 3 month old mice, followed by assessment of a range of measures of health 5 months later. Mouse age doesn't linearly relate to human age, but this is roughly equivalent to the range of early 20s to early 40s in humans. One would not expect to see dramatic signs of aging in 8 month old mice, but there are measurable differences, declines in function. This study demonstrates that the presence of a greater burden of senescent cells makes those declines worse.

Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters.

Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.

A limitation of our study is that the amount and composition of transplanted senescent cells does not accurately reflect senescent cell accumulation during physiological aging. Future research should include other models of senescence induction in the skin, including exposure to physiological levels of UV irradiation. Furthermore, to determine whether paracrine senescence is the causal factor driving the observed aging phenotypes, experiments involving the clearance of senescent cells using senolytic drugs or genetic models that enable the removal of p16 or p21 positive cells should be conducted. In addition, further research is needed to pinpoint which factors released by senescent cells in the skin drive the systemic effects observed in host tissues. Such mechanistic studies could open new avenues for therapeutic intervention.

The most well-studied mouse models of extended life span resulting from disrupted growth hormone signaling involve genetic changes that likely do more than just affect growth hormone metabolism. The usual challenges of cellular biochemistry apply, in that most proteins have more than one function. Here, researchers show that a selective knockout of only growth hormone still extends life, but not to the same extent as is observed in the better known models. Looking at the broader context of the influence of growth hormone metabolism on aging, it is worth recalling that the analogous human loss of function mutants, the condition known as Laron syndrome, do not appear to live notably longer than the rest of the population. As is the case for calorie restriction, effects in short lived species are larger than those in long-lived species such as our own.

The somatotrophic axis, comprised of growth hormone (GH) and GH-releasing hormone (GHRH) secreted from the pituitary or hypothalamus, respectively, is a powerful determinant of laboratory mouse longevity evidenced by the dramatic lifespan extensions that result from genetic interruption at any level of this axis in mice. This body of work suggests that the action of GH is a critical regulator of mammalian lifespan. A crucial limitation of these studies, however, is that mice typically treated as "GH-deficient" display defects in several other genes and hormones which leaves the direct contribution of GH unexplored.

Ames dwarf and Snell dwarf mice, deficient for GH as well as prolactin and thyroid-stimulating hormone, were among the first mice with defective somatotrophic signaling found to be long-lived. Mutant mice lacking a functional GHRH-receptor or functional GHRH also cannot be considered true models of "isolated GH deficiency" as the extrapituitary effects of GHRH, which have gained appreciation as important physiological regulators, could contribute to the lifespan extension reported in these mice. Additionally, mice with a targeted disruption of the GH-receptor (GHR) gene display dramatically elevated levels of GH.

To address this critical gap in knowledge, we carried out the first assessment (to our knowledge) of lifespan in mice with a targeted GH gene knockout in conjunction with metabolic assessment during adulthood. GH knockout (KO) mice maintained under specific pathogen-free conditions with ad-libitum access to standard rodent diet and water displayed a 21% extension in median lifespan over wild type littermates. It is noteworthy that while the differences in lifespan we observed between KO and wild type mice were significant, they are lesser in magnitude than the 40+% extensions reported in other models of somatotrophic disruption. This suggests that while GH deficiency clearly contributes to lifespan extension, an additive effect of additional gene/hormone deficiencies on lifespan may also exist.

Link: https://doi.org/10.1101/2024.09.18.613718

Evidence from animal studies strongly suggests an important role for cellular senescence in supporting cell populations in the brain in driving the onset and progression of age-related neurodegenerative conditions. Senescent cells accumulate with age in tissues throughout the body, the result of growing cell stress resulting from the molecular damage and disarray of aging on the one hand, but on the other hand also the problem of inefficient clearance, resulting from the growing inability of the immune system to destroy senescent cells in a timely fashion. Senescent cells energetically secrete a pro-inflammatory mix of signals, disruptive to tissue structure and function when sustained over the long term.

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression.

Recent research has linked disease-associated microglia to their transition into a senescent state - characterized by irreversible cell cycle arrest - in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets.

This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

Link: https://doi.org/10.1002/nep3.56

Both calorie restriction and intermittent fasting slow aging and extend life in short-lived mammals. In the short term, many measures of health are improved. In long-lived mammals such as our own species, the short term effects are very similar, but effects on life span are much smaller. The reasons why this is the case remain to be determined. Cellular biochemistry is enormously complex and calorie restriction and fasting produce sweeping changes in near every aspect of the operation of metabolism. Researchers can point to improvements in autophagy as the likely primary mechanism for benefits, but do not have an understanding as to why improved autophagy affects life span so differently in short-lived versus long-lived mammals.

Studies conducted separately to assess the effects of calorie restriction and intermittent fasting in rodents have generally indicated that calorie restriction has a larger effect on aging and longevity. Today's open access paper reports on a direct comparison between the two strategies in the same study, and comes to much the same conclusion. One novel aspect of the research is the use of genetically diverse mice known as diversity outbred mice, a model more representative of the differences in a natural population of mammals than is the case for the usual lineages with carefully cultivated similar genetics between individuals. This led to some interesting insights into differential effects of low calorie intake between mice with different characteristics.

Dietary restriction impacts health and lifespan of genetically diverse mice

Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice.

We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling, an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life.

Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

The choroid plexus is a structure responsible for producing and filtering cerebrospinal fluid, but likely has other important roles as well. The production of cerebrospinal fluid declines with age for reasons that are not all that well explored. A reduced flow of cerebrospinal fluid through the brain likely contributes to brain aging via an increased presence of the metabolic waste that is normally drained from the brain via cerebrospinal fluid flow. Hence the occasional paper such as this one, in which researchers attempt to make some inroads into mapping the age-related biochemical changes that take place in cells of the choroid plexus, one small step along the way to the construction of a bigger picture view of how aging affects the choroid plexus.

The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1).

CSF is composed of 99% water, and the remaining 1% is accounted for by proteins, ions, neurotransmitters, and glucose. A high water permeability of the blood-cerebrospinal fluid barrier (BCSFB), a physicochemical barrier established by choroid plexus (CP) epithelial cells, is essential for the optimal production of the CSF, and this is met by the abundant expression of water channels AQP4 and AQP1. CSF enters from the perivascular spaces surrounding arteries into the brain parenchyma through the AQP4 water channels in the astrocytic end-feet. AQP1 is a cGMP-gated cation channel that serves as a water channel and a gated ion channel in the choroid plexus, contributing to the regulation of CSF production.

Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJPs were also reduced in aged mice.

Our study highlights transcriptional level changes in the CP during aging. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.

Link: https://doi.org/10.1186/s12987-024-00574-0

A growing body of evidence suggests that composition of the gut microbiome - and changes in that composition - may be as influential on long-term health, aging, and age-related disease as well explored lifestyle factors such as exercise. Given the ability to cheaply and accurately determine the identity and size of microbial populations making up the gut microbiome via 16s rRNA sequencing, researchers are finding that many specific aspects of the microbiome both change with age and correlate with specific age-related diseases. The next step is to build robust approaches to producing permanent change in the gut microbiome, such as that achieved via fecal microbiota transplantation from a young donor to an old recipient, but with greater control over exactly what is delivered and the intended outcome.

With the introduction of novel molecular biological techniques and advances in next-generation sequencing technologies, we finally have a snapshot of the gut microbiome and its taxonomical and functional constituents. Various studies have been conducted on healthy elderly individuals to characterize their gut microbiome composition and identify alterations that help delay the onset of age-associated disorders. Although aging is a complex biological process that has yet to be fully understood, we have an increasing volume of evidence supporting the existence of a dialogue between the gut microbiome of a host and its aging process. Aging brings about changes in the gut microbiome, disrupting its balance and functionality, which can accelerate senescence through inflammatory processes and reduced production of beneficial metabolites.

Advancements in the different "omics" fields have provided us with a clear understanding of various host-microbe interactions and their influences on aging. Enrichment of certain taxa, such as Bifidobacterium, Christensenellaceae, and Akkermansia, has been shown to promote longevity and improve quality of life during senescence. To improve the gut microbiome and encourage healthy aging, techniques such as fecal microbiome transplantation (FMT) and oral probiotic treatment have been used. Administration of prebiotics and probiotics may mitigate age-related alterations linked to sarcopenia and longevity.

Since age-related disorders are known to increase intestinal permeability, regaining intestinal permeability by FMT may be a regenerative and successful medicinal technique in producing stem cells for the elderly. Nevertheless, more research is needed to determine whether FMT to old recipients from young donors restores the ability of stem cells to self-renew, regenerate, and differentiate, thereby improving lifespan. To pave the way for discovering therapeutic medications for extending lifespan and treating disorders linked to aging, more research into the interactions between intestinal stem cells and the microbiome is necessary.

Link: https://dx.doi.org/10.14218/ERHM.2024.00008

The categorization of cell states into neat taxonomy is an attempt to conceptually simplify a much more complex, analog underlying reality. Any two cells in a given category may be different in ways that turn out to be meaningful in some contexts. So it should be taken as read that the senescent cells that grow in number with age and contribute to age-related disease differ from one another in many ways, and that what we call senescence is at present an oversimplified big tent. It may well turn out require separation into smaller categories to aid continued research and development into ways to reduce the impact of cellular senescence on later life health.

Better understanding the many differences that can exist between any two given senescent cells is of great interest to researchers who are attempting to produce novel senolytic therapies that can selectively destroy these cells. The existing better explored target mechanisms of first generation senolytic drugs produce variable efficacy in clearance of senescent cells depending on tissue type, duration of senescence, reasons for the onset of senescence, and no doubt many other aspects of senescent biochemistry. The best senolytics to date clear only a fraction of senescent cells, that fraction varying by tissue. In today's open access paper, researchers present a view of cellular senescence as an emergent phenomenon driven by a range of distinct stress response packages, a step on the road to better understanding how to produce better senolytic therapies.

Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity

Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity (β-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells.

Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples. Genes regulating stress responses - including transcription factors and genes controlling chromatin accessibility - are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner.

We propose that 'senescence' cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, transcription factors, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.

Analysis of large omics data sets in the context of aging and mortality proceeds apace in the research community. On the one hand there is the production of aging clocks, algorithmic combinations of omics data generated via machine learning, in the attempt to produce a useful measure of biological age. On the other hand there are related analyses such as the one noted here, in which researchers attempt to correlate specific individual biomarkers obtained from a blood sample to age and mortality. Many, many metabolites circulate in the body, and it is certainly possible that some of these are better biomarkers for specific uses than the present consensus choices.

The plasma metabolome carries dynamic biological signals reflecting personal health status. Previous studies have demonstrated the potential of metabolomic biomarkers for disease and mortality risk prediction. With the availability of low-cost, standardized, high-throughput nuclear magnetic resonance (NMR) metabolomic profiling and the promotion of blood tests during medical checkups, the identification and quantification of aging-related metabolomic biomarkers hold potential for personalized health monitoring and anti-aging interventions.

Here, we present the largest aging-related metabolomic profile to date based on 325 NMR biomarkers from 250,341 individuals from the UK Biobank. A subset of 54 aging-related representative metabolomic biomarkers were identified based on their ability to predict all-cause mortality. These aging-related biomarkers are involved in diverse biological functions and metabolic pathways, which might serve as potential anti-aging intervention targets and facilitate further exploration of the mechanism of aging-related diseases. High-resolution analysis of the refined composition and structure of multiple lipoprotein-related biomarkers, enabled by NMR profiling, contributes greatly to unraveling the roles of lipid metabolism in the process of aging.

Link: https://doi.org/10.1038/s41467-024-52310-9

Channels by which cerebrospinal fluid leaves the brain are important to long term health, as they allow removal of metabolic waste such as the protein aggregates that characterize neurodegenerative conditions. It is thought that atrophy of these channels, including (a) passage through the cribriform plate and (b) the comparatively recently discovered glymphatic system, contributes to the aging of the brain by allowing molecular waste to build up to levels that change cell behavior for the worse. Here researchers repeat in human patients the demonstrations of glymphatic drainage of cerebrospinal fluid that have been carried out in laboratory animals. Leucadia Therapeutics is developing an implant to restore passage through the cribriform plate, but it remains to be seen as to how the more complex dysfunction of the glymphatic system will be best addressed.

The glymphatic pathway was described as a network of perivascular spaces (PVS) that facilitates the organized movement of cerebrospinal fluid (CSF) between the subarachnoid space and brain parenchyma. CSF mixes with interstitial fluid, promoting clearance of soluble by-products from the central nervous system. This is suspected to be impaired in sleep dysfunction, traumatic brain injury, and Alzheimer's disease.

Pioneering glymphatic studies in rodents showed CSF tracer flow through the subarachnoid space and into brain parenchyma along periarterial spaces. Human intrathecal contrast-enhanced MRI similarly demonstrated parenchymal contrast enhancement in a centripetal pattern from the subarachnoid space, providing early evidence for human glymphatic function. The PVS is postulated to be involved in this process, yet perivascular CSF tracer transport has not been observed in humans. This is a proof-of-principle study in which, by using intrathecal gadolinium contrast-enhanced MRI, we show that contrast-enhanced CSF moves through the PVS into the parenchyma, supporting the existence of a glymphatic pathway in humans.

Link: https://doi.org/10.1073/pnas.2407246121

Progress in medicine is painfully slow, in part thanks to the perverse incentives that drag down every heavily regulated field. But seven decades are left before we reach the closing years of this century. Seventy years in medicine is a long time. Consider what the medical science of the 1950s looked like in practice; consider what the treatment options looked like for common age-related diseases in that era, where they existed at all. Given that a longevity industry is just getting started, barely a decade old at this point, it seems a strange idea to bet against sizable gains in human life span before the end of the century. Even we play it safe and suggest that it will take a good 20 years or more to measure the degree to which novel forms of therapy extend healthy life in human patients, that still leaves a good long time for the research and development of rejuvenation therapies aimed at the repair of forms of molecular damage that cause aging.

Still, one can't argue against the diminishing returns produced by the old way of doing things when it comes to treatment and prevention of age-related disease. That encompasses public health measures aimed at reducing smoking (and now obesity, the largest problem of our era, as smoking was the largest problem of a past one), improved wealth, and the introduction of therapies that can modestly slow or reduce some of the consequences of aging without actually addressing its causes. Medicine that reduces blood pressure or lowers LDL-cholesterol, for example. Both are influential in the populations that use it, when considered from an epidemiological viewpoint where a 10-20% risk reduction is sizable across a population. But for an individual, a 10-20% risk reduction isn't all that great. It certainly isn't rejuvenation. But that is what the old approach to age-related disease gave us, marginal therapies, marginal outcomes.

The reason that betting against radical life extension seems foolish is that there are now earnest efforts underway to treat aging as a medical condition, a whole new approach to the problem of age-related disease. None of this has yet to reach the clinic in any widespread way, so who knows how effective the initial therapies will turn out to be. On balance, and over the course of decades, one would have to think that a biotech industry actively trying to slow and reverse aging by addressing its causes will make significantly greater progress towards longer healthy lives than a medical industry that was only trying to treat the symptoms of aging.

Implausibility of radical life extension in humans in the twenty-first century

More than three decades have passed since predictions were made about the upper limits to human longevity. Evidence presented here based on observed mortality trends in the worldʼs eight longest-lived populations and in Hong Kong and the United States, and metrics of life table entropy, indicate that it has become progressively more difficult to increase life expectancy. At ages 65 and older, the observed average rate of improvement in old-age mortality in the longest-lived populations evaluated here was 30.2% from 1990 to 2019. The impact of this level of mortality improvement, if experienced again over the next three decades, would yield only a 2.5-year increase in life expectancy at birth. This is a fraction of the 3-year per decade (for example, 8.7-year increase from 1990 to 2019) gain in life expectancy predicted by those claiming that radical life extension was forthcoming or already here. That is, old-age mortality has not been declining since 1990 at a pace that is even close to the rate of improvement required to achieve radical life extension in this century.

Where uncertainty remains is how much more survival time can be manufactured with the disease model that now prevails (shown here to have a declining influence on life expectancy) and the far greater uncertainty associated with future improvements in survival that may result from the deployment of gerotherapeutics or other advances in medicine that cannot be conceived of today. Because radical lifespan extension brought forth by yet-to-be-developed medical advances cannot be empirically evaluated over short timeframes, a limitation here (and within the field of aging in general) is that it is difficult to justify any numerical estimate of their future influence on life expectancy.

Forecasts about radical life extension in humans thought to be occurring now or projected to do so in the near term have already influenced the operations and financial structure of multiple industries. Results presented here indicate that there is no evidence to support the suggestion that most newborns today will live to age 100 because this would first require accelerated reductions in death rates at older ages (the exact opposite of the deceleration that has occurred in the last three decades). Furthermore, even if the 30.2% improvements in mortality in the 65-and-older population observed to have occurred in high-income nations from 1990 to 2019 occurred again, only a small fractional increase in survival to age 100 would ensue.

The evidence presented here indicates that the era of rapid increases in human life expectancy due to the first longevity revolution has ended. Given rapid advances now occurring in geroscience, there is reason to be optimistic that a second longevity revolution is approaching in the form of modern efforts to slow biological aging, offering humanity a second chance at altering the course of human survival. However, until it becomes possible to modulate the biological rate of aging and fundamentally alter the primary factors that drive human health and longevity, radical life extension in already long-lived national populations remains implausible in this century.

If there were a reliable way to prevent metastasis, the spread of cancerous cells throughout the body and generation of secondary tumors, few types of cancer would be life-threatening in the context of today's medical capabilities. Thus there is a lot to be said for the various lines of research aimed at finding ways to sabotage metastasis. Here researchers attempt to answer the question of why migrated metastatic cells sometimes fail to establish a secondary tumor, and point to a population of immune cells that may prove to be a useful target for anti-metatasis immunotherapy.

Cells that migrate from primary tumors and seed metastatic tumors are called disseminated cancer cells (DCCs). Some DCCs behave aggressively, immediately starting tumors in new tissue, while others remain in a state of suspended animation referred to as dormancy. "It's long been a mystery how some DCCs can remain in tissues for decades and never cause metastases, and we believe we've found the explanation." Breast cancer and many other types of cancer metastasize to the lungs. In research involving three mouse models of metastatic breast cancer, researchers determined that when breast cancer DCCs spread to the lung's alveoli, they are kept in a dormant state by immune cells known as alveolar macrophages.

Confirming the importance of alveolar macrophages in keeping DCCs dormant, researchers found that depleting them in the mice significantly increased the number of activated DCCs and subsequent metastases in their lungs compared to mice with normal levels of the immune cells. As DCCs become more aggressive, the researchers found, they become resistant to the pro-dormancy signals produced by alveolar macrophages. Ultimately, this evasion mechanism enables some DCCs to "wake up" from dormancy and reactivate to form metastases. Understanding how immune cells keep DCCs in check could lead to new anti-metastatic cell therapies among other strategies. For example, it may be possible to strengthen macrophage signaling so that DCCs never awaken from dormancy or find ways to prevent older DCCs from becoming resistant to dormancy signaling.

Link: https://www.eurekalert.org/news-releases/1060251

Researchers can use the strategy of Mendelian randomization to attempt to explore causation in human epidemiological data, provided that data includes information on gene variants associated with the outcomes of interest. Here, this approach is used to gain some insight into the direction of causation in the relationship between epigenetic age acceleration, an epigenetic age greater than chronological age, and the incidence of neurodegenerative conditions such as Alzheimer's disease.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age, GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge, (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6,618 to 482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (inverse-variance-weighted, IVW beta = -0.309). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD.

In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.

Link: https://doi.org/10.1111/acel.14271

Past studies have demonstrated that the economic cost of aging is enormous. It is not just a matter of the high medical cost of coping with a failing body and a panoply of conditions that cannot presently be cured or even much reversed. The lifetime cost of treating only cardiovascular disease is something like $750,000, for example. There is also the constant destruction of knowledge, capability, and ability to work. There is the opportunity cost of actions that cannot be taken. If everyone in the US gained a year of additional life, if aging was slowed by one year, $38 trillion in economic gains per year would be realized. These are staggering numbers.

In today's open access papers, the authors take a different approach to looking at the value of treating aging as a medical condition. What if every region of the world could adopt the age-related mortality of the best performing region? For each major cause of aging the authors take mortality rates in the best performing region as a benchmark, and consider mortality above this level to be avoidable. Which may or may not be entirely the case, but it is a decent place to start if running the numbers on what an incremental, near future advance in the treatment of aging might look like. As one might expect, the numbers are still very large.

Why do the differences between regions exist? Largely lifestyle choices, and then a layer of socioeconomic status and access to medical technologies on top of that. When it comes to cardiovascular disease risk, the average American is not outperforming the average Bolivian hunter-gatherer, despite the vast disparity in wealth. So strictly speaking, this isn't a discussion about medical technology. Nonetheless, the numbers are interesting in a world in which we may expect the near future introduction of treatments for aging that could have similar effect sizes to exercise, calorie restriction, weight loss, and other lifestyle considerations.

The economic value of reducing avoidable mortality

Living longer and healthier boosts individual and family welfare. As part of the World Bank's Healthy Longevity Initiative, we quantified the economic value of achieving the highest possible life span. We estimated the economic value of reducing avoidable mortality, defined as the difference between observed (or projected) mortality and lowest achieved (or projected) mortality, by world regions, sex, and age, between 2000 and 2021, with projection to 2050.

In 2019, 69% of mortality, or 40 million deaths, was avoidable. The economic value of avoidable mortality globally was 23% of annual income, meaning that, globally, populations would be willing to give up about one-fifth of their current income in exchange for a year living at the lowest achieved mortality rate. This value ranges from 19% in China to 34% in sub-Saharan Africa. Under the rapid-progress scenario, in which countries experience fast but plausible mortality reductions from 2019 to 2050, we would expect globally the gap between projected and frontier life expectancy to be halved by 2050, and the economic value after achieving this scenario is equivalent to 14% of annual income. Our work provides supportive evidence on the high economic value placed on improving health.

The economic value of reducing mortality due to noncommunicable diseases and injuries

With population aging, national health systems face difficult trade-offs in allocating resources. The World Bank launched the Healthy Longevity Initiative to generate evidence for investing in policies that can improve healthy longevity and human capital. As part of this initiative, we quantified the economic value of reducing avoidable mortality from major noncommunicable diseases and injuries. We estimated avoidable mortality - the difference between lowest-achieved mortality frontiers and projected mortality trajectories - for each cause of death, for 2000, 2019 and 2050, and for geographic regions, with high-income countries, India and China considered separately; we applied economic values to these estimates.

The economic value of reducing cardiovascular disease avoidable mortality would be large for both sexes in all regions, reaching 2-8% of annual income in 2019. For cancers, it would be 5-6% of annual income in high-income countries and China, and for injuries, it would be around 5% in sub-Saharan Africa and Latin America and the Caribbean. Despite the large uncertainty surrounding our estimates, we offer economic values for reducing avoidable mortality by cause and metrics comparable to annual incomes, which enable multisectoral priority setting and are relevant for high-level policy discussions around budget and resource allocations.

The interior of blood vessels is lined by the endothelium. With aging, cells of the endothelium exhibit stress, inflammation, and altered behavior, contributing to the development of atherosclerosis and negatively affecting performance of the vasculature. Here, researchers discuss the degree to which this aspect of degenerative aging is caused by the presence of senescent cells. Cells become senescent constantly throughout life, but in youth are cleared efficiently by the immune system. This clearance falters later in life, allowing senescent cells to grow in number to the point of becoming disruptive to tissue structure and function. Senolytic therapies to selectively clear senescent cells have proven to be beneficial in animal studies and are presently in human trials for a number of age-related conditions.

Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence.

We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified. We found a negative correlation in passaged cell cultures between a reduction in NO production with increased ES and the formation of reactive oxygen species and reactive nitrogen species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN).

Thus NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.

Link: https://doi.org/10.3390/ijms25189890

The metabolic responses to exercise and calorie restriction are so sweeping that there are many, many possible avenues by which drugs can mimic some of the effects. Researchers here try to get closer to the roots of these beneficial responses by using a molecule that will trigger the same reactions as two circulating signal molecules known to be important in regulating the response to exercise and fasting. This seems a reasonable strategy to try to capture a larger fraction of the benefits of exercise and fasting, but of course much more work is needed in order to see how this approach matches up to the sizable number of existing exercise mimetic and calorie restriction mimetic interventions.

Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest.

In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Link: https://doi.org/10.1021/acs.jafc.4c04849

Stem cell populations provide a supply of daughter cells needed for tissue function, but their activity - and this supply of new cells - declines with age. Stem cell populations can shrink in size, but aged stem cells also spend more time in quiescence rather than the production of daughter cells. This happens due to some combination of (a) age-related damage to stem cells and (b) age-related damage to the stem cell niche, the supporting cells that provide an environment in which the stem cells reside. For many stem cell types, researchers have demonstrated that old stem cells become more active when placed in a young environment, which suggests that there will be ways to improve stem cell function in older individuals.

The traditional approach to finding approaches to stem cell functional restoration, or indeed any other goal in medicine, is to (a) identify regulatory genes controlling the process of interest, here the maladaptive reduction in stem cell activity in response to an aged tissue environment, then (b) find small molecules that alter expression or protein interactions to either upregulate or downregulate the activity of a target regulatory gene. Today's open access paper is an example of the first step, in which researchers search for genes regulating the activity of neural stem cells. The generation of new neurons by neural stem cell populations and their subsequent integration into neural circuits is vital to memory and learning, but also critical to what little capacity the brain has to maintain itself and recover from injury. As for all stem cell populations, the activity of neural stem cells is reduced in older people. Forcing these cells back into action may produce a beneficial improvement in cognitive function.

CRISPR-Cas9 screens reveal regulators of ageing in neural stem cells

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing. Several genetic interventions have been found to ameliorate old brain function, but systematic functional testing of genes in old NSCs - and more generally in old cells - has not been conducted. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice.

Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age.

Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

Cognitive function declines with advancing age. The brain accumulates damage at the biochemical level, but also in the form of ruptured blood vessels and microbleeds. Supporting cells become inflammatory, myelin sheathing of axons becomes damaged, the delicate balance of complex mechanisms that supports the activities and connections of neurons runs awry. Add a stroke to all of this, and the pace of decline accelerates afterwards. The reasons why this is the case are likely more complex than simply an additional burden of inflammation, and the epidemiological paper here only demonstrates the outcome, not the mechanisms.

Stroke is a leading cause of disability and dementia worldwide, with projections suggesting a continued rise in its prevalence and burden. Recent studies have shown that cognitive impairment is highly prevalent after stroke, with cognitive deficits present in over a third of stroke survivors. However, the precise impact of stroke on the trajectory of cognitive function remains unclear. Previous studies, primarily hospital-based, have been unable to account for prestroke cognitive performance, and several population-based studies examining prestroke and poststroke cognitive function reported conflicting findings, likely due to variations in study design, sample characteristics, and statistical techniques.

This study aimed to address these inconsistencies by mapping the trajectory of cognitive function after stroke relative to the cognitive trajectory without a previous stroke using harmonized data from diverse population cohorts from the Cohort Studies of Memory in an International Consortium (COSMIC). The study included 20,860 participants with a mean (standard deviation, SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures.

Thus in this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

Link: https://doi.org/10.1001/jamanetworkopen.2024.37133

Researchers here find a role for TIMP3 overexpression in the progression of macular degeneration, an age-related deterioration of the retina that causes blindness. Interestingly, TIMP3 was previously shown to contribute to the age-related decline in stem cell function, and its removal appears beneficial in aged mice. The research noted here was conducted in vitro, using stem cells as a rough model of macular degeneration, which may explain why TIMP3 appeared as a relevant mechanism. It pays not to be too excited by research of this nature until positive results are produced in animal models, however.

The study utilized human stem cells to model age-related macular degeneration (AMD), overcoming the limitations of previous research using animal models. By examining genes associated with both AMD and rarer inherited forms of blindness called macular dystrophies, the researchers identified a key protein involved in the early stages of the disease. The retinal pigment epithelium (RPE), a layer of cells at the back of the eye, plays a crucial role in AMD. Over time, deposits of lipids and proteins, known as drusen, accumulate in the RPE. These deposits are often an early indicator of AMD.

The researchers discovered that a protein called tissue inhibitor of metalloproteinases 3 (TIMP3) is overproduced in AMD. TIMP3 inhibits the activity of enzymes called matrix metalloproteinases (MMPs), which are essential for eye health. Impaired MMP activity leads to increase in another enzyme which promotes inflammation and the formation of drusen. By using a small molecule inhibitor to block the activity of the enzyme associated with inflammation, the researchers were able to reduce drusen formation in their model, suggesting that targeting this pathway could be a promising strategy for preventing AMD.

Link: https://www.eurekalert.org/news-releases/1059721

The composition of the gut microbiome is influential on long term health and aging, possibly to a similar degree to lifestyle choices such as degree of physical exercise. Data shows that the relative sizes of microbial populations in the gut change with age in ways that provoke greater inflammation and reduce the production of beneficial metabolites. Conversely, it appears possible to produce lasting change in the gut microbiome, such as via fecal microbiota transplantation or therapies that cause the immune system to ramp up its destruction of problematic microbial species.

These approaches have yet to make their way into human medicine in any sizable way because regulators require a great deal more characterization of the microbiome and its alterations than presently exists. For example, given that microbial contributions to disease are far from fully mapped, and may proceed slowly over time, it is presently impossible to state in certainty that a fecal microbiota transplant will not introduce some novel problem for the recipient.

Nonetheless, there is considerable motivation to find ways to engineer therapeutic changes in the gut microbiome. Today's open access paper is one example of a continued flow of reviews and findings that report on distinct features of the gut microbiome in patients suffering from specific age-related conditions. Find ways to remove those features from the microbiome may turn out to be a viable approach to therapy for much of the panoply of age-related dysfunction and decline.

Association of Gut Microbiome with Muscle Mass, Muscle Strength, and Muscle Performance in Older Adults: A Systematic Review

Sarcopenia, characterized by age-related decline in muscle mass and function, significantly increases the risk of adverse outcomes such as impaired quality of life, falls, hip fractures, frailty, hospitalization, disability, and mortality. Individuals with sarcopenia have a higher likelihood of premature mortality compared to their age-matched counterparts. Sarcopenia also strongly predicts disability, defined as limitations in activities of daily living (ADL) and care home admissions. However, it is plausible that age-associated modifications in the gut microbiota and muscle tissue composition could be driven by shared underlying processes, such as chronic inflammation, dysfunction of the immune system, and changes in hormone levels, which could influence both microbiota alterations and the onset of sarcopenia.

Currently, there is no single effective therapeutic intervention for sarcopenia. The 'gut-muscle axis', which explores how the gut microbiome affects muscle mass, strength, and function in older adults, plays a crucial role in both the prevention and management of sarcopenia. Previous research indicates that diet composition and the gut microbiome change with age and are correlated with muscle mass decline, thereby impacting physical performance. Advanced age leads to gut microbiome dysbiosis, characterized by altered microbial diversity, predominant bacteria, and reduced beneficial bacterial metabolites. These biological processes, particularly those related to inflammation and the immune system, are greatly influenced by the gut microbiome. Studies show differences in gut microbiome composition, measured using RNA sequencing, between older and younger participants, marked by variations in alpha diversity//en.wikipedia.org/wiki/Alpha_diversity">alpha diversity (species diversity within a sample) and beta diversity (species diversity between samples). Animal studies support these findings, suggesting that variations in the gut microbiome and metagenome influence biological processes such as inflammation, nutrient bioavailability, and lipid metabolism, contributing to age-related muscle decline.

This review provides insight into potential novel interventions for sarcopenia prevention and treatment. A systematic search was conducted for studies published between 2002 and 2022 involving participants aged 50+. Studies were included if they assessed sarcopenia using at least one measure of muscle mass (skeletal muscle mass, bioelectrical impedance analysis, MRI), muscle strength, or muscle performance. The microbiome was measured using at least RNA/DNA sequencing or shotgun metagenomic sequencing. Twelve studies were analyzed. Findings revealed that a higher abundance of bacterial species such as Desulfovibrio piger, and Clostridium symbiosum and reduced diversity of butyrate-producing bacteria was associated with sarcopenia severity, as indicated by decreased grip strength, muscle mass, or physical performance. The gut microbiome plays a significant role in age-related muscle loss. Probiotics, prebiotics, and bacterial products could be potential interventions to improve muscle health in older adults.

The most widely used epigenetic clocks are built on DNA methylation data obtained from immune cells in blood samples. The research of recent years has indicated that different types of immune cell exhibit quite different characteristics of epigenetic aging, leading to some ongoing debate as to how best to interpret this data. There are other easily obtained sources of cells that lack this issue, however, such as a buccal swab of the interior of the cheek. Here, researchers discuss the ongoing development of CheekAge, a clock built on DNA methylation data obtained from a large buccal swab data set.

While earlier first-generation epigenetic aging clocks were trained to estimate chronological age as accurately as possible, more recent next-generation clocks incorporate DNA methylation information more pertinent to health, lifestyle, and/or outcomes. Recently, we produced a non-invasive next-generation epigenetic clock trained using DNA methylation data from more than 8,000 diverse adult buccal samples. While this clock correlated with various health, lifestyle, and disease factors, we did not assess its ability to capture mortality. To address this gap, we applied CheekAge to the longitudinal Lothian Birth Cohorts of 1921 and 1936.

To our knowledge, this is the first study to demonstrate that an aging biomarker optimized for buccal tissue can be applied to blood for mortality prediction. Our findings build on previous work from more than a decade ago, which found that buccal methylation data was highly informative for a variety of phenotypes and diseases. The magnitude of the hazard ratio for mortality prediction outcompetes all first-generation clocks tested and compares favorably to the next-generation blood-trained clock DNAm PhenoAge. These data suggest that adult buccal tissue, which is relatively painless and easy to collect in a variety of settings, may represent a rich source of aging biomarkers.

Link: https://doi.org/10.3389/fragi.2024.1460360

More funding is devoted to the exploration of partial reprogramming than any other approach to the treatment of aging as a medical condition, arguably more funding than all of the other approaches combined. Partial reprogramming recaptures processes that take place in early embryonic development, and is a matter of exposing aged cells to the Yamanaka factors for long enough to produce restoration of youthful epigenetic patterns, but not for so long as to produce a transformation of state into induced pluripotent stem cells. The present consensus is that this balance will be challenging to achieve safely in the context of a drug delivered to much of the body, where the right exposure time differs from cell type to cell type, but that isn't stopping researchers and companies from making the attempt.

Recent studies have shown that limited use of Yamanaka factors or chemicals that mimic their effects can partially reverse cellular or organismal aging. This has been observed in both in vitro human and mouse models, as well as in vivo mouse studies, without fully de-differentiating cells into a pluripotent state. These studies encompass various models, including healthy aged and diseased mice, such as progeroid mice, and involve pulsed, short-term, and medium-term reprogramming regimes; these we call "partial reprogramming" as long as no induction of pluripotency is observed.

Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of the interconnections among the data, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, it leads to enhanced chromatin accessibility, upregulation of chromatin modifiers, and improved mitochondrial activity. These changes are accompanied by shifts in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as dysregulation of extracellular matrix pathways.

Ultimately, until we achieve a more robust understanding of aging at the molecular level - and identify much more reliable biomarkers of biological age - the extent to which reprogramming can reverse aging will remain unclear. The effects and potential side effects of reprogramming are context-dependent, varying with the specifics of the reprogramming protocol (such as duration) and the characteristics of the target, including species and tissue or cell types involved. Nonetheless, reprogramming holds significant promise in reversing various biomarkers of aging.

Link: https://doi.org/10.20944/preprints202410.0122.v1

Any sufficiently complex set of biological data obtained from a population of individuals of varied ages (or even at a single age, provided that later outcomes are known) will exhibit differences that can be used to produce an aging clock. Machine learning approaches are applied to the data to find algorithmic combinations of values that produce a predictor of chronological age, or mortality, or risk of disease. Typically clocks output an age. This is a biological age, distinct from chronological age. A greater clock-predicted biological age than chronological age indicates a greater burden of age-related damage and dysfunction, a person who is aging faster than the average for the population whose data was used to produce the clock.

The growth of interest in the mainstream work of producing ever better epigenetic clocks, derived from data on the methylation status of specific CpG sites on the nuclear genome, this being a measure of changes in gene expression and cell behavior, has led to the creation of a great many other clocks. Clocks have been produced from other omics data, combinations of simple measures of healthy such as grip strength and complete blood count, and imaging data. Retinal imaging is a newly popular area of study in the production of aging clocks, for example.

In today's open access paper, researchers demonstrate that brain scans can also be used to produce potentially interesting aging clocks. This proliferation of different clocks may slow down at some point, or it may be that aging is sufficiently complex than no one or no few clocks will prove to be universally useful, and the future of aging clocks in medicine is that every specialty will have a few clocks to choose from on a case by case basis.

An estimate of the longitudinal pace of aging from a single brain scan predicts dementia conversion, morbidity, and mortality

Current neuroimaging-based approaches to measure aging, akin to first-generation epigenetic clocks, involve training models to predict chronological age from variability in MRI measures of brain structure in large multi-age samples. Researchers then typically quantify a "brain age gap," which reflects the difference between a participant's predicted and actual chronological age. A positive brain age gap is interpreted as evidence of accelerated brain aging. As with first-generation epigenetic clocks, these age-deviation approaches unavoidably mix model error (e.g., historical differences in environmental exposures, survivor bias, disease effects, measurement bias) with a person's true rate of biological aging.

Here, using a single T1-weighted MRI scan collected at age 45 in the Dunedin Study, we describe the development and validation of a novel brain MRI measure for the Pace of Aging. We call this measure the Dunedin Pace of Aging Calculated from NeuroImaging or "DunedinPACNI." Using data from the Human Connectome Project we evaluated the test-retest reliability of DunedinPACNI. Exporting the measure to the Alzheimer's Disease Neuroimaging Initiative (ADNI) and UK Biobank, we conducted a series of preregistered analyses designed to evaluate the utility of DunedinPACNI for predicting multiple aging-related health outcomes. To benchmark our findings, we compared effect sizes for DunedinPACNI to those for brain age gap. DunedinPACNI is the first brain-based measure trained to directly estimate longitudinal aging of non-brain organ systems.

Neuroimaging Initiative and UK Biobank neuroimaging datasets revealed that faster DunedinPACNI predicted participants' cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed the expected socioeconomic health gradient. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

Osteoarthritis, involving degeneration of cartilage tissue and underlying bone in joints, is characterized by chronic inflammation in the affected tissues. Unresolved inflammatory signaling is a feature of aging, disruptive to tissue structure and function. In many age-related inflammatory conditions, researchers are investigating the behavior of the innate immune cells call macrophages. Macrophages can switch between states known as polarizations, the most clearly distinguished of which are M1 (inflammatory and aggressive in attacking pathogens) versus M2 (anti-inflammatory and acting to aid regenerative processes). In many inflammation-associated conditions, macrophages appear overly biased towards M1, amplifying inflammation.

Primary osteoarthritis (OA) is a prevalent degenerative joint disease that mostly affects the knee joint. It is a condition that occurs around the world. Because of the aging population and the increase in obesity prevalence, the incidence of primary OA is increasing each year. Joint replacement can completely subside the pain and minimize movement disorders caused by advanced OA, while nonsteroidal drugs and injection of sodium hyaluronate into the joint cavity can only partially relieve the pain; hence, it is critical to search for new methods to treat OA.

Increasing lines of evidence show that primary OA is a chronic inflammatory disorder, with synovial inflammation as the main characteristic. Macrophages, as one of the immune cells, can be polarized to produce M1 (proinflammatory) and M2 (anti-inflammatory) types during synovial inflammation in OA. Following polarization, macrophages do not come in direct contact with chondrocytes; however, they affect chondrocyte metabolism through paracrine production of a significant quantity of inflammatory cytokines, matrix metalloproteinases, and growth factors and thus participate in inducing joint pain, cartilage injury, angiogenesis, and osteophyte formation.

The main pathways that influence the polarization of macrophages are the Toll-like receptor and NF-κB pathways. The study of how macrophage polarization affects OA disease progression has gradually become one of the approaches to prevent and treat OA. Experimental studies have found that the treatment of macrophage polarization in primary OA can effectively relieve synovial inflammation and reduce cartilage damage. The present article summarizes the influence of inflammatory factors secreted by macrophages after polarization on OA disease progression, the main signaling pathways that induce macrophage differentiation, and the role of different polarized types of macrophages in OA; thus, providing a reference for preventing and treating primary OA.

Link: https://doi.org/10.1186/s13018-024-05052-9

The common age-related degenerative conditions that affect muscle and bone are driven in part by the accumulation of senescent cells that takes place throughout the body with age. Senescent cells are created constantly throughout life, largely as a result of cells reaching the Hayflick limit on replication, but also due to forms of damage. In youth, these cells are cleared rapidly by the immune system, but this clearance falters with age allowing a population of lingering senescent cells to accumulate. These cells secrete pro-inflammatory, disruptive signals that degrade tissue structure and function.

Osteoporosis, sarcopenia, and osteoarthritis, three common musculoskeletal disorders that often coexist in the elderly population. The loss of bone and muscle mass and the progressive degradation of cartilage are the macroscopic effects of the complex pathological processes underlying these diseases, in association with an increased susceptibility to fractures and an elevated risk of falls. From a microscopic point of view, affected tissues are characterized by numerous cellular and molecular alterations that induce a state of replicative senescence, irreversibly compromising the quality of the musculoskeletal system. Not surprisingly, cellular senescence has recently emerged as a critical element in the pathophysiology of osteoporosis, sarcopenia, and osteoarthritis, highlighting the need for further studies to understand the intricate relationship between cellular senescence and musculoskeletal functions, as well as to develop effective strategies to mitigate and manage these debilitating conditions.

Cellular senescence has been suggested to be among the mechanisms responsible for the decline in regenerative function observed in muscle and bone stem cells with advancing age because of the up-regulation of certain proteins, including p16, p21, and p27, responsible for altered tissue metabolism. Particularly, senescent bone cells are known to release the senescence-associated secretory phenotype (SASP) that promotes osteoclast activity, inducing bone resorption and accelerating bone mass loss. In agreement, studies in mouse models have shown that the elimination of senescent cells improves bone mineral density and bone microarchitecture, counteracting the onset of osteoporosis. Furthermore, in skeletal muscle, the senescence of satellite cells, which are essential for muscle regeneration, significantly reduces tissue repair capacity. In this regard, experiments in mouse models have shown that the elimination of senescent cells improves muscle function and increases muscle mass, suggesting senolytics as potential strategies in the treatment of sarcopenia. Finally, the accumulation of senescent cells in joints has been suggested to contribute to cartilage degradation and synovial inflammation, exacerbating the joint deterioration that characterizes osteoarthritis.

Link: https://doi.org/10.3390/biomedicines12091948

The information of the mind is encoded in physical structures in the brain, with some debate over exactly which physical structures. Survival after cold water drowning is one example to demonstrate that all electrical activity in the brain can cease without erasing the mind. Therefore memory and all other aspects of the function of the mind must be recorded as physical structures. Given that this is the case, death does not have to be the end. If the brain is preserved sufficiently well at low temperature, then one can be dead but not gone. There is some greater than zero chance of restoration to life in an era of greater technological capabilities than ours.

A growing community feels that sizable gains in life expectancy, and rejuvenation therapies capable of adding significant life expectancy for old people, will be slow in arriving from the biotechnology community. Therefore, there must be a greater focus on improving present approaches to the cryopreservation of patients immediately following death, expanding the presently small cryopreservation industry, and offering some alternative to the grave and oblivion. A part of this effort is to publish and advocate; the path to improvement is actually quite clear. Indeed, the much longer path to producing technologies capable of restoring a cryopreserved individual is also quite clear. The technological capabilities needed can be clearly envisaged and enumerated, and have been.

Biostasis: A Roadmap for Research in Preservation and Potential Revival of Humans

Biostasis is the practice of preservation of humans for the long-term with the intent of future recovery, if this ever becomes feasible. Biostasis can be distinguished into two hypothetical modalities: (a) provably reversible preservation and (b) preservation of informational features in the body in a way that is not reversible with currently known technologies, with the hope that such technologies can be developed and implemented in the future. Provably reversible preservation, also known as suspended animation, is not yet possible for humans, and probably will not be possible anytime soon, absent incredibly rapid advances in preservation technology. Yet, contemporary biostasis methods do not need to be proved to be reversible now in order to allow for a potential chance at revival in the future. The primary justification of contemporary biostasis, which we adopt here, is the preservation of the brain, which most consider to be the seat of our memories, personalities, and identities. By preserving the information contained within the structures of the brain, we may one day be able to revive the individual using advanced future technologies, even though this would require society to bootstrap the development of those technologies while individuals remain under preservation. This practice is also called neural biostasis, brain preservation, or brain archiving. We use the more general term biostasis in this roadmap.

This roadmap is divided into seven main categories: pre-cardiac arrest factors, post-cardiac arrest stabilization, preservation compounds, preservation procedures, methods for measuring preservation quality, long-term preservation, and restoration and recovery. We have attempted to outline the current state of research and future directions for the field of biostasis, with a focus on the scientific and technical aspects of brain preservation for potential future revival. This roadmap touches on several directions, including the development of better chemical compounds and better delivery approaches for those chemicals. Continued research into platforms and chemicals that could improve neural tissue preservation, alongside research into surgical techniques, cannulation methods, perfusion parameters, and long-term storage methods, would all be enormously valuable.

Economic factors are crucial for any field of scientific research, and biostasis research is no exception. So far, funding for biostasis research has predominantly come from individuals and organizations with a vested interest in the field, such as cryonics companies and individual cryonicists. While this has allowed for some progress, the limited resources have constrained the scope and pace of research. To the best of our knowledge, there has never been specific funding awarded for biostasis research from any government agency. We believe that for the field to grow and reach its full potential, there is a need for funding from larger sources, such as government agencies, academic institutions, and philanthropic organizations without a specific focus on biostasis. However, this expansion of funding sources faces a significant challenge: many potential funders and members of the public are highly skeptical about the feasibility of biostasis. This creates a chicken-and-egg problem, where the field receives little funding because many people do not believe it is promising, but there has also been insufficient research to thoroughly investigate its potential.

Breaking this cycle will likely require innovative approaches to both research and public engagement. Possible strategies to address this include: (1) fostering collaborations between biostasis researchers and mainstream cryobiology or neuroscience labs to increase access to resources and the reliability of the research, (2) developing clearer roadmaps and milestones to demonstrate progress and potential, (3) engaging in more public outreach to address misconceptions and discuss ethical concerns, (4) exploring alternative funding models such as crowdfunding or decentralized science initiatives, and (5) leveraging funding for other research topics where synergies with problems relevant to biostasis exist and publishing resulting findings in reputable scientific journals. Additionally, emphasizing the potential spillover benefits of biostasis research to other fields, such as organ preservation for transplantation, treatment of acute brain injuries, or connectomics, could help attract broader interest and support. Overcoming these funding challenges will be critical for performing a thorough and objective examination of the true potential of biostasis technologies.

Researchers here discuss a well known problem in mouse studies of aging, the inconsistency in outcomes for many of the modestly age-slowing interventions tested to date. The high cost of life span studies means that there are fewer attempts to replicate results than would be desired, and study sizes tend to be smaller than desired. Researchers have pointed out that differences between studies in the setup of control groups may be a sizable part of the problem, and the authors of this paper agree.

Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups.

Incorporating many of these suggestions for optimal mouse husbandry and avoiding pitfalls of other lifespan studies, the rigorous National Institute of Aging Interventions Testing Program (ITP) has become a gold-standard for mouse longevity studies. In the ITP, studies are performed on both sexes, with large sample sizes and across three different centers to address idiosyncratic issues of mouse husbandry. Furthermore, the UM-HET3 mice used by the ITP are relatively long-lived compared to most inbred strains and genetically heterogenous, thereby reducing the likelihood that mice die of strain-specific pathologies, a factor that may confound lifespan data.

A majority of compounds tested by the ITP have not been previously published to extend lifespan in mice, thus we lack a "ground truth" for their expected effect size. Notably, however, the ITP has failed to replicate published lifespan extension for several compounds such as metformin, resveratrol, and nicotinamide riboside, raising concerns about the robustness of published mouse longevity data. Although differences in genetic background, age of treatment onset, husbandry, and dosing between the original study and the ITP cohorts may explain replication failures, another potential factor is methodological rigor.

In this manuscript, we reanalyze data from caloric restriction (CR) studies performed in multiple species, the ITP and other large mouse lifespan studies with a particular focus on control lifespan as one potential explanation for inflated effect sizes and lack of replicability. As a solution, we emphasize the importance of long-lived controls in mouse studies which should reach a median lifespan of around 900 ±50 days, or the comparison to appropriate historical controls, and we term this the "900-day rule".

Link: https://doi.org/10.1016/j.arr.2024.102512

Researchers here provide evidence for autophagy in astrocytes, a large supporting cell population in brain tissue, to be important in determining amyloid-β plaque burden in the aging brain. Autophagy is a recycling mechanism capable of breaking down unwanted proteins and structures. Astrocytes increase autophagic activity in the presence of the amyloid-β protein aggregates (plaques) characteristic of Alzheimer's disease, and in a mouse model that exhibits these plaques the degree of autophagy appears to determine the degree to which problematic amyloid-β is cleared from brain tissue.

Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of an animal model of AD.

Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of the LC3B gene and turns on a prolonged transcription of the SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal markers and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.

Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

Link: https://doi.org/10.1186/s13024-024-00740-w

A broad array of epidemiological evidence indicates that greater time spent being sedentary and inactive harms long-term health and increases mortality risk. Equally, a similar body of evidence indicates that greater physical activity has the opposite effect, at least up to a point that is far above the level of activity that most people undertake in their day to day lives. When looking at any specific aspect of age-related disease and functional decline, one might expect to find the same patterns, and indeed there are any number of studies in which this is the case.

Today's open access paper considers sedentary behavior and physical activity in the context of white matter hyperintensities, areas of damage in the brain produced by rupture of capillaries and related vascular issues. People accumulate these lesions as they age, each one unnoticed when it happens, but this damage accumulates to harm the function of the brain. As one might expect, more activity correlates with less of this damage to the brain, and the researchers speculate on the usual suspects when it comes to underlying mechanisms.

Associations between accelerometer-derived sedentary behavior and physical activity with white matter hyperintensities in middle-aged to older adults

White matter hyperintensity (WMH) volume measured with magnetic resonance imaging (MRI) serves as a significant indicator of the extent of cerebral white matter lesions, typically associated with ischemia due to small vessel disease. WMHs are frequently found in older cognitively unimpaired individuals, are linked with worse cognitive performance, particularly executive functions and processing speed, are associated with genetic risk of neurodegenerative disease, and can potentially impact both the onset and advancement of dementia related to both Alzheimer's disease (AD) and cerebrovascular disease (CVD). Here, we examine the potential associations of physical activity (PA) and sedentary behaviors (SBs), two modifiable lifestyle factors, with WMH volumes in middle-aged to older adults. In the UK Biobank, we found associations of both moderate-to-vigorous physical activity (MVPA) and SB with WMH volume, and the associations are not fully independent of each other.

A large number of studies have shown that engaging in greater amounts of MVPA is associated with improved vascular health and that SB is associated with vascular pathology and chronic disease. One potential vascular mechanism that could underlie these results is that MVPA may increase cerebral blood flow, which in turn may help prevent the development of high WMH loads. SB, on the other hand, has been linked with reduced cerebral blood flow which may lead to increased lesion load, though this finding has not been consistently replicated.

Our results also align with the growing body of literature emphasizing the synergistic effects of higher PA and reduced SB on various health outcomes. While previous studies have independently linked excessive SB and lack of MVPA with adverse brain health, our study demonstrates how these behaviors interact in their associations with WMH volumes. It is possible that the mechanisms linking PA and SB with WMH volumes may only partially overlap. For example, while both SB and MVPA have been linked with cerebral blood flow and vascular health in previous work, MVPA is also associated with the upregulation of neurotrophic factors (eg, Brain Derived Neurotrophic Factor or BDNF) that may provide additional compensatory protection against the impact of increased WMH volumes.

While our study was not designed to determine whether mechanistic pathways are fully or partially independent, the interactions found here suggest more work is needed to better understand how these two lifestyle behaviors may differentially impact brain lesion loads that may, in turn, influence the risk for cognitive decline and dementia related to both AD and CVD. Overall, our results highlight the importance of considering interactions between these key modifiable behaviors when examining their associations with brain health outcomes.

There is evidence for some stem cell populations to decline in function with age in part because of the aging of the surrounding stem cell niche, detrimental changes in the supporting cells making up the niche. The situation appears similar for oocytes, female germline cells. Their niche is the ovarian follicle, and researchers here show that aged oocytes undergo some degree of functional rejuvenation when placed into an environment that mimics the young ovarian follicle, at least as measured by metrics such as epigenetic profile and mitochondrial function.

An ovarian follicle is a basic functional unit in the mammalian ovary, composed of somatic cells (granulosa cells) that surround and support an oocyte (an immature egg cell) as it grows and matures before ovulation. The granulosa cells communicate with the oocyte to provide essential nutrients and components through channels known as transzonal projections. In turn, the oocyte provides key components that signal the growth and development of granulosa cells. Researchers tapped on this understanding of the relationship between somatic cells of the ovarian follicle and the oocyte to create hybrid ovarian follicles through an ex-vivo 3D culturing platform, building upon previous methods. The team then extracted the oocyte from its original follicular environment and transplanted it to a new follicular environment, whose own oocyte had been removed, to construct the hybrid ovarian follicle.

The researchers confirmed that aged granulosa cells, compared to young granulosa cells, exhibited an increase in the hallmarks of ageing, such as an increase in indicators of DNA damage and other factors linked to programmed cell death. They showed that this aged follicular environment can reduce the quality and developmental potential of a young oocyte.

The research team then created hybrid ovarian follicles containing an aged oocyte (i.e. an immature egg cell from an aged follicular environment) in a young follicular environment. The researchers demonstrated that the quality and developmental competence of the aged oocyte can be substantially, though not fully, restored through "nurturing" in a young follicular environment. The team found that the restoration of the quality of the aged oocyte was attributed to the reshaping of its metabolism and gene expression. The researchers discovered that the young granulosa cells, which were much better at establishing transzonal projections toward the aged oocyte, helped to facilitate this restoration. In addition, there was an improvement in the function and health of oocyte mitochondria, crucial organelles for energy production and cellular metabolism.

Link: https://news.nus.edu.sg/novel-approach-to-rejuvenate-aged-egg-cells/

Periodontitis, gum disease, is thought to contribute to a range of age-related conditions by allowing bacteria and bacterial products into the blood stream to provoke chronic inflammation. The risk of periodontitis is affected by the composition of the oral microbiome. Here, researchers show that the presence of some bacterial species is also correlated with risk of head and neck cancer. Chronic inflammation tends to produce a more hospitable environment for the growth of cancerous tissue.

Experts have long observed that those with poor oral health are statistically more vulnerable than those with healthier mouths to head and neck squamous cell carcinoma (HNSCC), a group that includes the most common cancers of the mouth and throat. While small studies have tied some bacteria in these regions (the oral microbiome) to the cancers, the exact bacterial types most involved had until now remained unclear.

Researchers analyzed data from three ongoing investigations tracking 159,840 Americans from across the country to better understand how diet, lifestyle, medical history, and many other factors are involved in cancer. Shortly after enrolling, participants rinsed with mouthwash, providing saliva samples that preserved the numbers and species of microbes for testing. Researchers then followed up for roughly 10 to 15 years to record any presence of tumors. The investigators analyzed bacterial and fungal DNA from the saliva samples. Then, they identified 236 patients who were diagnosed with HNSCC and compared the DNA of their oral microbes with that of 458 randomly selected study subjects who had remained cancer-free.

Of the hundreds of different bacteria that are routinely found in the mouth, 13 species were shown to either raise or lower risk of HNSCC. Overall, this group was linked to a 30% greater likelihood of developing the cancers. In combination with five other species that are often seen in gum disease, the overall risk was increased by 50%. This is the largest and most detailed analysis of its kind to date. It is also among the first to examine whether common fungi, organisms like yeast and mold that, along with bacteria, make up the oral microbiome, might play a role in HNSCC. The new experiments found no such role for fungal organisms.

Link: https://nyulangone.org/news/bacteria-involved-gum-disease-linked-increased-risk-head-neck-cancer

Autophagy and the ubiquitin-proteosome system (UPS) serve similar purposes in the cell. Both flag unwanted materials in the cell for recycling, and then break them down into raw materials for further protein synthesis. In the case of autophagy, materials are wrapped in an autophagosome membrane and then conveyed to a lysosome that dismantles structures and proteins using the enzymes that it contains. In the case of the UPS, ubiquitination of a protein allows that protein to enter a proteasome, the interior of which breaks it apart.

Both of these processes are used to remove excess and damaged molecules that may harm a cell. Up to a point, greater activity of these maintenance processes produces healthier, more resilient cells. Repeated across the entire organism, this leads to a slowing of degenerative aging. A number of approaches have been shown to upregulate autophagy. Fewer improve proteasomal function. In today's research materials, scientists report on an approach that improves both, and demonstrate slowed aging in flies as a result.

Scientists investigate a potential anti-aging drug that could preserve proteasomes and autophagy systems

Proteasomes are protein complexes that break down faulty proteins into smaller peptides. On the other hand, autophagy is a process by which cells degrade and recycle larger structures, including protein aggregates, through the formation of specialized vesicles. Both systems work in concert to maintain proteostasis, but the mechanism of their synergistic activation to mitigate the effects of aging is not well understood. "A few years ago, I learned from an academic conference that a certain drug called IU1 can enhance proteasomal activity, which encouraged our group to test its anti-aging effects."

The researchers employed an animal model for studying the aging process: fruit flies from the genus Drosophila. Since fruit flies have a short lifespan and their age-related muscle deterioration is quite similar to that in humans, Drosophila constitutes a valuable model for studying aging. They treated flies with the drug IU1 and measured various behavioral and proteostasis-related parameters. "Inhibiting the activity of ubiquitin specific peptidase 14 (USP14), a component of the proteasome complex, with IU1 enhanced not only proteasome activity but also autophagy activity simultaneously. We demonstrated that this synergistic mechanism could improve age-related muscle weakness in fruit flies and extend their lifespan."

Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging.

Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

A number of studies have indicated that poor sleep quality negatively impacts long term health. This analysis suggests that the correlation between poor sleep quality and increased mortality is mediated by other factors such as weight and chronic illness. In other words that underlying causes lead to both reduced sleep quality and increased mortality risk. If looking to improve long-term health, a focus on sleep may not be the right place to start for most people.

Inadequate sleep duration and poor sleep quality are becoming significant public health issues linked to cardiometabolic risk factors like obesity, particularly with an aging population. Approximately 20% of adults are impacted by health issues associated with substandard sleep quality or insufficient sleep durations. Research has demonstrated that the occurrence of dementia is indicative of a greater risk of future all-cause mortality . Furthermore, there is increasing evidence suggesting that both short and lengthy sleep durations, as well as other disturbances, are associated with higher risks of mortality from all causes. Limited attempts to assess the connection between sleep and neurodegenerative illnesses usually found that insufficient sleep length, low sleep quality, and sleep disorders were associated with negative outcomes that included dementia.

Considering the interconnection between sleep, dementia, and the rate of mortality, it is important to investigate the pathways and potential interactions among them. This study aims to investigate the relationship between poor sleep quality and dementia status with mortality risk. We examine this relationship independently of potential confounding factors, while also considering the influence of sex and race. The study is conducted using a sub-sample of the Health and Retirement Study (HRS) with complete algorithmically defined dementia status and probability outcomes. The participants in this sub-sample have a mean age of approximately 78 years. Furthermore, we conduct a simultaneous examination to assess the potential interaction between poor sleep quality and dementia outcomes in determining the risk of mortality.

Poor sleep quality was only directly related to mortality risk before adjustment for lifestyle and health-related factors. Therefore, the potential causal effect of poor sleep quality on mortality risk appears to be confounded by other lifestyle and health-related factors. Dementia was positively associated with mortality risk, particularly among individuals with better sleep quality and among males.

Link: https://doi.org/10.18632/aging.206102

Researchers here investigate a less commonly discussed aspect of Parkinson's disease, which is that patients reliably exhibit reduced uric acid levels in serum and cerebrospinal fluid. Present explanations for this phenomenon remain insufficient, and further research is needed to (a) understand why this happens and (b) whether pulling further on this thread could lead to useful therapies that can slow the progression of Parkinson's.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Despite the undetermined pathogenesis of PD, serum uric acid (UA) levels are decreased in patients with PD. A meta-analysis of dose-response studies established a correlation between a 6% increased risk of PD and every 1 mg/dL decrement in serum UA level. Although there is evidence of decreased UA levels in patients with PD, the causal relationship between UA levels and PD onset or progression remains unclear. Findings suggest that the reduction in serum UA levels in PD is not a causative factor in the onset or progression of the disease but rather a consequence of impaired mitochondrial function, altered gastrointestinal function, and impaired motor function, which may also influence the onset and progression of PD (reverse causation).

Alterations in purine metabolism are also key to understanding the pathophysiology behind lower UA levels in PD patients. UA production follows this pathway: inosine monophosphate (IMP) → inosine → hypoxanthine → xanthine → UA. Although the levels of inosine, hypoxanthine, and xanthine, which are "upstream" in the purine metabolic pathway, may affect UA levels, the "downstream" product in patients with PD, no past studies have explored upstream purine metabolism in the CSF and blood of patients with PD.

Our study compared serum and cerebrospinal fluid (CSF) levels of inosine, hypoxanthine, xanthine, and UA in PD patients and healthy controls. We analyzed 132 samples using liquid chromatography-tandem mass spectrometry. Results showed significantly lower serum and CSF UA levels in PD patients than in controls. Decreased serum hypoxanthine levels were observed in PD patients compared to controls with decreased CSF inosine and hypoxanthine levels. Our findings suggest that decreased UA levels in PD patients are influenced by factors beyond purine metabolism, including external factors such as sex, weight, and age. The observed reductions in serum and CSF hypoxanthine and CSF inosine highlight potential impairments in purine recycling pathways, warranting further research into alternative therapeutic strategies.

Link: https://doi.org/10.1038/s41531-024-00785-0

While considering your end of year charitable donations for 2024, why not get in early and donate to support mouse studies of multiple combined rejuvenation therapies presently underway at Longevity Escape Velocity (LEV) Foundation? Up to EUR 200,000 ($220,000 or so) of donations to the LEV Foundation will be matched during October, so donating now will bring greater funding to the table than donating later.

Donations from Didier Coeurnelle enable next phase of Robust Mouse Rejuvenation research program

Longevity Escape Velocity Foundation (LEVF) today welcomes two very generous donations from long-time supporter of longevity research and activism, Didier Coeurnelle. The first donation is 200,000 euros (approximately 220,000 US dollars). The second donation, of up to another 200,000 euros, is dependent on LEVF receiving matching gifts from other donors from 1st October until the end of the month (October 31st). These donations enable a key set of pre-study pilots ahead of the next phase of LEVF's groundbreaking investigations into the effects of combining different damage-repair interventions for middle-aged mice.

Longevity Escape Velocity (LEV) Foundation exists to conduct and inspire research to proactively identify and address the most challenging obstacles on the path to the widespread availability of comprehensively effective treatments to cure and prevent human age-related disease. Donations are processed free of charge by Every.org, a 501(c)3 non-profit, which will issue a tax receipt to you and disburse the full value of your gift (excluding only any applicable third-party fees) to us. Our partnership with Every.org markedly reduces administrative and regulatory overheads related to donations, enabling us to focus solely on realizing our mission.

A primary focus of LEV Foundation's work is to empirically demonstrate the feasibility and value of the divide-and-conquer approach to treating age-related disease - that is, the simultaneous deployment of therapies that independently address the distinct classes of damage that accumulate in aging bodies. In partnership with Ichor Life Sciences, we'll be conducting large-scale mouse lifespan studies of such therapeutic mixtures. To ensure the results of these studies are rapidly translatable to humans already in middle and old age, this program will focus solely on late-onset interventions. We anticipate that this program will deliver dramatic results both in scientific terms, and in illustrating to the general public the extraordinary potential of comprehensive rejuvenation medicine.

Why support the LEV Foundation? Because too few research organizations are working on combination therapies for the treatment of aging. Brian Kennedy's lab has demonstrated that combining small molecules that alter metabolism to modestly slow aging is a poor way forward: combine two mildly effective molecules and the result is as likely to be modestly accelerated aging as it is to be synergy in slowing aging. But what if one combines therapies that act on aging via repair of the known forms of cell and tissue damage that cause aging? These seem much more likely to exhibit synergies in improving health and extending life span. Fixing two problems should be better than fixing one, and the development of senolytic drugs to clear senescent cells has demonstrated in animal studies that fixing one problem can be pretty good for health and longevity.

But is anyone testing the available approaches to damage repair in combination? Not really, other than the LEV Foundation mouse studies. The obvious next step after developing a range of rejuvenation therapies that each address a single form of damage is to combine them, but even though this was always understood to be the obvious next step, it has been given little thought in research circles. Developing a better understanding of where the major challenges and benefits stand in the combination of approaches to rejuvenation is overdue, and a useful project.

Researchers here report on a novel omics analysis of changes in cell biochemistry produced by various approaches to slowing or reversing aspects of aging, giving rise to what they call a cell rejuvenation atlas. The researchers used their atlas to improve the understanding of how a few of the many regulators of cell behavior produce benefits in the context of aging, and suggest that this approach may yield further insights into targets for drug development to at least slow the progression of aging.

Current rejuvenation strategies, which range from calorie restriction to in vivo partial reprogramming, only improve a few specific cellular processes. In addition, the molecular mechanisms underlying these approaches are largely unknown, which hinders the design of more holistic cellular rejuvenation strategies. To address this issue, we developed SINGULAR (Single-cell RNA-seq Investigation of Rejuvenation Agents and Longevity), a cell rejuvenation atlas that provides a unified systems biology analysis of diverse rejuvenation strategies across multiple organs at single-cell resolution. In particular, we leverage network biology approaches to characterize and compare the effects of each strategy at the level of intracellular signaling, cell-cell communication, and transcriptional regulation.

Our approach successfully identified several previously known age-related transcription factors (TFs). For instance, we found Arntl to be a master regulator in rejuvenation, corroborating its earlier identification as the TF with the most significant age-related decline in activity in at least one prior analysis. However, only three other matching TFs were identified, with the sign of TF activity changes varying substantially by cell type. This suggests notable differences between transcriptional changes associated with aging and the regulators of rejuvenation. It also uncovered previously undocumented mediators of rejuvenation interventions. Moreover, in cases where the transcriptional mediators are known, our analysis provides novel insights.

For example, while the AP-1 complex formed by Fos and Jun has been described to regulate diverse cell functions, and in particular the inflammaging response, our analysis further demonstrates that different subunits and cofactors serve as master regulators of the response to specific interventions. In light of our findings and a recent study that highlighted an up-regulation of the Jun-Fos dimer expression, which is accompanied by increasing inflammation, it is plausible that AP-1 dimers composed of other subunits are responsible for inducing anti-aging effects.

Apart from the AP-1 complex, our analysis revealed the transcriptional stress response TFs NFE2L2 and MAF as master regulators of certain rejuvenation interventions in different cell types. Indeed, MAF and NFE2L2 have been shown to dimerize and regulate gene expression programs that protect against oxidative stress, which are lost with age. Moreover, over-expressing MAF has been shown to rescue these protective expression programs and preserve fitness in an animal aging model. Conversely, the reduced activity of NFE2L2 leads to increased cellular senescence and inflammation.

Link: https://doi.org/10.18632/aging.206105

Hearing loss emerges from the loss of sensory hair cells in the inner ear, or from the loss of axonal connections between these cells and the brain. It remains somewhat unclear as to which of these losses is the more important; the evidence is mixed. Age-related hearing loss is age-related because the accumulated damage of aging creates a hostile environment for hair cells and their axons. The precise mechanisms of dysfunction are debated, which are more or less important. The development of therapies is at the present time focused on replacement of hair cells rather than on addressing the root causes of hair cell and axon loss.

Age-related hearing loss (ARHL), recognized as the third most common chronic geriatric disease, affects approximately half of adults aged 85 years and over, significantly impairing the health and well-being of the elderly population, leading to communication challenges, social isolation, and cognitive decline. The relationship between aging and ARHL is complex, as the same molecular and cellular mechanisms that drive the aging process also contribute to the deterioration of auditory function. As the body ages, the auditory system becomes increasingly susceptible to the cumulative effects of multiple degenerative processes associated with aging, leading to the progressive hearing loss characteristic of ARHL. Despite advancements in identifying the age-related cellular and molecular changes in the inner ear, the long-standing question that remains is which precise mechanisms underlie the age-dependent degeneration of cochlear structure and function, as well as which methods can be used to preserve or reverse these processes.

Dysregulation of cellular pathways like senescence, autophagy, and oxidative stress, in addition to molecular pathways regulated by AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor-1 (IGF-1), and sirtuins (SIRTs) have each been implicated in hearing loss progression, but the specific causative factors and their direct roles on molecular and cellular pathways that lead to cochlear degeneration are not fully elucidated. Understanding how these pathways affect postmitotic hair cells, the stria vascularis, and the spiral ganglion cells is vital for elucidating the mechanisms of ARHL and developing therapeutic interventions to prevent or mitigate ARHL.

Calorie restriction (CR), well recognized for its healthspan and lifespan-extending properties, has also been shown to slow ARHL in both rodents and primates, but the specific molecular pathways modified by CR in the inner ear and the most effective CR mimetic compounds remain unclear. However, molecules targeting oxidative stress and mitochondrial dysfunction or using CR mimetics such as metformin and nicotinamide mononucleotide (NMN), as well as the potential of senolytics or senomorphics, may offer new treatment strategies for ARHL. Characterizing these fundamental aging pathways will not only enhance our understanding of general aging processes but also illuminate their role in ARHL.

Link: https://doi.org/10.3390/ijms25179705

The immune system declines with age, becoming overactive and inflammatory (inflammaging) while at the same time losing its capacity to destroy pathogens and errant cells (immunosenescence), and also becoming dysregulated and harmful in its participate in processes of tissue maintenance. It is well established that the practice of either intermittent fasting or calorie restriction can slow the progression of aging and, specifically, improve the function of the aging immune system. Since these interventions appear to produce their beneficial effects on cell behavior largely through improved autophagy, autophagy should most likely be the starting point for any consideration of how immune function is improved.

Autophagy is a complex set of processes that maintain the health of a cell by recycling excess and damaged proteins and structures, delivering them to a lysosome where they are dismantled into raw materials for further protein synthesis. Many of the approaches shown to modestly slow aging in laboratory species involve improvements in autophagy, as they are all different ways to tinker with the extensive regulatory machinery that controls the cellular response to low nutrient availability.

Up to a point, greater autophagy protects against damage and cell stress, and this adds up over time. Improved autophagy can reduce the pace at which cells become senescent, and thus lower the overall burden of lingering senescent cells in aged tissues. This reduces pro-inflammatory signaling. Similarly, improved autophagy can dampen innate immune reactions to the molecular damage of aging.

Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging

Aging is a complex process, associated with the accumulation of damaged molecules, progressive loss in structure and function of cells, tissues, and organs, and increased vulnerability to death. Even if the aging process is multifaceted and diverse, laboratory manipulation of genes in different laboratory model animals has increased the lifespan of these organisms. Most genes that are associated with increasing lifespan are part of the nutrient-sensing pathway and the mutation in these genes mimics the state of food shortage. Different mechanisms of fasting and calorie restriction (CR) have been linked with healthy aging trajectories in different organisms. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored.

Alongside other systems in the body, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. Of the two systems, the adaptive part of the immune system is most impacted by aging. Inflammation is a crucial process that facilitates the maintenance and restoration of tissue and the clearance of pathogens. On the other hand, chronic inflammatory processes are linked with different pathologies, like rheumatoid arthritis. Aside from this pathological involvement of chronic inflammation, the aging process is linked with a low-grade, chronic, and sterile inflammation (an inflammation without infection) termed as "inflammaging."

In general, evidence-based scientific experiments on fasting and calorie restriction have shown to promote healthy aging as well as to alleviate some markers of immunosenescence and inflammaging. Thus, similar to regular exercise, a vegetarian diet, etc., fasting/calorie restriction should also be considered part of a healthy lifestyle. Furthermore, fasting and calorie restriction increases the fitness of the immune system in fighting infection and cancer which are more common in the elderly. However, more data are needed especially on nutritional approaches including, the amount of nutrients, type of nutrients, and combination of nutrients that promote healthy aging and an effective immune response in humans. Furthermore, strategies on how to integrate fasting/calorie restriction in boosting immune response like the length of the intervention, and at what age is best to start fasting still need to be standardized so that its actual effect on the aging immune system can be clarified and used.

I'm not sure that I am entirely convinced, but here researchers argue that age-related mitochondrial dysfunction should be addressed in different ways in different organs. Certainly it is true that delivery strategies for many types of therapy must be different for different organs, and this is a major issue for cell therapies and gene therapies. But ways to improve mitochondrial function should, in principle, be beneficial wherever applied and whatever the present status of mitochondrial function.

As cellular power plants and critical production sites of reactive oxygen species (ROS), mitochondria play a pivotal role in the process of aging, and their dysfunction has been associated with age-related diseases. Mitochondria profoundly influence their cellular environment through their central roles in ATP production, ROS generation, ion homeostasis, and signaling events. Besides, once released into the extracellular space, several mitochondrial constituents, such as mitochondrial nucleic acids or metabolites, can act as danger-associated molecular patterns (DAMPs) that trigger innate immune responses and inflammation. Similarly, mitochondria can also be shed by stressed cells in extracellular vesicles, which carry DAMPs and can act in a paracrine and endocrine manner.

As cells age, mitochondria experience a decline in function, characterized by mitochondrial DNA mutations, increased oxidative stress, DAMP formation, decreased mitochondrial energy conversion, and hampered mitochondrial turnover and dynamics. Consequently, understanding the multifaceted roles of mitochondria is fundamental in deciphering their impact on the process of aging and their potential as anti-aging targets.

The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.

Link: https://doi.org/10.1016/j.pharmthera.2024.108710

The long-running yearly Aging Research and Drug Discovery Meeting (ARDD) in Copenhagen is five long days of presentations from academia and industry, focused on the development of therapies to treat aging in some way. That largely means efforts to manipulate metabolism in order to slow down the progression of aging, but there are always those who seek to repair forms of molecular damage in order to produce some degree of rejuvenation. The sheer number of presentations, and the multiple tracks, means that any commentary on ARDD can really only pick one presentation in ten to discuss at best - which is much the case here.

Michael Ringel of Boston Consulting Group gave a deep and fascinating talk on the evolutionary origins of aging. Geroscientists are mostly focused on how aging happens, but why it happens is also important. Several theories have been proposed. According to Ringel, those explanations can be divided into three broad categories: Mechanistic, Weakening Selection, and Optimization. The first one posits that aging happens due to the inability of evolution to eliminate physical constraints such as the damage that arises from normal biological processes. Basically, miracles don't happen. The second one means that, as organisms age and survival declines, there is less evolutionary pressure to maintain the traits that would keep them healthy later in life. Selection becomes so weak that random mutations, including those that accelerate aging or cause diseases, are no longer removed effectively from the gene pool. This allows aging and late-life deterioration to persist in the population. Michael argued that current empirical evidence is best explained by the optimization paradigm. This has an important implication: a vast majority of pro-longevity mutations, just like other mutations, are a step away from that carefully optimized state. If you look at a broader context of reproductive fitness, you will probably find how it is hurt by the mutation.

Some longevity biotechs don't shy from making big claims, and Maxwell Biosciences is one of them. Its goal is to create "a synthetic immune system" that would give us wide protection against microbial pathogens. Bacteria and viruses evolve quickly, developing drug resistance. Fungi can wreak a lot of havoc and are understudied. The body has defense mechanisms, but they dwindle and get overwhelmed as we age. One such mechanism is the antimicrobial peptide LL-37. Maxwell's LL-37-mimicking candidate kills viruses and bacteria by permeating their membranes and is effective even against highly resistant bacterial strains. Maxwell runs several high-profile collaborations and is wrapping up a study in rhesus macaques with results expected later this month. Human clinical trials will begin next year.

John Sedivy of Brown University reminded the audience that about half of our genome consists of repeated sequences, mostly transposons associated with viruses. While some transposons are benign "viral fossils" that lost their ability to replicate, a majority can still do it if the patches of the chromatin where they are located are derepressed. Transposon reactivation increases with age and has been linked to multiple age-related conditions. This can happen in a positive feedback loop: cellular senescence leads to chromatin opening, LINE-1 (the most ubiquitous retrotransposon) derepression, antiviral response, and then to chronic inflammation. Transposon Therapeutics, the company that John advises, is built on the idea that we can use existing reverse transcriptase inhibitors (such as anti-HIV drugs) against age-related retrotransposon activation. Studies in animal models show that these drugs can have a massive effect on inflammation, cellular senescence, and age-related cognitive decline. The company is already deep in clinical trials with censavudine, a reverse transcriptase inhibitor.

Link: https://www.lifespan.io/news/for-the-11th-year-in-copenhagen-highlights-from-ardd-2024/