Fight Aging! Newsletter, November 13th 2023

This study investigated the correlation among muscle strength, working memory (WM), and cortical hemodynamics during the N-back task of memory performance, and further explored whether cortical hemodynamics during N-back task mediated the relationship between muscle strength and WM performance. We observed that muscle strength (particularly grip strength) predicted WM of older adults in this cross-sectional study, which validated our hypothesis and expanded on previous research findings. Studies demonstrated that grip strength predicted executive function decline in patients with mild cognitive impairment. Other cross-sectional studies showed that grip strength and lower limb strength also predicted cognitive impairment. Previous research revealed that grip strength was positively linked to cognitive functions such as WM, language fluency, and word recall.

The reason why grip strength predicted working memory might be the control of muscles by the nervous system. Grip strength was influenced not only by muscle volume but also by the central nervous system, conversely, neurologic deterioration not only contributed to cognitive decline but might also be a factor in strength loss. This was consistent with the findings of the present study, where we found that greater muscle strength was associated with higher levels of activation in specific regions of the prefrontal cortex (PFC)/a> and better WM performance. The greater the muscle strength, the stronger the activity of the left dorsolateral prefrontal cortex (L-DLPFC) at a low WM load (i.e., 0-back). At moderate, high WM load (i.e., 1-, 2-back), the greater the muscle strength, the more active areas - additionally right dorsolateral prefrontal cortex (R-DLPFC), right frontopolar area (R-FPA), and left frontopolar area (L-FPA). Some studies suggested that the PFC played a crucial role in high grip strength performance, indicating that it may be the connection between grip strength and executive function. A systematic review found that resistance exercise improved brain function, particularly changes in the PFC, accompanied by improvements in executive function. Our findings further validated that a certain level of muscle strength was beneficial for brain health.

Furthermore, our finding that higher WM load was associated with fewer activation areas supported our hypothesis and was consistent with the compensation-related utilization of the neural circuit hypothesis, which suggested that older adults showed over-activations at a lower WM load, and under-activations at a higher WM load. Previous research found that higher levels of oxyhemoglobin concentration in the PFC of older adults during cognitive tasks were associated with better cognitive performance, particularly in the DLPFC, which was closely linked to WM. Additionally, studies showed that the level of PFC activation increased with increasing WM load in older adults, and then tended to stabilize or decrease. Older adults exhibited greater DLPFC activation than younger adults during WM tasks, and meta-analysis showed that when young people and older adults had the same cognitive performance, young people exhibited greater activity in left ventrolateral prefrontal cortex (L-VLPFC), while older people exhibited greater activity in L-DLPFC. These findings suggested that older adults could compensate for cognitive performance by activating more task-related brain regions, supporting the assumption of a positive neurobiobehavioral relationship between cortical hemodynamics and cognitive performance.

However, our study found cortical hemodynamics during N-back tasks did not mediate the relationship between muscle strength and WM performance. It can be inferred that an increase in muscle strength was associated with prefrontal cortex activation, thereby promoting positive effects on brain health.

Conventional wisdom in evolutionary theory considers aging as a non-selected byproduct of natural selection. Based on this, conviction aging was regarded as an inevitable phenomenon. It was also thought that in the wild organisms tend to die from diseases, predation, and other accidents before they could reach the time when senescence takes its course. Evidence has accumulated, however, that aging is not inevitable and there are organisms that show negative aging even. Furthermore, old age does play a role in the deaths of many different organisms in the wild also. The hypothesis of programmed aging posits that a limited lifespan can evolve as an adaptation (i.e., positively selected for) in its own right, partly because it can enhance evolvability by eliminating "outdated" genotypes. A major shortcoming of this idea is that non-aging sexual individuals that fail to pay the demographic cost of aging would be able to steal good genes by recombination from aging ones.

Here, we show by a spatially explicit, individual-based simulation model that aging can positively be selected for if a sufficient degree of kin selection complements directional selection. Under such conditions, senescence enhances evolvability because the rate of aging and the rate of recombination play complementary roles. The selected aging rate is highest at zero recombination (clonal reproduction). In our model, increasing extrinsic mortality favors evolved aging by making up free space, thereby decreasing competition and increasing drift, even when selection is stabilizing and the level of aging is set by mutation-selection balance. Importantly, higher extrinsic mortality is not a substitute for evolved aging under directional selection either. Reduction of relatedness decreases the evolved level of aging; chance relatedness favors non-aging genotypes. The applicability of our results depends on empirical values of directional and kin selection in the wild.

We found that aging can positively be selected for in a spatially explicit population model when sufficiently strong directional and kin selection prevail, even if reproduction is sexual. The view that there is a conceptual link between giving up clonal reproduction and evolving an aging genotype is supported by computational results.

Age-related musculoskeletal diseases such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IDD) critically affect the motor functions and quality of life of elderly individuals. Unfortunately, although various drugs, (such as bisphosphonates, recombinant human parathyroid hormone, denosumab for OP, and paracetamol for OA), have been approved for use, their benefits are limited due to side effects or the poor overall health of elderly individuals. Aging involves complex mechanisms, including genetic mutations, telomere shortening, epigenetic alterations, protein deformation, mitochondrial damage, and cellular senescence, which are responsible for the onset of age-related diseases. Thus, investigating and manipulating the mechanisms underlying aging are important future research goals. Among the fundamental mechanisms mentioned above, cellular senescence has received considerable attention in recent years.

Cellular senescence refers to the stable condition of cell cycle arrest, first described in the early 1960s. Senescent cells (SnCs) are produced in the early stages of embryonic development and accumulate with age. However, SnCs exert deleterious effects on tissues by secreting a plethora of inflammatory cytokines, chemokines, oxidative stress-related proteins, growth factors, and proteases, which is termed the senescence-associated secretory phenotype (SASP). Accumulated SnCs are a hallmark of aging and contribute to age-related diseases, including OP, diabetes, and Alzheimer's disease. Interestingly, SnCs have dual effects on tumour development, which may depend on the immune microenvironment or cell cycle stage, as cell cycle arrest is helpful for tumour suppression.

The skeletal system consists of bones, joints, cartilage tissues, and ligaments that work together to maintain homeostasis of the motor system and the internal environment. Bone remodeling occurs throughout life. Bone tissue comprises four types of cells: osteoblasts, osteoclasts, osteocytes, and osteoprogenitors. They undergo fundamental changes during the aging process. Senescent mesenchymal stem cells (MSCs) exhibit decreased osteogenesis and increased adipogenesis, moreover, senescent osteocytes or osteoclasts produce SASP. However, the underlying mechanisms by which SnCs and SASP regulate bone remodelling and induce disease are still under investigation. In this review, we summarise the role of senescence in the skeletal system, discuss its underlying mechanisms, and propose new strategies for treating age-related diseases by targeting senescence.

When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells - a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.

"It was commonly assumed that the observed alterations in the mitochondrial metabolism were a consequence of T-cell exhaustion." To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, researcher developed a new genetic model. It switches off the mitochondrial phosphate transporter (SLC25A3) and paralyses mitochondrial respiration in T cells. As a result, the T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells.

Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1-alpha). The accumulation of HIF-1-alpha protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion. "This HIF-1-alpha-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a 'metabolic checkpoint' in the process of T-cell exhaustion."

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells.

At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

Most previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on different organs such as the heart and the lungs. A new study unravels the immunological cascade that unfolds inside the actual site of exertion - the muscle. Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. It boosts the expression of genes that regulate muscle structure, metabolism, and the activity of mitochondria, the tiny powerhouses that fuel cell function. Mitochondria play a key role in exercise adaptation by helping cells meet the greater energy demand of exercise. In the new study, the team analyzed what happens in cells taken from the hind-leg muscles of mice that ran on a treadmill once and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.

The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation - greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon. Both groups had elevated levels of regulatory T cells (Treg cells) in their muscles. Further analyses showed that in both groups, Tregs lowered exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice. However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers - the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance, the experiments showed. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance and that regular activity over time is needed to yield benefits.

Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Animals that lacked Tregs had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hindleg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality. More importantly, animals lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness. These animals' muscles also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs. "The villain here is interferon. In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage. We've only looked in the muscle, but it's possible that exercise is boosting Treg activity elsewhere in the body as well."

Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.

Cellular senescence refers to a stable non-proliferative state that cells enter in response to various stresses. This process is implicated in the development of various age-related diseases, including body aging, tumors, and senile dementia. Recently, an increasing number of researchers have focused on the relationship between cellular senescence and metabolic disorders. First, key cells involved in metabolic regulation undergo age-related changes. In patients with diabetes, the proportion of aging β-cells in the pancreas increases, and eliminating these cells can effectively prevent the onset and development of diabetes. In adipose tissue, aging adipose precursor cells promote insulin resistance in adipose cells. In addition, aging endothelial cells contribute to the formation of atherosclerotic plaques and increase plaque instability.

Second, the secretory phenotype of senescent cells undergoes significant changes, resulting in the production of a variety of pro-inflammatory factors. This phenomenon is referred to as the Senescence-Associated Secretory Phenotype (SASP). As a result, the continued accumulation of senescent cells can cause chronic inflammation. This chronic inflammatory response is considered as an important contributor to metabolic diseases. Thus, senescent cells may contribute to the onset and development of metabolic diseases, including diabetes, in various ways.

Aging intervention therapies targeting the clearance of senescent cells via senolytics or the modulation of their SASP via senomorphics have increasingly attracted the attention of researchers investigating their potential role in metabolic diseases. This paper reviews the relationship between metabolic diseases and cellular senescence and discusses the role of cellular senescence in these disorders, thereby providing new insights into their treatment.

Theoreticians in the 1960s who were trying to wrap their heads around the principles of why and how animals on this planet age argued that senescence is "inevitable." As time goes by, organisms grow old, and their probability of dying increases. But research into a wide range of organisms suggests this almost definitely isn't the case: there's a growing variety in how creatures grow old. On all branches of the evolutionary tree, some animals live fast and die young and those that are so old we don't even know how to measure their age.

Female sand-burrowing mayflies have about five minutes to two hours to mate before they die. Giant Sunda rats live about half a year, while the Rougheye rockfish can live over 200. While many evolutionary principles behind this baffling discrepancy have started to surface, the molecular and biological reasons for aging - and why different animals do it at different rates - still baffles scientists daily. From an evolutionary perspective, however, it is possible to retroactively notice some patterns about what factors might have put these animals in their position on the spectrum.

In general, the bigger you are, the harder it is for another animal to kill and eat you. This is one of the hypotheses for why animals like the bowhead whale - the longest-lived mammal on the planet, sometimes reaching ages of up to 200 years - lives for so long: they don't have many predators out to get them. Elephants also live long for similar reasons, and the size factor would also explain why animals like mice, rats, and voles are so short-lived. They're an easier snack. Bats, though, are tiny, yet one of the longest-lived mammals, too - reaching 40 years old. From an evolutionary perspective, it doesn't matter that they're so tiny, because they're still really good at escaping predators.

There's some evidence that Greenland sharks can live up to 500 years, as can the ocean quahog. They live in extremely icy Arctic ocean environments, which is often associated with slow metabolism and maturation and correlates with living longer. Animals living and evolving in environments that allow them to escape mortality also easily preserve their longevity. Take the Galapagos tortoise. They live on an island and don't have natural predators, so they can take longer to reproduce and grow older - even past 150. Animals with the longest lifespans are often characterized by unique adaptations, habitat, and evolutionary factors that allow them to live for extended periods.

Osteoarthritis is the degeneration of cartilage and other tissues in joints and is the most common form of arthritis in Australia, with one in five people over the age of 45 having the condition. Often described as a 'wear and tear' condition, factors such as ageing, obesity, injury, and family history contribute to the progression of osteoarthritis. Researchers have discovered a novel population of stem cells - marked by the Gremlin 1 protein - responsible for the progression of osteoarthritis. Treatment with fibroblast growth factor 18 (FGF18) stimulated the proliferation of Gremlin 1 cells in joint cartilage in mice, leading to significant recovery of cartilage thickness and reduced osteoarthritis.

Gremlin 1 cells present opportunities for cartilage regeneration and their discovery will have relevance to other forms of cartilage injury and disease, which are notoriously challenging to repair and treat. It challenges the categorisation of osteoarthritis as wear and tear. "With this new information, we are now able to explore pharmaceutical options to directly target the stem cell population that is responsible for the development of articular cartilage and progression of osteoarthritis."

Though this discovery is limited to animal models, there are genetic similarities to human samples, and human trials are ongoing. Results of a five-year clinical trial study using FGF18, known clinically as Sprifermin, were published in 2021 with potential long-term clinical benefit and no safety concerns. Phase 3 of the Sprifermin trial is ongoing, and researchers envision public access to this treatment soon.

Chromatin provides an interface between genetic information and the environment, allowing an individual's experiences to shape the course of their life from within their cells. In order to store and protect genetic material, DNA is wrapped around histone proteins inside the nucleus, and this bundle of DNA and histones is termed chromatin. Histones do more than simply package DNA however, as the level of accessibility versus condensation of chromatin can impact the availability of DNA to binding by transcriptional machinery and therefore the expression of genes.

Aging affects nearly all aspects of our cells, from our DNA to our proteins to how our cells handle stress and communicate with each other. Age-related chromatin changes are of particular interest because chromatin can dynamically respond to the cellular and organismal environment, and many modifications at chromatin are reversible. Changes at chromatin occur during aging, and evidence from model organisms suggests that chromatin factors could play a role in modulating the aging process itself, as altering proteins that work at chromatin often affect the lifespan of yeast, worms, flies, and mice. The field of chromatin and aging is rapidly expanding, and high-resolution genomics tools make it possible to survey the chromatin environment or track chromatin factors implicated in longevity with precision that was not previously possible.

In this review, we discuss the state of chromatin and aging research. We include examples from yeast, Drosophila, mice, and humans, but we particularly focus on the commonly used aging model, the worm Caenorhabditis elegans, in which there are many examples of chromatin factors that modulate longevity. We include evidence of both age-related changes to chromatin and evidence of specific chromatin factors linked to longevity in core histones, nuclear architecture, chromatin remodeling, and histone modifications.

Mitohormesis is a process whereby mitochondrial stress responses, mediated by reactive oxygen species (ROS), act cumulatively to either instill survival adaptations (low ROS levels) or to produce cell damage (high ROS levels). The mitohormetic nature of extremely low-frequency electromagnetic field (ELF-EMF) exposure thus makes it susceptible to extraneous influences that also impinge on mitochondrial ROS production and contribute to the collective response. Consequently, magnetic stimulation paradigms are prone to experimental variability depending on diverse circumstances.

The failure, or inability, to control for these factors has contributed to the existing discrepancies between published reports and in the interpretations made from the results generated therein. Confounding environmental factors include ambient magnetic fields, temperature, the mechanical environment, and the conventional use of aminoglycoside antibiotics. Biological factors include cell type and seeding density as well as the developmental, inflammatory, or senescence statuses of cells that depend on the prior handling of the experimental sample. Technological aspects include magnetic field directionality, uniformity, amplitude, and duration of exposure. All these factors will exhibit manifestations at the level of ROS production that will culminate as a unified cellular response in conjunction with magnetic exposure. Fortunately, many of these factors are under the control of the experimenter.

This review will focus on delineating areas requiring technical and biological harmonization to assist in the designing of therapeutic strategies with more clearly defined and better predicted outcomes and to improve the mechanistic interpretation of the generated data, rather than on precise applications. This review will also explore the underlying mechanistic similarities between magnetic field exposure and other forms of biophysical stimuli, such as mechanical stimuli, that mutually induce elevations in intracellular calcium and ROS as a prerequisite for biological outcome. These forms of biophysical stimuli commonly invoke the activity of transient receptor potential cation channel classes, such as TRPC1.

Recently published studies suggest that the paracrine substances released by mesenchymal stem cells (MSCs) are the primary motive behind the therapeutic action reported in these cells. Pre-clinical and clinical research on MSCs has produced promising outcomes. Furthermore, these cells are generally safe for therapeutic use and may be extracted from a variety of anatomical regions. Recent research has indicated, however, that transplanted cells do not live long and that the advantages of MSC treatment may be attributable to the large diversity of bioactive substances they create, which play a crucial role in the control of essential physiological processes.

Secretome derivatives, such as conditioned media or exosomes, may provide significant benefits over cells in terms of manufacture, preservation, handling, longevity of the product, and potential as a ready-to-use biologic product. Despite their immunophenotypic similarities, the secretome of MSCs appears to vary greatly depending on the host's age and the niches in which the cells live. The secretome's effect on multiple biological processes such as angiogenesis, neurogenesis, tissue repair, immunomodulation, wound healing, anti-fibrotic, and anti-tumor for tissue maintenance and regeneration has been discovered. Defining the secretome of cultured cultivated MSC populations by conditioned media analysis will allow us to assess its potential as a novel treatment approach.

This review will concentrate on accumulating data from pre-clinical and clinical trials pointing to the therapeutic value of the conditioned medium. At last, the necessity of characterizing the conditioned medium for determining its potential for cell-free treatment therapy will be emphasized in this study.

Researchers have long known that levels of nucleotides like GTP control how fast DNA damage is repaired, which in turn controls sensitivity to therapies. Researchers previously thought that this only happened because nucleotides are the building blocks that form DNA. But these findings uncover an entirely new way that nucleotides control DNA repair. "GTP impacts resistance or sensitivity to treatment not just because it's a building block of DNA, as we previously thought. Instead of only affecting the physical structure of the DNA, it also acts as a signaler. The levels of GTP turn on a signaling pathway and give cells instructions to repair damaged DNA."

"In the future, we'd like to develop therapeutics that leverage the relationship between GTP and DNA damage response, both to make cancer cells more sensitive to chemotherapy and radiation and also to boost GTP levels to protect normal tissue from damage. We knew that depleting GTP might make brain cancers respond better to chemotherapy and radiotherapy. Now these findings show why that's happening." The discovery that GTP acts as a signaler helps explain the biological underpinnings of why focusing on GTP is a worthwhile pursuit and could help researchers figure out which patients will derive the most benefit from GTP modulators in the clinical trial.

Researchers have in the past demonstrated that the transmembrane protein CXCR4 plays a significant role in the development of atherosclerosis. The protein transmits signals to the cell interior. If CXCR4 is specifically silenced in arterial endothelial cells or in smooth muscle cells, it results in more severe atherosclerotic lesions. At the same time, there is increased leukocyte ingress into the cell, which leads to inflammatory processes. With regard to leukocytes, however, the presence of CXCR4 can also promote the development of inflammatory processes.

The researchers therefore searched specifically for microRNA molecules that are limited to vascular cells and are involved in the regulation of CXCR4. And indeed, they managed to identify a good therapeutic starting point for the treatment of atherosclerosis in the form of miR-206, a candidate which occurs only in endothelial cells and in vascular smooth muscle cells. In those sites, it downregulates the expression of CXCR4 by binding to the transcripts of the CXCR4 gene and preventing their conversion into the protein.

For therapeutic application, the effect of miR-206 needs to be suppressed. To this end, the researchers developed a so-called target-site blocker: a molecule that specifically interrupts interactions between miR-206 and the CXCR4 transcripts and thus only boosts its expression in the respective cells. The researchers were able to demonstrate the effectiveness of this approach in a mouse model and in human cells in the culture. Most notably, the blocker they developed was able to prevent atherosclerosis in the mouse model.

The causal relationship between gut microbiota and DNA methylation phenotypic age acceleration remains unclear. This study aims to examine the causal effect of gut microbiota on the acceleration of DNA methylation phenotypic age using Mendelian randomization. A total of 212 gut microbiota were included in this study, and their 16S rRNA sequencing data were obtained from the Genome-wide Association Study (GWAS) database. The GWAS data corresponding to DNA methylation phenotypic age acceleration were selected as the outcome variable. Two-sample Mendelian randomization (TSMR) was conducted.

The results from inverse-variance weighting (IVW) analysis revealed significant associations between single nucleotide polymorphisms (SNPs) corresponding to 16 gut microbiota species and DNA methylation phenotypic age acceleration. Out of the total, 12 gut microbiota species exhibited consistent and robust causal effects. Among them, 7 displayed a significant positive correlation with the outcome while 5 species showed a significant negative correlation with the outcome. This study utilized Mendelian randomization to unravel the intricate causal effects of various gut microbiota species on DNA methylation phenotypic age acceleration.

The gut microbiome, a community of trillions of microbes living in the human intestines, has an increasing reputation for affecting not only gut health but also the health of organs distant from the gut. For most microbes in the intestine, the details of how they can affect other organs remain unclear, but for gut resident bacteria L. reuteri the pieces of the puzzle are beginning to fall into place. Researchers have found that these bacteria reduce gut inflammation in adult humans and rodent models, suppress bone loss in animal models of osteoporosis and in a human clinical trial, promote skin wound healing in mice and humans and improve social behavior in six mouse models of autism spectrum disorder.

Of those effects of L. reuteri, the abilities to promote social behavior and wound healing have been shown to require signaling by the hormone oxytocin, but little was known about how this occurs. "Oxytocin is mostly produced in the hypothalamus, a brain region involved in regulating feeding and social behavior, as well as in other organs. Given that other brain-produced hormones also are made in the gut, we tested the novel idea that oxytocin itself was also produced in the intestinal epithelium where L. reuteri typically resides."

The researchers built up their case step by step. First, they reviewed single-cell RNA-Seq datasets of the intestinal epithelium, which show which genes are expressed in that tissue. They found that oxytocin genes are expressed in the epithelium of various species, including mice, macaques, and humans. Then, using fluorescence microscopy, the team revealed the presence of oxytocin directly on human intestinal organoids, also called mini guts, which are laboratory models of intestinal tissue that recapitulate many of its functions and structure. "We also determined a mechanism by which L. reuteri mediates oxytocin secretion from human intestinal tissue and human intestinal organoids. L. reuteri stimulates enteroendocrine cells in the intestine to release the gut hormone secretin, which in turn stimulates another intestinal cell type, the enterocyte, to release oxytocin."