Fight Aging! Newsletter, April 17th 2023

Researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin.

When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells. "Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response. We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis, and degenerative diseases."

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly.

Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.

Clouding this debate over limits to human lifespan is poor record keeping in the early twentieth century, and extreme age claims made for secondary gain. Norris McWhirter of the Guinness Book of World Records, wrote, "No single subject is more obscured by vanity, deceit, falsehood, and deliberate fraud than the extremes of human longevity". Mistakes in age claims can also arise due to dementia or confabulations. The maximum life span of humans is currently determined by Jeanne Calment, documented to have lived for 122 years. Controversy still exists over Jeanne Calment's age despite verified documentation. Although a sample of her blood is stored and analyses might help resolve the controversy, to date, it has not been allowed due to ethical constraints surrounding the informed consent signed at the time of sample donation. Even with proper documentation, Jeanne Calment's age is doubted because documentation alone can be falsified or misattributed to an heir as some have suggested

Highly accurate age estimators can be built based on DNA methylation levels. The high accuracy of epigenetic clocks has been replicated numerous times and would be one way to verify the age of individuals too old to have been counted accurately by nascent census methods. However, most current epigenetic clocks underestimate the ages of older individuals (due to the well-known regression to the mean effect) and lead to relatively low age correlations in the oldest old.

Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on 7,039 blood and saliva samples from individuals older than 40, including 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105+), and 25 samples from supercentenarians (aged 110+). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (younger than 40) are correlated (r = 0.55) with age effects in old individuals (older than 90).

We further present a chromatin state analysis of age effects in centenarians. Our chromatin state analysis reveals that mean methylation of PRC2 target sites continue to increase late in life while exhibiting increased variability. Similarly, the mean methylation levels of two negatively age-related chromatin states (EnhA1, TxEx4) do not exhibit any leveling off effect late in life. These results suggest that one will be able to build accurate centenarian clocks for people who live beyond 120 years. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library.

Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown-induced and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib.

Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice.

Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema. Senescence is a factor in the pathogenesis of chronic pulmonary diseases, including emphysema. Thus, senotherapy based on senolytics, senomorphics, and their combination has been recognized as a practicable strategy for the treatment of these diseases. Previous studies have reported on the efficacy of regorafenib in animal models of Alzheimer's disease and bleomycin-induced fibrosis. The role of regorafenib in the attenuation of senescence may provide an explanation for its beneficial effects in these disease models.

The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice.

In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR.

Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.

The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was shown to significantly boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging.

Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme Glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and caloric restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, also known as methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo.

Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy. In this review, we provide a detailed overview of the current evidence that glycine is a pro-longevity molecule, a so-called geroprotector. By exploring and synthesizing available data, we also offer a tentative mechanistic explanation for how this simple amino acid may target biological aging and prolong life.

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan.

We show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. The presence of odors from adult females produced an 8% increase in median lifespan of female mice, compared to the control group, and a 9% increase in the age at 90th percentile. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan.

Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.

Researchers identified 31 published clinical trials of so-called antiamyloid Alzheimer's drugs. All aim to eliminate beta amyloid, whose buildup many consider a driver of the disease. The drugs fell into two categories. One, secretase inhibitors, are traditional small-molecule drugs that target an enzyme that produces beta amyloid from a larger protein. These compounds have largely been abandoned because they didn't pan out in trials. The second category included monoclonal antibodies like lecanemab that directly target various forms of beta amyloid. Another antiamyloid antibody in the analysis, aducanumab, was approved in 2021 amid much controversy, and still others are in trials. Sixteen of the 31 trials researchers analyzed involved these lab-generated immune proteins.

Alzheimer's disease frequently causes the brain to shrink as the illness progresses. But the researchers found both types of antiamyloid drugs generally caused clinical trial participants to lose more brain volume than what was seen in Alzheimer's patients on a placebo. Lecanemab and another antibody, donanemab, currently in late-stage trials, both accelerated whole brain volume loss. People in two large lecanemab trials on the highest drug dose recorded, on average, a 28% greater brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter. The authors also reported that the antiamyloid antibodies - but not the secretase inhibitors - led to an increase in the size of brain ventricles, indicating they were filling with extra fluid. This can happen when nearby brain tissue atrophies. In people taking the now-approved dose of lecanemab, brain ventricle size increased by 36% more that it did in people on placebo - or an additional 1.9 mL.

Researchers then studied whether a type of brain swelling and bleeding called amyloid-related imaging abnormalities (ARIA), a well-documented side effect of the antibodies, was associated with the other brain changes. ARIA occurred in 21% of the 898 people taking lecanemab in a pivotal trial (as well as 9% on a placebo); most had no symptoms, but some did become severely ill and at least two died after extensive brain swelling and bleeding. Researchers found the experimental therapies with a higher rate of ARIA also generated a bigger average increase in the size of the ventricles. There's a logic behind this, though the connections haven't been proved. ARIA shows up on brain scans as inflammation, and generally, it's not controversial that neuroinflammation would lead to neurodegeneration.

Osteoarthritis (OA) is a major cause of disability and globally the most common musculoskeletal health issue with more than 30% of those over 45 years of age having sought treatment. In recent attempts to develop new treatments for patients it is now emerging that the multifaceted clinical pathology of OA is underpinned by particular molecular endotypes defined by distinct molecular mechanisms and signaling pathways, which may overlap. In OA these include 'low repair', 'bone cartilage', 'metabolic' and 'inflammatory' endotypes.

In attempting to understand the drivers of these endotypes, it is notable that obesity is a major risk factor for the development of OA. Excessive mechanical loading of the joint is often cited as the cause of the association between obesity and OA. However, studies also find that obesity increases the risk of developing OA in the hands, a non-load bearing joint, illustrating that the association is not solely due to pathological loading on the articular cartilage but may also be due to the chronic inflammatory metabolic effects of obesity.

Hand, hip, knee, and foot joint synovial tissue was obtained from OA patients (n = 32) classified as obese (BMI over 30) or normal weight (BMI 18.5-24.9). Targeted proteomic, metabolic, and transcriptomic analysis found the inflammatory landscape of OA synovial fibroblasts are independently impacted by obesity, joint loading, and anatomical site with significant heterogeneity between obese and normal weight patients, confirmed by bulk RNAseq. Further investigation by single cell RNAseq identified four functional molecular endotypes including obesity specific subsets defined by an inflammatory endotype related to immune cell regulation, fibroblast activation, and inflammatory signaling.

These cell types draw similarity to fibroblast subsets reported in rheumatoid arthritis (RA), suggesting OA pathogenesis in obese patients may be akin to the more inflammatory RA joint. Obese OA specific clusters are involved in the activation and recruitment of immune cells, which are reminiscent of 'immune-effector fibroblasts' reported in RA known to regulate and recruit immune cells. In conclusion, these findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints.

Extreme low temperatures are detrimental, but a moderate decrease in body temperature can have beneficial effects for the organism. In fact, lowering body temperature extends longevity in both poikilotherms (for example Caenorhabditis elegans, Drosophila melanogaster, and distinct fish species) and homeotherms such as rodents. Aging is a primary risk factor for neurodegenerative disorders that involve protein aggregation. Because lowering body temperature is one of the most effective mechanisms to extend longevity in both poikilotherms and homeotherms, a better understanding of cold-induced changes can lead to converging modifiers of pathological protein aggregation.

Here, we find that cold temperature (15 °C) selectively induces the trypsin-like activity of the proteasome in Caenorhabditis elegans through PSME-3, the worm orthologue of human PA28γ/PSME3. This proteasome activator is required for cold-induced longevity and ameliorates age-related deficits in protein degradation. Moreover, cold-induced PA28γ/PSME-3 diminishes protein aggregation in C. elegans models of age-related diseases such as Huntington's and amyotrophic lateral sclerosis. Notably, exposure of human cells to moderate cold temperature (36 °C) also activates trypsin-like activity through PA28γ/PSME3, reducing disease-related protein aggregation and neurodegeneration. Together, our findings reveal a beneficial role of cold temperature that crosses evolutionary boundaries with potential implications for multi-disease prevention.

The species Heterocephalus glaber, commonly known as the naked mole-rat, is a eusocial mammal endemic to the arid and semi-arid regions of northeast Africa. In the wild, naked mole-rats live an almost completely subterranean lifestyle, in colonies of up to 295 animals (average size is 60 animals/colony) that cohabitate a network of tunnels that the mole-rats dig themselves with their large, ever-growing incisors. Naked mole-rats are notable for their extreme lifespans, living longer than any other documented rodent, with the longest previously-reported lifespan of 37 years and many animals living beyond 30 years. These values are notable in the context of this species' small body size due to the strong correlation across species between that value and mammalian lifespan: maximum lifespan potential (MLSP) increases by 16% for each doubling of average species body mass.

For most mammalian species, lifespan is limited by an exponential increase in the per-day risk of death (i.e. mortality hazard) with age in accord with a statistical distribution first defined by Gompertz based on human mortality. The increase in mortality hazard with age is referred to as "demographic aging". We have previously shown H. glaber to achieve its exceptional longevity through defiance of this trend, exhibiting near constant mortality hazard across the full spectrum of observed lifespans, with no hazard increase evident even many-fold beyond their expected MLSP. For naked mole-rats, the lack of demographic aging is accompanied by seemingly-indefinite maintenance of many physiological characteristics that typically change with age. Naked mole-rats are resistant to age-related diseases such as cancer, neurodegeneration, and cardiovascular disease and show signs of tissue regeneration and remodeling preventing the deterioration of age-associated physiological function.

Here, we re-visited the demographic analysis of our naked mole-rat collection, with husbandry data now extended by five years across an expanded set of animals. We found our original conclusions of naked mole-rat mortality hazard being age-independent to be reproduced, using either the total sum of all historical data or only those data collected after our previous study - the latter qualifying as a replication study.

Regular endurance exercise training is an effective intervention for the maintenance of metabolic health and the prevention of many age-associated chronic diseases. Several metabolic and inflammatory factors are involved in the health-promoting effects of exercise training, but regulatory mechanisms remain poorly understood. Cellular senescence - a state of irreversible growth arrest - is considered a basic mechanism of aging. Senescent cells accumulate over time and promote a variety of age-related pathologies from neurodegenerative disorders to cancer. Whether long-term intensive exercise training affect the accumulation of age-associated cellular senescence is still unclear.

Here, we show that the classical senescence markers p16 and IL-6 were markedly higher in the colon mucosa of middle-aged and older overweight adults than in young sedentary individuals, but this upregulation was significantly blunted in age-matched endurance runners. Interestingly, we observe a linear correlation between the level of p16 and the triglycerides to HDL ratio, a marker of colon adenoma risk and cardiometabolic dysfunction. Our data suggest that chronic high-volume high-intensity endurance exercise can play a role in preventing the accumulation of senescent cells in cancer-prone tissues like colon mucosa with age. Future studies are warranted to elucidate if other tissues are also affected, and what are the molecular and cellular mechanisms that mediate the senopreventative effects of different forms of exercise training.

The telomerase reverse transcriptase (TERT) gene encodes the rate-limiting catalytic TERT protein, a subunit of telomerase. Studies on telomeres and telomerase have been conducted since the start of research on aging. Many studies have shown that defects in telomeres or telomerase exert a substantial influence on the development of aging-related diseases. Some in vivo experiments have already reported that TERT gene therapy exhibits exciting efficacy for treating diverse diseases. Researchers tentatively introduced AAV-mouse Tert into 12- and 24-month-old mice, and they found noticeable improvements in various aging-related molecular biomarkers. Interestingly, an increase in median lifespan was also observed. Later, researchers designed an AAV9 vector that expressed Tert in heart tissue to treat heart failure after myocardial infarction (MI). Intravenous injection of this vector into mouse models of myocardial infarction showed that mice with the vector expressing TERT had less damage to the cardiac indices of both structure and function, decreased mortality and improved biomarkers.

KL, another classic aging-related gene, has a much shorter research history than that of the TERT gene, just over twenty years. Exploring concrete mammalian models (mostly mouse models) of aging-related diseases has revealed the therapeutic effect of enhancing KL expression in neurodegenerative diseases, chronic kidney diseases, cardiovascular diseases, etc. Preclinical evidence has demonstrated that KL has broad therapeutic promise for treating various aging-related diseases. However, no interventional clinical trials have been conducted to assess the clinical potential of KL.

The entire human body is widely affected by vascular endothelial growth factor (VEGF), and the formation and function of blood vessels are highly reliant on VEGF. VEGF is negatively associated with aging, and its high VEGF expression has a protective effect on the cardiovascular system. However, many studies have identified it as a potential target in malignant tumors and it is regarded as a promoting factor. Therefore, it remains a concern whether it will induce cancer when applied in anti-aging gene therapy. Researchers conducted an experiment based on the hypothesis that vascular aging is a founding factor in organismal aging. Over an experimental period of more than 30 months, they reported increased lifespans and physiological function after applying the gain-of-function system of transgenic VEGF and AAV-assisted VEGF transduction. Thus, VEGF seems to play a paradoxical role in aging similar to the telomerase gene, which inspires further systematic and careful exploration of potential treatments.

Gene therapies, especially in the field of aging provide new hopes for treating diseases. However, not all aging-related genes have the potential to be the targets. Satisfactory efficacy is only achieved by combining them with an adaptive operational strategy and efficient carriers. Additionally, some genes may simply be predictors of prognosis or capable of screening out effective medications for diseases. To be a therapeutic target, the candidate gene should have a relatively distinct and clear role.

Preserving functional health and quality-of-life in old age is a major goal and global challenge in public health. The high rate of sedentary behavior that is characteristic of the older adult population exacerbates impairments of physiological and structural systems that are typically seen in the aging process. Achieving an understanding of the profound influence of physical activity on all aspects of health in old age is the driving force behind the emergence of "physical activity in old age" as a growing area of research. Accumulated evidence implies that being physically active and exercising is far superior to other optimal aging facilitators. Yet this area of research faces numerous constraints and obstacles.

Compared to other age groups, old age is typified by increased heterogeneity, which complicates research and renders practice harder to conduct. This heterogeneity is typical of physical performance as well as cognitive and behavioral performance. With respect to physcial activity (PA) in old age, a reductionist approach is often adopted. For example, PA programs may be developed to affect specific types of performance (e.g., muscle strength, aerobic endurance, and balance), by manipulating parts of an intact physiological movement system. However, one typical manifestation of aging is a heterogenous decline in these physiological systems. In healthy organs, these systems communicate with one another to maintain homeostasis; yet aging causes the breakdown of different physiological systems, which in turn may affect other more intact physiological systems, thereby interfering with this homeostasis. As such, this individual pattern of aging could imply the need for critically rethinking PA training principles for aging populations.

Due to the large heterogeneity of evaluation methods and PA interventions, standardized guidelines are lacking for assessing the benefits of PA programs for specific groups of older adults. While the literature presents numerous reports that employed specific criteria for assessing physical fitness, the PA programs that were used for such interventions are not always clearly described. Moreover, in addition to the lack of standardized assessment tools and intervention details, research studies fall short in providing guidelines for the standardized reporting of PA protocols - in terms of the type of PA, intensity, number of repetitions, and more. With exercise and other types of PA, there is clearly no "one-size-fits-all," especially in the diverse aged population. Yet, research on older populations is typically biased towards healthy and relatively young older adults, with certain groups of older individuals frequently being excluded from research on aging - especially in studies with PA interventions.

Despite evidence on the benefits of PA in advanced age, public health initiatives often fail to examine clinically relevant effects of PA on physical and cognitive health. For example, it has been hypothesized that the highly controlled environments in which some PA research is conducted limit its replicability in real-world community settings. While the efficacy of the PA intervention may perhaps be more clearly demonstrated in laboratory settings, there is a dearth of research that indicates its effectiveness when conducted in real-world conditions as well. In addition, the effect of PA in clinical populations may vary, based on the stage of the disease, the nature of a concomitant medical treatment, and the patients' current lifestyle.

Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta (Pdgfrβ) to prevent beige adipogenesis. We show that genetically deleting Pdgfrβ, in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation.

Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5. Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals.

Upon exposure to internal or environmental insults, ribosomes stand sentinel. In particular, stress-driven dysregulation of ribosomal homeostasis is a potent trigger of adverse outcomes in mammalians. The present study assessed whether the ribosomal insult affects the aging process via the regulation of sentinel organs such as the gut.

Analyses of the human aging dataset demonstrated that elevated features of ribosomal stress are inversely linked to intestinal barrier maintenance biomarkers during the aging process. Ribosome-insulted worms displayed reduced lifespan, which was associated with the disruption of gut barriers. Mechanistically, ribosomal stress-activated Sek-1/p38 signaling, a central platform of ribosomal stress responses, counteracted the gut barrier deterioration through the maintenance of the gut barrier, which was consistent with the results in a murine insult model. However, since the gut-protective p38 signaling was attenuated with aging, the ribosomal stress-induced distress was exacerbated in the gut epithelia and mucosa of the aged animals, subsequently leading to increased bacterial exposure.

Moreover, the bacterial community-based evaluation predicted concomitant increases in the abundance of mucosal sugar utilizers and mucin metabolic enzymes in response to ribosomal insult in the aged host. All of the present evidence on ribosomal insulting against the gut barrier integrity from worms to mammals provide new insights into the roles of ribosomes in the regulation of human longevity and susceptibility to gut-associated chronic diseases.