Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Alterations of the gut microbiome are associated with epigenetic age acceleration and physical fitness.

Epigenetic clocks can measure aging and predict the incidence of diseases and mortality. Higher levels of physical fitness are associated with a slower aging process and a healthier lifespan. Microbiome alterations occur in various diseases and during the aging process, yet their relation to epigenetic clocks is not explored. To fill this gap, we collected metagenomic (from stool), epigenetic (from blood), and exercise-related data from physically active individuals and, by applying epigenetic clocks, we examined the relationship between gut flora, blood-based epigenetic age acceleration, and physical fitness. We revealed that an increased entropy in the gut microbiome of physically active middle-aged/old individuals is associated with accelerated epigenetic aging, decreased fitness, or impaired health status. We also observed that a slower epigenetic aging and higher fitness level can be linked to altered abundance of some bacterial species often linked to anti-inflammatory effects. Overall our data suggest that alterations in the microbiome can be associated with epigenetic age acceleration and physical fitness.

Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based ageing clocks in older men: WASEDA'S Health Study.

DNA methylation-based age estimators (DNAm ageing clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between cardiorespiratory fitness (CRF), measured directly by expiratory gas analysis, and DNAm ageing clocks are largely unknown. We investigated the relationships between CRF and the age-adjusted value from the residuals of the regression of DNAm ageing clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of CRF to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65-72 years were used to appraise first- (i.e., DNAmHorvath and DNAmHannum) and second- (i.e., DNAmPhenoAge, DNAmGrimAge, and DNAmFitAge) generation DNAm ageing clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrient intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. Both oxygen uptake at ventilatory threshold (VO2 /kg at VT) and peak oxygen uptake (VO2 /kg at Peak) showed a significant negative correlation with GrimAgeAccel, even after adjustments for chronological age and smoking and drinking status. Notably, VO2 /kg at VT and VO2 /kg at Peak above the reference value were also associated with delayed GrimAgeAccel. Multiple regression analysis showed that calf circumference, serum triglyceride, carbohydrate intake, and smoking status, rather than CRF, contributed more to GrimAgeAccel and FitAgeAccel. In conclusion, although the contribution of CRF to GrimAgeAccel and FitAgeAccel is relatively low compared to lifestyle-related factors such as smoking, the results suggest that the maintenance of CRF is associated with delayed biological ageing in older men.

Intravenous Administration of Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSC) for Acute Respiratory Distress Syndrome Due to COVID-19 Infection.

The COVID-19 pandemic has posed significant therapeutic challenges in addressing acute respiratory distress syndrome (ARDS). This serious illness has caused numerous fatalities worldwide and has had profound health and economic impacts. Previous studies have shown that mesenchymal stem cells (MSCs) can suppress ARDS. In this case series, we report on the treatment of nine patients with a single intravenous dose of 100 million hypoxic cultured umbilical cord-derived MSCs (UC-MSCs). Following the intravenous administration of UC-MSCs, obtained from the lining of the umbilical cord, longitudinal laboratory analysis revealed a sustained decrease in inflammatory markers and stabilized pulmonary function in eight out of nine patients. UC-MSCs possess immunomodulatory and anti-inflammatory properties, enabling them to attenuate the cytokine storm and potentially aid in lung repair. Importantly, no adverse events associated with the treatment were observed. These findings collectively suggest that a cell-based approach significantly enhances the survival rate of ARDS induced by SARS-CoV-2 and offers a promising treatment option in both preclinical and clinical settings.

DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.

DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (ρ = 0.2, p = 6.4E - 4, r = 0.19, p = 1.2E - 3), Jumpmax (p = 0.11, p = 5.5E - 2, r = 0.13, p = 2.8E - 2), Gripmax (ρ = 0.17, p = 3.5E - 3, r = 0.16, p = 5.6E - 3), and HDL levels (ρ = 0.18, p = 1.95E - 3, r = 0.19, p = 1.1E - 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (ρ: - 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.

The Circulating Level of Klotho Is Not Dependent upon Physical Fitness and Age-Associated Methylation Increases at the Promoter Region of the Klotho Gene.

(1) Background: Higher levels of physical fitness are believed to increase the physiological quality of life and impact the aging process with a wide range of adaptive mechanisms, including the regulation of the expression of the age-associated klotho (KL) gene and protein levels. (2) Methods: Here, we tested the relationship between the DNA methylation-based epigenetic biomarkers PhenoAge and GrimAge and methylation of the promoter region of the KL gene, the circulating level of KL, and the stage of physical fitness and grip force in two groups of volunteer subjects, trained (TRND) and sedentary (SED), aged between 37 and 85 years old. (3) Results: The circulating KL level is negatively associated with chronological age in the TRND group (r = -0.19; p = 0.0295) but not in the SED group (r = -0.065; p = 0.5925). The age-associated decrease in circulating KL is partly due to the increased methylation of the KL gene. In addition, higher plasma KL is significantly related to epigenetic age-deceleration in the TRND group, assessed by the biomarker of PhenoAge (r = -0.21; p = 0.0192). (4) Conclusions: The level of physical fitness, on the other hand, does not relate to circulating KL levels, nor to the rate of the methylation of the promoter region of the KL gene, only in males.

DNAmFitAge: biological age indicator incorporating physical fitness.

Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. We develop blood-based DNAm biomarkers for fitness parameters gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets (average r between 0.16-0.48). We then use these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge is associated with low-intermediate physical activity levels across validation datasets (p = 6.4E-13), and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge is lower (p = 0.046) and DNAmVO2max is higher (p = 0.023) in male body builders compared to controls. Physically fit people have a younger DNAmFitAge and experience better age-related outcomes: lower mortality risk (p = 7.2E-51), coronary heart disease risk (p = 2.6E-8), and increased disease-free status (p = 1.1E-7). These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.

Fluorescent Cell Staining Methods for Living Hypsibius exemplaris Embryos.

The tardigrade Hypsibius exemplaris was chosen as a model system in part because animals and embryos are optically clear at all stages, facilitating the visualization of events in living material. Here we report new methods for introducing fluorescent dyes into developing H. exemplaris embryos, including methods for fluorescently marking mitochondria, lysosomes, membranes, and nuclei. The development of these techniques suggests approaches for attempting to introduce other molecules into embryos.