RESUMEN
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.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Persona de Mediana Edad , Microbioma Gastrointestinal/genética , Aptitud Física , Microbiota/genética , Aceleración , Envejecimiento/genética , Epigénesis Genética , Metilación de ADNRESUMEN
Aging is the greatest risk factor for numerous diseases and mortality, and establishing geroprotective interventions targeting aging is required. Previous studies have suggested that healthy dietary patterns, such as the Mediterranean diet, are associated with delayed biological aging; however, these associations depend on nationality and sex. Therefore, this study aimed to investigate the relationship between dietary patterns identified through principal component analysis and biological aging in older men of Japan, one of the countries with the longest life expectancies. Principal component analysis identified two dietary patterns: a healthy Japanese dietary pattern and a Western-style dietary pattern. Eight epigenetic clocks, some of the most accurate aging biomarkers, were identified using DNA methylation data from whole-blood samples. Correlation analyses revealed that healthy Japanese dietary patterns were significantly negatively or positively correlated with multiple epigenetic age accelerations (AgeAccel), including AgeAccelGrim, FitAgeAccel, and age-adjusted DNAm-based telomere length (DNAmTLAdjAge). Conversely, the Western-style dietary pattern was observed not to correlate significantly with any of the examined AgeAccels or age-adjusted values. After adjusting for covariates, the healthy Japanese dietary pattern remained significantly positively correlated with DNAmTLAdjAge. Regression analysis showed that healthy Japanese dietary pattern contributed less to epigenetic age acceleration than smoking status. These findings suggest that a Western-style dietary pattern may not be associated with biological aging, whereas a healthy Japanese dietary pattern is associated with delayed biological aging in older Japanese men. Our findings provide evidence that healthy dietary patterns may have mild beneficial effects on delayed biological aging in older Japanese men.
RESUMEN
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.
Asunto(s)
Capacidad Cardiovascular , Masculino , Humanos , Anciano , Metilación de ADN/genética , Envejecimiento/genética , Estilo de Vida , OxígenoRESUMEN
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.
Asunto(s)
Plasminógeno , Receptores de Superficie Celular , Ratones , Animales , Humanos , Plasminógeno/metabolismo , Receptores de Superficie Celular/metabolismo , Restricción Calórica , Hígado/metabolismo , Ratones Transgénicos , Serina Proteasas , Proliferación Celular , Músculos/metabolismoRESUMEN
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.
Asunto(s)
Biomarcadores Ambientales , Fuerza de la Mano , Femenino , Humanos , Masculino , Envejecimiento/genética , Aptitud Física , Metilación de ADN , Biomarcadores , Epigénesis GenéticaRESUMEN
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.
Asunto(s)
Metilación de ADN , Calidad de Vida , Masculino , Femenino , Humanos , Envejecimiento/genética , Ejercicio Físico , BiomarcadoresRESUMEN
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.