Effect of women's fertility and sexual development on epigenetic clock: Mendelian randomization study.

BACKGROUND AND OBJECTIVES: In observational studies, women's fertility and sexual development traits may have implications for DNA methylation patterns, and pregnancy-related risk factors can also affect maternal DNA methylation patterns. The aim of our study is to disentangle any potential causal associations between women's fertility and sexual development traits and epigenetic clocks, as well as to search for probable mediators by using the Mendelian randomization (MR) method. METHODS: Instrumental variables for exposures, mediators, and outcomes were adopted from genome-wide association studies data of European ancestry individuals. The potential causal relationship between women's fertility and sexual development traits and four epigenetic clocks were evaluated by inverse variance weighted method and verified by other two methods. Furthermore, we employed multivariable MR (MVMR) adjusting for hypertension, hyperglycemia, BMI changes, and insomnia. Then, combining the MVMR results and previous research, we performed two-step MR to explore the mediating effects of BMI, AFS, and AFB. Multiple sensitivity analyses were further performed to verify the robustness of our findings. RESULTS: Leveraging two-sample MR analysis, we observed statistically significant associations between earlier age at first birth (AFB) with a higher HannumAge, PhenoAge and GrimAge acceleration(ß = - 0.429, 95% CI [- 0.781 to - 0.077], p = 0.017 for HannumAge; ß = - 0.571, 95% CI [- 1.006 to - 0.136], p = 0.010 for PhenoAge, and ß = - 1.136, 95% CI [- 1.508 to - 0.765], p = 2.03E-09 for GrimAge respectively) and age at first sexual intercourse (AFS) with a higher HannumAge and GrimAge acceleration(ß = - 0.175, 95% CI [- 0.336 to - 0.014], p = 0.033 for HannumAge; ß = - 0.210, 95% CI [- 0.350 to - 0.070], p = 0.003 for GrimAge, respectively). Further analyses indicated that BMI, AFB and AFS played mediator roles in the path from women's fertility and sexual development traits to epigenetic aging. CONCLUSIONS: Our study suggested that AFS and AFB are associated with epigenetic aging. These findings may prove valuable in informing the development of prevention strategies and interventions targeted towards women's fertility and sexual development experiences and their relationship with epigenetic aging-related diseases.

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies.

FBXW7, a member of the F-box protein family within the ubiquitin-proteasome system, performs an indispensable role in orchestrating cellular processes through ubiquitination and degradation of its substrates, such as c-MYC, mTOR, MCL-1, Notch, and cyclin E. Mainly functioning as a tumor suppressor, inactivation of FBXW7 induces the aberrations of its downstream pathway, resulting in the occurrence of diseases especially tumorigenesis. Here, we decipher the relationship between FBXW7 and the hallmarks of cancer and discuss the underlying mechanisms. Considering the interplay of cancer hallmarks, we propose several prospective strategies for circumventing the deficits of therapeutic resistance and complete cure of cancer patients.

Low Crude Protein Diet Affects the Intestinal Microbiome and Metabolome Differently in Barrows and Gilts.

Low protein diets are commonly used in the growing-finishing pig stage of swine production; however, the effects of low dietary protein on the intestinal microbiota and their metabolites, and their association with pig sex, remain unclear. The present study aimed to assess the impact of a low crude protein (CP) diet on the gut microbiome and metabolome, and to reveal any relationship with sex. Barrows and gilts (both n = 24; initial body = 68.33 ± 0.881 kg) were allocated into two treatments according to sex. The four groups comprised two pairs of gilts and barrows fed with a high protein diet (CP 17% at stage I; CP 13% at stage II) and a low protein diet (CP 15% at stage I; CP 11% at stage II), respectively, for 51 d. Eight pigs in each group were slaughtered and their colon contents were collected. Intestinal microbiota and their metabolites were assessed using 16S rRNA sequencing and tandem mass spectrometry, respectively. The low protein diet increased intestinal microbiota species and richness indices (P < 0.05) in both sexes compared with the high protein diet. The sample Shannon index was different (P < 0.01) between barrows and gilts. At the genus level, unidentified Clostridiales (P < 0.05), Neisseria (P < 0.05), unidentified Prevotellaceae (P < 0.01) and Gracilibacteria (P < 0.05) were affected by dietary protein levels. The relative abundance of unidentified Prevotellaceae was different (P < 0.01) between barrows and gilts. The influence of dietary protein levels on Neisseria (P < 0.05), unidentified Prevotellaceae (P < 0.01) and Gracilibacteria (P < 0.05) were associated with sex. Metabolomic profiling indicated that dietary protein levels mainly affected intestinal metabolites in gilts rather than barrows. A total of 434 differentially abundant metabolites were identified in gilts fed the two protein diets. Correlation analysis identified that six differentially abundant microbiota communities were closely associated with twelve metabolites that were enriched for amino acids, inflammation, immune, and disease-related metabolic pathways. These results suggested that decreasing dietary protein contents changed the intestinal microbiota in growing-finishing pigs, which selectively affected the intestinal metabolite profiles in gilts.