Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

In vitro investigation on human development, disease modeling, and drug discovery has been empowered by human induced pluripotent stem cell (hiPSC) technologies that form the foundation of precision medicine. Race and sex genetic backgrounds have become a major focus of many diseases modeling and drug response evaluation in the pharmaceutical industry. Here, we gathered data from major stem cell repositories to analyze the diversity with respect to ethnicity, sex, and disease types; and we also analyzed public datasets to unravel transcriptomics differences between samples of different ethnicities and sexes. We found a lack of diversity despite the large sample size of human induced pluripotent stem cells. In the ethnic comparison, the White group made up the majority of the banked hiPSCs. Similarly, for the organ/disease type and sex comparisons, the neural and male hiPSCs accounted for the majority of currently available hiPSCs. Bulk RNA-seq and single-cell transcriptomic analysis coupled with Machine Learning and Network Analysis revealed panels of gene features differently expressed in healthy hiPSCs and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of different races and sexes. The data highlights the current ethnic and sex inequality in stem cell research and demonstrates the molecular biological diversity of hiPSCs and cardiomyocytes from different races and genders. We postulate that future efforts in stem cell biology, regenerative and precision medicine should be guided towards an inclusive, diverse repository reflecting the prevalence of diseases across racial and ethnic groups and the sexes, important for both common and rare disease modeling, drug screening, and cell therapeutics.

Background: Adverse remodeling in post-infarct myocardium includes weakened contractility due to substantial cardiomyocyte (CM) loss, augmented inflammatory and fibrotic responses, and re-organization of vasculatures. Current mechanistic understanding of cellular interaction within and between cardiac cell populations in post-injured myocardium remained limited. Aims: To identify molecular regulations converged in post-infarct heart cells. Methods and Results: We simultaneously analyzed total heart cells in post-infarct myocardium by using the latest single-nucleus (sn) dual transcriptomics-epigenomics approaches (snRNA-seq and snATAC-seq) in our new triple-transgenic multi-reporter mouse model featuring CM lineage tracking and maturity visualization. The compositions of cell types clustered based on transcriptomic profiles are highly comparable to those identified by open chromatin accessibility. There were significant reductions of CMs and endothelial cells, along with remarkable increases of immuno/inflammatory cells and cardiac fibroblasts in post-infarct hearts compared to controls, as revealed by comparable cell populations clustered based on transcriptomic profiles versus epigenomics chromatin accessibility profiles. We characterized the dual-omic molecular signatures of all heart cell populations from acute post-infarct murine hearts in contrast to controls. We identified the features as various molecular states in pseudotime trajectory, distinguishing each cell population and sub-cluster presented in diseased and normal hearts. Heart cells in post-infarct myocardium were clustered along the newer pseudotime series while those in control hearts were mostly located in earlier phases of the pseudotime trajectory. Lastly, we identified the signaling pathways and TFs enriched by differentially-expressed genes (DEGs) and the differentially active regions (DARs) of the chromatin in dedifferentiated CMs as well as other heart cell types and their relationships in post-MI and normal hearts. Conclusions: The results demonstrated the complex cellular and molecular remodeling at single-cell (nucleus) level in acute post-infarct hearts in which diverse and converging signaling networks may be targeted for heart failure therapeutics.