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Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a powerful new model system to study the basic mechanisms of inherited cardiomyopathies. hiPSC-CMs have been utilized to model several cardiovascular diseases, achieving the most success in the inherited arrhythmias, including long QT and Timothy syndromes (Moretti et al. N Engl J Med. 363:1397-409, ; Yazawa et al. Nature. 471:230-4, ) and arrhythmogenic right ventricular dysplasia (ARVD) (Ma et al. Eur Heart J. 34:1122-33, ). Recently, studies have applied hiPSC-CMs to the study of both dilated (DCM) (Sun et al. Sci Transl Med. 4:130ra47, ) and hypertrophic (HCM) cardiomyopathies (Lan et al. Cell Stem Cell. 12:101-13, ; Carvajal-Vergara et al. Nature. 465:808-12, ), providing new insights into basic mechanisms of disease. However, hiPSC-CMs do not recapitulate many of the structural and functional aspects of mature human cardiomyocytes, instead mirroring an immature - embryonic or fetal - phenotype. Much work remains in order to better understand these differences, as well as to develop methods to induce hiPSC-CMs into a fully mature phenotype. Despite these limitations, hiPSC-CMs represent the best current in vitro correlate of the human heart and an invaluable tool in the search for mechanisms underlying cardiomyopathy and for screening new pharmacologic therapies. [ABSTRACT FROM AUTHOR]

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that ?-ketoglutarate (?-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit ? is identified as a novel binding protein of ?-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that ?-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by ?-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by ?-KG requires ATP synthase subunit ? and is dependent on target of rapamycin (TOR) downstream. Endogenous ?-KG levels are increased on starvation and ?-KG does not extend the lifespan of dietary-restricted animals, indicating that ?-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases. [ABSTRACT FROM AUTHOR]