The life-long story of the heart starts concomitantly with primary differentiation events occurring in multipotent progenitors located in the so-called heart tube. This initially tubular structure starts a looping process, which leads to formation of the final four-chambered heart with a primary contribution of geometric and position-associated cell sensing. While this establishes the correct patterning of the final cardiac structure, it also provides feedbacks to fundamental cellular machineries controlling proliferation and differentiation, thus ensuring a coordinated restriction of cell growth and a myocyte terminal differentiation. Novel evidences provided by embryological and cell engineering studies have clarified the relevance of mechanics-supported position sensing for the correct recognition of cell fate inside developing embryos and multicellular aggregates. One of the main components of this pathway, the Hippo-dependent signal transduction machinery, is responsible for cell mechanics intracellular transduction with important consequences for gene transcription and cell growth control. Being the Hippo pathway also directly connected to stress responses and altered metabolism, it is tempting to speculate that permanent alterations of mechanosensing may account for modifying self-renewal control in tissue homeostasis. In the present contribution, we translate these concepts to the aging process and the failing of the human heart, two pathophysiologic conditions that are strongly affected by stress responses and altered metabolism.
