Life, death and immortality

Since the childhood of humanity, man has been fascinated by the concept of mortality and the idea of the presence of immortals, may they be heavenly creatures, demons from an ancient world or etheric beings walking the earth, unseen, among us mere mortals. How fascinating it must have been when scientists, for the first time, could actually see the biochemical structure that contains immortal information, our genetic code, and which is, in its own way, immortal when transmitted from one generation to the other. (In today’s world of highthroughput molecular biology, the sight of precipitated DNA in a test tube is, of course, no longer sensational. Rather, one might hear the occasional swear word when precipitation at that time in the protocol was not intended.) Creatures die, while their structural design plan does not. But not only are they capable of passing on these blueprints from generation to generation, but also to sacrifice individual cells or even tissues in a controlled manner for the common good of the whole body. In 2002, the Nobel committee awarded The Nobel Prize in Physiology or Medicine to Sydney Brenner, H. Robert Horvitz and John E. Sulston ‘for their discoveries concerning genetic regulation of organ development and programmed cell death’. Necrosis and apoptosis are no longer recent concepts, but have become textbook knowledge, but still their impact is huge in a number of physiological and pathophysiological settings. Since then, however, paradigms have shifted, with multiple forms of regulated necrosis coming into view and rendering the picture far more complex (Mal eth et al. 2013, Jouan-Lanhouet et al. 2014) – parthanatos, oxytosis, ferroptosis, netosis, pyronecrosis and pyroptosis being famous examples (Vanden Berghe et al. 2014). Acta Physiologica has recently featured a number of interesting studies, in which apoptosis and necrosis are key mechanisms within a wide spectrum of physiological and/or pathological processes. Several studies target the pathways regulating cell death and factors involved therein, such as HIF (Corcoran & O’Connor 2013) and H2S signalling (Lencesova et al. 2013), ghrelin (Yu et al. 2014) or the role of dietary factors (Lambert et al. 2014). Abed et al. (2013) recently investigated suicidal erythrocyte death, termed eryptosis, and the interaction of dying red blood cells with the vascular wall, with immediate implications for the physiological function of Klotho, a protein affecting mainly ageing and lifespan. The vascular wall itself is a key player in pathophysiological processes involved in the main causes of death and disability in the Western world, and programmed cell death processes, in turn, play major roles therein (Phalitakul et al. 2013, Liu et al. 2014). Recent studies have provided us with a much better insight into the pathophysiology of cell death mechanisms in complex disease entities such as diabetes mellitus (Hansen et al. 2014, Mapanga et al. 2014). At first sight, apoptosis and necrosis may appear as singular mechanisms, if not even opposed to one another. As usual in biomedicine, the truth is more complex: ischaemia/reperfusion injury not only involves both processes, but within this context, they influence each other. Programmed cell death is no longer synonymous to caspase-mediated apoptosis, and at least three different pathways of programmed necrosis have been identified in ischaemia–reperfusion injury (Linkermann et al. 2012). Both Rabadi & Lee (2014) and Lempi€ainen et al. (2013) studied ischaemic kidney injury and the role of protective factors acting beneficially therein through a reduction of apoptotic processes. In the heart, several protective mechanisms, both adaptive and therapeutically administered, have been tested (Murphy & Steenbergen 2008, Wang et al. 2014). So, while doing the routine apoptosis assay indispensable to get a project wrapped up – try to never lose the ability to wonder. Questioning everything, always, is what makes us scientists.