Daf-41/p23: A Small Protein Heating Up Lifespan Regulation.

Abstract

The life span of non-renewing organisms is determined by the potential of their individual cells to maintain their functions while aging. Nematodes, like Caenorhabditis elegans with their 20 days of adult life, have proven to be excellent model systems to study organismal lifespan, its variability, and its regulation [1–3]. Early on, the life span could be linked to environmental conditions, like growth temperature and food intake [1,4]. In general, in these experiments, organisms develop and age slower and live longer at lower growth temperatures. This is evident from a clear relationship between temperature and life span ranging from 35 days to 9 days upon temperature changes from 10 to 25.5 degrees [1]. On the higher end of this temperature range, C. elegans can enter the dauer state, which is also found in response to starvation or the presence of dauer pheromone [5– 7]. The formation of this stress-resistant state, which enables survival of the organism for longer than 3 months, requires morphological changes to the cuticule and inhibition of further development. Interestingly, it is entirely reversible without effects on the later adult life span [8]. This decision has been analyzed genetically in detail, identifying genes that promote dauer entry (DAF-c) and those that prevent dauer entry (DAF-d). These studies unravel the pathways, which cooperate in the decision whether to enter the path to the dauer state instead of normal development. The most prominent of those are the homologs of the insulin-like receptor DAF-2, the FOXO-transcription factor DAF-16, and the steroid hormone receptor DAF-12, amongst others [9–11]. The decision making requires the sensing of environmental factors and alteration of developmental programs in different tissues. Thus the number of genes influencing this decision is considerable. Interestingly, several genes that control the entry into the stressand starvation-resistant dauer state also exert control over the normal life span of the nematode [12,13]. Early aging markers include disorganization of muscular structure and reduction of pharyngeal activity and motility [14,15]. In this context, lower temperature, like some aging-related mutations, delays these early aging markers and likewise postpones later aging markers, like swallowing difficulties and general loss of motility. Despite knowing the individual function of many dauer-influencing genes, the reconstruction of regulated cellular pathways is complicated. This also originates from the fact that different cells are participating in the pathways as well as a contribution of humoral controls, implying that several individual cellular decisions culminate to regulate these pathways [16,17].