Abstract
It is proposed that the ageing process is linked to signaling from the germline such that the rate of ageing can be adjusted to the state of the reproductive system, allowing these two processes to co-evolve. Mechanistic insight into this link has been primarily derived from iteroparous reproductive models, the nematode C. elegans, and the arthropod Drosophila. Here, we examined to what extent these mechanisms are evolutionarily conserved in a semelparous chordate, Oikopleura dioica, where we identify a developmental growth arrest (GA) in response to crowded, diet-restricted conditions, which can extend its lifespan at least three-fold. Under nutritional stress, the iteroparative models sacrifice germ cells that have entered meiosis, while maintaining a reduced pool of active germline stem cells (GSCs). In contrast, O. dioica only entered GA prior to meiotic entry. Stress conditions encountered after this point led to maturation in a normal time frame but with reduced reproductive output. During GA, TOR signaling was inhibited, whereas MAPK, ERK1/2 and p38 pathways were activated, and under such conditions, activation of these pathways was shown to be critical for survival. Direct inhibition of TOR signaling alone was sufficient to prevent meiotic entry and germline differentiation. This inhibition activated the p38 pathway, but did not activate the ERK1/2 pathway. Thus, the link between reproductive status and lifespan extension in response to nutrient-limited conditions is interpreted in a significantly different manner in these iteroparative versus semelparous models. In the latter case, meiotic entry is a definitive signal that lifespan extension can no longer occur, whereas in the former, meiotic entry is not a unique chronological event, and can be largely erased during lifespan extension in response to nutrient stress, and reactivated from a pool of maintained GSCs when conditions improve.
Highlights
The progression of the ageing process can, in a number of organisms, be paused when they encounter unfavorable environmental conditions. This allows such organisms more latitude in coupling reproductive events to circumstances favorable for survival and growth. The importance of this link is strengthened by evidence from the nematode, Caenorhabditis elegans, and the fruitfly, Drosophila, that loss of germline stem cells (GSCs) extends lifespan through an evolutionarily conserved pathway involving FOXO-family transcription factors [1]
When O. dioica were cultured at high density, there was a rapid reduction of IdU incorporation in somatic endocycling cells from day 3 onwards (Fig. 1C) with full arrest attained at day 5 of culture under these dense conditions
FOXO transcription factors regulate the transcription of p27 in mammalian cells [69]. Consistent with these findings, we found the ortholog of FOXO/daf-16 was up regulated in growth arrest (GA) O. dioica (Danks et al, unpublished data) suggesting a conserved regulatory circuit in the up-regulation of Cyclin-dependent Kinase Inhibitors (CKI) transcripts
Summary
The progression of the ageing process can, in a number of organisms, be paused when they encounter unfavorable environmental conditions This allows such organisms more latitude in coupling reproductive events to circumstances favorable for survival and growth. The mouse, and more the Drosophila and C. elegans models have been at the centre of research on developmental growth arrest (GA), ageing/lifespan and the links of these processes to the reproductive axis They are used as a proxy for understanding the ageing process in humans, with respect to the effects of dietary restriction. All of these models have an iteroparative mode of reproduction, with multiple reproductive cycles over the life cycle. We have focused instead on a chordate, Oikopleura dioica, with a semelparous mode of reproduction, in which there is only a single reproductive episode before death
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