A twist in the FOXO tale: Edging closer to revealing the secrets of unlimited tissue renewal


Figure 1.

In the previous issue we published a work [1] presenting the central importance of Forkhead box O transcription factor family (FOXO) in an organism's response to environmental influences – a central question being that of how Hydra, and its stem cells, remain potentially forever young, whereas most other organisms age and die. Now we present a paper [2] that might answer that question by investigating the evolutionary diversification of FOXO since its beginnings in early animals. And, given FOXO's evolutionary ancientness, it's no surprise that much of the question has to do with food and sex.

It has been known for more than a decade that part of the signal to downregulate the insulin signalling pathway is under the control of the gonads (at least in the model system in C. elegans) [3]: a signal from germline cells (a sub-set of cells in the gonad) shortens lifespan by downregulating DAF-16 –the C. elegans homologue of FOXO – hence repressing its downstream consequences, one of which is longevity. Thus was explained the increase in longevity observed upon ablation of the germline cells (but not of the entire gonad, note).

On the other hand, the evolutionarily relevant question – and that which extends the paradigm to most exclusively sexually-reproducing species – is: why should the environmental constraint of nutrient deprivation extend lifespan? The intuitive answer for us humans is: because it optimizes reproductive success by restricting productive mating to periods of sufficient nutrients. In this scenario, the other side of the coin emerges: insulin-like signalling must, somehow, regulate the germline, and hence reproductive capacity. And, indeed – around 10 years after Hsin and Kenyon's publication [3] – that is what was discovered: insulin signalling stimulates proliferation of the larval germline cell cycle in C. elegans [4]. When nutrients are plentiful, the larval germline proliferates in response to insulin signalling, because reproduction is a ‘good bet’ under such circumstances.

Increase in germline leads to increased inhibitory signalling from germline to DAF-16/FOXO; hence a parallel arm of the network connecting nutrient abundance, reproductive capacity and longevity emerged: insulin-like signalling acts on the germline (at least in the dauer stage of C. elegans), which in turn inhibits DAF-16/FOXO activity, hence shortening lifespan (‘in return’ for reproduction, at least in the natural setting). A crucial part of the puzzle had been solved, and in certain subsequent experiments involving FOXO-mediated extension of life-span, compromised reproductive output was not witnessed. This not only confirms the directionality of causality of the phenomenon observed by Michaelson et al. [4], but – as Schaible and Sussman develop further – it suggests the potential for uncoupling lifespan from reproductive output: the phenomenon that appears as an inevitable trade-off in wild-type animals in nature might be possible to circumvent via suitable manipulation!

The effect that reduced insulin signalling has is what one would expect if it is (primarily) the germline that – particularly under nutrient deprivation – inhibits FOXO activity. However, although this makes perfect evolutionary sense from the perspective of a mammal, or even a worm, say, that is not at all how things were at the dawn of multicellular life. Here is where the puzzle starts, because Hydra doesn't go into a form of life-extending ‘suspended reproduction’ when the going gets tough: it tends to reproduce sexually, and one species of Hydra suddenly puts all of its resources into the sexual act, and then promptly dies. And yet – in its seeming asexual immortality under favourable conditions – Hydra is the temptress in our search for understanding the fundamental basis of indefinite cellular renewal.

In this context, Schaible and Sussman [2] present a very interesting new perspective on FOXO. In essence, it is that FOXO has but a single function in Hydra: to ensure a continually replenishing pool of pristine (as opposed to gradually aging) stem cells; in most of the later-evolving animal lineages, including humans, it has been partly ‘distracted’ from its original ‘immortality-promoting’ role: via co-option to other regulatory networks it evolved to mediate the extension of life span in aging organisms by enhanced maintenance of post-mitotic cells, as well as supporting stem cell proliferation. This is the crucial distinction: in aging organisms FOXO maintains a complex soma – via involvement in many pathways – enabling the organism to survive to sexual maturity, sexually reproduce ‘sufficiently’, and – on the way – adapt plastically to environmental challenges. Seen from a network perspective, FOXO is a hub, and the ‘routing’ of many pathways through it limits its engagement in any one [2] – similarly to the way in which a wireless network router limits bandwidth (and hence speed of data transfer) amongst users working simultaneously.

In Hydra, FOXO supports a life-history, the default ‘strategy’ of which is asexual reproduction via budding. Hydra's FOXO essentially works in one interest when nutrients are plentiful: the proliferative fitness of stem cells in the three tissues that will make the ‘endless’ procession of budding daughters. Hydra engages in asexual budding, or sexual reproduction, but – perhaps with the exception of one or two species (see [1]) – not both at once. It suppresses FOXO expression in head, foot and gametes (the parts not involved in budding), and in harsh conditions – notably, poor feeding conditions – the animal will resort to sexual reproduction, hence giving its genes a fighting chance to overcome environmental vagaries via recombination. In its natural setting it does not respond to caloric restriction via ceasing to reproduce and simply maintaining the soma: presumably it can't, because – applying Schaible and Sussman's reasoning – its FOXO has not evolved functions in somatic maintenance; at this point, FOXO's role in signalling a change in the environment – hence triggering sexual reproduction – takes the stage.

The twist in the story of FOXO – inherent in Schaible and Sussman's model – seems, indeed, to be consistent with Hydra's very contrasting reproductive ‘strategies’. Further, FOXO activity is definitely part of the response to environmentally imposed stress in Hydra [5]. However, in Hydra FOXO does not trigger the caloric restriction phenotype seen in many later-evolving lineages – and that might well be explained by the insights of Schaible and Sussman. FOXO is clearly at the evolutionary root of life-history responses to environmental influences, but during evolution, the functions of this crucial sensor have diversified greatly, concomitantly with a diversity of life-histories and reproductive ‘strategies’. The big question is now: can we untangle FOXO from its duties in the parallel processing of renewal and maintenance functions in ageing organisms – essentially uncoupling renewal from growth and sexual reproduction? Can we, thus, harness it for the most important challenge of healthy extended longevity: tissue renewal?


  • Andrew Moore

  • Editor-in-Chief