Speculation on FOXO in Organismal Complexity and the Evolution of Aging

Only lower organisms seem able to prosper via evolutionary strategies that involve some combination of agelessness, radical transformation of body structure, and hyperefficient regeneration. The candidates for truly immortal animals are few and far between: species such as Turritopsis dohrnii, a tiny jellyfish that runs its development cycle in reverse rather than age and die, and hydra, which might achieve immortality through exceedingly effective always-on tissue regeneration. Strategies of this nature can work because these are comparatively simple organisms, lacking the specialization and complexity of higher animals such as we mammals. Gaining a complex neural network and brain seems to go hand in hand with losing exceptional regenerative capabilities - which seems reasonable, although it is still an open question as to exactly why this is the case.

One thing to consider as a result is that while studying these apparently immortal species might teach us interesting things about biology, it probably won't result in anything of practical use in medicine in the near term. Bear in mind that it will be a long haul to mine useful medical applications from the far better funded and more advanced study of long-lived mammals such as naked mole rats and whales, which are very close relatives to us in comparison to jellyfish and hydra. But the biochemistry that keeps a hydra going is more likely to result in destruction and cancer than benefits if implemented in a human: many of our structures, especially those in the brain, need to be around for the long-term, not constantly replaced with new tissue, or discarded in the course of a radical change of body structure.

Here researchers make an early and speculative hypothesis on the role of FOXO in the move from simple, highly regenerative organisms to complex, less regenerative organisms. FOXO genes (the O category of the forkhead box family) have been studied for some years by researchers seeking to understand and catalog the means by which metabolism determines longevity. Like many other longevity-related genes they influence broad collections of central and important processes related to genetic transcription, cell proliferation, and stress tolerance. There is no simple set of dots to join between point A and point B: these are networks of interlinked feedback loops.

FOXO in aging: Did evolutionary diversification of FOXO function distract it from prolonging life?

In this paper we contrast the simple role of FOXO in the seemingly non-aging Hydra with its more diversified function in multicellular eukaryotes that manifest aging and limited life spans. From this comparison we develop the concept that, whilst once devoted to life-prolonging cell-renewal (in Hydra), evolutionary accumulation of coupled functionality in FOXO has since 'distracted' it from this role. Seen in this light, aging may not be the direct cost of competing functions, such as reproduction or growth, but the result of a shift in emphasis in a protein, which is accompanied by advantages such as greater organismal complexity and adaptability, but also disadvantages such as reduced regeneration capacity. Studying the role of FOXO in non-aging organisms might, therefore, illuminate the path to extend life span in aging organisms.

Stem cells and aging from a quasi-immortal point of view

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence?

This review discusses experimental studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging.

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