FoxO transcription factors in the maintenance of cellular homeostasis during aging

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The FoxO family of Forkhead transcription factors functions at the interface of tumor suppression, energy metabolism, and organismal longevity. FoxO factors are key downstream targets of insulin, growth factor, nutrient, and oxidative stress stimuli that coordinate a wide range of cellular outputs. FoxO-dependent cellular responses include gluconeogenesis, neuropeptide secretion, atrophy, autophagy, apoptosis, cell cycle arrest, and stress resistance. This review will discuss the roles of the mammalian FoxO family in a variety of cell types, from stem cells to mature cells, in the context of the whole organism. Given the overwhelming evidence that the FoxO factors promote longevity in invertebrates, this review will also discuss the potential role of the FoxO factors in the aging of mammalian organisms.

Section snippets

A traditional view of FoxO regulation and cellular function

Mammals have four isoforms of the FoxO transcription factor family, FoxO1, FoxO3, FoxO4, and FoxO6. Three of the four FoxO isoforms, FoxO1, FoxO3, and FoxO4, are crucially regulated by Akt-dependent phosphorylation at three specific sites in response to growth factor and insulin stimulation (Thr32, Ser253, and Ser315 for human FoxO3) [1, 2, 3, 4]. Akt-dependent phosphorylation of FoxO factors promotes FoxO export from the nucleus to the cytoplasm, thereby repressing FoxO transcriptional

Recently discovered signaling pathways regulating FoxO activity

Recent studies are providing further insights into the complexity of FoxO regulatory pathways. FoxO factors have been shown to be regulated by a variety of additional stress stimuli, including DNA damage, nutrient deprivation, cytokines, and hypoxia [30, 33•, 34•, 35•, 36•, 37•, 38•]. For example, DNA damage affects FoxO activity via cyclin-dependent kinase 2 (CDK2) [35]. CDK2 phosphorylates FoxO1 at Ser249, resulting in the sequestration of FoxO1 to the cytoplasm in the absence of DNA damage.

Functions of FoxO factors in the context of the whole organism: insights from invertebrates

Studies in invertebrates have shed light on the cellular role of FoxO factors in the context of the entire organism. In contrast to mammals, invertebrate model organisms possess just one isoform of the FoxO transcription factor family denoted DAF-16 for Caenorhabditis elegans and dFOXO for Drosophila melanogaster. The importance of DAF-16 in organismal metabolism and lifespan was revealed in a series of seminal studies on the insulin/FoxO pathway in worms. DAF-16 is necessary for the increase

In mammals, FoxO isoforms display differential but overlapping expression throughout the organism

In mammals, the FoxO family have a complementary but overlapping expression pattern both during development and in a variety of adult tissues [5, 51, 52, 53]. During mouse development, FoxO1 is detected at highest levels in the adipose tissue, FoxO3 is most expressed in the liver, FoxO4 in the skeletal muscle and FoxO6 in the central nervous system. In adult mice, FoxO1 is observed at the highest levels in adipose tissue, uterus, and ovaries, with lower levels in most other tissues including

An integrative model for FoxO function?

The extreme diversity of the cellular roles of the FoxO factors revealed from mammalian cell culture experiments has created a challenge to integrate these multiple roles into a unified model. In addition, many studies investigating FoxO regulation and function have been performed in immortalized or transformed cultured cell lines, which are out of the tissue context. Hence, it is difficult to extrapolate results to conditions in vivo, which are dependent on specialized cellular niches. Despite

FoxO factors increase organismal glucose levels and food intake by acting on regulatory cell types

Regulatory cells that control circulatory metabolites and hormones reside in the liver, pancreas, hypothalamus–pituitary axis, and adipose tissue. In these regulatory cells, FoxO appears to act at a number of different levels to systemically increase circulating glucose levels (Figure 2). For example, the ablation of FoxO1 in hepatic cells reduces glucose levels in newborn and adult mice, supporting the notion that FoxO factors promote increased glucose levels in the circulation [57]. FoxO1

FoxO factors restrict angiogenesis

The blood vessels of the circulatory system connect the ‘regulatory’ and ‘energy-utilizing’ tissues, and are composed of endothelial cells. Emerging evidence suggests that FoxO factors attenuate proliferation and migration of endothelial cells resulting in limited blood vessel formation (Figure 2). Acute deletion of FoxO1, FoxO3, and FoxO4 in endothelial cells of mice using an inducible Mx-Cre transgene revealed an age-progressive overproliferation of endothelial cells that resulted in

FoxO factors act to protect undamaged cells in energy-utilizing tissues in response to stress stimuli

The energy-utilizing cell types of the organism, such as those that reside in the skeletal muscle, nervous system, and immune system are responsive to the regulatory ‘pacemaker’ tissues such as the liver, pancreas, and hypothalamus (Figure 2). Although the entire set of stimuli that regulate FoxO in these energy-utilizing cells is not known yet, particularly for the immune system, it appears that the FoxO family becomes activated when the regulatory tissues and the vasculature are not

FoxO factors limit the expansion and regulate the terminal differentiation of stem/precursor cells and proliferative/tumorigenic cells

In addition to their roles in mature cell types, the FoxO transcription factors also play a role to limit the expansion of stem/progenitor cells of tissues such as the hematopoietic system (Figure 2). Acute deletion of FoxO1, FoxO3, and FoxO4 in adult murine bone marrow led to the expansion of both the myeloid and lymphoid lineages coupled with increased cell cycling of the long-term hematopoietic stem cells [79••], indicating that the FoxO family normally limits the proliferation of these stem

Conclusion

Although the regulation and roles of the FoxO family have been well studied, there is still a dearth of knowledge on the mechanisms that specify the decision between different cellular outputs in response to different environmental contexts for these promiscuous transcription factors. Similarly, it is not clear why four FoxO isoforms exist, though there is now evidence to suggest that their roles are not entirely overlapping [63••, 64•]. A model that emerges is that different FoxO isoforms bind

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize for not being able to cite all relevant papers because of space constraints. We thank members of the Brunet Lab and in particular Eric L. Greer, Victoria A. Rafalski, Dario R. Valenzano, and Valérie M. Renault for their helpful comments on the manuscript.

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