Reviewing FOXO Transcription Factors in Aging and Longevity

A number of the large FOX family of proteins, in particular the FOXO proteins, appear to play roles in the complex interaction between metabolism and aging. They are thus targets for investigation and potential intervention in that part of the research community interested in trying to slightly slow aging via pharmacology. The plan there is to alter the operation of cellular metabolism in ways that boost existing mechanisms of repair and maintenance, or slow the pace at which the damage that causes aging is generated. The response to calorie restriction is the best understood of such altered states of metabolism, and investigations of the mechanisms involved in calorie restriction have determined much of the present focus on specific genes and proteins for those interested in developing drugs to modestly slow aging. The past decade suggests that attempting to do this is both hard and expensive; at least a billion spent on sirtuin research, for example, produced no useful results in terms of therapies. Even if further billions produce useful drug candidates, they will still be at best as effective as calorie restriction, and while calorie restricted individuals enjoy health benefits they still age and die on much the same schedule as their unrestricted peers. This isn't the road to rejuvenation.

An exciting research area on FOXO transcription factors' impacting on longevity has arisen in recent years. Studies have been conducted to address their upstream regulation, their downstream effectors, and respective signaling pathways in various animal models. Consequently, how these FOXO-mediated programs affect cellular or tissue function and whether there is an effect at an organismal level, has also been scrutinized. Several lines of evidence suggest that FOXOs affect longevity in a pleiotropic fashion, influencing several cell-regulated activities such as stress resistance, metabolism, cell cycle arrest, and apoptosis.

A myriad of future work can be envisioned at this time. The induction of FOXO-mediated programs in tissues with distinct metabolic potential such as brain, muscle, or adipose tissue and with different stages of differentiation or metabolic conditions (nutrition, oxidative stress) will enlarge our knowledge of how FOXO factors affect cellular/organismal lifespan. To further comprehend how FOXOs affect longevity, it is of high importance to understand how human FOXO sequence variants (namely FOXO3A) affect protein expression, its structure, or transcriptional activity. In order to see how these variants translate into physiological profiles, future investigations should address how these variants affect the level of FOXO proteins and their downstream effectors in serum. This approach has been used successfully in patients with vitiligo, in which FOXO3A levels were shown to be decreased when compared with the control group.

Compression of morbidity relates to both extended lifespan and delayed onset of age-related diseases, such as cancer and cardiovascular disorders. The development of molecules targeting aging mechanisms that underlie a number of age-related diseases is an exciting field that is nowadays in its first steps. It is noteworthy that clinical trials to test lifespan extension in humans would be challenging and require markers that can detect difference in aging rate across a short time frame. But given the potential of FOXO proteins to impact on numerous disorders such as cancer, diabetes, neurodegeneration, or immune system dysfunction, novel therapeutic modalities based on FOXOs will most likely take place in the near future.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12427/

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