Reviewing Methods of Life Extension in Flies, From a Perspective of Maintaining Homeostasis

If you consider aging to be an accumulation of cellular and molecular damage, then loss of homeostasis in tissues - a progressive failure of stability and maintenance - is a consequence of that damage, and epigenetic changes shown to occur with aging are reactions to damage or driven by damage. The way to reverse the issue is to repair the damage. If, on the other hand, you consider aging to be a genetic program, then loss of homeostasis and damage are both consequences of these epigenetic changes. The way to reverse the issue is to restore epigenetic patterns to a youthful level.

Interestingly, while the majority of the research community holds the view that aging is damage accumulation, they also tend to work on projects that better fit the programmed aging hypothesis - aiming to use drugs to alter the operation of metabolism in order to slow aging, for example. This is most likely because these projects look more like past drug development and exploration of the molecular basis for disease, and are thus more palatable to conservative funding sources and regulatory bodies. This is just one of numerous ways in which the research community proceeds in a less than rational manner, following short term incentives at the expense of longer term goals.

Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster.

The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality.

Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.



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