Targeting GATA Transcription Factor to Upregulate Autophagy

Many approaches exist to boost the operation of the cellular housekeeping processes of autophagy in order to modestly slow the progression of aging. The improved health and longevity derived from the practice of calorie restriction largely occurs due to increased autophagy, for example. Disable autophagy, and studies have shown that the robust and reliable increase in life span in calorie restricted animals no longer occurs.

Cellular processes such as autophagy are regulated by a complex network of proteins, giving many possible points of intervention. Equally, it is a challenge to decipher such systems in order to find points of intervention that are not more trouble than they are worth. Present interventions to enhance autophagy that are making their way towards the clinic are calorie restriction mimetics, discovered compounds that recreate a little of a known good form of intervention. So far there has been little clinical progress in deliberate, targeted approaches to upregulating autophagy independently of the mechanisms of calorie restriction. Still, potential new targets in the regulation of autophagy, such as the example here, continue to appear year after year as research progresses.

A person born today will likely spend the last decade of her or his life suffering from age-associated conditions, like neurodegeneration, cardiovascular disease, diabetes, or cancer. Anti-aging strategies aim at closing this gap between life- and healthspan, either by behavioral - mostly dietary - interventions or by pharmacologically targeting cellular pathways that influence aging. Thus far, dozens of anti-aging compounds have been described, and most of them act via decreased nutrient signaling and/or reduced protein acetylation, which seems to be a common hallmark among pharmacological anti-aging interventions. Nevertheless, novel molecules, especially those acting via alternative pathways, are needed, since they might be used in new combinatory approaches.

In a recent study, we investigated different classes of flavonoids, a group of secondary metabolites from plants, for their ability to promote longevity. For that purpose, we conducted a high-throughput screen based on chronological aging of the yeast Saccharomyces cerevisiae, an established model for the aging of post-mitotic cells. The compound that most consistently improved the screened parameters was the chalcone 4,4'-dimethoxychalcone (DMC). Subsequent experiments unraveled that DMC administration prolonged lifespan in nematodes and fruit flies and decelerated cellular senescence in human cancer cells.

Many anti-aging compounds induce autophagy, an intracellular mechanism that recycles superfluous or damaged cellular material. DMC treatment led to elevated autophagy levels in all organisms tested, including yeast, nematodes, flies, mice and cultured human cells. Moreover - unlike many other anti-aging compounds - DMC treatment did not reduce mTOR signaling, and in yeast, the anti-aging effects depended neither on the mTOR component Tor1, nor on the sirtuin-1 homolog Sir2. Instead, a mechanistic screen in yeast revealed that DMC required the depletion of the GATA transcription factor (TF) Gln3 to exert its anti-aging effects.

GATA transcription factors (TFs) constitute a conserved family of zinc-finger TFs that fulfill diverse functions across eukaryotes. Accumulating evidence suggests that GATA TFs also play a role in lifespan regulation. This data places GATA TFs in the limelight as actionable targets for postponing age-associated disease.



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