User:Hlee626/sandbox

Indy (I'm Not Dead Yet) is the fly homolog of the human Na+/citrate cotransporter, SLC13A5. Indy is predominantly expressed in the fly midgut, fat body, and liver. It transports Krebs cycle intermediates, making it a metabolic regulator. In flies, reduction of Indy mRNA extends lifespan, causes phenotypical changes mimicking calorie restriction, and promotes intestinal cell homeostasis. These properties may allow Indy to be a therapeutic target for diet and age-related disorders.

Metabolic Regulation

The main function of Indy is as an uptake transporter of the Krebs cycle with a high affinity for citrate, impacting the activity of citrate dependent pathways. Citrate metabolism is a carbon source for fatty acid synthesis, and high levels of citrate decrease the activity of glycolysis and beta-oxidation pathways while increasing fatty acid synthesis. Low Indy levels reduce the transport of citrate into cytoplasm, causing decreased Krebs cycle activity and reduced ATP production. This reduction of ATP production results in increased generation of mitochondria to compensate for the loss in energy production. Reduced Indy expression prolongs fly lifespan, suggesting that the role of Indy is to alter lifespan by impacting metabolic regulation.

The mammalian homolog of Indy (mIndy) also has metabolic regulatory functions. In mice, decreased levels of Indy induces changes to mitochondria generation and metabolism. Decreased Indy also protects mice from obesity and insulin resistance, which is seen with aging and excessive calorie intake.

Role in Intestinal Cells

Intestinal cells contribute to regular functions such as food absorption and protection from pathogens. With age, intestinal stem cells in the midgut slow down in differentiation and are unable to produce enough functional cells to replace damaged cells. Aging is also characterized by loss of homeostatic capabilities by cells, preventing the cell from functioning.

Indy reduction results in metabolic changes that increase dPGC-1 levels, which decreases with age. dPGC-1 regulates metabolism through generation of mitochondria, and it decreases in expression with aging. This increase in dPGC-1 activity brought about by Indy preserves intestinal cell homeostasis and intestinal integrity, contributing to extension of lifespan.

Calorie Restriction

In flies, reduced Indy expression causes physiological changes similar to caloric restriction, such as reduced fat stores and insulin like protein expression. Indy reduction on a calorie restricted fly does not extend longevity any further than the lifespan of an only calorie restricted fly. Comparisons of mice with and without reduced Indy expression show differences that were highly similar to those seen between calorie restricted and calorie unrestricted mice.

Calorie restriction has shown to reduce Indy expression, suggesting a linkage between Indy reduction and lifespan extension by calorie restriction. This linkage may be through the nutrient sensing insulin-signaling pathway. In a calorie restricted situation, nutrients are low. This nutrient scarcity results in down-regulation of insulin signaling, allowing FoxO, a transcription factor, to move to the nucleus by preventing phosphorylation of FoxO. Mutant flies with reduced Indy show high FoxO localization in the nucleus, similar to a calorie restricted fly. The relation between Indy and insulin signalling is further supported by Indy mutant mice that show increased insulin sensitivity.