That the INDY gene can influence life span was one of the earlier discoveries made once researchers begin to manipulate the life span of short-lived species, spurred by the study of slowed aging via calorie restriction, and searching in earnest for the mechanisms by which metabolism determines the pace of aging. Progress is very slow in this part of the scientific community. Reviews of what is known of INDY are not that different today then they were a decade ago, and it remains an open question as to how relevant this is to humans. That INDY has effects related to preserved intestinal function in flies may just be a reflection of the great importance of the intestine in fly aging, and not an indication of what to expect in mammals.
Reduced gene expression of fly Indy and its worm homologues extends their life span by altering metabolism in a manner similar to calorie restriction (CR). Fly INDY and homologues in worms and mammals share a preference for transporting citrate. By regulating cytoplasmic citrate levels, INDY acts as a metabolic regulator in modulating glucose and lipid levels, and energy production in mitochondria. Metabolic changes associated with Indy reduction in the fly midgut results in dramatic changes in midgut physiology that lead to preserved intestinal stem cell (ISC) homeostasis. This is vital for replacement of damaged cells and the maintenance of midgut function illustrated by preserved intestinal integrity.
Indy reduction extends lifespan in male and female flies, but the effects of Indy reduction on ISC homeostasis have only been studied in female flies. Male and female flies have different gut pathologies and respond differently to stress and CR, with males having a delay in age-related gut pathology and lower ISC proliferation, while females respond better to stress and CR. Considering these differences, it would be of interest to determine the effects of Indy reduction on the midguts of male flies.
ISC homeostasis is regulated by multiple signaling pathways including IIS, Notch, EGF, Wnt/wingless, BMP/Dpp, JNK, and JAK/STAT, among others. It would be important to assess the status of different signaling pathways in flies with reduced Indy expression, as metabolic changes might delay age-associated activation of these pathways and could contribute to preservation of ISC homeostasis and longevity.
The data reviewed here support the role of INDY as a metabolic regulator: Indy expression changes in response to nutrient availability and requirements of the organism, which, by regulating citrate levels, controls energetic status of the organism to maintain tissue-specific metabolic requirements leading to preserved organismal health and homeostasis. Reduced INDY levels in the midgut could then prevent age-related ISC hyperproliferation by reducing the available energy for proliferation.