INDY, I'm Not Dead Yet, is one of the earliest of longevity-associated genes to be documented. Researchers uncovered its effects in flies at the turn of the century, something like half an eternity ago given the pace of modern biotechnology. Despite the rapid pace of progress in the field as a whole, the INDY gene is also an example of the extremely slow and incremental progression that is characteristic of any one specific line of research in molecular biochemistry. The open access paper I'll point out today is a review of what is presently known of INDY in flies and mammals, information gathered over the what is now going on for two decades of work. The focus is on the ways in which the beneficial effects of reduced levels of INDY appear quite similar to those of calorie restriction - though clearly it is a complicated overlap, because trying both reduced levels of INDY and calorie restriction either has no effect or shortens life span. Regardless, anything that looks a lot like calorie restriction tends to be treated as a potential road to the development of calorie restriction mimetic drugs in this day and age.
Why is progress slow when you follow any one particular thread in aging research? Well, for one funding for aging research is small in comparison to other fields of medical research. Secondly, cellular biochemistry is enormously complex. It does in fact tend to take a few years even now for any one group to make a single connection in the complex web that is cellular metabolism. Just moving the focus of research into INDY from flies to mice took a long time, and it is still clearly in its early stages when considered in the context of the bigger picture of identifying targets, developing drugs, and producing clinical treatments. Mapping and tinkering with metabolism is a good thing in the long term, as gaining a full understanding of our cells is - and should be - the goal of the life sciences, but it certainly isn't the fast road to meaningful interventions to slow or reverse the aging process. For that we need engineering approaches like SENS, turning what we already know of aging into repair treatments capable in principle of rejuvenation.
The Indy (I'm Not Dead Yet) gene encodes the fly homolog of the mammalian SLC13A5 transporter of the tricarboxylic acid (TCA) cycle intermediates. Reduced expression of the Indy gene in flies and worms extends longevity in all but one study. INDY is expressed on the plasma membrane of metabolically active tissues. In flies INDY is predominantly expressed in the midgut, fat body, and oenocytes (fly liver). In humans, Indy mRNA is mainly expressed in the liver, less in the brain and testis, while small levels of Indy mRNA expression were found in the kidneys, thymus, ovaries, adipose tissue, stomach, and colon.
Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction (CR). This is supported by similar phenotypes found in CR wild type flies and in Indy flies that were kept on a high calorie diet. These Indy flies have lower lipid levels, increased mitochondrial biogenesis, increased spontaneous physical activity and a reduction in components of the insulin-signaling pathway activity. Furthermore, Indy heterozygous flies laid more eggs during their life compared to controls. However, under CR condition, Indy heterozygous flies have reduced fecundity due to lower energy resource caused by the effect of reduced Indy on metabolism. Consistently, CR does not further extend longevity of long-lived Indy heterozygous flies and shortens longevity of Indy homozygous flies.
Preservation of intestinal stem cell (ISC) homeostasis has a key role in maintaining normal midgut function and contributes to extended health and longevity in flies. Changes in mitochondrial biogenesis found in the midgut of Indy flies, combined with increased antioxidant activity and reduced production of reactive oxygen species preserve ISC homeostasis and intestinal integrity in Indy flies. These changes maintain midgut function and mediate extended health and longevity of Indy flies.
Reduced activity of the Indy homologs in other organisms is associated with similar metabolic effects that mimic CR. siRNA mediated knockdown of Indy/CeNac2, the worm Indy homolog, results in worms that are smaller, have reduced lipid levels, and have extended longevity. Mammalian Indy (mIndy)-/- knockout mice are protected from the negative effects of aging or a high-fat diet on metabolism, which include hepatic fat accumulation, obesity, and insulin insensitivity. These mice have increased energy expenditure, reduced hepatic lipogenesis, increased mitochondrial biogenesis, and enhanced hepatic fatty acid (FA) oxidation. Whole-genome microarray studies comparing mIndy-/- and mIndy-/+ revealed that transcriptional changes found in the liver of mIndy-/- mice are 80% identical to changes found in the liver of CR mice. All of these findings confer that INDY reduction creates a state similar to CR.
In summary, reduction of Indy gene activity in flies and worms extends their health and longevity. Genetically reduced INDY expression has beneficial effects on metabolism and prevents diet-induced obesity in flies and mice, suggesting INDY as a target in the treatment of metabolic disorders in humans. By contrast, high levels of INDY are associated with negative effects on metabolism and health. Recently, increased hepatic levels of mINDY were linked to insulin resistance in obese humans. These findings illustrate both the relevance of the mIndy gene to human health and a highly conserved role for INDY in the metabolism of a broad range of species. Thus, mIndy has emerged as a novel target for the treatment of age- and diet-associated metabolic syndrome. The further development of mIndy inhibitors may additionally provide effective interventions targeting the debilitating health effects that are often associated with aging and will thereby allow a healthier life.