Fight Aging!

INDY was one of the earlier longevity-related genes to be robustly identified, a discovery made 20 years ago now. Much of the exploratory work on INDY was carried out in flies, though more than enough time has now passed for mouse data to have also emerged. The authors of today's review paper characterize the benefits resulting from a reduced expression of INDY as a calorie restriction mimetic effect, more or less. That is a fair enough shorthand for any approach that improves cellular maintenance processes in a way that modestly slows the aging process, resisting the accumulation of damage, dysfunctional cells, and chronic inflammation.

Most of the ways known to slow aging in short-lived species are quite similar, viewed from the high level. Given that these species exhibit a sizable plasticity of life span in response to environmental circumstances, achieved via upregulation of stress response mechanisms triggered by heat, cold, toxins, and low nutrient availability, most of what is discovered by any unbiased search are ways to trigger that same upregulation of stress response mechanisms. That has indeed been the case, with inhibition of INDY expression as one such approach. Unfortunately, this category of interventions just isn't as effective at extending life in longer-lived species, as demonstrated by the fact that calorie restriction itself adds only a few years to human life span at most, quite unlike the ~40% life extension observed in mice.

Still, calorie restriction does improve health in humans. It seems likely that out of this large range of ways to improve cellular maintenance, a fair number of drugs, like mTOR inhibitors, will emerge to produce modest gains in human patients. Likely very modest, an acceptable exchange for a low cost drug from the patient's perspective, but a grand waste of time and effort that should have gone elsewhere from the perspective of the billions spent on the drug development process in its later stages.

INDY - From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

I'm Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats.

As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers.

These results highlight a new connection between energy metabolism and cell proliferation. The overall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter-Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.