Investigations of the INDY Gene Illustrate that "Very Slow" is the Default Speed of Aging Research

Here I point out a recent review on the topic of INDY gene manipulations and consequent increased longevity via altered metabolic processes. Given just how long ago this gene was discovered, and how similar at a high level the research reviews on this topic are today in comparison to those of a decade ago, this line of work well illustrates that even in the more mainstream reaches of science, with better prospects for funding, early stage research into aging and longevity is really very, very slow.

INDY stands for "I'm not dead yet" and was named after it was discovered that reducing levels of the protein that this gene encodes has the effect of extending life in flies. That discovery was made fifteen years ago, almost a different era in the life sciences relevant to aging, back when longevity genes were a new and amazing thing, it wasn't the case that new ways to tinker with metabolism to modestly extend healthy life were being discovered and published on a near monthly basis, as is the situation today, and researchers were very reluctant to talk in public about the prospects for treating aging in humans because it would likely sabotage their careers. How things have changed.

There is no necessary reason for aging research to very, very slow, as opposed to merely slow, or at least no necessary reason that cannot be corrected. Yes, it is the case that getting things done in life science research is painfully slow in comparison to, say, starting a business selling shoes. A great deal of available funding passes through very bureaucratic channels, there is not enough funding to avoid long delays between phases of a research program in order to seek new grants, and then it takes a few years in the middle to actually get anything meaningful accomplished in the lab. In aging research the situation is made worse if you want to run life span studies in species that live for a few years, such as mice. The need for life span studies as the bottom line of "did it work?" in longevity science is something that everyone in the research community would like to do away with. That seems feasible given progress towards markers for biological age, but there is a way to go yet on that front before researchers can make quick measurements before and after a prospective rejuvenation therapy and feel confident that the data will be useful in place of years of running a life span study.

But as for the rest of it, given more money the aging research community could be just as dynamic and productive as, say, the stem cell research community. Still slower than starting up a shoe business, but moving about as rapidly as you can expect from the life sciences. To speed things up further would require, at the least, radical surgery on the regulatory framework of the FDA, or an enormous influx of funding akin to the Apollo program or similar. At the end of the day it comes down to being a reasonable expectation that you should wait five to ten years to see how any particular program turns out, and absent a lot of funding you might still be waiting around fifteen or twenty years later. Five years is about long enough to get one thing accomplished in a life science program, or to figure out that whatever it was you were trying doesn't really work.

So back to INDY as our illustration of this point. The association with increased longevity was established in 2000, and establishing proximate mechanisms and deciding that the alterations to metabolism from lack of INDY looked a lot like calorie restriction was accomplished within a few more years. After that there was something of a hiatus of meaningful progress as judging by a review from 2013, with intervening years dotted with replication of INDY effects in other species such as mice and nematode worms, and more methodical exploration of the chains of biochemical connections leading into and out of the proximate mechanisms. Just last year researchers had come far enough to decide that intestinal stem cell populations had a lot to do with the longevity effect, but then this seems to be generally important in flies, and so any mechanism that extends life probably does much the same.

This year, the paper linked below finally comes to the point at which it is suggested that perhaps INDY is a drug target that someone should look into vis a vis treating aging and the diseases of aging. That can be taken as the starting point for a pretty long process of thought and work and delay. Perhaps something will come of it in some lab somewhere, perhaps not. You might, by analogy, look at the situation for heat shock proteins or other ways to trigger greater cell maintenance via autophagy as potential drug targets to modestly slow aging. That has been seriously suggested for years now, but I've yet to see any meaningful movement in that direction. Bear in mind that I'm not talking about SENS rejuvenation research here, that is still in the process of becoming a large concern, I'm talking about the core mainstream focus of the research community, which is at present to build drugs that might slightly slow down aging - not something we should expect to produce useful results any time soon, but comparatively well funded and supported. That these and many similar projects move erratically if at all is, I think, one symptom of an underfunded and divided field of research, in which many researchers are not at all interested in treating aging, and there is far too little money for all that should be done or could be done to build a better future.

The role of INDY in metabolism, health and longevity

The Drosophila I'm Not Dead Yet (Indy) gene encodes a plasma membrane transporter of Krebs cycle intermediates with highest affinity for citrate. In flies INDY is predominantly expressed in the midgut, which is important for food absorption; the fat body, which modules glycogen and fat storage, and oenocytes (fly liver), which is the site of lipid mobilization and storage. Thus, reduction in INDY reduces uptake, synthesis and storage of nutrients and affects metabolic activity. Reduction of Indy expression in both flies and worms extends longevity by a mechanism that is reminiscent of calorie restriction (CR), which is an environmental manipulation that extends longevity in a variety of species. Flies with reduced INDY levels experience many of the physiological changes that are commonly observed in CR flies. Such changes include altered lipid metabolism and insulin signaling, as well as enhanced mitochondrial biogenesis and spontaneous activity

Studies investigating the function of mammalian Indy (mIndy) show the highest levels of expression in the liver and brain. Similar to the trend of Indy expression in flies, mRNA levels were found to change during starvation in rat hepatocytes and mice liver. Furthermore, studies in mIndy-/- mice show similar effects in mitochondrial function, as well as lipid and glucose metabolism in the liver as those previously described in less complex organisms and in mice on CR. Together, these data suggest that the level and location of INDY serves to regulate and possibly mediate metabolic responses to nutrient availability during aging.

It is thought that these physiological changes are due to altered levels of cytoplasmic citrate, which directly impacts Krebs cycle energy production as a result of shifts in substrate availability. Citrate cleavage is a key event during lipid and glucose metabolism; thus, reduction of citrate due to Indy reduction alters these processes. With regards to mammals, mice with reduced Indy (mIndy-/-) also exhibit changes in glucose metabolism, mitochondrial biogenesis and are protected from the negative effects of a high calorie diet.

The recent work completed by our lab and others support a role for INDY as a regulator of metabolism whose transcriptional levels change in response to calorie content of the food, as well as in response to energetic requirements of the organism. The similar effects of INDY reduction on metabolism in flies, worms, and mice suggest an evolutionary conserved and universal role of INDY in metabolism. Together, these findings suggest that INDY could be potentially used as a drug target for treatment of obesity and Type II Diabetes in humans. Further investigation on the mechanism of INDY reduction could provide valuable information regarding the means to a healthier and more productive life.

Comments

The research we care about is regenerative medicine (e.g., stem cells), and that is advancing at an exponential rate.

There are endless research issues one could pursue. Setting money asides, you can't expect the best researchers to focus on and advance what is, by your own admission, something not very promising.

Posted by: Daniel Lemire at June 30th, 2015 6:17 AM

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