The Discovery of the
"I'm-Not-Dead-Yet" Gene

Doubling Lifespan

Some days it pays to get out of bed, and last December 15 was such a day. On that morning a headline boldly announced the discovery of a new longevity gene.1 If this gene can be altered slightly in humans, as the study claimed has already been done in the fruit fly Drosophila, it may give everyone the potential to live at least 130 years or more, and for some, the opportunity to live to a maximum of 180 years - 50% longer than any previously documented lifetime. If this breakthrough could be ready in time, is there anything else you'd like for Christmas, this year or next?

The newly discovered gene, which the scientists who discovered it call Indy (for I'm not dead yet) from a line in the film Monty Python and the Holy Grail,* really lives up to its name, because when this gene is slightly altered (mutated) in a particular way, the result is a longevity bonanza. In a group of 5430 male and female fruit flies, the average lifespan doubled from 35 days to 71 days, and the maximum lifespan increased by 50% to 110 days. Aren't you glad you got up today?

Remarkably, altering the Indy gene appears to have no negative consequences: the life-extended flies were as healthy and fit as the normal flies with the unaltered gene. Better yet, say the scientists, we humans have the same gene, and in all likelihood, it serves the same purpose in us; it may be able to increase not only our average lifespan but also our maximum lifespan.

If these views are correct, science may need only discover how to alter this gene in humans so that we might reap the life-extending benefits that other species have experienced from caloric restriction, but without the liability - the 30% fewer calories consumed every day for at least half a lifetime to achieve perhaps a 30% maximum extension.

The authors have announced that Indy is a drug target. So naturally,drug companies are salivating over this prospect, and so, dear reader, are we but our approach would be different. As we are discovering from understanding the mechanisms of caloric restriction, there are two ways to skin a cat, or a gene. Just as the nutrient nicotinamide can increase the body's supply of the gene-silencing cofactor molecule NAD (see Applying the Secrets of Caloric Restriction - Feb. 2001), with the possibility of life extension, perhaps another nutrient may be able to limit the activity of the sodium dicarboxylate cotransporters or to reduce their synthesis and efficiency thus mimicking the slight alteration of the Indy longevity gene and take us well into the twenty-second century, if we're lucky.

Is this exciting? You bet, and the news media have already turned it into good news, saying (read it in The New York Times) that "the discovery opens a new area in the fast-developing field that studies life extension."2 Bless our souls! This is exactly what many of us have been saying (in reference to other discoveries) for 20 years or longer. The breakthroughs are coming! The big breakthroughs are coming!

The Indy gene codes for the synthesis of a cellular membrane protein that transports energy-cycle intermediates within the cells of our body. Without this protein, our primary energy generator - the Krebs cycle** - would be disrupted, and the production of energy would lessen or would lose efficiency.3

The researchers postulate that Indy affects lifespan through its protein's effect on the absorption and utilization of energy metabolites, triggering a state similar to caloric restriction through a decrease in selected nutrients crossing the cell's membrane. A nondietary restriction in calorie use takes place, thus reducing the effective caloric content of food.

Until now, caloric restriction has been a moot proposition, with far-off benefits, and then only after a life of self-deprivation for those willing to live like monks, with caloric intake reduced by 30% or more. But the Indy gene may offer a backdoor route to the benefits of caloric restriction without the deprivation of actual caloric restriction.

The year 2000 has been remarkable in many ways, but none as exciting as the first-draft complete sequencing of the human genome, one of the most important achievements in the history of science.4 A banner year for biotechnology, the first year of the new millennium (it was actually the last year of the old millennium, but who cares?) saw the genomic mapping of organisms ranging from yeast to worm to fly to human. Like the discovery of the Indy gene, there is undoubtedly much more to come in 2001 and beyond, now that this great new vista in human biology has been opened.

Yet some longevity researchers have expressed surprise at the speed of discovering Indy - within months after completion of the human genome's first draft - as well as the elegance (read simplicity out of complexity) of a single-gene theory of aging.

Given the dominance of the pharmaceutical industry in this and virtually every other biomedical field, it is not surprising that many researchers say that one day the benefits of caloric restriction may be available simply by taking a drug. Isn't it possible, perhaps even likely, that taking a nutrient might do the same?

It's tempting to say that the worm turns, considering that there is a developing connection with work being done with the C. elegans flatworm, another source for longevity genes. Interestingly, one of the genes that has been discovered to alter the lifespan of these flatworms, the Daf gene, is also involved with metabolism, although it is one that alters insulin utilization. It has been postulated that the mechanism through which a mutation in the C. elegans' Daf gene extends lifespan may be through a similar alteration in energy use.5

The pharmaceutical companies probably already have drug versions of Indy mutators on their drawing boards in order to create a metabolic state similar to caloric restriction. This would be much like Viagra's® bypassing of the well-established mechanism of arginine, which produces similar benefits but by a nutritional route.

The discovery of Indy is expected to provide key insights into the role of energy balance and aging, something that the scientific nutrition community welcomes. This is likely to have ramifications for the thinking that will create tomorrow's new support systems for gene therapy. These developments may very well alter the course of the future for dietary supplements and create a field that merges with genetics in ways that are only beginning to be clear. The production of abundant NAD with nicotinamide supplementation is one such hope


  1. Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 2000 Dec 15;290(5499): 2137-40.
  2. Kolata G. I'm not dead yet; stumbling on a genetic mutation that lives up to its name. The New York Times, December 15, 2000, p A20.
  3. Dimroth P, Schink B. Energy conservation in the decarboxylation of dicarboxylic acids by fermenting bacteria. Arch Microbiol 1998 Aug;170(2):69-77.
  4. Pennisi E. Genomics comes of age. Science 2000 Dec 22;290(5499):2220-1.
  5. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000 Nov 9;408(6809):255-62.

* When the call goes out to "bring out your dead," one of the presumed corpses sits up and declares, "I'm not dead yet."

** Sir Hans Krebs, who won the Nobel Prize for working out the mechanism of this process, preferred the term "tricarboxylic acid cycle," which stresses the important role of these organic acids in energy generation.

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