“Go to the ant, my son
Observe her ways
—King Solomon, Proverbs (free translation)
Undoubtedly, you have seen pictures of those emaciated characters who follow a starvation diet in the name of living a long, long life. The normal daily diet of an adult male contains about 2,000-2,400 calories. The “calorie restriction” people limit their diet to is about half of that. They may live longer, but are they happier? Hard to tell; they are going to die hungry but maybe also happy, for the ordeal is finally over.
One of the organisms that provided the “intellectual” basis for this cruel and unusual experiment in long living is called C. elegans.
Where in the world is C. elegans?
Caenorhabditis elegans (Caeno: recent; rhabditis: rod; elegans: nice), is a free-living, non-parasitic soil nematode that can be safely used in the laboratory and is common around the world. It is small (about 1 mm in length) and has a short life cycle. From egg to egg takes about 3 days, and its life span is around 2 to 3 weeks under suitable living condition. What is unique to this organism is that wild-type (normal, non-mutated) individuals contain a constant 959 cells. The position of cells is constant as is the cell number. Moreover, it is transparent. It is easy to track cells and follow cell lineages. This provides a great tool for research on how genes influence cell fate. These traits enable the study of the biology of a single cell in an intact, living organism.
The genome size of C. elegans is about a hundred million base pairs. This is approximately 20X bigger than that of E. coli and about 1/30 of that of humans. But, as its genome is surprisingly similar to that of humans (40% homologous), C. elegans became an attractive organism in the study of human biology and diseases.
The insulin-like pathway of C. elegans
Among those remarkably human-like genes are the ones that control energy metabolism, and specifically those coding for an insulin-like pathway. Genetic analysis now conclusively demonstrated that several of those genes, when mutated, extended life through reducing the activity of this insulin signaling pathway; in other words, life was extended by reducing the metabolic rate. Conversely, there is now considerable evidence showing that senescence (aging) is associated with increased metabolic rate.
Therefore, a logical conclusion would be that an insulin-like pathway drives senescence in C. elegans by enhancing metabolic activity. Right? Not quite… Genetic manipulation has now demonstrated that it is the insulin-like pathway specifically in neurons, not muscle or other highly metabolically active tissues, that regulate lifespan in C. elegans. And consider this: In humans, the neurons most sensitive to insulin are probably the hypothalamic neurons that regulate metabolism and body weight, destruction of which leads to profound metabolic impairment.
Biology never ceases to confound our most “obvious” theories. Although many hypotheses were offered to explain this unexpected discovery, in truth scientists were stymied.
A tantalizing clue
In a paper published this week in Nature, scientists from the University of Washington in Seattle reported on an intriguing discovery. They screened 88,000 chemicals for the ability to extend the lifespan of adult C. elegans. They found that a drug that was once used as an antidepressant in humans, increased lifespan by 30%. The drug, a tricyclic, is called mianserin and was marketed as Tolvol, before being largely phased out of the market.
Its mode of action is interesting; it blocks two serotonin receptors, SER4 which signals the presence of food, and SER3, which signals starvation, in C. elegans. But the blocking action of the drug is not equal—it blocks SER 4 (food available) ten fold more than SER3 (starvation). The authors state, “In this way, mianserin might potentially create a ‘perceived’ state of starvation that, despite adequate food intake, would activate mechanisms of lifespan extension downstream of dietary restriction.”
Or in other words, it is not the actual caloric restriction and starvation that is responsible for lifespan extension. It is rather the perception of starvation that causes the brain to activate the mechanisms that lead to life extension. Which may explain the original observation that disruption of the insulin pathway in neurons, and not in muscles or other “obvious” tissues, that leads to prolongation of lifespan.
Another example of mind over body. Or is it perception trumps reality?
Whatever the philosophical musings this experiment evokes, the practical implication is awesome: We won’t have to spend a lifetime on a starvation diet in order to live an extra few years. Drugs will be available that would allow us to literally have the cake, eat it, and live long enough to tell the tale to our great-great-great grandchildren.