Over the last decade or so, two of the most promising avenues of research in gerontology (the study of aging) and the search for means of extending human life have been on the effects of restricting diet and the activity of the hormone insulin. Numerous studies have shown that caloric restriction (not starvation, but a deliberate and substantial decrease in the amount of calories) has a positive correlation with longevity. Organisms live longer if they live on minimal diets. In a similar vein numerous studies have also shown that reduction in the activity of insulin, a hormone with chemical influence in processes such as metabolism, stress response and cell development, increases longevity.

A team of Princeton scientists, headed by Coleen Murphy, assistant professor of molecular biology, wondered if these two approaches to increasing lifespan had any impact on cognitive ability. (For ‘cognitive’ read ‘mental functions’ including perception, recognition, memory, problem solving, and ‘thinking,’ however that is defined.) Their research, published May 18 in the Public Library of Science, Biology shows that as is so often the case, there are trade-offs.

The scientists chose as their laboratory specimen the old friend of the biologist, C. elegans, the flatworm. The worm has a simple nervous system, which makes it easier to study. It also has a short lifespan, about two to three weeks, which makes cause and effect in the aging process much easier to observe than in say, humans, who take decades to show signs of aging. Of course, what is observed in flatworms does not directly or perfectly translate into identical observations in humans – but there are important and fundamental similarities based on activity at the molecular level. That is what interests the scientists.

Another reason for choosing C. elegans is that mutant varieties have been developed with long life spans (exceeding three weeks). Comparing these worms with their normal brethren could provide insight concerning the effects of diet and insulin. However, there was an interesting question: How do you measure the cognitive ability of flatworms? You don’t exactly hand them a questionnaire, however, you can make them take a test. In fact, a test Pavlov (and his dogs) would have recognized.

The worms were trained to associate food (nice juicy bacteria) with the smell of a chemical called butanone. To humans butanone smells like a sickly sweet combination of butterscotch and acetone. Who knows what it smells like to a flatworm, but they generally avoid it – not, however, when there’s food to be had. After a specific length of training, the worms were tested over a period of days for their reaction to the smell of butanone: if they moved toward the smell, they remembered the association with food. If they didn’t move toward it, the association was forgotten.

It turned out that normal worms have pretty good memories. After seven 15 minute training sessions, young worms could be motivated by smell=food for at least 16 hours. (Translated into human scale, that would be the equivalent of remembering something for 3 to 6 years.) This ‘long term memory’ in the worm would fade after about 24 hours and totally disappear after 40 hours (again, this is roughly 8-15 years in human terms). Not bad, however, the tests also showed that after four days of adulthood, normal worms lose their ability to form any long term memories.

The result with the mutant (long lived) worms was more revealing. One of them has a defective gene for the use of insulin; the other a genetic defect that limits the amount of food it can ingest. The mutant worm with calorie restrictions had normal short-term memory but severely impaired long-term memory – less than 24 hours compared to 40 for the normal worms. However, they could continue to form long-term memories well beyond the normal 4 day limit. The insulin deficient worms had yet a different pattern: their short-term memories lasted much longer, about six hours (3 times normal), but long term memory lasted a normal 40 hours. They could form short memories for a longer than normal time, but long-term memories could not form after the normal 4 days.

These results confirm that the insulin and dietary conditions which affect longevity also affect cognitive ability – sometimes positively, sometimes not.

The researchers were able to find a commonality for the effect among the worms, which was a protein identified as CREB. This type of protein binds to DNA to regulate the expression of genes and has been associated with long-term memory in many other animals. In the worms, it also has a crucial role in the formation of long-term memories, but no role in short-term memory. For example, in young flatworms with insulin deficiency, there was a high level of CREB, which correlates to their stronger long-term memories. This and other correlations point to CREB as a focal point for further studies at the molecular level. The research team will use DNA microarray techniques to look for other proteins that may be involved in the cognitive ability of aging. As Dr. Murphy explains:

“I’m optimistic because we know these longevity mechanisms in C. elegans are conserved in higher organisms, and there are reasons to believe that they could have similar effects on lifespan and cognitive function in humans,” she said. “But these results also suggest that not every way of extending lifespan is good for cognitive function, which has huge implications for the development of therapies to maintain memory.

[Source: Princeton University]