Aptly, a week before Thanksgiving Day, Nov. 19, 2002, the U.S. Federal Trade Commission issued a press release to the media on Weight-Loss Advertising. The agency's review of 300 slimming ads that ran during 2001 in TV, radio, magazines, direct mail and e-mail solicitations, found that 55 percent made at least one false or unsubstantiated claim.

Typically, the pitches promised: "You can lose 18 pounds in one week!" "No need for dietary restrictions or exercise!" "The more you eat, the more you lose!" One personal testimonial testified: "Seven weeks ago I weighed 268 pounds; now I'm down to just 148 pounds - without changing my eating habits!" The report noted that deception in weight-loss advertising has worsened year after year, despite "an unprecedented level of FTC enforcement."

Fast forward to Thursday, Jan. 23, 2003, when one of the nation's most respected research facilities, the Harvard-affiliated Joslin Diabetes Center in Boston, put out a press release headlined: "Study shows it someday may be possible to stay slim, avoid Type 2 diabetes - and live longer - while eating what you want." This is no April Fool's hoax, but serious science. So what's going on?

Joslin's president and director, diabetologist/endocrinologist C. Ronald Kahn, is senior author of a paper in the current Science, dated Jan. 24, 2003. Its title: "Extended longevity in mice lacking the insulin receptor in adipose [fat] tissue."

"The major point of this paper," Kahn told BioWorld Today, "is that this particular genetically engineered mouse, having no insulin action in its fat, is an animal that is leaner, and resistant to developing obesity - either in the natural way, by aging, or even when they're forced to overeat. Therefore the animals are resistant to the metabolic consequences of obesity, particularly development of diabetes - and they live longer."

Kahn observed, "There's a correlation between longevity in both rodents and humans - and it's a negative one. The more overweight an animal is, generally the shorter its life span. In humans the same is true.

"The important aspect of this finding," he continued, "was that in most previous kinds of experimental conditions, researched in mice for over 60 years, the separation between dietary intake and body weight has been impossible. So in general, obese animals eat more than lean animals. And making them leaner by food restriction will improve their longevity."

KO Mice Eat Hearty, Stay Healthy, Live Longer

"Here in our experiment," Kahn went on, "is an animal that has a disconnect between its body fat and its food intake. It's lean because of its genetic modification, yet it eats a normal amount per mouse. Because it's leaner, it ingests more per gram of body weight. So we asked the question that could not be posed before: What is more important, how much the animal eats or how much fat it has in terms of its longevity? And the answer, our study showed in a very clean genetic sense, is how much fat it carried, not how much it consumed.

"This is important also," Kahn pointed out, "because it gets to the questions of metabolic mechanism of dietary restriction, leanness and longevity. Classically, most people thought about caloric restriction as being beneficial, because it decreased the amount of potentially toxic substances one might take in the diet. So dietary restriction and leanness were good because you took in less that would adversely affect longevity. What this suggests is not so much that what comes through your mouth is what matters, as how much is being produced or stored in fat. So it really points us toward adipose tissue as opposed to dietary intake as being the culprit."

Kahn and his co-authors generated 250 newborn knockout mice, bereft of a fat-specific insulin receptor. "The insulin receptor," he explained, "is a member of the family of receptor tyrosine kinases, which is the molecule we knocked out. That was the very first step in insulin signaling, which is the surface membrane receptor, which eliminates all of these intracellular pathways. That receptor plays a specific role in obesity and insulin-resistance diabetes."

The Joslin team asked their 250 mice: "Does being lean in and of itself promote longevity, even if you're eating a normal or more than normal amount?"

Insulin Signaling Receptor KO'd Tissue By Tissue

"We modified mouse embryonic stem cells, then put those back into an embryo that was still in the blastocyst stage. The technique we used is called the Cre-lox recombination system. It's been in use now for four or five years, but we were the first to apply it to problems of diabetes insulin action and resistance. Basically it allowed us to selectively KO the insulin-receptor signaling system in every tissue of the mouse body, one at a time - the fat, the muscle, the liver, the brain, the beta cells, and we have others in process. One telling tissue is the perigonadal fat pad - next to the testes and ovaries. That's where mice accumulate a lot of fat. So it's a very powerful genetic technique for doing this genetic dissection.

"In this mouse model," Kahn summed up, "a reduction in fat mass - achieved without caloric restriction - significantly extended life span. KO mice at all ages had a life span increase on average of 18 percent, or 134 days - from 753 to 887 days. Moreover, at 30 months of age, normal survival, when 45 to 54 percent of control mice had died, more than 80 percent of KO mice were still alive.

"In research now ongoing," Kahn recounted, "we are trying to figure out mechanistically how does having less fat allow mice to live longer, healthier lives? And we're also hoping to figure out if there is a biochemical way by which we could reproduce this same effect. It would be like developing a beneficial drug or chemical that could be given to animals. We're not very far along yet in that direction. There are some chemicals that will block the insulin receptor in all tissues, and we will have to design one that would work on one tissue at a time. Meanwhile," Kahn concluded, "Joslin has a patent application pending on this work, of which I am senior inventor."