Restrict Your Calories To Live Longer

A Diet for the Immune System

As we age, so do our immune systems. It's why senior citizens are encouraged to get yearly flu shots. But researchers have found a way to keep the immune systems of monkeys young and healthy as they age by putting them on an extreme diet called "caloric restriction," which is the only proven way to dramatically extend lifespan in animals.

"Caloric restriction is probably one of the more spectacular biological manipulations," says Janko Nikolich-Zugich, an immunologist at Oregon Health and Science University. "It has been known for over 70 years now that it can extend life by about 30 percent.

And when we say caloric restriction we typically mean ... taking about a third fewer calories, or about 30 percent [of] calories, compared to what you would take if you had no dietary restriction at all. And ... not only do animals live longer under this treatment, but also they're much, much healthier. They don't seem to be showing many of the diseases characteristic of old age."

Monkeys were placed on a calorie-restricted diet at Oregon Health and Science University.
Previous research showed that caloric restriction also led to an improved immune response in rodents, so Nikolich-Zugich wanted to see if the same was true in "long-lived" animals like monkeys. So he and his team split a group of 42 monkeys into two groups—one on caloric restriction and one on a regular diet—for a period of three and a half years.

As they reported in Proceedings of the National Academy of Sciences, monkeys on caloric restriction had significantly stronger immune systems. They had more immune cells overall, and, most significantly, had more of a valuable type of immune cell called a naïve T cell. Most naïve T cells are created early in life. Once they get called into action to fight a specific pathogen, they turn into "memory T cells" that are only capable of fighting that specific pathogen. But naïve T cells are capable of attacking any pathogen, including ones the body has never encountered.

"As we use this naïve T cell reserve, we're less and less really prepared to fend off new pathogens," says Nikolich-Zugich. "And this is exactly one of the problems in old age. We don’t seem to be able to defend against some of the new pathogens that keep attacking us. And a typical case that you will see are the new strains of flu, where the elderly have serious problems combating them and we have [tens of thousands of deaths per year] due to flu related disease in the elderly population."

Janko Nikolich-Zugich and his colleagues found that monkeys on a calorie-restricted diet had more of a valuable type of immune cell.
Not only were there more of these kinds of cells in the caloric restriction group, but Nikolich-Zugich's team found the cells also seemed to function better. They introduced certain antibodies to the T cells in the laboratory (not in the animals themselves) and the T cells from the caloric restriction group proliferated and reacted much more vigorously.

Previous research by Nikolich-Zugich and H. Daniel Lacorazza, published in the Journal of Immunology suggested that aging reduces immune system function because the body starts producing more of a certain kind of T cell, called T cell clonal expansions, that are less effective in fighting disease. But he says it's possible that the bodies of the monkeys on caloric restriction were instead still making new naïve T cells.

"We could see a very dramatic improvement compared to what we normally see," says. "We could clearly show that caloric restriction had [a] very major impact on the makeup of the immune system and on its function, suggesting that one of the effects of caloric restriction on longevity might be through the improvement of the function of the immune system."

A "Drastic" Diet
While such a dramatic effect on health and aging may be alluring, Nikolich-Zugich stresses that the caloric restriction diet is probably too extreme for people, and potentially unsafe. There are people who are trying to adopt the diet into their lifestyle, but scientists have not yet tested the diet in people.


"People really should not jump on this treatment without careful consideration and knowing what it is," says Nikolich-Zugich. "The way a lot of [scientists] think about caloric restriction is that it represents a mild stress. It sort of represents like, taking a little bit of a poison and then you get used to it. And then you’re really, really good at tolerating large doses of stress. And that's a cautionary note; you might cross a threshold point where the organism is not able to react with this constructive adaptation to caloric restriction. You might instead actually really only show the detrimental side."

Instead, the point of his research is to understand how caloric restriction works at the molecular level. Knowing that might allow us to reap the benefits without enduring the diet.

"If we can understand which signaling pathways inside the cell are being stimulated or which might be inhibited, then you can use pharmacological intervention to really achieve much of the same effect," says Nikolich-Zugich. "If we can understand at the molecular levels what's happening then we should be able to devise treatments that would really not require necessarily for people to go on a fairly drastic diet…[and] trick [their bodies] into thinking that they’re on caloric restriction."

As to whether a more moderate diet might help our immune system, he says it's possible, but unproven.

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Obesity Cured by Antibiotics??

Dec. 20, 2006 -- A link between obesity and the microbial communities living in our guts is suggested by new research at Washington University School of Medicine in St. Louis. The findings indicate that our gut microbes are biomarkers, mediators and potential therapeutic targets in the war against the worldwide obesity epidemic.

In two studies published this week in the journal Nature, the scientists report that the relative abundance of two of the most common groups of gut bacteria is altered in both obese humans and mice. By sequencing the genes present in gut microbial communities of obese and lean mice, and by observing the effects of transplanting these communities into germ-free mice, the researchers showed that the obese microbial community has an increased capacity to harvest calories from the diet.

"The amount of calories you consume by eating, and the amount of calories you expend by exercising are key determinants of your tendency to be obese or lean," says lead investigator Jeffrey Gordon, M.D., director of the Center for Genome Sciences and the Dr. Robert J. Glaser Distinguished University Professor. "Our studies imply that differences in our gut microbial ecology may determine how many calories we are able to extract and absorb from our diet and deposit in our fat cells."

That is, not every bowl of cereal may yield the same number calories for each person. People could extract slightly more or slightly less energy from a serving depending upon their collection of gut microbes. "The differences don't have to be great, but over the course of a year the effects can add up," Gordon says.

Trillions of friendly microbes reside in the intestine, where they help to digest food that the body can't on its own, such as the complex sugars found in grains, fruits and vegetables. As part of the digestive process, the microbes break down nutrients to extract calories that can be stored as fat.

The researchers focused on two major groups of bacteria - the Bacteroidetes and the Firmicutes - that together make up more than 90 percent of microbes found in the intestines of mice and humans. In an earlier study, they compared genetically obese mice and their lean littermates. The obese mice had 50 percent fewer Bacteroidetes and proportionately more Firmicutes. Moreover, the differences were not due to a bloom of one species in the Firmicutes or a diminution of a single or a few species of Bacteroidetes: virtually all members of each group were altered.

In one of this week's Nature articles, Ruth Ley, Ph.D., a microbial ecologist in Gordon's group, reports on her investigation into whether these findings also held true among obese humans. She followed 12 obese patients at a Washington University weight loss clinic over a one-year period. Half the patients were on a low-calorie, low-fat diet and half were on a low-calorie, low carbohydrate diet.

At the outset of the study, the obese patients had the same type of depletion of Bacteroidetes and relative enhancement of Firmicutes as the obese mice. As the patients lost weight, the abundance of the Bacteroidetes increased and the abundance of Firmicutes decreased, irrespective of the diet they were on. Moreover, not one particular species of Bacteroidetes but the entire group increased as patients lost weight.

In a companion paper in the same journal, Peter Turnbaugh, a Ph.D. student in Gordon's lab, compared the genes present in the gut microbial communities of the obese and lean mice using the newest generation of massively parallel DNA sequencers.

The results of these so-called comparative metagenomic studies revealed that the obese animals' microbial community genome (microbiome) had a greater capacity to digest polysaccharides, or complex carbohydrates. By transferring the gut microbial communities of obese and lean mice to mice that had been raised in a sterile environment (germ-free animals), he confirmed that the obese microbial community prompted a significantly greater gain in fat in the recipients.

Gordon notes that these findings represent steps in a long journey designed to understand the contributions of our microbial self to our health. "Our microbial cells outnumber our human cells by as much as 10 fold and, and they may contain 100 times more genes than our own human genome," Gordon says.

These studies raise a number of questions, according to Gordon. "Are some adults predisposed to obesity because they 'start out' with fewer Bacteroidetes and more Firmicutes in their guts?" he asks. "Can features of a reduced Bacteroidetes-Firmicutes enriched microbial community become part of our definition of an obese state or a diagnostic marker for an increased risk for obesity? And can we intentionally manipulate our gut microbial communities in safe and beneficial ways to regulate energy balance?"

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