Sci. Aging Knowl. Environ., 26 February 2003
A growing number of researchers are finding that calorie restriction is not all it's cracked up to be. The regimen--long hailed as the only way to retard aging in a wide variety of animals--produces some distasteful side effects and doesn't always work
Abstract: The benefits of dietary restriction are well documented: Creatures that consume one-third fewer calories are leaner, livelier, and longer lived than their fully fed kin. But such drastic dieting also has a dark side. Restricted animals get chilled and pick up infections unusually easily, and they're less fertile than their more portly compatriots are. Furthermore, cutting calories doesn't enhance longevity in all animals, according to several studies. These observations have many researchers wondering what dietary restriction--or a drug that mimics its effects--might do for people who are hoping to live longer and healthier lives.
Lay down your fork and extend your life-span! It's not a scam but a sentiment that finds equal welcome in blockbuster diet books and gerontological journals. Backed by more than 6 decades of solid research, scientists tout calorie restriction (CR) as the only intervention that retards aging and lengthens life-span in a variety of creatures, from yeast and worms to laboratory mice and rats (see Masoro Review and "Aging Research Grows Up"). Although studies on primates are still in their infancy, some people interested in prolonging their lives are already putting the idea into practice.
But is this antiaging wonder diet really the greatest thing since saying no to sliced bread? Despite their enhanced longevity, animals consuming 20% to 40% fewer calories than their well-fed brethren might not be the picture of perfect health, according to a growing number of studies. The results suggest that dietary restriction has its drawbacks, and that researchers will need to separate its benefits from its less savory side effects before applying it to humans. At the same time, studies in Mediterranean fruit flies and certain strains of mice indicate that cutting calories does not guarantee long life in all animals, leading some scientists to question anew whether CR--or a pill that might mimic its effects on aging--would ever work in people.
Dietary or calorie restriction is not starvation. Animals on a standard CR regime enjoy meals that are nutritionally balanced, containing adequate proteins, carbohydrates, vitamins, and minerals. They simply eat less than the critters in the cage next door, who are allowed access to the laboratory equivalent of an all-you-can-eat buffet--a diet described as ad libitum ("at one's pleasure"), or ad lib for short.
The results of such dietary moderation are largely positive. Rodents on restricted chow develop fewer tumors and other diseases and in general remain healthier than animals that are allowed to gorge. They are sleek and lean, with well-regulated blood glucose and insulin concentrations and a robust resistance to toxins, heat stress, and oxidative assault. They even look--and act--younger than their couch-potato comrades do. "If you put a wheel in their cage, they'll run forever," says Steven Austad, an evolutionary biologist at the University of Idaho in Moscow. Fasting mice jog 6 or 8 kilometers per night, as opposed to the standard mouse trot of less than 1 km. "Calorie restriction minimizes the period in which an animal is morbid, sitting around its cage, waiting to meet its maker," says Arlan Richardson, a gerontologist at the University of Texas Health Science Center (UTHSC) in San Antonio. Best of all, they tend to live 20% to 40% longer than their gluttonous companions do.
For all its advantages, though, dietary restriction is no worry-free sip from the fountain of youth. Mice and rats on a restricted diet are smaller and less muscular than their ad lib-fed kin are; they are more sensitive to the cold, more susceptible to bacterial infection, slower to heal wounds, and much less fertile as well. "People want to believe [that] these animals are more robust in every way," says Austad. But, says Richardson, they tend to fare poorly when it comes to engaging in activities that require a great deal of energy.
"To say that restricted animals are the picture of health is just garbage," concludes Rajindar Sohal, a biochemist at the University of Southern California (USC) in Los Angeles.
Chills, Ills, and Fewer Thrills
That the CR rodents should be more sensitive to the cold is perhaps not such a surprise. In all studies of dietary restriction, the animals are thinner, with less fat--or insulation--and fewer energy reserves than their more porky pals have. Even their body temperature is lower than normal--by several degrees in most dieting mice.
Perhaps more troubling is the observation that mice that cut calories early in life succumb more easily to bacterial infection than do animals that eat all they want. Immunobiologist Gabriel Fernandes and his UTHSC colleagues harvested macrophages--immune cells that patrol the body's tissues and ingest invading microbes--from both restricted and well-fed mice. In an article in Clinical and Diagnostic Laboratory Immunology, they report that macrophages from mice consuming 40% fewer calories than ad lib-fed animals produce fewer immune-boosting interleukins when exposed to lipopolysaccharide, a major cell wall component of many bacteria, including Escherichia coli. Furthermore, the restricted rodents are more prone to peritonitis: When the researchers poked a hole in the animals' colons, a treatment that mimics a burst appendix, the skinny mice did not survive as long as their chunkier lab mates did. CR might hamper the maturation of the immune system, particularly macrophages, in young mice, Fernandes concludes. More work is needed to determine how CR might affect the immune response in older animals--and whether it operates the same way in people.
The longevity diet's effect on rodents' reproduction is well documented. Calorie-deprived females show reduced fertility: Female rats cycle less frequently and have smaller litters; female mice are nearly sterile. Calorically challenged males also experience difficulties when it comes to mating. In a small, unpublished study, Richardson found that male mice raised on a restricted diet are so small that well-fed females of the same age can brush off their sexual advances with ease. His conclusion: "In the wild, [it's] better to be big and fat if you want to reproduce."
Lost in the Wild
Such observations raise the question of how these lean little beasts would fare in nature. The consensus is, probably not well. They're not equipped to weather the cold, and they'd be easy pickin's for most predators. In a small, unpublished study, Austad found that restricted mice can't sprint as fast as their fully fed kin can. "This would be another drawback in the real world," he notes. Of course, laboratory mice, no matter how well they're fed, wouldn't do too well in the wilderness: They're born and bred in a climate-controlled, germ-free environment and wouldn't know a predator from a postdoc. But ad lib-fed animals would probably last longer than their calorie-seeking compatriots because they'd start with more body fat. "So it would take them longer to starve," says George Roth, a gerontologist at the National Institute on Aging in Baltimore.
Mice in the wild are not as pudgy as their pampered laboratory relations are. But neither are they like calorically deprived lab mice (see Austad Perspective). "They're smaller, but they're not emaciated; they don't show the same leanness as restricted mice," says Richard Miller, a gerontologist at the University of Michigan, Ann Arbor. And they're fertile. Therefore, mice are probably not calorically restricted in the wild, although, Miller points out, "there must certainly be episodes in nature when food is scarce. So it's possible that these animals can respond to such scarcity by entering a physiological state that extends their life-span." Austad finds that wild mice do benefit from dietary restriction in the lab--data he presented at the 2002 Gerontological Society of America meeting in Boston. "Their average life-span is not very different, but their maximum longevity is enhanced, " he says. "A few of the restricted wild guys live a really long time."
Flies in the Ointment
Even if its unwelcome consequences could be minimized, CR might not make centenarians of us all. The diet does not boost longevity in all animals in which it has been tested. Unlike Drosophila melanogaster, Mediterranean fruit flies (Ceratitis capitata) fed diets ranging from 30% to 100% of ad libitum amounts saw no change in their life expectancy of about 100 days, as reported last year in Aging Cell (see "The Road More Traveled" and "Not in Medflies"). Some scientists have questioned the conclusion that CR augments longevity in Drosophila because the flies had access to unlimited amounts of diluted food, and no one knows exactly how much they consumed. Still, the researchers studying Ceratitis were so surprised that calorie cutting didn't tweak life-span that they repeated their entire experiment--with 2400 flies on 12 different diets. "We thought we must have done something wrong," says James Carey, a biodemographer at the University of California, Davis. "So we ran the whole thing again and got exactly the same response." Carey is not alone. Sohal reports similar results--or lack of results--in houseflies reared on restricted diets. And certain species of rotifer--a tiny, wheel-shaped, water-dwelling beastie--similarly fail to respond to dietary deprivation by living longer than their plankton-bloated brothers and sisters do, as reported in the Journal of Gerontology.
Researchers have several theories to explain why dietary restriction might work in some species and not others. One possibility is that organisms normally strike a balance between procreation and personal maintenance. Creatures that are able to adjust that balance will live longer when underfed. In other words, the animals that respond to restriction are the ones that can curtail reproduction to keep themselves alive.
This hypothesis is supported by both the Medfly and rotifer studies. Synchaeta pectinata, one of three rotifer species that derive no benefit from dietary deprivation, does not alter its procreation protocol one whit when starved. "Their eggs are even the same size as normal," says Kevin Kirk, an evolutionary biologist at New Mexico Tech in Socorro. "So they basically just reproduce themselves to death in, like, half a day." Female Medflies also continue to lay eggs regardless of their state of satiety. As reported in an article in Science, the same flies do live longer if they're fed a diet of pure sugar; on this regimen, females have no proteins to put in their eggs, so they don't make any. Taken together, these results suggest to Carey that dietary restriction extends life-span in large part by shutting down reproduction.
In CR experiments on mice and rats, the sexes are caged separately, and the animals aren't allowed to breed. Carey predicts that if restricted rodents were allowed to bear young, the longevity-enhancing effect of dietary restriction would disappear. Think of it as an evolutionary strategy for animals that have to cope with lean times in the wild: When environmental conditions prevent reproduction, he says, "you really have no choice. Under those circumstances, you're going to live longer. But if you can reproduce, you're better off doing so. Even if you're unsuccessful, even if it kills you. You should try to produce a few offspring, because you don't know if conditions will ever improve."
Sohal doesn't buy the "reproductive tradeoff" theory. "You could make the same argument for any of the other adverse affects of dietary restriction," he says. "Do animals also trade off their ability to heal wounds just so they can live longer? It's just silly."
Instead, Sohal speculates that the animals that benefit from CR are those that are physiologically flexible and can regulate their metabolism in response to food intake. "A fly doesn't have that luxury," says Sohal. "Its rate of metabolism is dictated by the temperature of the environment." Some rodents can slow their metabolism when times are tough and resources are scarce--witness their drop in body temperature when subjected to CR. Humans, however, cannot depress their metabolism in the same way. "We primates have a very tight range in which we can physiologically function," says Marc Tatar, an evolutionary biologist at Brown University in Providence, Rhode Island. Our bodies operate best around a certain temperature. "We may not thrive--or survive--under the sorts of CR conditions that extend life in other mammals," says Tatar.
CR might not even work in all mouse strains. Fernandes identified one such strain in the mid-1970s. Now Sohal has found another. In a soon-to-be-published study, the USC researcher and his colleagues show that a commonly used inbred mouse does not respond to dietary restriction by outlasting its fully fed cousins. Rather than using these mice as furry little nails in the coffin of CR, Sohal looks forward to turning them into the perfect negative control. They should allow him to eliminate side effects that result simply from the reduced intake of calories--loss of muscle and body fat, for example. Instead of comparing starving animals to sated ones, Sohal will be able to compare mice that live longer in response to CR to those that don't. Such an experiment could allow him to tease out just what it is about dietary restriction that enhances longevity.
At the University of Colorado, Boulder, behavioral geneticists Brad Rikke, Tom Johnson, and a battalion of hungry mice are pursuing a similar goal. Rikke and Johnson have developed a set of 77 related strains of mice that they hope will allow them to separate genetically the different components of the CR response: changes in body weight, temperature, blood glucose and insulin concentrations, and so on. "I think the approach will prove to be informative," says Miller. Suppose, for example, that one strain of mouse, when subjected to dietary restriction, shows enhanced longevity and a decreased concentration of the insulin-like growth factor IGF-1--a hormone that appears to be involved in longevity in Caenorhabditis elegans, Drosophila, and mice (see "One for All")--but no drop in body temperature. Such a finding would suggest that limiting IGF-1 is important for long life, whereas lowering of body temperature is an unnecessary side effect--information that would be of interest to anyone wishing to design a CR mimetic (see Longo and Finch Review).
The Joys of Deprivation
It's tough to say what all of this means for humans who hope to add decades to their lives by slashing their calorie intake by one-third. Thankfully, we don't have to worry too much about predators, and we protect ourselves from most environmental stresses by living indoors and wearing clothes. Even so, if the studies on rodents are any indication, a human raised on CR might wind up an 80-pound wimp with a waning libido who wears wool sweaters in summer and lives in constant fear of encountering a Caesar salad laced with Salmonella. "I would not like to have that phenotype, myself," says Roth.
Whether a CR diet would extend life-span in humans is still unclear. Roth's studies in primates are still in the early stages, but so far the results look similar to those obtained from experiments performed on rodents (see "Monkey in the Middle"). Macaques reared on a diet with 30% fewer calories than ad lib-fed animals are smaller, with less muscle mass and a slightly depressed body temperature, than monkeys that eat their fill are. But their blood insulin concentrations drop, they have fewer tumors, and, 15 years into the experiment, a smaller percentage have died, compared to age-matched, fully fed animals, although too few monkeys have died to render the longevity results statistically significant. "So calorie restriction should work in people," says Roth, "if they had the gumption to stick to it."
The trouble is, most humans would never be able to follow such a draconian diet. "In practical terms, it's a nonissue," says Austad. "Everybody knows [we] should eat less, and nobody does it." Hence, the interest in developing mimetics--compounds that would produce the positive effects of CR, such as enhancing longevity, while evading some of its less pleasant side effects, such as muscle wasting and infertility. Roth and others are currently searching for such life-extending dietary supplements.
So the recognition that CR has its drawbacks has not derailed those who are interested in exploring its effects on life-span. "Nothing is all good," says Richard Weindruch, a gerontologist at the University of Wisconsin, Madison. Of course, researchers who have seen the positive effects of dietary restriction may be somewhat "prejudiced," adds Roth.
That bias concerns Colorado's Tom Johnson, who says he has had trouble publishing studies that run counter to the notion that CR is a universal cure-all for aging. "People who have their careers invested in something don't want to see it disproved," he says. "It's a problem in the aging field in general. There's so much emotional content behind the subject matter."
That's why it's important that researchers continue to evaluate critically this dietary regime--examining its pitfalls and its payoffs--to assess how it works and where it fails. "The truth will come out in the end," says Sohal. "That's all that matters."
February 26, 2003
Karen Hopkin is a freelance writer in Somerville, Massachusetts. She won't be passing up the cherry pie until all the data are in.
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