Calorie restrictive eating for longer life? The story we didn’t hear in the news

This should have been the lead:

The long-awaited research on the effects of calorie restriction on aging in rhesus monkeys from the University of Wisconsin and Wisconsin National Primate Research Center have just been released. It found no statistically significant difference in the number of deaths among the monkeys who’ve been eating a calorie-restrictive diet for more than 20 years compared to the monkeys who’ve been allowed to eat ad lib all day as much as 20% over their normal calories.

But that’s not what made the news, of course. Instead, we’ve been bombarded with a thousand news stories all reporting in lockstep that low-calorie diets have been proven to add years to our lives.

We are, once again, witnessing marketing and media reporting from press releases — in this case, one from the University of Wisconsin-Madison and lead researcher, Dr. Richard Weindruch; and another from the magazine, Science, where the results were published (and are viewable for $15.). You’ll find no critical examinations of the study in the press releases, no careful evaluations weighing the risks and benefits of caloric restriction, or any mention of downsides at all. The study was presented as providing “compelling evidence” that calorie restriction extends lifespans and slows aging, and suggesting that genes may be responsible.

What’s up?

As we know, whenever we hear a health statistic, the first question we should ask ourselves is how a statistic is defined. Definitions are everything. Only by reading critically can we begin to decipher the wordsmithing, the art of marketing. Read carefully what Dr. Weindruch said in his press release:

We have been able to show that caloric restriction can slow the aging process in a primate species. We observed that caloric restriction reduced the risk of developing an age-related disease by a factor of three and increased survival.

A stronger clue came from this quote in the press release:

There is a major effect of caloric restriction in increasing survival if you look at deaths due to the diseases of aging.

The lower mortality claimed among the monkeys on the calorie restricted diet were achieved only after eliminating 37% of the monkey deaths. They defined mortality as “age-associated deaths” and eliminated any cause of death they didn’t believe was associated with aging. As the supplemental data explains, 16 deaths from “non-age-associated causes were censored and their age of death used as the time variable in the regression.”

Science doesn’t really work that way. Researchers can’t simply ignore the evidence that doesn’t support their hypothesis. That would be the difference between research done to build evidence to support a hypothesis, from science that is objectively studying a hypothesis.

Only one mainstream news article noted this technique. If readers searched diligently, they found it buried about 460 words into a New York Times article, while this finding wasn’t even mentioned in nearly all the other news stories. The Times article noted:

If caloric restriction can delay aging, then there should have been significantly fewer deaths in the dieting group of monkeys than in the normally fed comparison group. But this is not the case. Though a smaller number of dieting monkeys have died, the difference is not statistically significant, the Wisconsin team reports.

No statistical difference. It was a null study that to date has failed to support the calorie restriction hypothesis.

The non-aging-related causes of death included monkeys who died while taking blood samples under anesthesia, from injuries or from infections, such as gastritis and endometriosis. These causes may not be aging-related as defined by the researchers, but they could realistically be adverse effects of prolonged calorie restrictions on the animals’ health, their immune system, ability to handle stress, physical agility, cognition or behavior.

As we know, the most important endpoint in medical interventions is all-cause mortality. Selectively looking at only one cause of death, while ignoring that more patients died from something else, is not evidence to support the efficacy of a treatment. “The treatment worked, but the patient died” is not good medicine that considers the whole patient.

The researchers also used age-related causes of death as meaning the age-associated diseases most prevalent in humans, cancer and heart disease. But, the authors explained, “typically, cardiovascular disease is not detected in caged animals, though on physical exam, a heart murmur may be noted.” So, they used noninvasive techniques to evaluate murmurs, as well as monitor the animals for the presence of tumors.

Another misconception repeated in mainstream media coverage was that the calorie restricted monkeys were eating 30% fewer calories than normal. Again, few people read carefully or went to the study methodology to understand that the monkeys were really eating about 30% less than the control monkeys. In actuality, the control animals were overfed 20% more than their usual diet, while the CR monkeys’ diets were adjusted to keep them about 30% less than the control monkeys. As an earlier report on this study’s methodology explained:

Since 1989, we have been studying the effects of a moderate (30%) adult-onset dietary restriction (DR) in a nonhuman primate model. We chose a rhesus monkey (Macaca mulatta) model… The effects of aging and DR are being analyzed longitudinally in adult male rhesus monkeys, ranging in age from 8 to 14 years (average 9.3 years) at study onset… The 30 rhesus monkeys used in this study were born at and have lived their entire lives at the Wisconsin National Primate Research Center… [In 1994, an additional 30 females and 16 males were added to the study.] Prior to the start of the study, animals were monitored for individual baseline food intakes of a purified diet (10% fat, 15% protein) for 3 months. Animals were then randomized to either Control or Calorie Restricted groups based on their baseline food intakes. Food allotments for the CR animals were then reduced by 10% per month for 3 months to reach the intended 30% DR. Control animals were fed 20% more than their average daily intake…

If anything, this study could be used to lessen fears that “overeating” is deadly. But, of course, that wouldn’t support today’s marketing of anti-obesity and politically correct lifestyles of pristine, low-calorie eating.

Disclosures

Whenever we see science by press release giving us only one side of the story, turning to the disclosure statements can sometimes help us figure out what’s going on and what may be being marketed.

But the press releases didn’t include disclosure statements.

One mainstream news story, the Wall Street Journal, however, revealed that these findings “give new impetus to researchers and companies, including GlaxoSmithKline PLC, that are searching for a drug to mimic the beneficial effects” of caloric restriction. It also disclosed that Dr. Weindruch is the co-founder of LifeGen Technologies LLC, “that works with drug makers to quantify the effect of possible life-extending drugs.”

The rest of a disclaimer can be found by going to LifeGen’s website. As it explains:

LifeGen was co-founded in November 2000 by Drs. Richard Weindruch and Tomas A. Prolla, professors at the University of Wisconsin-Madison and leaders in the fields of gerontology and genetics. Drs. Prolla and Weindruch were the first scientists to use DNA microarrays ("gene chips") to measure gene activity in mammalian tissues. Their research is the subject of several pending patents filed by the University of Wisconsin-Madison and licensed to LifeGen Technologies…

LifeGen Building and LabLifeGen Technologies is discovering the genes associated with aging by using DNA microarrays to compare the activity of tens of thousands of genes in young and aged animals and humans. The same approach is being used to study how the aging process is retarded by caloric restriction (CR), which is the only intervention proven to increase maximum lifespan and retard aging in a diverse array of species. LifeGen has a patent application pending for the use of such "gene expression profiling" as a method to measure the progression of the aging process at the molecular level in individual organs.

This disclosure may make more sense of Dr. Weindruch’s comment to the New York Times that his study “offered ‘very encouraging’ signs that resveratrol could duplicate in people some of the effects of caloric restriction.” [Resveratrol anti-aging research was covered here.]
As a report by Rand Corporation said a few years ago, a pill that could mimic the effects of caloric restriction, claimed to increase human lifespan to 112-140 years, would be one of the biggest money-makers in medicine, at an estimated $8,800 a year, per person, worldwide.

The Wisconsin National Primate Research Center on the University of Wisconsin-Madison campus, is heavily supported by tax dollars through the National Institutes of Health, National Center for Research Resources, grants. WNPRC received $91 million in research grants in 2008 alone.

The idea that calorie restriction extends lifespan is nearly a century old, but the life extension movement and anti-aging medicine, also known as lifestyle medicine, and anti-aging diets gained momentum with Dr. Roy Walford in the 1980s and his The 120 Year Diet books. After his death from Lou Gehig’s Disease in 2004, his student, Richard Weindruch, M.D., at the University of Wisconsin took up the reigns.

Null studies are particularly hard sells, which may partly explain why we seldom hear about them. Understandably, if your entire life’s work, a university’s prestige and decades of funding have been devoted to something, it would be hard to say “never mind” and shut it all down.

A glimpse at the science

The promotion of caloric restriction is rife with poor science and considering only half the story. And, in contrast to its widespread coverage in pop culture, it’s far from mainstream medicine or science. “Today there are a lot of very healthy people who look like skeletons because they bought into this,” said Raj Sohal, professor at the University of Southern California's School of Pharmacy earlier this year. The anti-aging strategy, popularly known as caloric restriction (CR), may be a pointless, frustrating and even more importantly, a dangerous pursuit, he said.

It’s impossible to give a comprehensive review of the CR literature in a blog post. But for those interested, here is a glimpse into the scientific arena, other sides of the story, and what doctors and researchers are talking about.

Humans are not other life forms. Much of what we know about biochemistry, such as DNA replication and repair, is derived from studies of lower life forms, such as yeast cells and bacteria. And aging science comes largely from studies using yeasts, rodents, roundworms, fruit flies and animal models. But human physiology and aging can be very different from that of organisms, rodents and animals. As proven time and again in medical research, what happens even in other mammals may not be representative of human biology. As professor João Pedro de Magalhães at the Integrative Genomics of Ageing Group at the University of Liverpool explains:

Even in animals that age gradually, such as mice, there is no a priori reason to expect them to age for the same causes and mechanisms as humans. One problem is that all models organisms are considerably shorter-lived than humans and were developed for laboratory research based on their high fertility. Not only this means that there are different evolutionary processes acting on these organisms and on humans, but selection for fertility may have also selected for short lifespans in laboratory strains that generate bias in aging studies. In other words, the life-extending alleles found in these organisms may actually be simply restoring lifespan to what is normally found in the wild. The fact that wild-derived mouse strains take longer to reach sexual maturity and live significantly longer than common laboratory strains supports this view. Moreover, laboratory strains are often genetically homogeneous, which provides more consistent results, but also gives rise to discrepancies between strains on the effects of genes or interventions.

What isn’t widely reported is that calorie restriction doesn’t extend lifespan in all species. Even among mice, it can extend lifespan in some strains, while even increasing mortality in others. [Which studies do you think we’ll be most likely to hear about?] In some transgenic mice, lifespan can be prolonged in mouse genotypes when there’s an imbalance between calories and energy (mice bred for obesity) but not in other strains or under normal conditions, as researchers reported earlier this year in the Journal of Nutrition. Rats aren’t like people in another way, as we’ve learned. They have so little gray matter in their brains that they will pig out on anything that tastes good without appetite control because they are missing ingestive controls. They don’t even have enough neural brain connections between the brainstem and viscera to be coordinated enough to vomit or burp!

Most interesting, calorie restriction doesn’t extend average lifespans in wild-derived mice, but only in certain laboratory mice bred to be adapted to specific conditions and which may not be representative of the species. “The inability of CR to extend lifespan of wild-derived mice, which were not adapted to laboratory conditions like typical laboratory mouse strains, may suggest that CR is in part an artifact of breeding animals specifically for laboratory studies,” said professor Magalhães. Explaining human aging based on research in model organisms, even mice, is problematic,” he said, exampling the differences in biological outcomes of telomerase deficiency, linked to cellular aging (senescence).

A review of the research comparing aging among species published by the University of Liverpool explained that maximum lifespan, while not perfect, is still the best means we have for comparing aging among different species. But there is one factor that has to be considered, wrote professor Magalhães: body size. While there are a few exceptions, on average, bigger species live longer. Even among primates, longer-lived species tend to be bigger with bigger brains. Yet, failing to understand the survival advantage of larger size, he said, means “we could make the mistake of correlating some physiological factor with body size, not with longevity or aging.”

“For example, early studies indicated that DNA repair capacity was higher in longer-lived mammals, arguing that DNA repair was a factor in aging," he wrote. "Yet it has been argued that the correlation between DNA repair and longevity is due to the fact that bigger animals live longer and, for reasons unrelated to aging, have better DNA repair mechanisms. In other words, the evolution of aging rates and DNA repair may have been related to body size and thus independent from one another.”

Could anti-aging medicine be pursuing a spurious correlation, perhaps, not unlike the now largely discredited 50-year old anti-oxidant free-radical theory that simply hasn’t held up to the evidence?

Exaggerated claims. As Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, said, CR doesn’t increase lifespan. Their research recently predicted that maximum lifespan gain that humans might see from caloric restriction could be two percent. From an evolutionary standpoint, he explained, mice who subsist on less food for a few years is analogous, in terms of natural selection, to humans who survive 20-year famines. But nature seldom demands that humans endure such conditions.

Similar conclusions were reached by Dr. Aubrey D.N.J. de Grey with the Department of Genetics at the University of Cambridge, UK. Species have widely evolved to be able to adapt to transient periods of starvation. “What has been generally overlooked is that the extent of the evolutionary pressure to maintain adaptability to a given duration of starvation varies with the frequency of that duration,” he said. “This generalization is strikingly in line with available data, leading (given the increasing implausibility of further extending human mean but not maximum lifespan in the industrialized world) to the biomedically and commercially sobering conclusion that interventions which manipulate caloric intake or its sensing are unlikely ever to confer more than 2 or 3 years' increase in human mean or maximum lifespan at the most.”

“Unbiased statistics on the characteristics of humans populations engaged in voluntary CR are hard to come by,” wrote Speakman and Hambly. Unrealistic expectations may be fostered by exaggerated claims in popular books and analyses based on selective studies and anecdotes, but “when more studies are included in the analysis, even this expectation [of benefits from CR started in middle age] is unrealistic.”

Studies of caloric restrictive diets for weight loss in humans, they said, make it clear that caloric restriction is also largely ineffective in the long term. It is next to impossible for humans to sustain semi-starvation forever. Nor has it ever been shown to be healthful, no matter what age, young people to seniors. “Nutritionists interested in the nutrition of the elderly repeatedly emphasize the benefits of maintaining intake and body mass in late life,” they said, for instance. “It is possible that late-life restriction might serve to bring forward this terminal weight loss, thereby shortening lifespan, consistent with the rodent studies.”

Prolonged overeating, just as prolonged restrictive eating, isn’t natural in humans and, in fact, is inordinately difficult to maintain healthfully. Animal studies can’t provide evidence of whether CR is feasible in humans, they said, because such research doesn’t reflect the real world. Laboratory animals spend their lives in a cage, equivalent in relative size to a medium lounge.

By contrast, humans need to perform at least some level of activity to function effectively in society. Measurements of body condition in rodents under CR suggest large reductions in fat-free body mass (skeletal muscle) and also bone mass. This may not be a problem given the lifestyle of the captive mouse, but for humans these problems may elevate the risk of falls and of osteoporotic fractures. Rodent colonies are also generally maintained as specific pathogen-free environments, so the animals do not need to fight off diseases. Obviously this does not extend to free-living humans; so if immune function of CR subjects were to be compromised, they might also suffer elevated disease (and mortality) risks.

Missing balance of risks for people. We still don’t know the mechanism by which CR could extend lifespan in humans, said professor Magalhães. To date, there are no studies showing evidence that semi-starvation or any form of caloric restriction benefits human longevity or improves health outcomes in people. Far from it.

The body of medical evidence is decisive about the adverse effects on human health of prolonged periods of being underfed, whether intentional or not. JFS has covered at length the wide range of adverse effects documented by weight loss, dieting and restrictive eating. Medicine has also long recognized the numerous adverse effects of hunger and semi-starvation on health, medical outcomes and wellbeing in people.

Researchers and clinicians from a wide range of specialties are writing about the health concerns associated with CR. “Despite the ‘magic’ of CR, this intervention in humans may present itself with a number of health concerns which may not be applicable or impact the life of experimental animals, but may do so in humans,” said professors of the School of Pharmacy at Wingate University in North Carolina.

The claims surrounding CR are based primarily on changes on some biomarkers believed to correlate with age-related diseases, such as cholesterol and blood sugars. Unpopular to acknowledge, however, is the fact that the effects of chronic caloric restrictions are the same regardless of the specific dietary nutrients, wrote professors John R. Speakman and Catherine Hambly at the School of Biological Sciences at the University of Aberdeen in Scotland. Even research by Weindruch and Walford had shown this more than two decades ago. Any form of starvation or caloric reduction will lower those health indices while food intake is being restricted, unrelated to the quality of the diet. In other words, making the food more “nutrient-dense” as claimed by CR advocates, doesn’t make caloric restrictions more healthful or lessen certain adverse effects. And adding a vitamin pill doesn’t make people better fed or give them enough to eat.

Restricting food for decades to extend life by a couple of years might be more acceptable if it weren’t accompanied by perpetual hunger, said professors Speakman and Hambly. Their research, however, found that hunger never really goes away. Even after 50 days of CR in mice (about 5 people years), hunger had not diminished and when the mice were taken off the restrictive diet, they were hyperphagic (gorged).

Nourishment is one of life’s greatest pleasures, as well as one of its most basic necessities. Advising people to live their lives obsessed with counting calories and restrained eating, where the pleasures of eating are replaced by punitive dietary regimens and chronic hunger, and where avoiding death becomes the main preoccupation of living, takes on more of a religious ideology, than sound science.

“One can say CR might add some years to your life but it will not be a life worth living,” wrote professor Magalhães. There’s the mental stress of being hungry all the time, he said, which can lead to depression and anxiety behaviors, as have been observed in CR studies. “CR also makes people feel less energetic, less alive. And finally there are the sexual problems: diminished libido is a common side-effect in people under CR and infertility is also possible.” CR has also been reported to reduce the ability to fight infection and research has suggested it might even leave motor neurons more vulnerable to degeneration.

Increasing numbers of professionals are critical of the CR movement for ignoring whole classes of negative outcomes resulting from chronic hunger, such as on behavioral and cognitive function and quality of life, including sociability, curiosity and emotionality. Lifelong restriction is being recommended without consideration of its effects on psychology and behavior, eating disorder clinicians wrote in a 2004 issue of European Eating Disorders Review. “Promotion of CRL for people is irresponsible in the absence of more reassuring data on the full range of expected outcomes,” they wrote. “The available evidence suggests that nutrient-dense CRL in animals—just like nutrient-poor semi-starvation in people—is associated with a number of adverse effects. Those include abnormal food-related behaviour, heightened aggression and diminished sexual activity.”

“It is already clear—in part from research conducted within the framework of CR—that the food focus and asexuality of semi-starvation are not mitigated with micronutrients,” they added. Nor is there evidence that vitamin-enrichment of caloric restrictive diets will reduce the depression, decreased sociability and narrowed scope of interests seen in semi-starvation. As they explained:

The relevance of the classic Minnesota study of human CR [covered here] is specifically disavowed, on the grounds that substandard nutrition must have been responsible for the depression, irritability, social withdrawal, asexuality, fatigue and food preoccupation that subjects experienced. The implication is that if only the Minnesota volunteers had received a few more grammes of protein and an extra dash of riboflavin and vitamin A in their 1570 kcal/day ration, they would have been symptom-free on CR . Yet the glimpses of animal behaviour on impeccable low-calorie regimens suggest that most of the same phenomena run alongside the salutary physiology of CR.

Most clinicians recognize that the adverse physiological and psychological effects of undereating seen in the Minnesota dieting study are the same as those seen in anorexia nervosa, and people with disordered eating and food fears, driven by what is believed to be a pursuit of health. The weight of evidence accumulated for decades, as the eating disorder clinicians noted, suggests that natural selection has built into humans powerful and predictable mechanisms to maintain homeostatis and ensure survival:

Their purpose is to get the organism to eat, by keeping it narrow-minded, self-centred, goal-directed, food-obsessed and at least moderately miserable until that mission is accomplished. Nature knows her business on all of these levels: the molecular, cellular and physiological and the behavioural, cognitive and affective…

It has often been observed that chronic hunger changes individuals and societies more profoundly, predictably and uniformly than any other circumstance humans commonly encounter.

They strongly emphasized that healthcare professionals promoting caloric restrictions — whether it claimed to be for health, weight loss or longevity — have an obligation to consider “the package deal” and cannot pick and choose benefits, while ignoring “inconvenient” adverse effects on every human body:

Advocates of CR have the burden of proof that processes known to go awry on CR of varying quality will not be disrupted by the regimen they recommend. They cannot make that case without paying close attention to variables they have thus far ignored. We anticipate that once CR researchers do so, they will be unable to make the case at all.

© 2009 Sandy Szwarc