Eat less, live longer?

by Laura Cassiday

IN GREEK mythology, the tale of the Trojan prince Tithonus is a tragic one. His lover, the goddess Eos, asks Zeus to grant him eternal life, but forgets to specify eternal youth. Time passes, and while the goddess of dawn stays young and beautiful, Tithonus degenerates into bedridden senility. Eventually Eos shuts him in a chamber of her celestial palace, where his feeble voice can be heard begging for death.

Dreams of eternal youth feature in many cultures throughout history, but it was only in the 20th century that research into longevity really began. Much about ageing is still mysterious - we don't even know the underlying reasons why we journey into old age. There are many lines of enquiry into how to live longer, though, with one of the most intriguing being calorie restriction: in effect, going on a lifelong diet.

Calorie restriction dramatically extends not only the lifespan of laboratory animals, but also their "healthspan" - how long they live free of disease. On the assumption that it has the same effect in people, some individuals have already adopted a restricted diet. The latest evidence suggests that while calorie restriction is indeed beneficial for humans, when it comes to lifespan extension, it may not be the whole story.

The good news is that we might be able to delay ageing without cutting our food intake. "There's a definite possibility that if you balance the diet correctly, a longer lifespan can be achieved without full food restriction," says Matthew Piper, a researcher into ageing at University College London.

Interest in calorie restriction began in 1935, when scientists made the surprising discovery that rats on a reduced-calorie diet lived longer, provided they were supplemented with sufficient vitamins and minerals. The idea sounds counter-intuitive; after all, a state of starvation is not usually conducive to health. But there seems to be a window of benefit. While lifespan is reduced if calories are cut too drastically, it can be extended by cutting them moderately (see graph).

Calorie restriction has since been shown to extend the lives of other organisms including yeast, nematode worms, fruit flies and mice. Mice, for example, live up to 50 per cent longer if their calorie intake is cut by 30 to 50 per cent. What's more, mammals are protected from a number of age-associated maladies such as cancer, heart disease, type 2 diabetes and Alzheimer's disease.

It is unclear why eating less should make animals live longer. While a restricted diet triggers numerous changes at the molecular and genetic levels, only some of these are common across all the species tested. However, there does seem to be a general principle that a dearth of nutrients causes organisms to divert resources away from growth and reproduction and towards basic survival functions. From an evolutionary perspective, these adaptations could help an organism survive famine.

Longevity pioneers

The million-dollar question is whether calorie restriction has a similar effect in people. Humans are longer-lived and clearly harder to study than flies or mice, but recently two sources of evidence have hinted that it does.

The first comes from a 20-year study of rhesus macaques, a species obviously closer to humans than worms and mice. When the macaques were about 10 years old, equivalent to young adulthood in humans, half the group were placed on a diet in which they received 30 per cent fewer calories than the others. While none has yet beaten the record for the longest-lived macaque in captivity (about 40 years), the latest results, reported last year, look promising. About 80 per cent of the calorie-restricted monkeys were still alive when the study was published, beating the control group's survival rate of 50 per cent. And the dieting animals were one-third less likely to have died from an age-related disease (Science, vol 325, p 201).

The second strand of evidence comes from studying people who are practising calorie restriction. The first enthusiasts banded together through an email forum in the early 1990s. The group has since evolved into the Calorie Restriction Society International, which now has over 3000 members who refer to themselves as "CRONies", short for Calorie Restriction with Optimal Nutrition.

Needless to say, this lifestyle is not for everyone. Some people report struggling with hunger pangs, and the society warns on its website that side effects can include feeling cold, poor wound-healing and temporary infertility. But many CRONies insist that hunger is not a big problem and that they actually feel happier and healthier on their frugal diet (see "A day in the life of a CRONie").

CRONies typically cut calories by 10 to 30 per cent of the recommended intake, and most hover around the lower limit of "normal" body mass index, at 18.5 kilograms per height-in-metres squared. To ensure they get all the nutrients they need without busting their calorie quota, their diet is mainly vegetable-based and must be carefully planned, often with the help of a computer program. "People think calorie restriction involves tiny portions, but these people are eating huge amounts of low-calorie, nutrient-dense food," says Luigi Fontana, a professor of medicine at Washington University in St Louis and head of the Division of Nutrition and Aging at the Italian National Institute of Health, who has studied CRONies for the past eight years.

As with the macaques, it is too soon to tell if calorie restriction extends lifespan. The oldest people in Fontana's studies are only in their 70s - the average life expectancy for Americans. But there is evidence suggesting that it extends healthspan. In 2007, Fontana showed that CRONies have optimal metabolic profiles, and low blood pressure and cholesterol levels (Experimental Gerontology, vol 42, p 709). "They have hearts that are 15 years younger than those of typical Americans their age," he says.

So far, so good. But Fontana has found a notable difference in the way people and animals respond to calorie restriction, and it is not great news. It involves a hormone made by the liver called insulin-like growth factor 1.

IGF-1 has emerged as an important promoter of ageing. IGF-1 levels are lower than normal in worms, flies and mice on a restricted diet, and this is thought to be at least partly responsible for their longer lifespan. When it comes to people, however, CRONies have the same IGF-1 levels as the rest of us.

The explanation for this anomaly may lie in a new theory about how diet affects ageing. This says that it may not only be the drop in calories that is responsible for lifespan extension - in some species at least, perhaps it is also the accompanying drop in dietary protein.

One piece of evidence for this idea comes from studies in fruit flies and rodents. If these animals are fed special diets with less amino acids - the building blocks of proteins - they can eat as many calories as they want and still live longer. "These results clearly show that you don't need to restrict calories as a whole to get lifespan extension," says Piper, an author of the study on flies (Nature, vol 462, p 1061).

Further support for this idea comes from studying the molecular pathways inside cells that affect lifespan. A molecule called TOR has been found to set off a chain of reactions that boost cell growth at the expense of longevity. Blocking TOR increases lifespan in all organisms studied to date, including yeast and mice (Aging Cell, vol 9, p 105). Crucially, the most potent activators of TOR are amino acids.

Where does the protein theory leave the CRONies? Fontana noticed that the people in his study group were eating high levels of protein, about 1.7 grams per kilogram of body weight per day. This is more than the US government-recommended intake of 0.8 g/kg/day, and higher than that in a typical American's diet, about 1.2 g/kg/day.

Accelerated ageing

So Fontana asked six CRONies to cut their protein intake to 0.95 g/kg/day while maintaining their usual calorie intake. After only three weeks on the low-protein diet, the CRONies showed a 25 per cent drop in their levels of IGF-1 (Aging Cell, vol 7, p 681). "Even if the CRONies are restricting their calories severely, if they're eating a high-protein diet, they're probably negating some of the most important beneficial effects," says Fontana.

If the new theory is right, then the whole concept of calorie restriction needs to be rethought. The very term would be misleading; Fontana and others have started referring to dietary restriction instead. As news of the study has spread, some CRONies have already reduced their protein intake.

The protein theory is bad news for people on low-carbohydrate weight-loss plans like the Atkins diet. "I'd be wary of diets that put a heavy emphasis on protein," says Piper. "It's hard to see how that could be healthy." Fontana goes one step further, saying that high-protein diets could risk accelerated ageing and cancer.

It's good news, however, for people already on low-protein diets, like vegans, who avoid eating meat, eggs and dairy products. In 2007, Fontana showed that vegans have lower levels of IGF-1 than meat-eaters (Rejuvenation Research, vol 10, p 225).

There may be another reason for vegans to celebrate. Studies on flies and rodents suggest that cutting intake of one particular amino acid, called methionine, lengthens life to a similar degree as calorie restriction. Proteins in meat and other animal products have high levels of methionine, so a vegan diet would score well by that measure, too (Medical Hypotheses, vol 72, p 125).

If calorie restriction would be hard for most people, calorie and protein restriction would be doubly so. Those determined to live to 130 may want to give it a shot, but for the rest of us, simply sticking to recommended dietary protein levels could have benefits for both lifespan and healthspan. "Protein restriction is much less difficult to maintain than [calorie] restriction and may be more powerful in reducing IGF-1 in humans," Fontana said in a recent review (Science, vol 328, p 321).

For those who don't fancy changing their diet, a more tempting prospect is a pill that replicates the effects without the hard work. Drug firms have taken a keen interest in trying to find such calorie-restriction mimetics, as they are sometimes called.

A decade ago the main focus was on signalling molecules called sirtuins that reduce the expression of several ageing-related genes. Reports that resveratrol, a compound found in red wine, extended lifespan in some species by activating sirtuins boosted sales of red wine and resveratrol supplements. Resveratrol still has supporters, but inconsistent animal data have since dampened much of the enthusiasm.

The focus has lately switched to finding compounds that block TOR. One such agent is a drug called rapamycin, an immunosuppressant given to recipients of organ transplants. Last year rapamycin was found to extend the lifespan of mice, even in those started on the drug in later life, equivalent to 60-year-old humans (Nature, vol 460, p 392). However, because people don't live in a sanitised lab environment, rapamycin's strong immunosuppressive effects make it an unlikely candidate for a practical anti-ageing drug. Similar compounds that are less toxic would be more promising.

Another candidate is a drug called metformin, already used to treat type 2 diabetes. Metformin also blocks TOR, and lengthens lifespan in worms and mice (Cell Metabolism, vol 11, p 390). Does metformin slow ageing in people too? Studies published earlier this year suggest that diabetics taking metformin do get less cancer (Diabetes Care, vol 33, p 322). "The major risk factor for cancer, above all others, is ageing," says David Gems at University College London. He calls the studies a "smoking gun of a more generalised effect of metformin on ageing, rather than just strictly diabetes".

While metformin is less toxic than rapamycin, it, too, can have side effects, such as nausea and diarrhoea. So researchers may have a way to go before they find the perfect longevity pill.

And it would be premature to consider the case proven for the protein theory of lifespan extension. Even Fontana acknowledges there may be other nutrients that play a role, such as fatty acids or cholesterol. Others have speculated that it may be the ratio of calories to protein that is key.

In the meantime, the best bet for warding off ageing and disease could still be the time-honoured advice to eat your greens. Perhaps if vegetables had been the food of the gods, Tithonus could have enjoyed a few more quality years with Eos.

* * *

A day in the life of a CRONie
Paige Collins-Rideout, a 39-year-old medical transcriptionist in Blue Ridge, Georgia, does not look like she needs to diet, but that is exactly what she is doing. Collins-Rideout is a CRONie (which stands for Calorie Restriction with Optimal Nutrition), a member of a group who believe that eating a carefully controlled diet with 10 to 30 per cent fewer calories than recommended is key to a longer, healthier life.

For the past year-and-a-half, Collins-Rideout has been limiting her food intake to 1500 calories per day. At 1.7 metres (5 feet, 6 inches) tall, she weighs only 50 kilograms (110 pounds).

Vitamin-rich foods such as sweet potatoes, broccoli, spinach, eggs and whole grains are staples of Collins-Rideout's diet. Perhaps surprisingly, she says she is rarely hungry, although she admits to occasionally succumbing to unhealthy snacks like fried jalapeños. "Once in a great while I'll have something like that," she says. "Then I'm ready to go back to healthy eating."

There are downsides. Because it is hard to get the recommended levels of vitamins and minerals without supplements, which CRONies generally avoid, calorie restrictors often invest a great deal of time in planning and tracking their diet. To avoid becoming too underweight, Collins-Rideout has also cut back on her running - she used to jog 5 kilometres per day. She also says that social eating can be difficult.

But she says benefits of her diet include improved mood, sleep, mental clarity and memory. She has no desire to live to be 100, though. "My goal is to slow the ageing process so that when I get to retirement, I'll have the energy and vitality to actually live," she says. "I can't imagine going back to any other way of life."

Laura Cassiday is a science journalist based in Denver, Colorado

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