Humans Respond Differently Than Mice to CR

http://www.sciencedaily.com/releases/2008/09/080924151018.htm

Differences Between People And Animals On Calorie Restriction

ScienceDaily (Sep. 24, 2008) — Calorie restriction, a diet that is low in calories and high in nutrition, may not be as effective at extending life in people as it is in rodents, according to scientists at Washington University School of Medicine in St. Louis.

Previous research had shown that laboratory animals given 30 percent to 50 percent less food can live up to 50 percent longer. Because of those findings, some people have adopted calorie restriction in the hope that they can lengthen their lives. But the new research suggests the diet may not have the desired effect unless people on calorie restriction also pay attention to their protein intake.

In an article published online this month in the journal Aging Cell, investigators point to a discrepancy between humans and animals on calorie restriction. In the majority of the animal models of longevity, extended lifespan involves pathways related to a growth factor called IGF-1 (insulin-like growth factor-1), which is produced primarily in the liver. Production is stimulated by growth hormone and can be reduced by fasting or by insensitivity to growth hormone. In calorie-restricted animals, levels of circulating IGF-1 decline between 30 percent and 40 percent.

"We looked at IGF-1 in humans doing calorie restriction," says first author Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University and an investigator at the Istituto Superiore di Sanità in Rome, Italy. "For years, we have been following a cohort of people from the CR Society who have been on long-term calorie restriction. We found no difference in IGF-1 levels between people on calorie restriction and those who are not."

The CR Society members, who call themselves CRONies (Calorie Restriction with Optimal Nutrition), had been on a calorie-restriction diet for an average of seven years when Fontana did the measurements, but their IGF-1 levels were virtually identical to sedentary people who ate a standard, Western diet.

Because calorie restriction is linked to extraordinary increases in maximal lifespan in rats and mice, Fontana and colleagues at Washington University, including principal investigator John O. Holloszy, M.D., professor of medicine, have been involved in a scientific study that compares calorie restriction to exercise and measures many biological factors linked to longevity and health. Called the CALERIE study (Comprehensive Assessment of the Long term Effects of Reducing Intake of Energy), the project randomly divided 48 people into three groups: Eighteen cut their caloric intake by 25 percent for one year. Another 18 started exercising to increase their energy expenditure by 25 percent for a year. A third group of 10 people didn't change anything.

At the end of that year, the investigators measured IGF-1 levels in all three groups. Again they found no reductions in the group on calorie restriction.

"That was puzzling because it was the first time we hadn't seen agreement between mice and rats on calorie restriction and humans on calorie restriction," Fontana explains. "But we know there are two major influences on IGF-1 levels: calorie intake and protein intake. So we decided to look at the influence of protein."

Again, Fontana had a ready-made study group. His team has been following a population of strict vegans for several years. They tend to eat less protein than the CRONies from the CR Society, so he compared IGF-1 levels between the two groups.

"The vegans had significantly less circulating IGF-1, even if they were heavier and had more body fat than CRONies," he says. "Protein in the diet seemed to correlate with the lower levels of IGF-1. The strict vegans took in about 10 percent of their total calories from protein, whereas those on calorie restriction tended to get about 23 or 24 percent of calories from protein."

The investigators wanted to take one more look at the relationship between dietary protein and IGF-1, so Fontana asked a group of CRONies to eat less protein for a few weeks. He says it was not easy to cut protein because those on calorie restriction have to do a lot of calculating and juggling to ensure they take in very few calories and still get adequate nutrition. Increasing dietary protein is one way many CRONies guard against becoming malnourished.

"But six of them agreed to lower their protein intake," Fontana explains, "and after three weeks their circulating IGF-1 declined dramatically."

Previous research from Fontana's group had found that a diet lower in protein might protect against some cancers. These more recent findings suggest lowering protein also might be important to longevity. Fontana admits his evidence is preliminary, but the findings suggest that when people adjust their diets to improve health and lengthen life, they should control not only calories and fat but also keep an eye on protein.

Fontana isn't proposing radical low-protein diets. Instead, he is suggesting the current recommended daily allowance (RDA) for protein, which is 0.82 grams of protein per kilogram of body weight, or about 56 grams of protein for an average, adult man and 46 grams for an average, adult woman. Most people, including CRONies, consume much more protein than the RDA recommendation.

"It's much easier to restrict protein than to restrict calories," he says. "If our research is on the right track, maybe humans don't need to be so calorie restricted. Limiting protein intake to .7 or .8 grams per kilogram per day might be more effective. That's just a hypothesis. We have to confirm it in future studies."

Until then, Fontana suggests people might want to look at protein consumption and tailor it to RDA recommendations. Traditionally, he says, nutritionists have not worried about people eating too much protein, but these findings suggest perhaps they should.

Journal references:

1. Fontana et al. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell, 2008; 7 (5): 681 DOI: 10.1111/j.1474-9726.2008.00417.x
2. Fontana L, Klein S, Holloszy JO. Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. American Journal of Clinical Nutrition, vol. 84; pp. 1456-1462, Dec. 2006

Adapted from materials provided by Washington University School of Medicine, via EurekAlert!, a service of AAAS




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I still have to look at the papers to see whether the majority of non-vegans' protein was coming from animal products, or if excessive plant protein can induce high IGF-1 as well. If not, this research dovetails nicely with prior studies showing protein, and, more specifically, methionine restriction increase lifespan.

Legumes for Longevity Says Multi-National Study

http://www.ncbi.nlm.nih.gov/pubmed/15228991

Asia Pac J Clin Nutr. 2004;13(2):217-20.Links
Legumes: the most important dietary predictor of survival in older people of different ethnicities.
Darmadi-Blackberry I, Wahlqvist ML, Kouris-Blazos A, Steen B, Lukito W, Horie Y, Horie K.

Public Health Division, National Ageing Research Institute, Melbourne, Australia. i.blackberry@nari.unimelb.edu.au

To identify protective dietary predictors amongst long-lived elderly people (N= 785), the "Food Habits in Later Life "(FHILL) study was undertaken among five cohorts in Japan, Sweden, Greece and Australia. Between 1988 and 1991, baseline data on food intakes were collected. There were 785 participants aged 70 and over that were followed up to seven years. Based on an alternative Cox Proportional Hazard model adjusted to age at enrollment (in 5-year intervals), gender and smoking, the legume food group showed 7-8% reduction in mortality hazard ratio for every 20g increase in daily intake with or without controlling for ethnicity (RR 0.92; 95% CI 0.85-0.99 and RR 0.93; 95% CI 0.87-0.99, respectively). Other food groups were not found to be consistently significant in predicting survival amongst the FHILL cohorts.

40% and 80% Methionine Restriction Reduce MitROS

Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver.
Caro P, Gómez J, López-Torres M, Sánchez I, Naudí A, Jove M, Pamplona R, Barja G.

Departamento de Fisiología Animal-II, Facultad de Ciencias Biológicas, Complutense University, c/Jose Antonio Novais-2, Madrid 28040, Spain.

Dietary restriction (DR) lowers mitochondrial reactive oxygen species (ROS) generation and oxidative damage and increases maximum longevity in rodents. Protein restriction (PR) or methionine restriction (MetR), but not lipid or carbohydrate restriction, also cause those kinds of changes. However, previous experiments of MetR were performed only at 80% MetR, and substituting dietary methionine with glutamate in the diet. In order to clarify if MetR can be responsible for the lowered ROS production and oxidative stress induced by standard (40%) DR, Wistar rats were subjected to 40% or 80% MetR without changing other dietary components. It was found that both 40% and 80% MetR decrease mitochondrial ROS generation and percent free radical leak in rat liver mitochondria, similarly to what has been previously observed in 40% PR and 40% DR. The concentration of complexes I and III, apoptosis inducing factor, oxidative damage to mitochondrial DNA, five different markers of protein oxidation, glycoxidation or lipoxidation and fatty acid unsaturation were also lowered. The results show that 40% isocaloric MetR is enough to decrease ROS production and oxidative stress in rat liver. This suggests that the lowered intake of methionine is responsible for the decrease in oxidative stress observed in DR.

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The abstract really should have specified the measurable oxidation differences in 40% vs. 80% methionine restriction. Are the effects additive, or is there a minimum threshold for positive results, beyond which no further benefits are derived?

Every Other Day Feeding Schedule Mimics Dietary Restriction without Lowered IGF-1

http://www.ncbi.nlm.nih.gov/pubmed/18593280?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed


1: Rejuvenation Res. 2008 Jun;11(3):621-9.Click here to read Links
Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver.
Caro P, Gómez J, López-Torres M, Sánchez I, Naudi A, Portero-Otín M, Pamplona R, Barja G.

Department of Animal Physiology-II, Complutense University, Madrid, Spain.

It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected. It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR. Based on these facts, we have studied the effect of EOD DR on the rate of mitochondrial reactive oxygen species (ROS) production, oxygen consumption, and the percent free radical leak (FRL) of well-coupled liver mitochondria, the marker of mtDNA oxidative damage 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG), the content of complexes I to IV of the respiratory chain, the apoptosis inducing factor (AIF), PGC1-alpha, UCP2, five different markers of oxidative damage to proteins and the full fatty acid composition on C57BL/6 mice liver. It was found that EOD DR decreased ROS production in complex I but not in complex III without changes in oxygen consumption. As a result, FRL was decreased in complex I. Oxidative damage to mtDNA (8-oxodG) and protein oxidation, glycoxidation and lipoxidation were also lower in the EOD restricted group in comparison with the control one while the degree of fatty acid unsaturation was held constant. The EOD group also showed decreases in AIF, PGC1-alpha, and UCP2. These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.

PMID: 18593280 [PubMed - indexed for MEDLINE]

Methionine Restriction Reduces MitROS

http://www.fasebj.org/cgi/content/abstract/20/8/1064

© 2006 FASEB
Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins
Alberto Sanz*, Pilar Caro*, Victoria Ayala{dagger}, Manuel Portero-Otin{dagger}, Reinald Pamplona{dagger} and Gustavo Barja*,1

* Department of Animal Physiology-II, Complutense University, Madrid, Spain;

{dagger} Department of Basic Medical Sciences, University of Lleida, Lleida, Spain

1Correspondence: Departamento de Fisiología Animal-II, Facultad de Ciencias Biológicas, Universidad Complutense, c/Antonio Novais-2, Madrid 28040, Spain. E-mail: gbarja@bio.ucm.es

Previous studies have consistently shown that caloric restriction (CR) decreases mitochondrial reactive oxygen species (ROS) (mitROS) generation and oxidative damage to mtDNA and mitochondrial proteins, and increases maximum longevity, although the mechanisms responsible for this are unknown. We recently found that protein restriction (PR) also produces these changes independent of energy restriction. Various facts link methionine to aging, and methionine restriction (MetR) without energy restriction increases, like CR, maximum longevity. We have thus hypothesized that MetR is responsible for the decrease in mitROS generation and oxidative stress in PR and CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their longevity. We have found, for the first time, that MetR profoundly decreases mitROS production, decreases oxidative damage to mtDNA, lowers membrane unsaturation, and decreases all five markers of protein oxidation measured in rat heart and liver mitochondria. The concentration of complexes I and IV also decreases in MetR. The decrease in mitROS generation occurs in complexes I and III in liver and in complex I in heart mitochondria, and is due to an increase in efficiency of the respiratory chain in avoiding electron leak to oxygen. These changes are strikingly similar to those observed in CR and PR, suggesting that the decrease in methionine ingestion is responsible for the decrease in mitochondrial ROS production and oxidative stress, and possibly part of the decrease in aging rate, occurring during caloric restriction.—Sanz, A., Caro, P., Ayala, V., Portero-Otin, M., Pamplona, R., Barja, G. Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins.


Key Words: mitochondria • methionine restriction • caloric restriction • free radicals • aging • DNA damage • oxidative damage

Diet and Mortality Patterns in Japan

http://circ.ahajournals.org/cgi/content/meeting_abstract/116/16_MeetingAbstracts/II_789-a

(Circulation. 2007;116:II_789.)
© 2007 American Heart Association, Inc.

Population-Based Risks for CHD and Mortality
Abstract 3485: A Japanese Diet and 19-Year Mortality: NIPPON DATA80.
Yasuyuki Nakamura1; Hirotsugu Ueshima2; Takehito Hayakawa3; Yoshikuni Kita4; Robert D Abbott5; Akira Okayama6

1 Kyoto Womens Univ, Kyoto, Japan
2 Tomonori Okamura, Takashi Kadowaki, Shiga Univ of Med Science, Otsu, Japan
3 Fukushima Med Univ, Fukushima, Japan
4 Shiga Univ of Med Science, Otsu, Japan
5 Shiga Univ of Med Science &Univ of Virginia Sch of Medicine, Kyoto, Japan
6 National Cardiovascular Cntr, Suita, Japan

Objectives:

Although dietary patterns are associated with death from several causes, few studies have examined the association between Japanese diet and mortality outcomes.

Methods:

We analyzed the relationship between a healthy Japanese diet and all-cause and cause-specific mortality using the database from NIPPON DATA80. At baseline in 1980, data on history, physical examinations, and blood biochemical measurements were collected on study participants aged 30 years and over from randomly selected areas in Japan. A nutritional survey was conducted using food-frequency methods. We defined a measure of a healthy Japanese diet based on 7 components. They included egg intake ≤ 2 eggs/week, fish intake ≥ once in 2 days, meat intake ≤ 2 times/week, tsukemono (preserved roots or leaves of seasonal vegetables) intake ≥ once per day, infrequent intake of soup with noodles, use of low salt soy sauce, and occasional drinking. If a dietary component was part of a typical daily diet, it was scored as one and zero otherwise. Thus, the total Japanese diet score ranged from 0 to 7, with 0 being least healthy and 7 being most healthy. Participants were divided into approximate tertiles of dietary scores (0 –2, 3 and 4 –7 scores). After excluding participants with co-morbidities, we followed 9,086 participants (44% men) for 19 years.

Results:

There were 1823 all-cause and 654 cardiovascular deaths during the follow-up. With the dietary score group 0 –2 serving as a reference, the Cox multivariate adjusted hazard ratios for groups with score 3 and scores 4 –7 for all-cause mortality were 0.92 (95% confidence intervals: 0.83–1.04) and 0.78 (0.70 – 0.88) (trend P < 0.0001). For cardiovascular mortality they were 0.91 (0.75–1.10) and 0.80 (0.66 – 0.97) (trend P = 0.022).

Conclusion:

Adherence to a healthy Japanese diet was associated with an approximate 20% lower rate of all-cause and cardiovascular mortality. While Japanese are exceptionally long-lived, placing greater emphasis on the intake of foods that are low in salt could increase longevity in Japan further.

New England Centenarian Study Basic Summary

http://www.sunjournal.com/story/262078-3/LewistonAuburn/Doctors_advice_on_living_to_100/

Doctor's advice on living to 100

- Staff Writer Bonnie Washuk
Tuesday, April 22, 2008

BOSTON - The number of people who live to 100, like Lewiston's Libby Goldman, is low, about 1 out of 8,000, says Dr. Thomas Perls, director of the New England Centenarian Study at Boston University's Medical Center.

Of those who live to be 100, "the larger numbers aren't doing so well," Perls said Monday. Only 20 percent are lucid.

Those in that minority can keep going to 101, 102, 103 and beyond, "as long as their minds are sharp," Perls said.

"Some people say, 'Who would want to live to 100?' I say most of us," if the disabilities associated with old age are compressed to the very end of life, he said.

The vast majority of those who live to 100 have lived independently through their early 90s, Perls said. The world's oldest known person today is Edna Parker of Shelbyville, Ind., who celebrated her 115th birthday April 20. People who live to 110 are "supercentenarians" and are rare, Perls said.

There are three common traits of centenarians, according to research in the New England Centenarian Study:

• Good genes. They have "significant genetic advantages" and lack genes that predispose them to diseases, Perls said. Longevity often runs in families.

• Good health habits. Most don't drink or smoke, and they exercise. They're not overweight.

• They manage stress well. Perls guessed that Libby Goldman was "gregarious and optimistic." People who live to 100 "find humor in their daily lives." They have stress, but "they seem to be able to let go of it easily."

To learn more about the New England Centenarian Study at Boston University's Medical Center, go to: http://www.bumc.bu.edu/Dept/Home.aspx?DepartmentID=361


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Not too helpful, as it's all stuff we knew. I think stress is the biggest problem for most people. The good news is that if you're exercising and eating properly, stress is less likely to be a problem anyway. And what better excuse to block out time for your favorite activities and to hang out with good friends?

Centenarian Blue Zones

Source: http://www.startribune.com/17163371.html

Centenarians: Living, learning

By RANDY A. SALAS, Star Tribune

Last update: March 31, 2008 - 5:53 PM

By Gianluca Colla

Dan Buettner with 100-year-old Felipe Gudoy, in Costa Rica's Nicoya penninsula.

Aging only has an accelerator pedal, Dan Buettner says -- there is no brake. So the key to living longer is simple: Don't step on the gas.

But how do you do that? For a clue, the Minneapolis author and explorer traveled the world to find so-called Blue Zones, places where the people live much longer and in greater number than is the norm. He and a team of researchers then studied those people to find common links that might translate into a longer life for anyone.

The result is Buettner's new book, "The Blue Zone: Lessons for Living Longer From the People Who've Lived the Longest" (National Geographic, $26).

In three years of research, Buettner found four Blue Zones, places where people have up to a three times better chance of living to 100 than we do: Okinawa in Japan, a mountainous region in Sardinia in Italy, the Nicoya Peninsula in Costa Rica, and Loma Linda, Calif. He joined with the National Institute on Aging to come up with a methodology to understand each region's culture of longevity and then backed it up with epidemiology studies.

"It's not just Dan Buettner's observations," he said.

Dr. Greg Plotnikoff, director of the Institute for Health and Healing at Abbott Northwestern Hospital in Minneapolis, joined Buettner in Okinawa to vet the author's field work there. He praised Buettner's big-picture approach to studying the centenarians.

"It's not just 'What did you have for breakfast Mrs. Jones?' It's the whole context," Plotnikoff said. "This is why I'm such a big supporter of Dan's work. He's starting from a different perspective."

The gist of Buettner's findings, which he will discuss Wednesday during a sold-out book-launch presentation at Minneapolis Central Library and Friday at the SweatShop Health Club in St. Paul, should be good news to most people.

"Typically, when Americans think, 'I want to live longer or stay younger,' they jump to supplements or to diets or to exercise programs," Buettner said. "But the biggest 'Aha!' for us was that the things that truly give you extra quality years and make you look and feel younger now are easy and don't cost anything."

Dr. Steven Miles, a geriatrician and a professor of medicine and bioethics at the University of Minnesota, said he generally agrees with the tips derived from Buettner's findings.

"On the other hand, you really don't need to go and look at exotic subcultures to derive these rules," Miles said. "They can be derived relatively easily right here at home."

Buettner condensed the lessons in "The Blue Zone" to five tips:

1. Be naturally active.

That means gardening, walking with friends, playing with the kids and other everyday activities.

"The type of physical activity you enjoy is probably much better for you in the long run than anything else you can do, such as running marathons or triathlons or pumping iron," Buettner said.

Also consider changes that force spontaneous exercise, such as getting rid of the TV remote control so you have to get up whenever you want to change the channel or using a shovel instead of a snowblower.

2. Hang out with the right people.

If you spend your time with people who eat fast food and don't exercise, you're likely to pick up the same habits.

"This has a huge, profound impact on your lifestyle," Buettner said. He cited the extensive Framingham Heart Study, which found that obesity can be "socially contagious."

3. Reduce calories.

Before each meal, elders in Okinawa recite an adage to remind themselves to stop eating before they're full. You can do that more easily by replacing your 12-inch dinner plates with smaller ones.

"Every single meal, you'll cut 20 to 30 percent of the calories," Buettner explained, "because a big cue for telling us whether or not we're full is, is our plate empty?"

He added that University of Minnesota research suggests that people who eat a big breakfast tend to eat fewer calories throughout the day than people who skimp on their morning meal.

4. Restrict meat intake.

The easiest way to do this, Buettner said, is to stop buying meat at the grocery store. That will cut meat from your daily life but still allow you to eat it on special occasions or when you dine with your family and friends.

"The longest-lived people in the world eat meat less than four times a month," he said. "I think not eating meat adds an easy half a dozen years to your life."

5. Have a sense of purpose.

Two ways to do so are reconnecting with your religion and volunteering.

"As your job wanes down and your kids grow up, that's when it's hugely important to have a sense of purpose," Buettner said.

He's working on a new project about happiness and said he has found that 80 percent of the things that optimize your lifestyle also make you happier.

"By just putting a little more energy in the right areas of our life, it will have a huge payoff," he said.

"The power is in the repetitiveness, in doing it for a long time and making it your lifestyle. The key is to change your environment -- your social environment, your work environment -- because that will last. A diet won't. An exercise program won't."

Here's to a long life.

Randy A. Salas • 612-673-4542


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If the link is still active, I highly recommend following it for the captioned photo gallery; among the pictures are a 99-year old man waterskiing (his secret, it says, is his physical activity, eating small portions of good food, and that his weight is the same as it was when he enlisted in the service for WWII) and a centenarian woman who starts every morning by walking a mile through the halls of her building, then goes to the gym to cycle for 6-8 miles, and finishes off with weight training. If those pictures don't inspire you, you're doomed!

The Okinawan adage they recite before eating is a concept known as "harahachibu," or eating only until one feels 80% full. My mother always struggles to remember that one ("hairy hotsy boo-boo?").