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




* * *

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.

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.

* * *

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]

Older News: Sluggish Thyroid Isn't All Bad News...

...to a point, of course. Untreated hypothyroidism is associated with heart problems, but within a presumably healthy range, tipping the lower end of the thyroid hormone scale tends to be associated with longevity: http://www.sciencedaily.com/releases/2006/10/061010022316.htm

Here's the scoop:

Longer-lived Rodents Have Lower Levels Of Thyroid Hormone

ScienceDaily (Oct. 12, 2006) — The thyroid may play an important role in longevity, with longer-lived rodents showing significantly lower levels of a thyroid hormone that speeds metabolism, a new study has found.

The study further strengthens the theory that the faster an animal's metabolism, the shorter its life, and vice versa, said Mario Pinto, the study's lead author. The thyroid releases hormones that regulate metabolic rate.

"Thyroid hormones are key regulators of metabolism and have been widely implicated to influence longevity," the authors wrote. Pinto will present the study "Differential thyroid hormone activity in rodents with different life spans" at a poster session Oct. 9 at Comparative Physiology 2006: Integrating Diversity. The study was carried out by Pinto and Rochelle Buffenstein, City College of New York.

Thyroid key to metabolic rate

The thyroid gland produces thyroxine (T4) which converts to triiodothyronine (T3) in the presence of iodine. T3 is the active component of T4 and is the key hormone in regulating metabolism, Pinto said. When an animal becomes cold, for example, its body converts T4 to T3 to speed metabolism and warm the body, he explained.

"Mice strains that exhibit extended longevity tend to have lower thyroid hormone concentrations than shorter living strains," the authors wrote. "Significant declines in thyroid hormone correlate well with enhanced maximum lifespan."

The study compared the levels of these thyroid hormones among four groups of rodents with different life spans: mice, guinea pigs, Damara mole-rats and naked mole-rats. Mice live to about three and a half years; guinea pigs live to six years; Damara mole-rats to 15 years; and naked mole-rats to 28 years.

The animals were of different ages, but at comparable points in their life spans. For example, the mole-rats, which live 28 years, were two years old. The mice, which live about 3.5 years, were six months old. The study determined the levels of T3 and T4 for each animal.

T4 levels vary the most

T4 levels varied significantly between all of the groups, with the shorter-lived groups having higher levels of T4 than longer-lived groups. The mice, for example, had twice as much T4 as the Damara mole-rats and had and three times more than that of the naked mole-rats, Pinto reported. There was also a significant difference in T3 levels between the naked mole-rats and the guinea pigs, but not between any of the other groups

"These hormone concentration differences correlate with maximum species lifespan and suggest an important regulatory role of thyroid hormone in longevity," the researchers concluded. However, because T3, levels did not differ significantly among all the groups, further research in this area using larger sample sizes (numbers of rodents in each group) is needed, Pinto said.

Adapted from materials provided by American Physiological Society, via EurekAlert!, a service of AAAS.

(Emphasis mine).

It's that dang-blasted metabolism again; can't live with it, can't live without it! That which nourishes me also kills me! Et cetera, and so forth, and on. Looks like the best way to extend life is to slow down the speed of life. It's kind of like your life is prerecorded as one film, and you want more of it, you have to watch it in slow-motion. Let's just hope it's more Fellini than 2 Fast 2 Furious, because I wouldn't want the equivalent of stretching out that shitscreen.

In seriousness, I wonder if this also has to do with the sex disparity in longevity. I had long chalked it up to size differences and health habits (women eat healthier, require fewer calories, drink less, take fewer health risks, etc.), but come to think of it, when I worked in a pharmacy, every synthroid-swiper with an underactive thyroid was female, without exception. Those are extreme cases, but I wonder if that's the tail end of a distribution that has most women shifted metabolically in a slow-burning direction. Perhaps estrogen isn't the only culprit for women's greater propensity for fat storage and aversion to weight loss (hello the women of The Biggest Loser!). But perhaps that's why they also make up 85% of all centenarians.

This also lends weight to the possibility that size differences aren't the cause of longevity as much as mutations causing lower growth hormone levels that simultaneously slow aging and reduce size. Note that the tiny mice had higher levels than the larger, longer-lived species with lower levels that correlated with their respective lifespans.

I'm concerned and confused and bewildered in some ways, because the study states that levels of hormone T3 did not appreciably differ between species, whereas its bioactive converted form, T4, did differ and correlate with aging differences. What scares me is that iodine is responsible for this conversion process, and I have seen other studies that implicate dairy intake, one of the greatest dietary sources of iodine, as being a distinctly life-extending food preference among the oldest old. Perhaps it wasn't a lifelong preference, but only adopted later, which beneficially boosts their IGF-1 and thyroid hormones to more youthfully functioning levels (and perhaps prevents muscle wasting as a worthwhile bonus)? I also recall that aboriginal Australians had no trace of cardiovascular disease in spite of largely animal-based sustenance. What was found was that they lacked iodine in their diet, which when supplemented, caused them to grow from their small statures (men were about 5'4", like Asians) to European-typical heights. Without any other changes to their lifestyles, these larger, iodine-ridden folks started developing signs of cardiovascular disease like Europeans as well. I've seen this interpreted as ye olde height problem a-gain, but perhaps it comes down to iodine boosting T3 to T4 conversion, thus boosting metabolism.

Oldish News: Low Glucose Metabolism Reduces Free Radical Damage

Centenarians often have low levels of triglycerides and are lean. Snell dwarf mice have modeled nicely how a beneficial mutation in preferential metabolism can slow the aging process by minimizing the oxidative damage from metabolizing glucose by favoring fat metabolism instead.

From ScienceDaily last November: http://www.sciencedaily.com/releases/2007/11/071121162443.htm
--reprinted here:

Fat Hormone May Contribute To Longevity

Altered fasting metabolism may contribute to the
increased longevity of Snell dwarf mice (bottom).
(Credit: Terry Combs)

ScienceDaily (Nov. 23, 2007) — Both humans and mice that manage to live to a ripe, old age show a clear change in their glucose metabolism, but it's unclear whether this change alone can increase lifespan.

Using a mouse model of longevity, Terry Combs and colleagues report that changes in metabolism can indeed increase longevity. They demonstrated that long-lived Snell dwarf mice burn less glucose and more fatty acids during periods of fasting, and as a result produce fewer free radicals.

The key to this switch may be adiponectin, a hormone produced by fat cells that helps lower glucose production and stimulates cells to use fat for energy instead. The researchers found that Snell mice had three times as much adiponectin in their blood as control mice; Snell mice also had fewer triglycerides in their cells, indicative of higher fat metabolism.

The benefit of burning fats instead of glucose for energy is that it produces fewer oxygen radicals which can damage cells and exacerbate the effects of aging. Confirming this, Combs and colleagues found far less free radical damage, measured as the frequency of a chemical modification on protein known as carbonyl groups, in Snell mice than controls.

Article: "Low utilization of circulating glucose after food withdrawal in Snell dwarf mice" by Natasha L. Brooks, Chad M. Trent, Carl F. Raetzsch, Kevin Flurkey, Gunnar Boysen, Michael T. Perfetti, Yo-Chan Jeong, Simon Klebanov, Kajal B. Patel, Valerie R. Khodush, Lawrence L. Kupper, David Carling, James A. Swenberg, David E. Harrison, and Terry P. Combs

Adapted from materials provided by American Society for Biochemistry and Molecular Biology, via EurekAlert!, a service of AAAS.

(Emphasis mine).

I'm wondering if some of the results were confounded by the size differential, i.e., all things equal, smaller animals within most any species tend to live longer than their larger counterparts. Without bothering to delve into the details of the original research paper myself, I'm guessing they're competent enough to correct for body size when evaluating the disparity in longevity.

Note how in true media fashion, the title is accurate but somewhat misleading in regard to the important bit here, which is that any preferential reduction in glucose metabolism in favor of fatty-acid energy sourcing could minimize oxidative stress--no favorable mutations in adiponectin production required.