Calorie restriction slows pace of aging in healthy adults

by Columbia University's Mailman School of Public Health

Credit: CC0 Public Domain

In a first of its kind randomized controlled trial an international team of researchers led by the Butler Columbia Aging Center at the Columbia University Mailman School of Public Health shows that caloric restriction can slow the pace of aging in healthy adults. The CALERIE intervention slowed pace of aging measured from participants' blood DNA methylation using the algorithm DunedinPACE (Pace of Aging, Computed from the Epigenome). The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention. The results are published online in the journal Nature Aging.

26 fev "In worms, flies, and mice, calorie restriction can slow biological processes of aging and extend healthy lifespan" says senior author Daniel Belsky, Ph.D., associate professor of epidemiology at Columbia Mailman School and a scientist with Columbia's Butler Aging Center. "Our study aimed to test if calorie restriction also slows biological aging in humans."

The CALERIE Phase-2 randomized controlled trial is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the U. S. to a 25 percent calorie-restriction or normal diet for two years. CALERIE is an acronym for 'Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy'.

To measure biological aging in CALERIE Trial participants, Belsky's team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. "Humans live a long time," explained Belsky, "so it isn't practical to follow them until we see differences in aging-related disease or survival. Instead, we rely on biomarkers developed to measure the pace and progress of biological aging over the duration of the study." The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.

In the primary analysis Belsky and colleagues focused on three measurements of the DNA methylation data, sometimes known as "epigenetic clocks". The first two, the PhenoAge and GrimAge clocks, estimate biological age, or the chronological age at which a person's biology would appear "normal". These measures can be thought of as "odometers" that provide a static measure of how much aging a person has experienced. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. DunedinPACE can be thought of as a "speedometer".

"In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks," noted Calen Ryan, Ph.D., Research Scientist at Columbia's Butler Aging Center and co-lead author of the study. "The difference in results suggests that dynamic 'pace of aging' measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age."

Our study found evidence that calorie restriction slowed the pace of aging in humans" Ryan said. "But calorie restriction is probably not for everyone. Our findings are important because they provide evidence from a randomized trial that slowing human aging may be possible. They also give us a sense of the kinds of effects we might look for in trials of interventions that could appeal to more people, like intermittent fasting or time-restricted eating."

A follow-up of trial participants is now ongoing to determine if the intervention had long-term effects on healthy aging. In other studies, slower DunedinPACE is associated with reduced risk for heart disease, stroke, disability, and dementia. "Our study of the legacy effects of the CALERIE intervention will test if the short-term effects observed during the trial translated into longer-term reduction in aging-related chronic diseases or their risk factors," says Sai Krupa Das, a senior scientist and CALERIE investigator who is leading the long-term follow up of CALERIE participants.

DunedinPACE was developed by Daniel Belsky and colleagues at Duke University and the University of Otago. To develop DunedinPACE, researchers analyzed data from the Dunedin Longitudinal Study, a landmark birth cohort study of human development and aging that follows 1000 individuals born in 1972-73 in Dunedin, New Zealand. Researchers first analyzed the rate of change in 19 biomarkers across 20 years of follow-up to derive a single composite measure of the Pace of Aging. Next, the researchers used machine-learning techniques to distill this 20-year Pace of Aging into a single-time-point DNA methylation blood test. The values of the DunedinPACE algorithm correspond to the years of biological aging experienced during a single calendar year, providing a measure of the pace of aging.

More information: Daniel Belsky, Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial, Nature Aging (2023). DOI: 10.1038/s43587-022-00357-y. www.nature.com/articles/s43587-022-00357-y

Study finds calorie restriction lowers some risk factors for age-related diseases

Credit: Peter Häger/Public Domain

A National Institutes of Health-supported study provides some of the first clues about the impact of sustained calorie restriction in adults.

02 sept 2015--Results from a two-year clinical trial show calorie restriction in normal-weight and moderately overweight people did not have some metabolic effects found in laboratory animal studies. However, the researchers found calorie restriction modified risk factors for age-related diseases and influenced indicators associated with longer life span, such as blood pressure, cholesterol, and insulin resistance. The study was reported in the September, 2015 issue of Journal of Gerontology: Medical Sciences.
Calorie restriction is a reduction in calorie intake without deprivation of essential nutrients. It has been shown to increase longevity and delay the progression of a number of age-related diseases in multiple animal studies. Called Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE), the randomized trial was funded by the National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of NIH. It was conducted at Washington University in St. Louis, Louisiana State University's Pennington Biomedical Research Institute in Baton Rouge, and Tufts University in Boston. The study coordinating center was at Duke University in Durham, North Carolina.
CALERIE was designed to test the effects of calorie restriction on resting metabolic rate (after adjusting for weight loss) and body temperature, which are diminished in many laboratory animal studies and have been proposed to contribute to its effects on longevity.
"The study found that this calorie restriction intervention did not produce significant effects on the pre-specified primary metabolic endpoints, but it did modify several risk factors for age-related diseases. It is encouraging to find positive effects when we test interventions that might affect diseases and declines associated with advancing age," notes NIA Director Richard J. Hodes, M.D. "However, we need to learn much more about the health consequences of this type of intervention in healthy people before considering dietary recommendations. In the meantime, we do know that exercise and maintaining a healthy weight and diet can contribute to healthy aging."
In laboratory animals, calorie restriction's favorable effects on life span have generally been found when it is begun in youth or early middle age. An equivalent trial in people would take decades. However, shorter trials can determine feasibility, safety and effects on quality of life, disease risk factors, predictors of life span and effects on mechanisms influenced by calorie restriction in laboratory animal studies. CALERIE was a two-year randomized controlled trial in 218 young and middle-aged healthy normal-weight and moderately overweight men and women to measure these outcomes in a calorie restriction group, compared with a control group who maintained their regular diets.
The calorie restriction participants were given weight targets of 15.5 percent weight loss in the first year, followed by weight stability over the second year. This target was the weight loss expected to be achieved by reducing calorie intake by 25 percent below one's regular intake at the start of the study. The calorie restriction group lost an average of 10 percent of their body weight in the first year, and maintained this weight over the second year. Though weight loss fell short of the target, it is the largest sustained weight loss reported in any dietary trial in non-obese people. The participants achieved substantially less calorie restriction (12 percent) than the trial's 25-percent goal, but maintained calorie restriction over the entire two-year period. The control group's weight and calorie intake were stable over the period. The study found a temporary effect on resting metabolic rate, which was not significant at the end of the study, and no effect on body temperature.
Although the expected metabolic effects were not found, calorie restriction significantly lowered several predictors of cardiovascular disease compared to the control group, decreasing average blood pressure by 4 percent and total cholesterol by 6 percent. Levels of HDL ("good") cholesterol were increased. Calorie restriction caused a 47-percent reduction in levels of C-reactive protein, an inflammatory factor linked to cardiovascular disease. It also markedly decreased insulin resistance, which is an indicator of diabetes risk. T3, a marker of thyroid hormone activity, decreased in the calorie restriction group by more than 20 percent, while remaining within the normal range. This is of interest since some studies suggest that lower thyroid activity may be associated with longer life span.
The study also assessed calorie restriction's effects on mood (particularly hunger-related symptoms) and found no adverse effects. No increased risk of serious adverse clinical events was reported. However, a few participants developed transient anemia and greater-than-expected decreases in bone density given their degree of weight loss, reinforcing the importance of clinical monitoring during calorie restriction.
"The CALERIE results are quite intriguing. They show that this degree of sustained calorie restriction can influence disease risk factors and possible predictors of longevity in healthy, non-obese people. It will be important to learn how calorie restriction at this level affects these factors despite the lack of the predicted metabolic effects," said Evan Hadley, M.D, director of NIA's Division of Geriatrics and Clinical Gerontology and an author of the paper. "Since this group already had low risk factor levels at the start of the study, it's important to find out whether these further reductions would yield additional long-term benefits. It also would be useful to discover if calorie restriction over longer periods has additional effects on predictors of health in old age, and compare its effects with exercise-induced weight loss."
More information: Ravussin, E., et al., A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci (2015) 70 (9): 1097-1104.DOI: 10.1093/gerona/glv057

Provided by National Institutes of Health

Key To Healthy Long Life Could Lie In Balancing Protein Intake Rather Than Calorie Restriction

05 dec 2009--UK researchers studying flies suggest that balancing protein intake rather than reducing calories may be the key to healthy ageing; their findings may explain why calorie restriction, cutting down food intake while making sure the diet contains enough vitamins, minerals and other essential nutrients, appears to benefit health, and also in some organisms, to increase longevity.

The study is the work of Dr Matthew D W Piper from the Institute of Healthy Ageing in the Department of Genetics Evolution and Environment at University College London, and colleagues, and a paper on it appeared online on 2 December in the journal Nature.

Previous research suggests that calorie or dietary restriction, reducing food intake while making sure the diet contains enough vitamins, minerals and other essential nutrients, causes many organisms, including mice, rats, Rhesus monkeys, and fruit flies (drosophila) to live longer and with better health.

There is also evidence that calorie restriction results in greater health in humans too, but whether it increases our lifespan is not so clear.

But there is a downside: dietary restriction diminishes fertility: a female fruit fly on a calorie restricted diet reproduces less frequently and when she does, she produces fewer offspring, although her reproductive span is longer.

The researchers suggest this is an evolved survival trait; when in short supply, essential nutrients are diverted from supporting reproductive systems to keeping the organism alive.

The UCL Institute of Healthy Ageing researchers wanted to investigate this in more detail: was it calorie restriction per se that led to increased health benefits, or was it the effect of reducing specific nutrients?

For the study, which was funded by the Wellcome Trust and Research into Ageing, Piper and colleagues observed what happened when they fed female fruit various diets comprising yeast, sugar and water, but with different amounts of essential nutrients such as vitamins, lipids and amino acids.

They found that varying the amounts and proportions of amino acids in the diet affected the lifespan and fertility of the female fruit flies, but there was little or no effect when they varied the other nutrients.

On closer investigation they found that the amino acid methionine was crucial to extending lifespan and reducing fertility: when they added it to a low calorie diet it boosted fertility without reducing lifespan, and curiously, when they reduced it in a high calorie diet it extended lifespan.

Piper told the press that:

"By carefully manipulating the balance of amino acids in the diet, we have been able to maximise both lifespan and fertility."

"This indicates that it is possible to extend lifespan without wholesale dietary restriction and without the unfortunate consequence of lowering reproductive capacity," he added.

Piper explained that in the past we thought it was the amount of protein in the diet that was important, but this study shows that in flies, and he suggests this is likely to be the same for other organisms too, the balance of amino acids can affect health later in life.

"If this is the case for humans, then the type of protein will be more important," said Piper, explaining that it is not simply a case of telling people to eat more or fewer nuts to live longer, "it's about getting the protein balance right, a factor that might be particularly important for high protein diets, such as the Atkins diet or body builders' protein supplements".

Although the fruit fly does not look like a human, and we have about four times the number of genes that they have, many of the discoveries about how fly genes behave can often be matched against human couterparts.

Dietary restriction appears to be an evolutionary trait, occuring in organisms from yeast to monkeys, suggesting these mechanisms are preserved in genes that we all have in common, or that have largely similar properties. This opens the possibility of using organisms like the fruit fly to study how dietary restriction works and to translate that into the human equivalent.

Amino acids are the building blocks of life: they make up proteins, complex organic compounds that take part in nearly every process necessary for keeping an organism alive. Methionine is an important amino acid because it is essential to the formation of all proteins.

Proteins are made naturally in the body, and we also source them from a variety of foods, including meat, dairy, nuts, pulses and soya derivatives like tofu.

Methionine occurs in naturally high levels in foods such as sesame seeds, Brazil nuts, wheat germ, fish and meats.

"Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila."
Richard C. Grandison, Matthew D. W. Piper & Linda Partridge.
Nature, Published online 2 December 2009
doi:10.1038/nature08619

Researchers note differences between people and animals on calorie restriction

St. Louis, 25 sept 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.
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Fontana L, Weiss EP, Villarreal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell vol. 7 (5); Doi: 10.1111/j.1474-9726.2008.00417.x