How does caloric restriction prevent the negative effects of aging in cells

What is calorie restriction

According to National institute of aging

Calorie restriction means reducing average daily caloric intake below what is typical or habitual, without malnutrition or deprivation of essential nutrients.

What Are the Different Forms of Calorie Restriction and Fasting?

Calorie restriction is a consistent pattern of reducing average daily caloric intake, while fasting regimens primarily focus on the frequency of eating. The fasting diet may or may not involve a restriction in the intake of calories during non-fasting times.

What’s the Evidence from Human Studies of Calorie Restriction?

Some study results suggest that calorie restriction may have health benefits for humans, but more research is needed before we understand its long-term effects. There are no data in humans on the relationship between calorie restriction and longevity.

Some people have voluntarily practiced extreme degrees of calorie restriction over many years in the belief that it will extend lifespan or preserve health. Studies on these individuals have found markedly low levels of risk factors for cardiovascular disease and diabetes.

The studies have also found many other physiologic effects whose long-term benefits and risks are uncertain, as well as reductions in sexual interest and the ability to maintain body temperature in cold environments. These people generally consume a variety of nutritional supplements, which limits knowing which effects are due to calorie restriction versus other factors.

To conduct a more rigorous study of calorie restriction in humans, NIA supported a pioneering clinical trial called Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE).

In CALERIE, 218 young and middle-aged, normal-weight or moderately overweight adults were randomly divided into two groups. People in the experimental group were told to follow a calorie-restriction diet for 2 years, while those in the control group followed their usual diet.

The study was designed to have participants in the experimental group eat 25 percent fewer calories per day than they had regularly consumed before the study. Although they did not meet this target, they reduced their daily caloric intake by 12 percent and maintained, on average, a 10 percent loss in body weight over 2 years. A follow-up study 2 years after the intervention ended found that participants had sustained much of this weight loss.

It’s important to note that calorie-restriction regimens are not starvation diets. The weight loss achieved with calorie restriction in the CALERIE trial resulted in body weights within the normal or overweight range.

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Compared to participants in the control group, those in the calorie-restriction group had reduced risk factors (lower blood pressure and lower cholesterol) for age-related diseases such as diabetes, heart disease, and stroke. They also showed decreases in some inflammatory factors and thyroid hormones.

There is some evidence that lower levels of these measures are associated with longer lifespan and diminished risk for age-related diseases. Moreover, in the calorie-restricted individuals, no adverse effects (and some favorable ones) were found on quality of life, mood, sexual function, and sleep.

The calorie-restriction intervention did cause slight declines in bone density, lean body mass, and aerobic capacity (the ability of the body to use oxygen during exercise). However, these declines were generally no more than expected based on participants’ weight loss. Other short-term studies have found that combining physical activity with calorie restriction protects against losses of bone, muscle mass, and aerobic capacity.

Some CALERIE participants also experienced brief episodes of anemia (diminished number of circulating red blood cells that carry oxygen through the body). Overall, these findings indicate that while the degree of calorie restriction in CALERIE is safe for normal-weight or moderately obese people, clinical monitoring is recommended.

If you want to reduce levels of inflammation throughout your body, delay the onset of age-related diseases, and live longer, eat less food. That’s the conclusion of a new study by scientists from the US and China that provides the most detailed report to date of the cellular effects of a calorie-restricted diet in rats.

While the benefits of caloric restriction have long been known, the new results show how this restriction can protect against aging in cellular pathways, as detailed in Cell.

“We already knew that calorie restriction increases life span, but now we’ve shown all the changes that occur at a single-cell level to cause that,”

says Juan Carlos Izpisua Belmonte, a senior author of the new paper, professor in Salk’s Gene Expression Laboratory and holder of the Roger Guillemin Chair.

“This gives us targets that we may eventually be able to act on with drugs to treat aging in humans.”

Aging is the highest risk factor for many human diseases, including cancer, dementia, diabetes and metabolic syndrome. Caloric restriction has been shown in animal models to be one of the most effective interventions against these age-related diseases. And although researchers know that individual cells undergo many changes as an organism ages, they have not known how caloric restriction might influence these changes.

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Watch the full video below

In the new paper, Belmonte and his collaborators including three alumni of his Salk lab who are now professors running their own research programs in China compared rats who ate 30 percent fewer calories with rats on normal diets. The animals’ diets were controlled from age 18 months through 27 months. (In humans, this would be roughly equivalent to someone following a calorie-restricted diet from age 50 through 70.)

At both the start and the conclusion of the diet, Belmonte’s team isolated and analyzed a total of 168,703 cells from 40 cell types in the 56 rats. The cells came from fat tissues, liver, kidney, aorta, skin, bone marrow, brain and muscle. In each isolated cell, the researchers used single-cell genetic-sequencing technology to measure the activity levels of genes. They also looked at the overall composition of cell types within any given tissue. Then, they compared old and young mice on each diet.

Many of the changes that occurred as rats on the normal diet grew older didn’t occur in rats on a restricted diet; even in old age, many of the tissues and cells of animals on the diet closely resembled those of young rats. Overall, 57 percent of the age-related changes in cell composition seen in the tissues of rats on a normal diet were not present in the rats on the calorie restricted diet.

“This approach not only told us the effect of calorie restriction on these cell types, but also provided the most complete and detailed study of what happens at a single-cell level during aging,”

says co-corresponding author Guang-Hui Liu, a professor at the Chinese Academy of Sciences.

Some of the cells and genes most affected by the diet related to immunity, inflammation and lipid metabolism. The number of immune cells in nearly every tissue studied dramatically increased as control rats aged but was not affected by age in rats with restricted calories. In brown adipose tissue one type of fat tissue a calorie-restricted diet reverted the expression levels of many anti-inflammatory genes to those seen in young animals.

“The primary discovery in the current study is that the increase in the inflammatory response during aging could be systematically repressed by caloric restriction”

says co-corresponding author Jing Qu, also a professor at the Chinese Academy of Sciences.

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When the researchers homed in on transcription factors essentially master switches that can broadly alter the activity of many other genes that were altered by caloric restriction, one stood out. Levels of the transcription factor Ybx1 were altered by the diet in 23 different cell types. The scientists believe Ybx1 may be an age-related transcription factor and are planning more research into its effects.

People say that ‘you are what you eat,’ and we’re finding that to be true in lots of ways,” says Concepcion Rodriguez Esteban, another of the paper’s authors and a staff researcher at Salk. “The state of your cells as you age clearly depends on your interactions with your environment, which includes what and how much you eat.”

The team is now trying to utilize this information in an effort to discover aging drug targets and implement strategies towards increasing life and health span.

Other researchers on the study were Shuai Ma, Shuhui Sun, Lingling Geng, Moshi Song, Wei Wang, Yanxia Ye, Qianzhao Ji, Zhiran Zou, Si Wang and Qi Zhou of the Chinese Academy of Sciences; Xiaojuan He, Wei Li, Piu Chan and Weiqi Zhang of Xuanwu Hospital Capital Medical University; Xiao Long of Peking Union Medical College Hospital; and Guoji Guo of Zhejiang University School of Medicine.

The work and researchers involved were supported by grants from the National Key Research and Development Program of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Commission of Health and Family Planning, Advanced Innovation Center for Human Brain Protection, the State Key Laboratory of Membrane Biology, the Moxie Foundation, and the Glenn Foundation.

Sources National institute of aging

Salk Institute

Get the full research paper here

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