How caloric restriction prevents negative effects of aging in cells

Peas on plate, dieting concept (stock image).

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 on February 27, 2020.

"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.

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.

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.

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Materials provided by Salk Institute. Note: Content may be edited for style and length.

Daily exposure to blue light may accelerate aging, even if it doesn't reach your eyes

Woman looking at blue light from at computer screen 

Prolonged exposure to blue light, such as that which emanates from your phone, computer and household fixtures, could be affecting your longevity, even if it's not shining in your eyes.

New research at Oregon State University suggests that the blue wavelengths produced by light-emitting diodes damage cells in the brain as well as retinas.

The study, published today in Aging and Mechanisms of Disease, involved a widely used organism, Drosophila melanogaster, the common fruit fly, an important model organism because of the cellular and developmental mechanisms it shares with other animals and humans.

Jaga Giebultowicz, a researcher in the OSU College of Science who studies biological clocks, led a research collaboration that examined how flies responded to daily 12-hour exposures to blue LED light -- similar to the prevalent blue wavelength in devices like phones and tablets -- and found that the light accelerated aging.

Flies subjected to daily cycles of 12 hours in light and 12 hours in darkness had shorter lives compared to flies kept in total darkness or those kept in light with the blue wavelengths filtered out. The flies exposed to blue light showed damage to their retinal cells and brain neurons and had impaired locomotion -- the flies' ability to climb the walls of their enclosures, a common behavior, was diminished.

Some of the flies in the experiment were mutants that do not develop eyes, and even those eyeless flies displayed brain damage and locomotion impairments, suggesting flies didn't have to see the light to be harmed by it.

"The fact that the light was accelerating aging in the flies was very surprising to us at first," said Giebultowicz, a professor of integrative biology. "We'd measured expression of some genes in old flies, and found that stress-response, protective genes were expressed if flies were kept in light. We hypothesized that light was regulating those genes. Then we started asking, what is it in the light that is harmful to them, and we looked at the spectrum of light. It was very clear cut that although light without blue slightly shortened their lifespan, just blue light alone shortened their lifespan very dramatically."

Natural light, Giebultowicz notes, is crucial for the body's circadian rhythm -- the 24-hour cycle of physiological processes such as brain wave activity, hormone production and cell regeneration that are important factors in feeding and sleeping patterns.

"But there is evidence suggesting that increased exposure to artificial light is a risk factor for sleep and circadian disorders," she said. "And with the prevalent use of LED lighting and device displays, humans are subjected to increasing amounts of light in the blue spectrum since commonly used LEDs emit a high fraction of blue light. But this technology, LED lighting, even in most developed countries, has not been used long enough to know its effects across the human lifespan."

Giebultowicz says that the flies, if given a choice, avoid blue light.

"We're going to test if the same signaling that causes them to escape blue light is involved in longevity," she said.

Eileen Chow, faculty research assistant in Giebultowicz's lab and co-first author of the study, notes that advances in technology and medicine could work together to address the damaging effects of light if this research eventually proves applicable to humans.

"Human lifespan has increased dramatically over the past century as we've found ways to treat diseases, and at the same time we have been spending more and more time with artificial light," she said. "As science looks for ways to help people be healthier as they live longer, designing a healthier spectrum of light might be a possibility, not just in terms of sleeping better but in terms of overall health."

In the meantime, there are a few things people can do to help themselves that don't involve sitting for hours in darkness, the researchers say. Eyeglasses with amber lenses will filter out the blue light and protect your retinas. And phones, laptops and other devices can be set to block blue emissions.

"In the future, there may be phones that auto-adjust their display based on the length of usage the phone perceives," said lead author Trevor Nash, a 2019 OSU Honors College graduate who was a first-year undergraduate when the research began. "That kind of phone might be difficult to make, but it would probably have a big impact on health."

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Materials provided by Oregon State University. Original written by Steve Lundeberg. Note: Content may be edited for style and length.