If you want to decrease levels of inflammation throughout your body, delay the commencement of age-related diseases, and live longer, maintain your diet. That’s the outcome of a new study by scientists from China and the US that provides the most comprehensive report till now of the cellular effects of a calorie-restricted diet in rats. Though the benefits of caloric restriction have always been known, the new results proved how this restriction can defend against aging in cellular pathways, as described in Cell on February 27, 2020.
“We already knew that calorie restriction increases age span, but now we’ve shown all the changes that happen at a single-cell level to cause that,” says Juan Carlos Izpisua Belmonte, a senior author of the new paper, instructor in Salk’s Gene Expression Laboratory and possessor of the Roger Guillemin Chair. “This gives us goals that we may ultimately be able to act on with medications to treat aging in humans.”
Aging is the greatest risk factor for many human diseases, including dementia, cancer, diabetes and metabolic syndrome. Caloric restriction has been presented in animal models to be one of the most effective intrusions against these age-related diseases. And though researchers know that individual cells endure many changes as an organism ages, they have not known how caloric restriction might impact these changes.
In the new research paper, Belmonte and his associates — including three graduates of his Salk lab who are presently professors running their research programs in China — compared rats who had 30 percent lesser calories with rats on normal diets. The animals’ diets were regulated from age 18 months to 27 months. (In humans, this would be approximately equivalent to somebody following a calorie-restricted diet from age 50 to 70.)
At both the beginning and the ending of the diet, Belmonte’s team separated and analyzed a sum of 168,703 cells from 40 cell types in the 56 rats. The cells derived from liver, fat tissues, bone marrow, kidney, aorta, skin, brain and muscle. In each separated cell, the researchers used single-cell genetic-sequencing technology to gauge the activity levels of genes. They also looked at the general composition of cell types within any particular tissue. Then, they compared young and old mice on each diet.
Most of the changes that happened as rats on the normal diet grew older didn’t take place in rats on a restricted diet; even in old age, several of the tissues and cells of animals on the diet closely looked like those of young rats. Generally, 57 percent of the age-related changes in cell composition seen in the tissues of rats on a normal diet were not existent in the rats on the calorie restricted diet.
“This method not only conveyed to us the effect of calorie restriction on these cell types, but also offered the most complete and thorough study of what happens at a single-cell level while aging,” says co-corresponding author Guang-Hui Liu, a lecturer at the Chinese Academy of Sciences.
Some of the genes and cells most affected by the diet related to inflammation, immunity and lipid metabolism. The number of immune cells in approximately every tissue studied intensely increased as control rats aged but was not impact by age in rats with limited calories. In brown adipose tissue — one form of fat tissue — a calorie-restricted diet returned the expression levels of several anti-inflammatory genes to those observed in young animals.
“The key discovery in the current study is that the increase in the inflammatory reaction during aging could be systematically suppressed by caloric restriction” says co-corresponding writer Jing Qu, also a lecturer at the Chinese Academy of Sciences.
Once the researchers homed in on transcription factors — basically master switches that can largely change the activity of many other genes — that were changed by caloric restriction, one stood out. Levels of the transcription factor Ybx1 were changed by the diet in 23 diverse cell types. The scientists believe Ybx1 may be an age-related transcription factor and are intending more research into its effects.
“Experts often say that ‘you are what you eat,’ and we’re discovering that to be true in many ways,” says Concepcion Rodriguez Esteban, another of the paper’s authors and a staff investigator at Salk. “The condition of your cells as you age clearly relies on your interactions with your environment, which involves what and how much you eat.”
The team is now trying to use this information in an effort to find aging drug targets and apply strategies towards increasing health and life span.
The work and researchers included were supported by funds from the Natural Science Foundation of China, the National Key Research and Development Program of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, Advanced Innovation Center for Human Brain Protection, Beijing Municipal Commission of Health and Family Planning, Beijing Natural Science Foundation, , the State Key Laboratory of Membrane Biology, the Moxie Foundation, and the Glenn Foundation.