In Rats, Calorie Restriction Started in Later Life Prevents Many Age-Related Changes in Gene Expression
Researchers here apply modern genomics approaches to assessing the ability of calorie restriction to slow the progression of aging. As is usually the case, beyond greater understanding of the complexities of the metabolic response to calorie restriction, the goal is to find potential points of intervention that have as yet gone unremarked. Single genes where expression might be changed in order to mimic some fraction of the response to a lower calorie intake. Taken more broadly, exploration that might lead to the development of novel calorie restriction mimetics represents a sizable fraction of all present work on intervention in the aging process. It isn't clear that it merits that much of a focus, given that the practice of calorie restriction doesn't have anywhere near the same size of effect in long-lived species such as our own as is the case in short-lived species such as the rats used here.
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 a new paper, researchers 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, the researchers 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. 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.
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.
Link: https://www.salk.edu/news-release/eat-less-live-longer/