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.t.
“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.
The illustration represents the ways in which caloric restriction affects various aspects of cellular function, with the overall result of reducing inflammation and the activity of many aging-related genes. The image is credited to Salk Institute.
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.”
Credit: Salk Institute.
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.
Funding: 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.
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 authors report no financial or other conflicts of interest.
Diet restriction has been documented to have a positive effect on the life span of rodents and various invertebrate species. In fact, research spanning more than 60 years has shown that diet restriction is the only nutritional intervention that consistently extends the life span of animals.
In previous studies, diet restriction increased median and maximum life span (ie, survival time of the longest-lived decile) of rodents, despite differences in species, strains, experimental designs, nutritional variables, environmental conditions, and predispositions for naturally occurring causes of death.
To our knowledge, the effect of diet restriction on life span of larger mammals has not been determined. Studies involving the effects of diet restriction on life span of primates are ongoing, but concluding data are not yet available because these species are so long-lived.
Nonetheless, investigators have found that diet restriction does have a mitigating effect on a number of age-related diseases of primates.
Studies of diet restriction and life span also have facilitated evaluation of aging markers that may have value as signals for preventive medical intervention or treatment earlier in life. Markers that have been evaluated in these types of studies include body fat content and serum or plasma concentration of glucose, insulin, triglycerides, cholesterol, and triiodothyronine
In a previous 2-year study8 of the effect of restricted food intake on development of orthopedic disease in Labrador Retrievers, we found that limiting food intake had a beneficial effect on the development of hip joints.
The study subsequently was extended and directed toward determining the effect of diet restriction on the life span of this group of dogs and evaluating potential markers of aging.
Results of this study indicate that diet restriction significantly increased median life span in this group of dogs. To our knowledge, this is the first study to docu- ment that diet restriction increases survival time in mammals larger than rodents. In studies of rodents, diet restriction consistently increased median and maximum life span.
In the present study, median life span was increased by diet restriction, but maximum life span was not significantly different between groups.
The smaller number of subjects in the present study, compared with the numbers in previous rodent studies, may explain the lack of statistical significance between groups in regard to maximum life span, since the 90th percentile estimates from our study involve outcome of just 3 dogs/group. In the present study, diet restriction also was associated with a longer median time to first treatment of osteoarthritis (the most com- mon chronic disease among dogs in this study) and a longer median time to first treatment of any chronic condition.
Lean body mass was significantly higher among dogs in the controlled-feeding group than among dogs in the restricted-feeding group. Reasons for this finding are not resolved by our data, but the difference might relate at least partly to metabolic needs of a greater body mass, as well as to the higher food intake.
Decreases in lean body mass late in life (after 9 years of age among controlled-feeding dogs and after 11 years of age in restricted-feeding dogs) might have been a consequence of deteriorating physiologic function associated with aging or disease, with delayed expres- sion among dogs in the restricted-feeding group. Similar findings with respect to changes in lean body mass have been found in studies of rodents.15
A consistent observation in diet restriction studies, including the present study, has been excessive fat deposition in animals in which diet was not restricted. Even though obesity typically occurs with overfeeding, investigators have demonstrated that longevity of rodents is more closely related to amount of food con- sumption than to degree of adiposity.
Genetically obese and nonobese mice of the same strain were studied to separate the effects of food restriction from the effects of adiposity. Genetically obese food-restricted mice had a mean body weight similar to that of control mice but had 50% more adipose tissue, even though the obese mice were fed a third less. However, the obese food-restricted mice lived longer, indicating that longevity effects were related primarily to food con- sumption.
In the present study, body fat content of dogs in the restricted-feeding group ranged from 12 to 20% of body mass. Mean body condition score for these dogs ranged from 4 to 5, and median time to onset of treatment for osteoarthritis or any chronic condition was significant- ly longer than for dogs in the controlled-feeding group.
An association between high body fat content and increases in incidence and severity of chronic diseases has been reported in other studies.
Lower morbidi- ty rates also have been reported for food-restricted pri- mates with body fat content ranging from 10 to 22%,20 which closely parallels our observations.
Mean serum triglycerides concentration among dogs in the restricted-feeding group was approximately 15% lower than mean concentration among dogs in the controlled-feeding group, which was similar to data reported for rodents and primates.
However, mean serum cholesterol concentration was not significantly different between groups. A decrease in serum choles- terol concentration in response to diet restriction has been demonstrated in primates,3 but responses in rodents have been inconsistent.
The lack of difference between groups in the present study might be explained by the amount of food restriction imposed by the design of our study or by the diet formulation, or it may rep- resent a true species difference. Higher serum total T3 concentration, as found in controlled-feeding dogs in the present study, has been observed in rodents and humans in which food intake was not restricted.
Overfeeding increases deiodination of thyroxine to T3, whereas carbohydrate restriction and weight reduction reduce serum T3 concentration.
The observation that baseline serum glucose and insulin concentrations were significantly lower among dogs in the restricted-feeding group parallels findings of studies involving rodents and primates and suggests commonality in glucose metabolism among rodents, primates, and canines.
The actual caloric intake needed to achieve a desired extension of life span and improved health varies among individual dogs because of high intrinsic variation in caloric requirements both within breeds and within the species as a whole.
Use of DEXA to estimate lean body mass and body fat mass is not practical in pri- vate veterinary practice, and as an alternative, we rec- ommend that for purposes of health and longevity, dogs be fed to maintain a body condition score less than 5.