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.
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