Mechanism behind calorie restriction, lengthened lifespan uncovered

Almost a century ago, scientists discovered that
cutting calorie intake could dramatically
extend lifespan in certain animal species.
Despite numerous studies since, however,
researchers have been unable to explain
precisely why. Now, investigators at the Lewis
Katz School of Medicine at Temple University
(LKSOM) have broken past that barrier.

In new work published online September 14 in
Nature Communications, they are the first to
show that the speed at which the epigenome
changes with age is associated with lifespan
across species and that calorie restriction slows
this process of change, potentially explaining
its effects on longevity.

“Our study shows that epigenetic drift, which is
characterized by gains and losses in
Deoxyribonucleic Acid (DNA)/genetic material
methylation in the genome over time, occurs
more rapidly in mice than in monkeys and
more rapidly in monkeys than in humans,”
explains Jean-Pierre Issa, MD, Director of the
Fels Institute for Cancer Research at LKSOM,
and senior investigator on the new study. The
findings help to explain why mice live only
about two to three years on average, rhesus
monkeys about 25 years, and humans 70 or 80

Chemical modifications such as DNA
methylation control mammalian genes, serving
as bookmarks for when a gene should be used
– a phenomenon known as epigenetics.
“Methylation patterns drift steadily throughout
life, with methylation increasing in some areas
of the genome, and decreasing in others,” says
Dr. Issa. Previous studies had shown that these
changes occur with age, but whether they were
also related to lifespan was unknown.
Dr. Issa’s team made their discovery after first
examining methylation patterns on DNA in
blood collected from individuals of different
ages for each of three species – mouse,
monkey, and human. Mice ranged in age from
a few months to almost three years, monkeys
from less than one year to 30 years, and
humans from age zero to 86 years (cord blood
was used to represent age zero).

Age-related variations in DNA methylation
were analyzed by deep sequencing technology,
which revealed distinct patterns, with gains in
methylation in older individuals occurring at
genomic sites that were unmethylated in young
individuals, and vice versa.

In subsequent analyses, striking losses in gene
expression were observed in genomic regions
that had become increasingly methylated with
age, whereas regions that had become less
methylated showed increases in gene
expression. Investigation of a subset of genes
affected by age-related changes in methylation
revealed an inverse relationship between
methylation drift and longevity. In other
words, the greater the amount of epigenetic
change – and the more quickly it occurred – the
shorter the species’ lifespan.

“Our next question was whether epigenetic
drift could be altered to increase lifespan,” says
Issa. One of the strongest factors known to
increase lifespan in animals is calorie
restriction, in which calories in the diet are
reduced while still maintaining intake of
essential nutrients. To examine its effects, the
researchers cut calorie intake by 40 percent in
young mice and by 30 percent in middle-aged
monkeys. In both species, significant
reductions in epigenetic drift were observed,
such that age-related changes in methylation in
old animals on the calorie-restricted diets were
comparable to those of young animals.

With the latest findings, Issa and colleagues are
able to propose a new mechanism – the
slowing of epigenetic drift – to explain how
calorie restriction prolongs life in animals.
“The impacts of calorie restriction on lifespan
have been known for decades, but thanks to
modern quantitative techniques, we are able to
show for the first time a striking slowing down
of epigenetic drift as lifespan increases,” he

The findings have important implications in
health research, where recent studies have
suggested that greater amounts of epigenetic
drift increase the risk of age-related diseases,
including cancer. “Our lab was the first to
propose the idea of modifying epigenetic drift
as a way of modifying disease risk,” says Issa.
“But why epigenetic drift occurs faster in some
people and slower in others is still unclear.”
Issa’s team hopes to soon identify additional
factors that impact methylation drift. Such
factors could potentially be altered to slow
drift, having major impacts on age-related
disease prevention. 

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