Researchers
detect age-related differences in DNA from blood
Researchers have discovered age- and
health-related differences in fragments of DNA found floating in the
bloodstream (not inside cells) called cell-free DNA (cfDNA). These differences could someday be used to determine biological age — whether a person’s body functions as older or younger than their chronological age, the researchers say.
In a proof-of-concept study,
researchers extracted cfDNA from blood samples from people in their 20s, people
in their 70s, and healthy and unhealthy centenarians.
The team led by Nicola Neretti, an assistant professor of molecular biology, cell biology and biochemistry at Brown University, detected differences in how the DNA was packaged in the four groups.
The team led by Nicola Neretti, an assistant professor of molecular biology, cell biology and biochemistry at Brown University, detected differences in how the DNA was packaged in the four groups.
Specifically, they found nucleosomes
— the basic unit of DNA packaging in which a segment of DNA is wrapped around a
protein core — were well-spaced in the DNA of the volunteers in their 20s but
were less regular in the older groups, especially the unhealthy centenarians,
Neretti said.
Additionally, the signal from nucleosome spacing for the healthy centenarians was more similar to the signal from the people in their 20s than people in their 70s.
Additionally, the signal from nucleosome spacing for the healthy centenarians was more similar to the signal from the people in their 20s than people in their 70s.
Nucleosome packing is one aspect of
the epigenome — the collection of heritable changes that affect gene expression
or activity without affecting the DNA sequence, or genome
“Among other traits, healthy centenarians
preserve the epigenomic profile of younger individuals,” Neretti said.“
As with anything in aging, many things work together, and it is not clear what the cause or the effect is. With our cfDNA test, we hope to gain understanding of these epigenetic changes and what they mean.”
As with anything in aging, many things work together, and it is not clear what the cause or the effect is. With our cfDNA test, we hope to gain understanding of these epigenetic changes and what they mean.”
Message in a bottle
Scientists first found cfDNA in the
blood of cancer patients, and the fragments can be useful for diagnosing
cancer. Earlier research has found that cfDNA is produced by dying cells, and
as the cells die, the DNA is cut in between nucleosomes, Neretti said.
The team at Brown used next-generation
sequencing of the cfDNA combined with complex computational analysis to
reconstruct the pattern of nucleosome spacing in different regions of the
genome — both areas that are typically open for expressing genes as well as
areas that are normally tightly packed.
The cfDNA extraction and sequencing processes were developed in collaboration with Ana Maria Caetano Faria from the Universidade Federal de Minas Gerais in Brazil.
The cfDNA extraction and sequencing processes were developed in collaboration with Ana Maria Caetano Faria from the Universidade Federal de Minas Gerais in Brazil.
“cfDNA is somewhat like a message in
a bottle that captures what the cell looked like, epigenetically speaking,
before it died,” Neretti said.
“A lot of cellular machinery is involved in maintaining nucleosome spacing, and these components can go downhill as you age. The nucleosomes don’t move apart or become more dense themselves. The nucleosome spacing is just the read-out of the changes of that machinery.”
“A lot of cellular machinery is involved in maintaining nucleosome spacing, and these components can go downhill as you age. The nucleosomes don’t move apart or become more dense themselves. The nucleosome spacing is just the read-out of the changes of that machinery.”
However, he added, changes in
nucleosome packing produce changes in the accessibility of different parts of
the genome, which leads to even more things going awry, including the freeing
of normally locked-down genetic elements called transposons.
The team did detect a reduction in
cfDNA signals at the beginning of two common transposons with increasing age.
This suggests that these transposons are less locked-down in the unhealthy
centenarians and people in their 70s and thus more likely to be “copying and
pasting” themselves into the genome, causing genetic mayhem.
Future work
The study only analyzed the cfDNA of
12 individuals from Bologna, Italy — three from each group.
The samples were collected by collaborator Claudio Franceschi, from the University of Bologna. A larger study is needed to gain the information necessary to use these epigenetic markers to predict biological age, Neretti said.
However, because the cfDNA test uses easy-to-collect blood instead of invasive tissue samples, he thinks it will be straightforward to expand the proof-of-concept study.
The samples were collected by collaborator Claudio Franceschi, from the University of Bologna. A larger study is needed to gain the information necessary to use these epigenetic markers to predict biological age, Neretti said.
However, because the cfDNA test uses easy-to-collect blood instead of invasive tissue samples, he thinks it will be straightforward to expand the proof-of-concept study.
“Ideally, you would like to track a
population of individuals over 20 or 30 years to see how each individual’s
epigenome changes, and the rate of change, as they age,” he said. A large study
could allow the association of epigenomic differences with health conditions,
lifestyles or diets, he added.
Meanwhile, the research team is
refining the test.
They are working to optimize the
process of extracting cfDNA from blood. In mice, they can reliably get the
amount of cfDNA they need from a quarter teaspoon of blood.
Neretti thinks that they don’t need to sequence the whole genome to detect the age- and health-related epigenetic changes. For this study, they did whole-genome sequencing, but he expects that sequencing 2 to 5 percent of the genome could be sufficient.
Neretti thinks that they don’t need to sequence the whole genome to detect the age- and health-related epigenetic changes. For this study, they did whole-genome sequencing, but he expects that sequencing 2 to 5 percent of the genome could be sufficient.
In addition to refining the
nucleosome positioning analysis, the researchers would like to study another
kind of epigenetic marker — DNA methylation patterns — in the cfDNA, Neretti
said. This would provide additional information, including markers that can
indicate what tissue the cfDNA came from. Determining the sources of cfDNA at
different ages — or what tissues are experiencing a lot of cell death — could
provide insights into the aging process.
Better understanding the epigenetic
changes of the aging process could aid in developing treatments
for age-associated disorders or someday be used to determine whether your
body is aging faster or slower than typical, Neretti added.
The first author of the paper was
Yee Voan Teo, a doctoral student in molecular biology, cell biology
and biochemistry at Brown.In addition to Faria and Franceschi, other authors on
the paper include Miriam Capri, Cristina Morsiani and Grazia Pizza from the
University of Bologna.
The National Institutes of Health
(grant R01-AG050582) and the Brown-Brazil Collaborative Research Fund (grant
GFT640009) supported the research.