Researchers detect age-related differences in DNA from blood

December 20, 2018

PROVIDENCE, R.I. [Brown University] -- 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 findings were published on Friday, Dec. 21, in the journal Aging Cell.

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.

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."

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.

"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."

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.

"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.

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.
-end-
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.

Brown University

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.