Cells, environment and aging: finding the connections

Stanford researchers find key differences in younger and older people’s immune cells, noting more diversity with age that goes beyond genetics

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STANFORD, Calif.—A recent news release/article on the Stanford University website notes that discoveries by Stanford University School of Medicine researchers could possibly go a long way toward explaining why older people’s immune systems often don’t work so well, why different people’s immune systems age at different rates and why the environment matters more than heredity in generating these age-related differences. The findings were published April 26 in the journal Cell.
The researchers believe these insights could lead to new ways of dealing with age-related disease and possibly mediating the aging process itself in some ways.
In treading this path, the Stanford scientists made use of mass cytometry technology that quickly and accurately determines which proteins single cells are being instructed by the body to produce, as well as the degree to which individual cells of the same type receive alternate instructions. The researchers analyzed hundreds of millions of immune cells one by one and discovered that older people’s immune cells get, as the Stanford website article notes, “a fuzzier set of marching orders than do those of younger people.”
The scientists focused on chemical marks affixed to proteins called histones, which closely associate with DNA in the cell nuclei of all living creatures that aren’t bacteria or closely related one-celled organisms. As Stanford notes, it is known that these so-called epigenetic marks “are more than mere graffiti.”
More pointedly, “They’re instructions rendering stretches of DNA—and the genes residing in those stretches—alternatively accessible or off-limits to the massive mobile molecular machines that read our genes. Ultimately, they orchestrate the production of the proteins our genes encode,” said Dr. P.J. Utz, a professor of immunology and rheumatology at the Stanford med school who shares senior authorship of the study with Dr. Purvesh Khatri, an assistant professor of biomedical informatics and of biomedical data science, and basic life-sciences research associate Dr. Alex Kuo. Lead authorship is shared by basic life-sciences research associate Dr. Peggie Cheung and postdoctoral scholar Dr. Francesco Vallania.
As the researchers note, although virtually every cell in our bodies contains the same DNA, any one person’s skin cells, fat cells and nerve cells differ can vastly from one another in their protein content and, therefore, in their function. Stanford’s communications and public affairs office points out that “by specifying which genes are to be active or quiescent, the constellation of epigenetic marks along a cell’s DNA largely directs and defines the cell’s overall behavior.”
These marks, moreover, are in flux, Stanford notes; unlike genes, which don’t change much, these marks “can be rapidly affixed to or expunged from histones upon a cell’s exposure to pathogens, nutrients, growth factors or hormones, or upon changes in the cell’s internal state — for example, when it’s time for the cell to undergo division, or as the cell ages.” And so any given cell’s protein output, along with its current “work agenda,” changes in response.
“Barring the odd mutation or some fraying of the tips of your chromosomes, your DNA stays essentially the same as you get older,” said Khatri. “But while for the most part our genes don’t change much as we age, how active each of them is can change quite considerably in either direction over time.”
The white blood cells that are a hallmark of the immune systems, as a result, show significant changes in gene-activation levels as the body ages and, as Khatri notes, our immune system usually doesn’t work as well as we age compared to our younger years.
“The immune system plays a prominent role in all kinds of diseases,” he said. “By focusing too heavily on genetics, we’re ignoring the implications of human immunology and environmental influences that act on it.”
The Stanford team hypothesized that aging-related changes in immune cells’ genes might arise from flux in the pattern of epigenetic marks on the cells’ histones. They set out to determine whether and how much, for any given immune cell type, these patterns diverged between different people or between different individual cells of the same type in any single person’s blood.
For the study, Kuo and Cheung spent more than a year designing “molecular barcodes” that would permit mass cytometry to specify the amounts of each of 40 different types of epigenetic marks and 30 additional identifying features in 22 different immune cell types, and more than another year conducting experiments with them. In all, the ensuing experiments generated some 21.7 billion data points. Vallania devised the specialized techniques for analyzing this otherwise overwhelming wealth of information.
The researchers found that for many of the immune-cell types, older peoples’ cells on average carried substantially more histone marks than those of younger ones. In addition, older people showed more cell-to-cell variation in how much their histones were marked up than did younger people.
Then, to assess environmental versus genetic influences on histone marking patterns, the researchers obtained blood samples from identical and fraternal twin pairs. Identical twins share the same DNA sequences. They also share a common intrauterine environment, and, if raised together, reasonably similar childhood environments; fraternal twins, although their DNA is no more similar than that of typical siblings, share their intrauterine and, if raised together, childhood environments.
Histone-marking patterns between older identical twins diverged substantially more from one another than those in younger twin pairs. The differences between older identical twins were effectively equal to the differences between genetically unrelated people. Data analysis indicated that the observed histone-mark divergence among older people comes from nonheritable factors: food, sleep, exercise, infections, our jobs, what city we live in and other sources of physical or psychological stress and relief that act on us throughout our lives.
What does this potentially mean for something like drug discovery and development? Well, as Stanford points out, “Medications targeting the enzymes that affix some histone marks are approved for some cancer indications. Utz and Khatri are now examining histone-marking patterns of other diseases to see if any are characterized by elevated or diminished levels of specific types of marks. They speculate that histone-mark analysis may lead to drugs that, by reversing histone-mark deviations from the healthy state, could treat diseases characterized by those deviations.”

SOURCE: Article/news release by Bruce Goldman, a science writer for the medical school’s Office of Communication & Public Affairs. Content has been edited for posting on the DDNews website. The original story can be found here.

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