In a study to be published in Cell, 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.
It's known that these so-called epigenetic marks are more than mere graffiti. "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 co- senior author said.
The numerous types of white blood cells in our immune systems show marked changes in gene-activation levels as we age. We also know that as we age, our immune system usually doesn't work so well, another co-senior noted.
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.
To make these determinations, the scientists modified a technique called mass cytometry. This method allows multiple features of a single cell to be characterized simultaneously as specialized molecular barcodes that have been attached to it strike a detector, revealing not only the cell's identity but also its state -- for example, immature versus mature, or activated versus quiescent. The cells are incinerated and their remains flung at a detector in rapid-fire sequence. Although the cells themselves have gone up in smoke, their incombustible barcodes hit the detector and are identified and catalogued. In this way, the individual identities and states of huge numbers of cells can be quickly ascertained.
The researchers found that for many of the immune-cell types, older people's cells bore, on average, 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.
Medications targeting the enzymes that affix some histone marks are approved for some cancer indications. The authors 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.
Older people's immune system diverge more
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