What is more important in determining how we age? Research shows that age often plays a greater role than genetics in gene expression and susceptibility to disease

Amid much speculation and research about how our genetics affect the way we age, a study from the University of California, Berkeley, now shows that individual differences in our DNA matter less as we age and become more susceptible to it. aging diseases, such as diabetes and cancer.

In a study examining the relative effects of genetics, aging and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are far more important than genetic variation in influencing the expression profiles of many of our genes as we age. older. The level at which genes are expressed—that is, up or down in activity—determines everything from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

“How do your genetics — what you got from your sperm donor and your egg donor and your evolutionary history — influence who you are, your phenotype, like your height, your weight, whether or not you have heart disease?” said Peter Sudmant, assistant professor of integrative biology at UC Berkeley and a member of the campus’s Center for Computational Biology. “A huge amount of work has been done in human genetics to understand how genes are turned on and off by human genetic variation. Our project came about by asking, ‘How is that affected by a person’s age?’ And the first result we found was that your genetics actually matter less as you get older.”

In other words, while our individual genetic makeup can help predict gene expression when we’re younger, it’s less helpful in predicting which genes increase or decrease as we age — over 55 years of age in this study. For example, identical twins have the same set of genes, but as they age, their gene expression profiles diverge, meaning twins can age very differently from each other.

The findings have implications for efforts to correlate diseases of aging with genetic variation in humans, Sudmant said. Such studies should perhaps focus less on genetic variants that affect gene expression in pursuit of drug targets.

“Almost all common human diseases are diseases of old age: Alzheimer’s, cancers, heart disease, diabetes. All of these diseases increase in prevalence with age,” he said. “Huge amounts of public resources have gone into identifying genetic variants that predispose you to these diseases. What our study shows is that, well, actually, as you get older, genes matter less to your gene expression. And so, perhaps, we need to be aware of that as we try to identify the causes of these aging diseases.”

Sudman and his colleagues reported their results in the journal this week nature communication.

The Medawar . Hypothesis

The findings are consistent with Medawar’s hypothesis: genes activated when we are young are more constrained by evolution because they are critical to ensuring we survive to reproduce, while genes expressed after we have reached reproductive age are under less evolutionary pressure. So you would expect a lot more variation in how genes are expressed later in life.

“We all age in different ways,” Sudmant said. “While young individuals are closer together in terms of gene expression patterns, older individuals are further apart. It’s like a drift through time as gene expression patterns become more and more erratic.”

This study is the first to look at both aging and gene expression in such a wide variety of tissues and individuals, Sudmant said. He and his colleagues built a statistical model to assess the relative roles of genetics and aging in 27 different human tissues from nearly 1,000 individuals and found that the impact of aging varies widely — more than twenty-fold — between tissues.

“Across all tissues in your body, genetics is about equally important. It doesn’t seem to play a role more in one tissue or the other,” he said. “But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, adipose tissue, age plays a much stronger role than your genetics in driving your gene expression patterns.”

Sudmant and colleagues also found that Medawar’s hypothesis does not hold for all tissues. Surprisingly, in five types of tissues, evolutionarily important genes were expressed at higher levels in older individuals.

“From an evolutionary perspective, it’s counterintuitive that these genes have to be switched on, until you get a closer look at these tissues,” Sudmant said. These five tissues are the tissues that constantly change during our lifetime and also cause the most cancers. Each time these tissues replace themselves, they run the risk of creating a genetic mutation that can lead to disease.

“I think this tells us a little bit about the limits of evolution,” he said. “For example, your blood always has to multiply in order to live, and so these super-preserved, very important genes have to be turned on late in life. This is problematic because it means those genes will be prone to get somatic mutations and get excited forever.” in a bad, cancerous way. So it gives us a bit of a perspective on what the limitations of life are like. It puts limits on our ability to continue living.”

Sudmant noted that the study indirectly indicates the effect on aging of a person’s environment, which is the impact of everything but age and genetics: the air we breathe, the water we drink, the food we eat, as well as our level of exercise. The environment accounts for up to a third of changes in gene expression with age.

Sudmant is conducting similar analyzes of the expressed genes in several other organisms — bats and mice — to see how they differ and whether the differences are related to the different lifespans of these animals.

UC Berkeley graduate students Ryo Yamamoto and Ryan Chung are co-first authors of the paper. Other co-authors include Juan Manuel Vazquez, Huanjie Sheng, Philippa Steinberg, and Nilah Ioannidis. The work was supported by the National Institute of General Medical Sciences (R35GM142916) of the National Institutes of Health.

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