Age vs. Genetics: Which Matters More in How You Age?

People age differently, including former presidents. Ronald Reagan developed Alzheimer’s disease in the late 80s and died of complications from the disease at age 93. Franklin Roosevelt, shown at 62, died of a cerebral hemorrhage at age 63. Jimmy Carter, introduced in 2019 at the age of 95, suffered from cancer, but is now 98 years old and still active. Our genetics, our environment and our age all play an important role in our health, but which one is the most important? A new study at UC Berkeley shows that in many cases, age plays a more important role than genetics in determining which genes in our bodies are turned on or off, affecting our susceptibility to disease.

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

In a study of the relative effects of genetics, aging, and the environment on how about 20,000 human genes are expressed, researchers found that aging and the environment are far more important than genetic variation in influencing the expression profiles of many of our genes. Earlier. 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 does your genetics — what you got from your sperm donor and your egg donor and your evolutionary history — affect who you are, your phenotype, like your height, your weight, whether or not you have heart disease?” said Peter Sudmant, an assistant professor of integrative biology at UC Berkeley and a member of the campus’ Center for Computational Biology. “Immense work has been done in human genetics to understand how genes are turned on and off by human genetic variation. Our work came about by asking, “How is this affected by a person’s age?” And the first result we found was that your genetics actually matters 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 useful at predicting which genes go up or down when we’re older—in this study, over age 55. Identical twins, for example, have the same set of genes, but as they grow older, their gene expression profiles diverge, meaning the twins can age very differently from each other.

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

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

Sudmant and his colleagues reported their results this week in the journal Nature communications.

The case of Medawar

The findings are consistent with Medawar’s hypothesis: Genes that turn on when we’re young are more constrained by evolution because they’re critical to ensuring we survive to reproduce, while genes that are expressed after we reach reproductive age are under less evolutionary pressure. Thus, one would expect much more variation in how genes are expressed later in life.

diagram showing the effects of aging

The relative importance of genetics and age in the control of gene expression as a function of evolutionary constraints. Genes further to the right along the x-axis are more evolutionarily “constrained” and therefore more likely to be important in human disease. (Image: Peter Sudmant, UC Berkeley)

“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 shift in time as patterns of gene expression become more and more unstable.”

This study is the first to examine both aging and gene expression in such a wide variety of tissues and individuals, Sudmant said. He and his colleagues created 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 twentyfold—between tissues.

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

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

“From an evolutionary perspective, it’s inconceivable that these genes should be turned on, until you take a close look at these tissues,” Sudmant said. These five tissues happen to be the ones that constantly turn over throughout our lives and also produce the most cancers. Every time these tissues are replaced, they risk creating a genetic mutation that can lead to disease.

“I guess that tells us a little bit about the limits of evolution,” he said. “Your blood, for example, must always be multiplying to live, and so these highly conserved, very important genes must be activated late in life. This is problematic because it means that these genes will be prone to somatic mutations and will forever be turned on in a bad, cancerous way. So it gives us a little perspective on what the limitations of life are like. It puts limits on our ability to continue living.”

Sudmant noted that the study indirectly shows the effect on aging of one’s environment, which is the effect of everything besides age and genetics: the air we breathe, the water we drink, the food we eat, but also our levels of physical activity. us exercise. Environment accounts for up to one-third of gene expression changes with age.

Sudmant is conducting similar analyzes of gene expression in several other organisms—bats and mice—to see how they differ and whether the differences relate to the different lifespans of these animals.

UC Berkeley graduate students Ryo Yamamoto and Ryan Chung are first authors of the paper. Other co-authors are 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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