Age plays a more important role than genetics in influencing gene expression profiles as we age

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

In a study of the relative effects of genetics, aging and environment on the expression of around 20,000 human genes, researchers found that aging and environment are far more important than genetic variation in so affecting the expression profiles of many of our genes as we get older. The level at which genes are expressed -; that is, snapped up or down in activity -; governs everything from our hormone levels and metabolism to mobilizing enzymes that repair the body.

How Do Your Genetics Work -; what you got from your sperm donor and your egg donor and your evolutionary history -; affect who you are, your phenotype, such as B. your height, your weight, whether you have heart disease or not?. Much work has been done in human genetics to understand how genes are turned on and off by human genetic variation. Our project grew out of the question, “How does a person’s age affect that?” And the first finding we found was that your genes are actually less important as you get older.”

Peter Sudmant, UC Berkeley Assistant Professor of Integrative Biology and Fellow of the Center for Computational Biology

In other words, while our individual genetic makeup can help predict gene expression when we’re younger, it’s less useful for predicting which genes are up or down when we’re older -; in this study older than 55 years. Identical twins, for example, have the same genes, but as they age, their gene expression profiles diverge, meaning twins can age very differently.

The findings have implications for efforts to correlate age-related diseases with genetic variation in humans, Sudmant said. Such studies should perhaps focus less on genetic variants affecting gene expression when pursuing drug targets.

“Almost all common human diseases are diseases of old age: Alzheimer’s, cancer, heart disease, diabetes. All of these diseases increase with age,” he said. “Enormous amounts of public funding have been invested in identifying genetic variants that predispose you to these diseases. What our study shows is that as you age, genes are less important to your gene expression. And so perhaps we need to be aware of that as we try to identify the causes of these diseases of old age.”

Sudmant and his colleagues reported their findings in the Journal this week nature communication.

Medawar’s hypothesis

The results are consistent with Medawar’s hypothesis: genes that are activated when we’re young are more constrained by evolution because they’re critical for us surviving to reproduce, while genes that become expressed after we’ve reached reproductive age are exposed to less evolutionary pressure. So one would expect a lot more variation in the way genes are expressed later in life.

“We all age differently,” Sudmant said. “While young people are closer together in terms of gene expression patterns, older people are further apart. It’s like drifting through time as gene expression patterns become 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 created a statistical model to assess the relative roles of genetics and aging in 27 different human tissues from nearly 1,000 people and found that the effects of aging vary widely -; more than twenty times -; under tissues.

“Across all tissues in your body, genetics are about equally important. It doesn’t seem like it plays a major role in one tissue or another,” he said. “But aging varies greatly between different tissues. In your blood, colon, arteries, esophagus, adipose tissue, age plays a much stronger role than genetics in controlling your gene expression patterns.”

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

“From an evolutionary perspective, until you look closely at these tissues, it’s counterintuitive that these genes should be turned on,” Sudmant said. These five tissues are the ones that rotate constantly throughout our lives and also produce most cancers. Each time these tissues replace themselves, they risk creating a genetic mutation that can lead to disease.

“I think that tells us a little bit about the limits of evolution,” he said. “Your blood, for example, always needs to multiply in order for you to live, and so these super-conserved, very important genes have to be turned on late in life. This is problematic because it means these genes will be prone to getting somatic mutations and being turned on in a bad, cancerous way forever. So it gives us a kind of perspective on what the limits of life are. It puts limits on our ability to go on living.”

Sudmant noted that the study indirectly shows the effects of aging on one’s environment, which are the effects of everything but age and genetics: the air we breathe, the water we drink, the food we eat , but also our level of physical activity. The environment accounts for up to a third of the 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 work. 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.