Age vs Genetics: What’s More Important in Determining How We Age? Study shows age often plays a bigger role than genetics in gene expression and susceptibility to disease

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, their activity is increased or decreased—determines everything from our hormone levels and metabolism to mobilizing enzymes that repair the body.

“How does your genetics – what you received 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, assistant professor of integrative science Biology at UC Berkeley and a member of the campus’s Center for Computational Biology. “A lot of 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.”

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 will be turned up or down when we’re older—greater than 55 in this study. 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 between tissues – more than 20-fold.

“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 has 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 little perspective on what life’s limitations are like. 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 is the influence of everything but age and genetics: the air we breathe, the water we drink, the food we eat 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.