Berkeley universities

What is most important in determining how we age? Study shows age often plays bigger role than genetics in gene expression and susceptibility to disease

Amid much speculation and research about how our genetics affect how 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 prone. diseases of aging, such as diabetes and cancer. .

In a study of the relative effects of genetics, aging and environment on how some 20,000 human genes are expressed, researchers found that aging and environment are far more important than genetic variation in affecting the expression profiles of many of our genes as we evolve. older. The level at which genes are expressed – that is, increased or decreased 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 developmental history – influence who you are, your phenotype, like your height, weight, whether you have or no heart disease? said Peter Sudmant, an assistant professor of integrative biology at UC Berkeley and a member of the campus’ Center for Computational Biology. “There has been an enormous amount of work done in human genetics to understand how genes are turned on and off by human genetic variation. Our project was born out of asking, ‘How is this influenced by the age of a individual?’ And the first result we found is that your genetics 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 go up or down when we’re older – in this study, more than 55 years. Identical twins, for example, 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 impact gene expression when pursuing drug targets.

“Almost all common human diseases are diseases of aging: Alzheimer’s, cancers, heart disease, diabetes. All of these diseases increase in prevalence with age,” he said. “Massive amounts of public resources have been devoted to identifying genetic variants that predispose you to these diseases. What our study shows is that, in fact, as you age, genes matter less to your gene expression. And so, perhaps, we need to take that into account when we try to identify the causes of these diseases of aging.”

Sudmant and his colleagues reported their findings this week in the journal Nature Communication.

The Medawar hypothesis

The results are consistent with Medawar’s hypothesis: genes that are activated when we are young are more evolutionarily limited because they are essential for ensuring our survival and reproduction, while genes expressed after reaching old age to procreate are under less evolutionary pressure. Thus, one would expect much more variation in how genes are expressed later in life.

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

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 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 significantly – more than twenty times – between fabrics.

“In every tissue in your body, genetics matter about the same. It doesn’t seem like it plays a bigger role in one tissue or another,” he said. “But aging is very different between different tissues. In your blood, your colon, your arteries, your esophagus, your fatty tissue, age plays a much bigger role than your genetics in driving your expression patterns. genetic.”

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

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

“I guess that tells us a bit more about the limits of evolution,” he said. “Your blood, for example, still has to proliferate in order for you to live, and so those super-conserved and very important genes have to be turned on late in life. That’s problematic because that means those genes are going to be susceptible to having somatic mutations and getting excited forever in a bad, cancerous way. So that gives us a bit of a perspective on what the limits of life are. It puts limits on our ability to continue living.

Sudmant noted that the study indirectly indicates the effect on aging of one’s environment, which is the impact of something quite different from age and genetics: the air we breathe, the water we drink, the food we eat, but also our levels of physical exercise. Environment accounts for up to a third of gene expression changes with age.

Sudmant is conducting similar analyzes of genes expressed 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 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.