Distinct roles of aging and genetics on expression phenotypes

Research conducted by the University of California, Berkeley, found that individual distinctions in human DNA matter less as people age and become more susceptible to aging disorders like diabetes and cancer.

Distinct roles of aging and genetics on expression phenotypes
People age differently, including former presidents. Ronald Reagan developed Alzheimer’s disease in his late 80s and died from complications of the disease at the age of 93. Franklin Roosevelt, shown at 62, died of a brain hemorrhage at the age of 63. Jimmy Carter, shown in 2019 at the age of 95, has suffered from cancer but is now 98 years old and still active. Genetics, the environment, and age all play important roles in human health, but which of these is the most important? A new UC Berkeley study suggests that in many cases, age plays a more important role than genetics in determining which genes in the human body are turned on or off, influencing the susceptibility to disease. Image Credit: University of California, Berkeley

The scientists found that aging and the environment are significantly more important than genetic diversity in modifying the expression profiles of many of the genes as individuals age in a study of the relative effects of genetics, aging, and the environment on how approximately 20,000 human genes are expressed.

The degree to which genes are expressed—that is, how active they are—impacts everything from hormone levels and metabolism to the mobilization of enzymes that repair human bodies.

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, such as your height, your weight, whether or not you have heart disease. There’s been a huge amount of work 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 influenced by an individual’s age?’ And the first result we found was that your genetics actually matter less the older you get.”

Peter Sudmant, Assistant Professor, Integrative Biology, University of California, Berkeley

Peter Sudmant is also a member of the campus’s Center for Computational Biology.

In other words, while a particular genetic makeup can predict gene expression when individuals are younger, it is less beneficial when they are older—in this case, older than 55 years. Identical twins, for instance, have an identical set of genes, but their gene expression profiles diverge as they age, implying that twins can mature very differently.

The observations have ramifications for efforts to link aging disorders to genetic diversity in humans, according to Sudmant. When investigating drug targets, such research should probably focus less on genetic variations that influence gene expression.

Almost all human common diseases are diseases of aging: Alzheimer’s, cancers, heart disease, diabetes. All of these diseases increase their prevalence with age. Massive amounts of public resources have gone into identifying genetic variants that predispose you to these diseases.”

Peter Sudmant, Assistant Professor, Integrative Biology, University of California, Berkeley

Sudmant adds, “What our study is showing is that, well, actually, as you get older, genes kind of matter less for your gene expression. And so, perhaps, we need to be mindful of that when we’re trying to identify the causes of these diseases of aging.”

The study was published in the journal Nature Communications.

Medawar’s hypothesis

The results are consistent with Medawar’s notion that genes expressed after humans reach reproductive age are under less evolutionary pressure. Genes expressed during infancy are more confined by evolution since they are essential for ensuring that people live to reproduce. As a result, a far greater variety in how genes are expressed later in life is to be expected.

We’re all aging in different ways. 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.”

Peter Sudmant, Assistant Professor, Integrative Biology, University of California, Berkeley

According to Sudmant, this work is the first to examine aging and gene expression in such a broad range of tissues and people. In 27 different human tissues from almost 1,000 individuals, he and his co-workers developed a statistical model to evaluate the relative contributions of genetics and age.

They discovered that the influence of aging varied greatly—by more than 20-fold—among the tissues.

Sudmant explains, “Across all the tissues in your body, genetics matters about the same amount. It doesn’t seem like it plays more of a role in one tissue or another tissue. But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, fat tissue, age plays a much stronger role than your genetics in driving your gene expression patterns.”

Sudmant and colleagues discovered that Medawar’s hypothesis is not applicable to all tissues. Interestingly, significant evolutionary genes were expressed at higher levels in five types of tissues in older people.

Sudmant says, “From an evolutionary perspective, it is counterintuitive that these genes should be getting turned on, until you take a close look at these tissues.”

These five tissues are the ones that regularly turn over throughout life and create the majority of malignancies. Every time these tissues replace themselves, a genetic mutation that might lead to disease is created.

Sudmant details, “I guess this tells us a little bit about the limits of evolution. Your blood, for instance, always has to proliferate 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 that those genes are going to be susceptible to getting somatic mutations and getting turned on forever in a bad, cancerous way. So, it kind of gives us a little bit of a perspective on what the limitations of living are like. It puts bounds on our ability to keep living,” added Sudmant.

According to Sudmant, the research suggests that factors other than age and genetics, including the air, water, food, as well as levels of physical activity, have an influence on aging. Up to one-third of the changes in gene expression with age are caused by the environment.

Similar investigations of the expressed genes in other organisms, including mice and bats, are being carried out by Sudmant to determine how they differ and whether those differences are related to the lifespans of the various species.

Source:
Journal reference:

Yamamoto, R., et al. (2022) Tissue-specific impacts of aging and genetics on gene expression patterns in humans. Nature Communications. doi.org/10.1038/s41467-022-33509-0.

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