Amid much speculation and research about how our genetics affect the best way we age, a University of California, Berkeley, study now shows that individual differences in our DNA matter less as we grow old and develop into liable to diseases of aging, reminiscent of diabetes and cancer.

In a study of the relative effects of genetics, aging and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are much more essential than genetic variation in affecting the expression profiles of lots of our genes as we grow old. The extent at which genes are expressed -; that’s, ratcheted up or down in activity -; determines the whole lot from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

How do your genetics -; what you bought out of your sperm donor and your egg donor and your evolutionary history -; influence who you’re, your phenotype, reminiscent of your height, your weight, whether or not you could have heart disease?. There’s been an enormous amount of labor done in human genetics to know how genes are turned on and off by human genetic variation. Our project got here about by asking, ‘How is that influenced by a person’s age?’ And the primary result we found was that your genetics actually matter less the older you get.”

Peter Sudmant, UC Berkeley assistant professor of integrative biology and member of Center for Computational Biology

In other words, while our individual genetic makeup may also help predict gene expression after we are younger, it’s less useful in predicting which genes are ramped up or down after we’re older -; on this study, older than 55 years. Similar twins, for instance, have the identical set of genes, but as they age, their gene expression profiles diverge, meaning that twins can age much in a different way from one another.

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.

“Just about all human common diseases are diseases of aging: Alzheimer’s, cancers, heart disease, diabetes. All of those diseases increase their prevalence with age,” he said. “Massive amounts of public resources have gone into identifying genetic variants that predispose you to those diseases. What our study is showing is that, well, actually, as you grow old, genes sort of matter less on your gene expression. And so, perhaps, we have to be mindful of that after we’re attempting to discover the causes of those diseases of aging.”

Sudmant and his colleagues reported their results this week within the journal Nature Communications.

Medawar’s hypothesis

The findings are consistent with Medawar’s hypothesis: Genes which might be turned on after we are young are more constrained by evolution because they’re critical to creating sure we survive to breed, while genes expressed after we reach reproductive age are under less evolutionary pressure. So, one would expect so much more variation in how genes are expressed later in life.

“We’re all aging in other ways,” Sudmant said. “While young individuals are closer together when it comes to gene expression patterns, older individuals are further apart. It’s like a drift through time as gene expression patterns develop into an increasing number of erratic.”

This study is the primary to have a look at each aging and gene expression across such a wide selection of tissues and individuals, Sudmant said. He and his colleagues built a statistical model to evaluate the relative roles of genetics and aging in 27 different human tissues from nearly 1,000 individuals and located that the impact of aging varies widely -; greater than twentyfold -; amongst tissues.

“Across all of the tissues in your body, genetics matters concerning the same amount. It doesn’t seem to be it plays more of a task in a single tissue or one other tissue,” he said. “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 also found that Medawar’s hypothesis doesn’t hold true for all tissues. Surprisingly, in five sorts of tissues, evolutionary essential genes were expressed at higher levels in older individuals.

“From an evolutionary perspective, it’s counterintuitive that these genes ought to be getting turned on, until you’re taking an in depth take a look at these tissues,” Sudmant said. These five tissues occur to be those that continuously turn over throughout our lifespan and in addition produce essentially the most cancers. Each time these tissues replace themselves, they risk making a genetic mutation that may result in disease.

“I assume this tells us a bit bit concerning the limits of evolution,” he said. “Your blood, as an example, all the time has to proliferate so that you can live, and so these super-conserved, very essential genes must be turned on late in life. That is problematic since it implies that those genes are going to be vulnerable to getting somatic mutations and getting turned on without end in a nasty, cancerous way. So, it sort of gives us a bit little bit of a perspective on what the constraints of living are like. It puts bounds on our ability to maintain living.”

Sudmant noted that the study not directly indicates the effect on aging of 1’s environment, which is the impact of the whole lot apart from age and genetics: the air we breathe, the water we drink, the food we eat, but additionally our levels of physical exertion. Environment amounts to as much as a 3rd of gene expression changes with age.

Sudmant is conducting similar analyses of the expressed genes in several other organisms -; bats and mice -; to see how they differ and whether the differences are related to those animals’ different lifespans.

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.

Source:

University of California – Berkeley

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.