Fertility-Boosting Genes May Shorten Lifespan, Study Says

Genetic mutations that boost fertility may also shrink longevity, according to a new review published in Science Advances on Dec. 8, 2023. The study’s findings strongly support a 1950s evolutionary theory seeking to explain aging.

Under the microscope, we have:

The double-edged sword of genetic mutations, the story behind the study

The downside to evolution, aging as a side effect of natural selection

The paradox, the rise of global life expectancy despite genes that shorten life

The implications, this study’s impact on the science of aging and longevity

What are genetic mutations?

As the human race evolves, so does its DNA. Changes in the sequence of DNA are known as genetic mutations. These mutations, which occur during cell division, can lead to genetic variations, which are differences in gene sequences between individuals and communities of a species.

Variations can be passed from parents to children, empowering natural selection and evolution over time. Genetic changes, i.e., mutations, may produce positive or negative effects on the human body.

Sometimes, they produce both.

Geneticists call this double-edged genetic sword 'pleiotropy,' which holds that a single variation can affect multiple traits. Depending on the situation, one mutation might be both beneficial and harmful to an organism, something known as antagonistic pleiotropy.

In 1957, American evolutionary biologist George Williams applied the idea of antagonistic pleiotropy to longevity, presenting a hypothesis called the antagonistic pleiotropy theory of aging. It remains one of the leading hypotheses for aging, which biologists also call senescence.

Since the 50s, some case studies and data have supported Williams’ theory, but it needed stronger human evidence to boost its validity. This new genetic study on fertility and aging published in Science Advances may have found just what Williams’ decades old hypothesis needed.

Is aging a side effect of evolution?

The University of Michigan-led research team directed by Jianzhi Zhang and Erping Long reviewed genetic, reproductive, and death-registry data from 276,000 European-descent volunteers in the United Kingdom's Biobank database, the world's largest genetic project. Their exhaustive review of the volunteers' genes and health found that lifespan has a genetically negative correlation with reproduction. This means that genetic mutations boosting fertility tend to decrease longevity.

The researchers found more than just a few of these mutations. They found hundreds – each tending to increase fertility in young people while hindering longevity in their older years.

According to the study’s authors, Dr. Zhang and Dr. Long, people with genetic variances promoting reproduction are less likely to live beyond age 76. They found that fertility-boosting genetic mutations grew in prevalence over generations from 1940 to 1969, showing humans continue to evolve and propagate the trait.

Aging appears to be a side effect of evolution. Natural selection over time is picking through genes and choosing mutations that bolster reproduction instead of a long life.

“These results provide strong support for the Williams hypothesis that aging arises as a byproduct of natural selection for earlier and more reproduction. Natural selection cares little about how long we live after the completion of reproduction, because our fitness is largely set by the end of reproduction,” said Zhang, a distinguished professor in the U-M Department of Ecology and Evolutionary Biology.

Biologists use the term fitness to describe characteristics that increase one’s fertility.

In their exhaustive review of the U.K.’s Biobank, Long and Zhang also found that two children may be an ideal number of offspring for general longevity, a finding that supports results from earlier studies, like the Framingham Heart Study.

Having fewer or more kids lowers the lifespan.

Jianzhi Zhang

“Interestingly, we found that when you control for the genetically predicted amount and timing of reproduction, having two kids corresponds to the longest lifespan,” Zhang said.

Global increase in lifespan despite the mutations

Still, contrary to Zhang’s research, human life expectancy has risen steadily worldwide from 46.5 years in 1950 to 73 years in 2023.

Why is life expectancy rising if genetic mutations favor fertility over longevity?

Long and Zhang note that compared to modern improvements, like medical and technological advances, genetic factors hold less influence over lifespan than environmental factors.

“These trends are primarily driven by substantial environmental shifts, including changes in lifestyles and technologies, and are opposite to the changes caused by natural selection of the genetic variants identified in this study,” wrote Long and Zhang.

This contrast indicates that, compared with environmental factors, genetic factors play a minor role in the human phenotypic changes studied here.

Dr. Erping Long and Dr. Jianzhi Zhang

Implications for the science of aging

The antagonistic pleiotropy hypothesis of aging is not new, but scientists have yet to study it in humans sufficiently. With its large sample size, this new study is one important step for understanding aging-related diseases and the power of environmental factors, helping future scientists link genetic variants to health problems in older adults.

For example, research may eventually link genetic mutations to 'inflammaging,' the low-grade chronic inflammation that increases with age. Scientists may find ways to manipulate the mutations to increase longevity.

However, as common genetic variations demonstrate, tinkering with one thing may negatively impact another.

Key takeaways:

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