Scientists might have found support for the antagonistic pleiotropy theory of aging, which suggests that evolution selects some genetic traits that are associated with shorter lifespans because they also help us reproduce [1].
Evolution needs you to reproduce, not live long
Shouldn’t evolution favor longer lifespans, so that animals have more time to procreate? To answer this question, one theory invokes antagonistic pleiotropy, a phenomenon in which a genetic trait positively influences reproduction while also negatively influencing longevity [2]. If the tradeoff is a net positive for passing genes along, such genetic variants will be selected for despite shortening lifespan. Some tentative evidence in favor of this theory already exists. For instance, genetic variants associated with coronary artery disease also tend to be associated with a higher number of offspring [3].
A new study published in Science Advances puts this antagonistic pleiotropy theory to the test by using the vast trove of genetic and health information collected by UK Biobank. Since most people whose data is stored in UK Biobank are still alive, the researchers began by testing the participants’ reproductive traits against their parents’ lifespans.
Theory-supporting results
The researchers established that the three traits chosen – age at first birth, age at first sex, and number of children fathered – genetically correlated with parental lifespan. Earlier first sex and reproduction, along with a greater number of children, were all associated with shorter lifespans. Genetic correlation is the proportion of variance that two traits share due to genetic causes. In other words, it is a measure of how much genetic factors that influence one trait also affect another trait. UK Biobank also records the number of full brothers and sisters of each participant, which allowed the researchers to examine the genetic correlation between parental reproduction and parental lifespan. Here, too, a significant negative correlation emerged.
While the lifespans of many UK Biobank participants are unknown, others have already passed away. This enabled the researchers to investigate the correlation between reproductive traits and the probability of survival to various ages, up to 76. Based on 583 genetic variants associated with various reproductive traits, the researchers calculated polygenic scores that measure genetic predisposition for those traits. The scores were divided into three categories – low, medium and high – and those categories showed a robust correlation with survival rates from age 40 to age 76: that is, people with the lowest reproductive polygenic scores had higher chances of living to an advanced age.
Interestingly, average polygenic scores for all traits steadily increased from earlier to later cohorts, meaning that the prevalence of those traits in the population has grown with time. This might be happening due to natural selection for better reproduction versus longer lifespans. All those results, according to the authors, support the antagonistic pleiotropy theory.
Many possible mechanisms
The researchers then moved to discovering and analyzing the specific genetic variants involved. 123 of the 583 reproduction-associated variants had a significant effect on the probability of reaching the age of 76, with many more cases of antagonistic pleiotropy than of concordant pleiotropy (98 versus 28). In other words, less than one fourth of the variants that affect both reproduction and lifespan affect them in the same direction.
The researchers compared this to 100 sets of 583 randomly selected variants. None of those sets contained as many longevity-related variants, and those variants were not skewed towards antagonistic pleiotropy. The researchers calculated that, compared to random variants, those associated with reproduction were 4.9 times more likely to affect lifespan and 7.5 times more likely to do so antagonistically.
There are many possible molecular mechanisms behind those correlations. For instance, one of the reproduction-associated variants was also associated with an increased risk of several types of cancer, while others were associated with such diseases as osteoarthritis and cardiovascular diseases. Interestingly, most reproduction-associated variants reside in non-coding regions and probably play complex regulatory roles.
Using the U.K. Biobank, we performed a series of trait-level and variant-level analyses to test the antagonistic pleiotropy hypothesis of the evolution of human aging at the genomic scale. At the trait level, we observed a strong negative genetic correlation between reproduction and parental life span as well as that between parental reproduction and parental life span, found that the probability of survival to the age of 76 is negatively correlated with PGSs for reproduction, and detected increases in these PGSs over 25 years. At the variant level, we found that alleles associated with higher reproduction tend to be associated with lower survival to the age of 76 and that frequencies of some of these alleles have increased over the years in a pattern consistent with the action of positive selection. These findings together provide strong genome-wide evidence for the antagonistic pleiotropy hypothesis of aging in humans.
Literature
[1] Long, E., & Zhang, J. (2023). Evidence for the role of selection for reproductively advantageous alleles in human aging. Science Advances, 9(49), eadh4990.
[2] Williams, G. C. (2001). Pleiotropy, Natural Selection, and the Evolution of Senescence: Evolution 11, 398-411 (1957). Science of Aging Knowledge Environment, 2001(1), cp13-cp13.
[3] Byars, S. G., Huang, Q. Q., Gray, L. A., Bakshi, A., Ripatti, S., Abraham, G., … & Inouye, M. (2017). Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLoS Genetics, 13(6), e1006328.
