A basic fact of male biology may be responsible for men's short lifespans

Why do males typically have shorter lives than females?

That’s the question that evolutionary biologist Doris Bachtrog has been exploring in her lab at the University of California, Berkeley. And finally, she’s encountered an answer: A new study on flies from Brachtrog’s lab suggests the repeating DNA found in the Y-chromosome might be responsible for males’ shorter lifespan.

This finding was published Thursday in PLOS Genetics.

Let’s back up — Inside human cells are strings of DNA (deoxyribonucleic acid). Genes are a specific part of DNA; they give instructions to cells to make certain proteins. The remaining DNA is called heterochromatin. Heterochromatin is very densely packed DNA and has a variety of functions. Some heterochromatin helps regulate genes, while other heterochromatin protects the integrity of chromosomes. Bachtrog and colleagues are interested in why chromosomes can, in turn, become toxic.

It’s established that, in every animal species where there is a lifespan difference between sexes, the sex with the equivalent of the Y chromosome has a shorter lifespan. One theory for why this is has to do with repeating sequences of DNA. Both sexes have repeating sequences of DNA, but the Y chromosome has significantly more than the X chromosome.

“XX females have some heterochromatin, but much less so than XY males, since the number of repeats on the Y chromosomes is much much larger than on the X,” Bachtrog tells Inverse.

This theory is called the “toxic Y effect.”

What’s new — In the study, Bachtrog and colleagues wanted to test for an association between sexes with heteromorphic (different from each other, so XY as opposed to XX) sex chromosomes, sex-specific heterochromatin, and repetitive DNA sequences.

Specifically, the team wanted to examine transposable elements (TE). These are repeated sequences of DNA that are constrained or “silenced” by that dense packing but — if that tense packing is removed — have the potential to move from one genomic location to another.

A useful species for this line of study are fruit flies which, according to the study authors, have “well-established” Y-chromosomes and a notoriously short lifespan. Also, the male fruit flies have about twice as much repeating DNA as the females.

The researchers found that when male fruit flies are young, the repeat DNA is packed so tightly that the repeat sections of DNA are effectively turned off.

As the fly aged, however, these repetitious sections became less tightly packed together. This, in turn, can lead to the repeated DNA sections being transcribed — that’s when cells following the directions to create proteins. And once they’re out of those densely packed constraints, there’s the possibility that they can move around to other genomic locations.

Bachtrog explains that transposable elements will “cut themselves out of particular regions of the genome [causing DNA damage], and insert into a new region [and can cause genes to become inactive if they insert into a gene].”

Why this matters — Given that previous studies suggest that when this repeat DNA is activated fruit flies experience difficulties like memory loss and DNA damage, the study results make the case for more research into repeat DNA and heterochromatin.

“Like in flies, human males tend to live shorter than females.”

While fruit flies are clearly not a perfect analog for humans — for one thing, a fruit fly’s Y chromosome is far more repetitive than a human’s — in this case, there are useful similarities.

“Humans contain large stretches of repetitive DNA, and heterochromatin alterations have been identified as drivers of human aging,” Bachtrog says. “Like in flies, human males tend to live shorter than females, suggesting that differences in heterochromatin content may contribute to sex-specific aging in our species as well.”

Next, Bachtrog says she’s planning to use the fruit fly model developed in this study to research “the molecular basis of heterochromatin loss, and sex-specific differences.”

Plenty of other things — including diet, exercise, and even the strength of our social connections — also contribute to how long we live. But understanding how our DNA also contributes to longevity is still important. It helps explains a mysterious element of life on a fundamental level. It also points to how these assumed side-effects of being alive can one day be manipulated, especially with technologies like CRISPR potentially on the horizon.

Abstract: Sex-specific differences in lifespan are prevalent across the tree of life and influenced by heteromorphic sex chromosomes. In species with XY sex chromosomes, females often out-live males. Males and females can differ in their overall repeat content due to the repetitive Y chromosome, and repeats on the Y might lower survival of the heterogametic sex (toxic Y effect). Here, we take advantage of the well-assembled young Y chromosome of Drosophila miranda to study the sex-specific dynamics of chromatin structure and repeat expression during aging in male and female flies. Male D. miranda have about twice as much repetitive DNA compared to females, and live shorter than females. Heterochromatin is crucial for silencing of repetitive elements, yet old D. miranda flies lose H3K9me3 modifications in their pericentromere, with heterochromatin loss being more severe during aging in males than females. Satellite DNA becomes de-repressed more rapidly in old vs. young male flies relative to females. In contrast to what is observed in D. melanogaster, we find that transposable elements (TEs) are expressed at higher levels in male D. miranda throughout their life. We show that epigenetic silencing via heterochromatin formation is ineffective on the TE-rich neo-Y chromosome, presumably due to active transcription of a large number of neo-Y linked genes, resulting in up-regulation of Y-linked TEs already in young males. This is consistent with an interaction between the evolutionary age of the Y chromosome and the genomic effects of aging. Our data support growing evidence that “toxic Y chromosomes” can diminish male fitness and a reduction in heterochromatin can contribute to sex-specific aging.