Mother's Curse

It's a harsh world for us men. Oh, sure, we've got all the political and economic power, and we've got most of the guns, but step into a senior citizens' center and you'll notice the preponderance of elderly women. Men die younger, on average. I'm also acutely aware of the growing disparity as we get older: my wife seems to be aging at about half the rate I do. If you've been watching House of Cards on Netflix, you may have noticed that the character played by Kevin Spacey, face a bit puffy and deeply lined, is married to a character played by Robin Wright (Princess Buttercup!) who is looking fabulous: mature, a bit severe, but still looking great. This situation is not unusual.

This is not fair. The average life expectancy of women in the US is 80 years, while men live to be about 75.

Why?

It's not sufficient to say it just is that way; we have to dig deeper and figure out the differences. Part of the answer is that human males have a youthful history of riskier behavior than females, but again we have to ask why: what is driving men to do stupid stunts that lead to higher rates of mortality? But even if we have a good answer for that one, it doesn't address that other problem, the accelerated rates of male senescence. I've survived my heightened risk of death by misadventure, so why am I getting increasingly decrepit while women my age are looking more fit and healthy?

Part of the answer may be in your genes, your mitochondria, and evolution. Mitochondria play an extremely important set of roles in aging. They hold the keys to cell death and responses to cancer; most apoptotic responses are triggered by the release of signals from the mitochondria. Mitochondria are the agents that produce energy for the cell, and also produce reactive oxygen species in their normal operation. You may be hearing the hype about anti-oxidants, and are diligently taking cofactors and vitamin pills to reduce, hypothetically, the deleterious effects of these avidly destructive molecules, but the primary source of those oxidants is by the activity of mitochondria. There are overt hereditary diseases of mitochondria, like LHON and MELAS which reveal the importance of mitochondria in normal metabolism, but there are also other diseases like Alzheimer's and Parkinson's that have a mitochondrial component that plays a role in the severity of the effects. And aging is a disease that is also associated with mitochondrial function.

But wait, you're thinking, mitochondria are equally important in men and women, so how can they account for a difference between the sexes?

Keep in mind that mitochondria are not magically autonomous. They contain about 35 genes essential for metabolism, and use about a thousand more that come from the nuclear genome, so there's a significant amount of information shuttling back and forth between the nucleus and the mitochondrion. There are also epigenetic influences: mitochondrial states are known to modulate states of DNA methylation in the nucleus. And obviously, there are subtle differences in between the nuclear genomes of men and women, and probably even greater epigenetic differences between the two. So here we have two complex genetic units, the nucleus and the mitochondria, interacting with one another, and in a perfect world they'd be beautifully fine-tuned and singing in harmony with one another…but at the same time we have sex differences in the nuclear genetics, which complicates the problem of matching the two.

And this is where evolution steps in. There's a genetic problem here.

The inheritance of mitochondria is asymmetric: you only get them from your mother, and your father makes no mitochondrial contribution at all. Your father's mitochondrial contribution dies with him and is not passed on. What does that mean? It means that there can be no selection to fine tune mitochondria to the male nuclear genome. As a recent paper by Wolff and Gemmell explains:

The asymmetry in mtDNA inheritance, however, becomes problematic in the case of traits that affect exclusively males and shared traits that, if compromised, have a disproportionally greater effect on males than females. In this instance mutations that harm males but leave females unaffected will escape purifying selection and lead to the accumulation of a mutational load in the mitochondrial genome detrimental to male-specific traits; a scenario described as mother's curse. Male reproductive traits have long been in the limelight as ideal candidates to fall victim to this mechanism. Compelling support for such male specific reproductive effects comes from a recent study. Using a fly model, Innocenti et al. expressed five different naturally occurring mtDNA variants alongside a standardized nuclear genome and profiled the resulting gene expression within these mitolines. A pronounced asymmetry in nuclear gene expression profiles was observed between males and females with the majority of affected transcripts being overexpressed only in males and highly over-represented in male reproductive tissues. Overall, this study suggests that naturally occurring mtDNA variability exerts a much stronger effect on male fitness than it does on female fitness, strongly supporting the concept of mother's curse. This finding is well in line with a range of studies that identified either mtDNA variants or specific mito-nuclear lineages as associated with male reproductive impairment across a variety of taxa.

The name "mother's curse" is a bit unfair. It's not just the maternal contribution that affects us males, but the fact that our nuclear genomes (which are derived from both our mother and father) may be subtly out of synch with our mitochondrial genomes (which are derived exclusively from our mother). Don't blame your mom for your wrinkles and grey hair, guys — you should still call her on Mother's Day.

Two other points to make: 1) this phenomenon of greater male senescence is universal, and seems to be found all across multicellular phyla. Apparently, earlier death is something that actually is a guy thing. 2) While there aren't opportunities to directly select for greater compatibility between mitochondria and nuclei in males, don't count inclusive fitness out. Male mortality can obviously effect female survival, so you can have indirect effects that promote better male survival.

It suggests that males are not only subject to heightened risks of disease and infertility, but implies that across almost all eukaryotic life they will have shorter lives simply as a consequence of the maternal inheritance of the mitochondrial genome. The diminutive mtDNA plays David to the nuclear Goliath because of the inability of selection to eliminate mutations harmful to males, but neutral or beneficial to females, under most scenarios. Recent theoretical work suggests that, under scenarios in which there are high levels of positive-assortative mating and strong inclusive fitness, the indirect costs to females may be great enough to enable selection to remove mtDNA types deleterious to males but not females. However, on the whole there is little opportunity for deleterious mtDNA mutations to be selectively eliminated from populations, unless they have direct fitness costs to females.

Hmmm. I should probably do things that make sure my health and fitness are correlated with my female partner's health and fitness, so that my mitochondrial-nuclear matching is relevant to the survival of my offspring. Yeah, that's the ticket. I should start consciously thinking that way.

Wolff JN, Gemmell NJ (2013) Mitochondria, maternal inheritance, and asymmetric fitness: Why males die younger. Bioessay 35(2):93-9. doi: 10.1002/bies.201200141.