Fight Aging!

Simple questions often have complex answers, and are challenging to definitively resolve. Why do women tend to live longer than men? That is a question with a great many potential answers. Since females live longer than males in many other species, it seems unlikely to be a matter of culture or technology, however. It is something more fundamental that emerges over the course of evolutionary time given the existence of genders. This open access paper surveys the field of thought on gender and life expectancy in order to lead in to a discussion of sex chromosomes in the evolution of this disparity in life span.

Like many topics in the present day study of aging, this will become of only academic interest in the coming era of rejuvenation therapies. Why would we be concerned about any modest natural disparity in life span given the existence of methods of enhancing healthy human longevity by decades or more? It is far more important to focus on the realistic prospect of producing rejuvenation therapies, and then ensuring that they can be produced cheaply and distributed widely, than on examining the present state of aging across populations.

An obvious difference between men and women are the sex chromosomes, which could impact aging and longevity in a number of ways. A first obvious effect of having sex chromosomes is that males have one X and are hemizygous for that chromosome while females have two Xs. In women, however, X-chromosome inactivation (XCI) means that only one X is expressed in each cell. This implies that if present in a male, a deleterious mutation on the X will always be expressed. If present in a female, it will depend whether the mutation is recessive or dominant and whether that female is homozygous or heterozygous for this mutation. This mechanism, called the "unguarded X", could contribute to aging and longevity.

A general prediction of the unguarded X is that, in XY systems, males should die faster. In some species (e.g., birds, butterflies), females are heterogametic (i.e., have different sex chromosomes); these systems are called ZW (females: ZW, males: ZZ). The W is equivalent to the Y and the Z to the X. In these systems, the unguarded Z effect should result in the opposite pattern: ZW females should die faster. Until recently, however, very little data was available and they tended to support the idea that sex chromosomes would not have a major role in sex-specific aging patterns.

Some recent data have changed this view. Researchers have investigated the connection between sex chromosomes and aging/longevity by compiling data on adult sex ratios (ASRs) as a proxy for the sex gap in longevity and sex chromosome types (XY, ZW) for 344 species of tetrapods (including mammals, birds, lizards, crocodiles, snakes, amphibians), by far the largest dataset analyzed so far. They found a strong statistical association between the sex chromosome type and ASRs. In the XY species, ASRs are female-biased, which suggests that males tend to die younger, whereas it is the opposite pattern in ZW species.

Some other recent data suggests that the unguarded X/Z might be just one mechanism among several. In Drosophila, the Y chromosome, despite its very small gene content, has a major effect on the epigenetics of the other chromosomes. In old male flies, Y chromatin is more open and transposable elements tend to be de-repressed, which could result in those elements jumping around in the male genome, causing deleterious mutations and speeding up aging. To further test the idea that the Y chromosome causes faster aging in males than in female flies, researchers looked at aging and longevity in XXY females and monosomic X and XYY males, and confirmed that the Y increases aging in Drosophila. This suggests that sex chromosomes may contribute to aging through a "toxic Y/W" effect because of particularly high transposable element content.

Link: https://doi.org/10.1186/s13293-018-0181-y