The Killer Chromosome

Why do men die earlier?

Yuri Deigin, Geektimes

Do you think it's only men who live less than women? Tell this to the mantis, he will laugh. Although no, he has nothing to laugh at, his head was eaten by a female after intercourse.

So, females live longer in the vast majority of species known to science. For those who doubt this, I advise you to look at 37 pages of data from the book Why Men Die Younger: Causes of Mortality Differences by Sex, especially Appendix F – there are 100 types, no less:

And the statistics given there for different countries (albeit for 1998) are very indicative:

Someone thinks that we Y-noses live less than women because we are so bold and sharp, and in our youth we are more prone to craving for various dangerous stupidities like riding motorcycles or playing American football. But this is not so – the probability of death in men is higher at any age, even in the quiet 60 and 70.

Therefore, smart people understand that Kashcheev's death is hidden in... the Y chromosome. No wonder castration prolongs life: in one American experiment by 20% (13.6 years), and in Korean eunuchs by 30-40% (15-19 years).

But the most interesting thing is that, maybe, life extension can be achieved without castration! And simply by removing or epigenetically "turning off" certain "deadly genes" on the Y chromosome itself. This is exactly what the Bulgarian (Tsoneva) and Soviet ones established back in the 1980s. (Kuznetsova) scientists studying male centenarians:

"Previously, data on the relationship between large C-blocks on the Y chromosome and longevity in the Bulgarian population were published (Tsoneva et al., 1980), as well as data on the increased frequency of "very large" C-blocks in centenarians over 80 years old in Edinburgh (Buckton et al., 1976). …
A long Y-chromosome, as well as a large C-segment on the Y-chromosome are typical for long-lived Ukrainian and Abkhaz men.
Thus, we have established a link between the variants of an individual variant of chromosomal polymorphism on the Y chromosome and male longevity in different regions."

What are C-blocks? I will try to convey my understanding, but I would be very grateful for a more detailed explanation from experts in the comments. So, in my understanding, in the case of the Y chromosome, C-blocks are inactive, "off" parts of the chromosome. Formally, C-blocks are those parts of the chromosome that are highlighted during the procedure of C–staining or C-banding treatment of chromosomes with a special dye:

Other types of bands, such as R- and C-bands, can be obtained using the giemsa stain. The type of bands produced depends on the extent of denaturation induced on the chromosome structure [10]. C-banding … reveals the AT-rich centromere, which consists of constitutive heterochromatin.
This technique involves acid treatment, hot saline incubation, and alkali treatment of the chromosomes. These treatments depurinate the DNA and break the DNA backbone, which then cause the extraction of the DNA from certain regions of the chromosomes. C-bands (figure 4.4) are produced due to this differential extraction of the DNA.
It was observed that the DNA in the C-bands is more resistant to extraction than the DNA in the other regions of the chromosomes. This is due to the stronger interaction of the proteins, which protects the DNA from extraction, with the DNA in the C-bands than in the other regions of the chromosomes [22].  (Source)

As I understand it, these methods of various staining and subsequent highlighting of chromosomes were used in those ancient times when PCR technology did not yet exist (invented in 1983), gene sequencing was a long and expensive pleasure, and the identification of methylation patterns was not even thought about yet. With the help of different illumination methods, it was possible to somehow differentiate the various structural and functional segments of chromosomes. At one time, Soviet scientists were actively engaged in such analysis, in particular, the Y chromosome.

Specifically, the C-banding method usually highlights constitutive heterochromatin, which is a highly condensed DNA that is mainly present around centromeres or telomeres. Since such DNA is highly compressed, it is not expressed, that is, these sites are not active. But in the case of the Y chromosome, almost all of the DNA is in such a compressed state - see the lower right corner in the photo:

Such compression, or condensation, of chromatin occurs using the same mechanisms that are responsible for the standard epigenetic "shutdown" (inactivation) of genes. This inactivation occurs both at the histone level and at the level of DNA methylation itself.

And so, if I interpret their work correctly, in the studies of Tsoneva and Kuznetsova, the centenarians had a more significant part of the Y chromosome in such a compressed state than in the control group, which leads me to think that in this way they had epigenetically turned off some genes that are usually active in other men and their activity earlier brings them to the grave. 

A small digression for those who stumbled on phrases like "epigenetically turned off" or "methylation" and generally have a vague idea of what epigenetics is. 

Epigenetics is a "superstructure" over genetics (epi- = over), a mechanism for controlling genes. Rather, there are several such mechanisms: methylation of the genes themselves, acetylation or methylation of histones on which these genes are "wound", and many other things that fall under the definition of epigenetic control.

Why do genes need to be controlled at all? Firstly, because the DNA of an organism is the same in all types of cells, and different sets of genes must be active in a brain cell and a skin cell. And also because different genes are responsible for different stages of the development of the organism – the caterpillar and the butterfly have a very different activity profile of these very genes. As with us, in fact: some genes are active in the womb, others in childhood, and still others in old age. And, by the way, with age, the on/off profile of various genes changes in almost the same way for all people. What formed the basis of the concept of the "methylation clock" as a biomarker of aging. But this is a completely different topic.

So, returning to my hypothesis about the methylated genes on the Y chromosome of Bulgarian and Soviet centenarians. What gave me this idea? And the fact that in 1987 in America, geneticist Kirby Smith found 14 Amish men who had some genes removed on the Y chromosome, and who lived 20% longer than their non-mutated counterparts (82 years versus 68-71 years):

A source: The Future of Aging: Pathways to Human Life Extension by Gregory M. Fahy, Michael D. West, L. Stephen Coles, Steven B. Harris 

The most interesting thing is that the Y chromosome is very small: there are only 71 coding genes on it. Therefore, ideally, it would be very cool to figure out exactly which areas were removed from these Amish. By the way, Kirby Smith is still alive and continues to work at Johns Hopkins University, and his DNA samples are most likely preserved. Sequencing them would be a simple matter for him – he is a professor of genetics there, after all. I have suggested a couple of times to Gregory Fahey (the author of that wonderful book on aging from which I took the above table) to write on this topic again, but he is not eager yet. 

Svetlana Mikhailovna Kuznetsova is also alive, and even, as far as I can tell, continues to work at the D.F. Chebotarev Institute of Gerontology in Kiev. I'm thinking of writing to her, too, in case she still has DNA samples of those Soviet centenarians. 

By the way, in light of all the above, it was interesting to hear about a recent study by a big fan of metformin, Nir Barzilai, which showed that the deletion of the third exon in the growth hormone receptor positively affects the life expectancy of men, but not women. After all, the age pattern of secretion and the levels of growth hormone in the sexes are very different, so maybe his study showed a mechanism similar to the aforementioned Y-mutants. Here is the survival curve of homozygous d3-GHR mutants compared to heterozygous and wild type:

It is true that some publications claim that the work of Barzilai et al. showed that homozygosity for d3-GHR helps to live 10 years longer, wrong. It's just that at the time of the beginning of his study, the average age (age at recruitment) of a subgroup of 16 homozygous subjects was 10 years higher than the other 180 members of the cohort. But, as can be seen from the survival graph, the median pancreas in homozygous companions is only 6-7 years higher than that of the control group, and the maximum is generally less.

In any case, the fact that the Y chromosome harbors some secrets of potential longevity and does not really want to reveal them to us yet, seems to me more and more plausible.

Sources: Why Men Die Younger: Causes of Mortality Differences by Sex. Barbara Blatt Kalben

The Future of Aging: Pathways to Human Life Extension. Gregory M. Fahy et al.

Portal "Eternal youth" http://vechnayamolodost.ru  23.06.2017