Sunday, March 16, 2014

The puzzle of menopause

Human females appear to be unique in the animal kingdom in that they live far beyond the end of their fertility period.  Typically, menopause occurs in the 4th decade of life, and women can expect to live to their 8th decade.  In men, however, fertility continues to near the end of life.  In men, although there are clear declines affecting the endocrine system, testicular function, and structure of the sperm chromosomes, there appears to be no andropause, that is, men retain a significant probability of fertility, but not women.  (In 1935, three physicians reported what may be the oldest American father on record, a 94 year old North Carolina man who married a 27 year old widow and fathered a child.)  

In contrast to humans, in chimpanzees fertility continues in both females and males until near the end of life.  That is, whereas in women menopause is a mid-life event, in chimpanzee females it is a late-life event.  Why?

A genetic wall of death beyond the fertility years
In 1966, W.D. (Bill) Hamilton, a just minted PHD student in biology, who would  later be called "nature's oracle" because of his mathematical reasoning, and whose work would  lay the foundation for the "selfish gene" of Richard Dawkins, used a mathematical model of genetics to demonstrate that from an evolutionary standpoint, genes that protect against disease and expand the lifespan beyond the age of fertility would tend to be eliminated with natural selection, and so animals should not live much longer than their end of fertility.  

Bill's argument went as follows: imagine four genes that are expressed in females and give immunity against some lethal disease but are expressed only in one particular part of life.  The first gene is expressed in the 1st year of life, the second gene in the 15th year, the third gene in the 30th year, and the fourth gene in the 45th.  Now imagine that fertility ends before age of 45.  If so, the fourth gene confers much less advantage than the first three.  This model explained the fertility-age relationship in men, but could not explain why women lose their fertility at around the midpoint of their life.

Evolutionary biologists have been puzzled by the fact that human females have escaped this “wall of death” that, at least theoretically, looms after menopause, and appears to be present in many other animals.  Numerous theories have been offered.  Perhaps in the past, human longevity was too short for females to experience menopause (defined as surviving for at least one year in good health beyond the last menstrual cycle), and so menopause is a byproduct of increased longevity unique to humans.  Perhaps by entering into menopause, older mothers increased the survival probability of their children and grandchildren (grandmother effect).  Perhaps reproductive aging was more severe than somatic aging, and so unlike other functions that could proceed at less than some high level of accuracy, reproduction in females could not, and therefore stopped when a threshold level of accuracy was reached. 

The jury is still out on whether any of these theories are supported by evolutionary data.  However, the most interesting new hypothesis proposes that women experience menopause at mid-life because of behavior of men.

Male sexual preference may lead to female menopause
In 2007, Shripad Tuljapukar and colleagues revisited Hamilton’s mathematical model of human evolution and like Hamilton assumed that there were genes that gave resistance to fatal diseases at certain age of life.  Unlike Hamilton, they assumed these genes existed in both males and females.  They added to Hamilton’s model a matrix representing mating preference.  In this matrix, \$ M_{i,j} \$ represented the probability of a male age \$ i \$ to mate with a female of age \$ j \$, and if both were fertile, to produce an offspring.  They found that if there was a gene that gave resistance to a fatal disease at say the 45th year in women, and this gene did the same thing in men, then both men and women would benefit from this gene because the older men would continue to be fertile and produce babies with the younger women. The interesting idea was that selection would favor survival of both males and females as long as one of the two groups could reproduce with the fertile sub-population of the other group.

But this idea was not entirely satisfactory because the same model would predict that it was better if females could extend their fertility period and like males, never experience menopause.  Sure, having one group live longer than the menopause age of another group would make both groups live longer, but why did natural selection produce menopause in females, but not males?  That is, what is the origin of female menopause in the first place?

In 2013, Richard Morton and colleagues used a similar mathematical model of genetic evolution, but started with the assumption that prolonged fertility was the ancestral state of both males and females.  That is, they assumed that at some distant past, neither males nor females experienced menopause.  They also assumed existence of a sex-specific infertility causing mutation in the genome which would produce menopause.  They asked about the conditions that might lead to this gene being expressed early in females, but not males.  

They found that if males and females had no preference for the age of their partner, then infertility-causing mutations would not become sex specific.  That is, if the age of the partner did not matter to a male or a female, reflected in the matrix \$ M_{i,j} \$, then both males and females would remain fertile into old age.  However, if males preferred younger females, then something interesting happened: female fertility declined without a loss in their longevity, resulting in female menopause, but male menopause never occurred.  The interesting idea was that a male preference for mating with a younger female would specifically affect fertility in females, limiting it and producing menopause.

An amazing prediction of this model is that evolution could have proceeded in a very different path: if females had shown a preference for mating with younger males, then fertility would have declined in the older males, resulting in male menopause, while allowing females to maintain fertility into old age.

Ramajit Raghav, an Indian man who was reported to have fathered a child at 97 years of age.

R. Caspari and S.H. Lee (2004) Older age becomes common late in human evolution. Proceedings of the National Academy of Science 101:10895-10900.

W.D. Hamilton (1966) The moulding of senescence by natural selection. Journal of Theoretical Biology 12:12-45.

J.G. Herndon et al. (2012) Menopause occurs late in life in the captive chimpanzee (Pan troglodytes) Age 34:1145-1156.

R.A. Morton, J.R. Stone, R.S. Singh (2013) Mate choice and the origin of menopause. PLoS Computational Biology 9:e1003092.

F.I. Seymour, C. Duffy, and A. Koerner (1935) A case of authenticated fertility in a man aged 94. Journal of American Medical Association 105:1423-1424.

S.D. Tuljapurkar, C.O. Puleston, and M.D. Gurven (2013) Why men matter: mating patterns drive evolution of human lifespan.  PLoS One 8:e785.