Sunday, January 10, 2010

Weismann Theory of Programmed Death

August Weismann (1834–1914), the great German theorist and experimental biologist of the 19th century, was one of the first biologists to use evolutionary arguments to explain aging. His initial idea was that there exists a specific death-mechanism designed by natural selection to eliminate the old, and therefore worn-out, members of a population.

The purpose of this programmed death of the old is to clean up the living space and to free up resources for younger generations. Weismann probably came to this idea while reading the following notes of Alfred Russel Wallace (one of Darwin's contemporaries and a co-discoverer of natural selection), which he later cited in his essay “The Duration of Life”: “…when one or more individuals have provided a sufficient number of successors they themselves, as consumers of nourishment in a constantly increasing degree, are an injury to those successors. Natural selection therefore weeds them out, and in many cases favors such races as die almost immediately after they have left successors.”

Weismann enthusiastically accepted and developed further this idea, which also corresponded well with the hiring practices of German universities of that time whereby new candidates had to wait for the death of an old professor in order to obtain positions.

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Weismann's Evolutionary Theory and the Cell Division Limit 
Suggesting the theory of programmed death, Weismann had to think about the exact biological mechanisms for this death program and came to an idea that there is a specific limitation on the number of divisions that somatic cells might undergo. Specifically, he suggested “that life span is connected with the number of somatic cell generations which follow after each other in the course of an individual life, and that this number, like the life span of individual generations of cells, is already determined in the embryonic cell”. Weismann tried to explain “the different life span of animals by making it dependent on the number of cell generations, which was the norm for each different species”.

Remarkably, his purely theoretical speculation over the existence of a cell division limit received a dramatic further development. In brief, Weismann's theory of the cell division limit was initially challenged by Alexis Carrel and Albert Ebeling, who published findings that chicken fibroblast-like cells can be cultivated like microorganisms in cell culture indefinitely (at least for 34 years). Many researchers know now that the concept of cell division limit, which became known as the Hayflick limit, was ultimately confirmed.

The triumph of Weismann's idea of a cell division limit did not help, however, to justify his theory of programmed death. The cells stopped dividing, but no programmed cell death occurred. Moreover, the hypothesis was put forward that this cell growth arrest is in fact beneficial for organism survival because it protects against cancer. It was also suggested that the cell division limit may have relevance to another evolutionary theory of aging: the antagonistic pleiotropy theory.

Evolution of Weismann's Views on the Evolution of Aging
While discussing Weismann's evolutionary theory of aging, it is important to know that his scientific views evolved significantly over the course of his life. When Weismann himself became older, he stopped writing about the “injuriousness” of the old, changed his evolutionary views, and considered old organisms not as harmful but simply neutral for the biological species:

“…in regulating duration of life, the advantage to the species, and not to the individual, is alone of any importance. This must be obvious to any one who has once thoroughly thought out the process of natural selection. It is of no importance to the species whether the individual lives longer or shorter, but it is of importance that the individual should be enabled to do its work towards the maintenance of the species.…The unlimited existence of individuals would be a luxury without any corresponding advantage”.

Remarkably, few scientists noticed that Weismann changed his mind on his own earlier theory. Weismann's later, corrected version of the theory — that aging is not an adaptive trait but rather simply a neutral trait — did not receive as much attention as his famous earlier theory of programmed death. After his death in 1914, his name became forever associated with the earlier, not the later, version of his theory. This can be seen in the 1922 edition of the book The Biology of Death written by Raymond Pearl:
“In his famous address of 1881 on the duration of life, Weismann propounded the thesis that death was an adaptation, advantageous to the race, and had arisen and was preserved by natural selection. Probably no more perverse extension of the theory of natural selection than this was ever made”.

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Testing the Theory of Programmed Death
Subsequent studies confirmed that Weismann's decision to abandon the initial idea of programmed death was a wise one. Many scientific tests of the programmed death hypothesis were made since Weismann proposed his theory.

One way of testing the programmed death hypothesis is based on a comparison of lifespan data for individuals of a single species in natural (wild) and protected (laboratory, domestic, civilized) environments. If the hypothesis is correct, there should not be very large differences in the lifetimes of adult individuals across compared environments. Indeed, for a self-destruction program to arise, take hold, and be maintained in the course of evolution, it must at least have some opportunity, however small, of expression in natural conditions. Consequently, the age at which such a program is “switched on” cannot be too high. Otherwise, because of the high mortality in the wild from predators, hunger, infections, and harsh natural conditions, no one would live to the fateful age, and the self-destruction mechanism could not be expressed. It follows from this that lifespans in even the most favorable conditions cannot significantly exceed the ages reached by the most robust individuals in the wild, if, of course, the tested concept is correct.

Analysis of the actual data reveals, however, a picture completely opposite to what would be expected from the programmed death theory: the lifespans of organisms in protected environments greatly exceed the lifespans observed in natural conditions.

For example, the chaffinch (Fringilla coelebs) can live for 29 years in captivity. However, in the wild this is practically impossible, since about half of all birds perish in the course of a year from hunger, cold, disease, and attack by predators, and the mean life span is only 1.4 to 1.5 years. As a result of this high mortality, only 0.1% of the initial number of chaffinches survives to age 11.

Similar observations have been made for field voles (Microtus arvalis Pall). In protected laboratory conditions, the average lifespan of voles is about 7 to 8 months while individual specimens survive to 25 months. In the wild, however, the average lifespan of voles is only 1.2 months while only 0.1% of the original number of voles survives to 10 months.

As for primates, the median lifespan (age at 50% survival) of chimpanzees (Pan troglodytes) living in captivity is between 23 years (males) and 30 years (females), and almost 20% of captive female chimpanzees survive to age 50. However, in the wild “natural” conditions the median lifespan is only 8 years, and almost nobody survives to age 50.

Observations like these are common for many biological species. Thus, if one attempts to estimate the age of programmed death on the basis of lifespans in laboratory conditions, it becomes clear that no death program could arise or be maintained in evolution if only because it would not be able to come into operation in natural conditions where practically no individual lives to the required age.

The same conclusion is reached from an analysis of data on the human lifespan. At present, the mean life expectancy in developed countries is about 70 to 80 years while the documented record for longevity is 122 years. If we take these figures as an estimate for age range in which the death program is switched on, we are forced to admit that such a program could not have arisen in human evolution since, according to palaeodemographic data, virtually nobody survived to such an age. For example, only half of those born in the Late Palaeolithic (30,000 to 10,000 B.C.) reached 8 to 9 years, and only half of those born in the Neolithic (6,000 to 2,000 B.C.) reached 26 years.

Moreover, even in the Middle Ages (9th to 12th centuries), life expectancy at birth was no greater than 27 to 29 years. Investigations of the skeletons of American Indians have shown that only 4% of the population survived to age 50 even as late as in the 18th century. Note for comparison that the probability of surviving to this age in the developed countries is 94 to 96%. If these facts are compared, it is difficult to refrain from posing the following question: Can the guaranteed destruction of a few old people who are chance survivors and doomed in the wild be a sufficient evolutionary basis for the formation and preservation of a special self-destruction program in the human genome? Viewed in this light, the inconsistency of the programmed death hypothesis becomes clear.

The second way to test the programmed death hypothesis is to study the dependence of death rates on an animal's age. If this theory is correct, then the age-dependence of death rates should change dramatically (explode) after some critical age later in life when the alleged death program comes into action. There should be a breaking point in the dependence of death rates on an animal's age, and this breaking point should be particularly evident in genetically homogeneous stocks of animals kept in standard laboratory conditions. This prediction was carefully tested by studying hundreds of published life tables compiled for many dozens of different biological species, including humans. This study found that the age-dependence of death rates is very smooth and monotonic without any signs of some critical age or breaking point later in life corresponding to an expected mortality explosion. For example, in humans the death rates start to increase with age as early as age 20, and the mortality trajectory follows a simple monotonic Gompertz-Makeham curve. Moreover, the actual death rates at extreme old ages are even lower than expected according to the monotonic Gompertz-Makeham model, which is completely opposite to the prediction of the programmed death theory.

Finally, if the question whether death is programmed is approached from the evolutionary point of view, it becomes obvious that special mechanisms for the termination of life could hardly help the individual to fight successfully for his survival and the survival of his progeny. On the contrary, those individuals in whom the action of such a program of self-destruction had been impaired by some spontaneous mutation would quickly displace all the remaining individuals. This is because they would produce more offspring in their longer lifespan, or at least they could increase the survival of their offspring by providing longer parental support.

In 1957 George Williams, the author of another evolutionary theory of aging summarized critical arguments against the programmed death theory (called Weismann's theory for historical reasons). Here is the partial list of his most forceful critical arguments that have now gained even more strength and support:

  1. “The extreme rarity, in natural populations, of individuals that would be old enough to die of the postulated death-mechanism”. 
“The failure of several decades (now, century) of gerontological research to uncover any death-mechanism”; “The difficulties involved in visualizing how such a feature [program for death] could be produced by natural selection”.

There is, however, one good reason why this defunct theory of programmed death should not be ignored or forgotten, and it is that the ghosts of this dead theory are still found everywhere, including in the Encyclopedia Britannica, which states that “locked within the code of the genetic material are instructions that specify the age beyond which a species cannot live given even the most favorable conditions”. This concept, however, proved to be inconsistent with the observed mortality kinetics at advanced ages.

Moreover, attempts are made to revive Weismann's theory of programmed death by suggesting an existence of a special suicide program for the whole organisms (called phenoptosis), which performs “very important functions, purifying…communities of organisms from unwanted individuals”. According to this hypothesis, programmed death “is supposed to prevent the appearance of asocial monsters capable to ruin kin, community and entire population”. Thus, Weismann's evolutionary theory of programmed death still remains an issue of scientific discussions.

The renewed interest in programmed aging (design-limited life span) in the late 20th century can be explained by the number of major developments that spoke to the major objections to Weismann's concept:

  1. There is now substantial agreement that aging (as opposed to death, per se) does have evolutionary consequences. Aging causes weakness, increased susceptibility to disease and environmental conditions, reduced mobility, and reduced sensory acuity, all of which plausibly reduce survival and reproduction potential. These effects begin to occur at rather young ages.
  1. Our certainty in the absolute truth of traditional evolutionary mechanics theory has dramatically declined because of conflicts between the theory and a wide variety of observations. This led to development of alternative evolutionary mechanics theories that support Weismann's concept.
  1. Experimental evidence (such as aging genes) increasingly favors programmed aging.
As for August Weismann, he should be credited with at least four significant contributions to aging studies:

  1. Suggesting the first evolutionary theory of aging that attracted the attention of other researchers. 
  2. Abandoning his own theory when he understood that it was incorrect. This decision cleaned up the intellectual space for new evolutionary theories of aging. 
  3. Correctly predicting the existence of a cell division limit without having any data at all (on the basis of theoretical inspiration alone!). 
  4. Formulating the germ plasm theory, i.e., that the body is strictly divided into two types of cells: the germ cells (sperm or ova cells), which are the only cells transmitting hereditary information to the offspring, as opposed to all other “somatic”cells, with a prophetic claim of “the perishable and vulnerable nature of the soma”.
Implications for medicine
The idea that organisms were designed to age as opposed to aging as a result of some fundamental limitation offered considerable promise for anti-aging efforts.

Sources and Additional Information:


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