St. Petersburg Proceedings
The programmed death phenomena, aging, and the Samurai law of biology

Dedicated to the memory of my dear friend and co-worker, Andrey Dmitrievich Kaulen, who departed too soon—deceased 13 August 2000
https://doi.org/10.1016/S0531-5565(01)00109-7Get rights and content

Abstract

Analysis of the programmed death phenomena from mitochondria (mitoptosis) to whole organisms (phenoptosis) clearly shows that suicide programs are inherent at various levels of organization of living systems. Such programs perform very important functions, purifying (i) cells from damaged (or unwanted for other reasons) organelles, (ii) tissues from unwanted cells, (iii) organisms from organs transiently appearing during ontogenesis, and (iv) communities of organisms from unwanted individuals. Defence against reactive oxygen species (ROS) is probably one of primary evolutionary functions of programmed death mechanisms. So far, it seems that ROS play a key role in the mito-, apo-, organo- and phenoptoses. Here a concept is described which tries to unite Weismann's concept of aging as an adaptive programmed death mechanism and the alternative point of view considering aging as an inevitable result of accumulation in an organism of occasional injuries. It is suggested that injury accumulation is monitored by special system sending a death signal to actuate a phenoptotic program when the number of injuries reaches some critical level. The system in question is organized in such a way that the lethal case appears to be a result of phenoptosis long before occasional injuries make the functioning of the organism impossible. This strategy is supposed to prevent the appearance of asocial monsters capable to ruining kin, community and entire population. These relationships are regarded as an example of the Samurai law of biology: ‘It is better to die than to be wrong’. It is stressed that for humans these cruel regulations look like an atavism that should be overcome to prolong the human life span.

Introduction

For aerobic organisms, molecular oxygen always creates a problem because it is a precursor of so-called reactive oxygen species (ROS). Among these the hydroxyl radical (OH·) is the most dangerous since thermodynamically it can oxidize any compound of biological origin (redox potential, +1.35 V), the activation energies for such oxidations being very low. Oxidation of DNA is of especially dramatic consequence due to damage to genetic information. This is why biological evolution invented a multilevel system of the anti-oxygen defence that strongly reduces the danger of oxygen.

Recent progress in cell biology studies has clearly revealed that programmed death mechanisms are actuated when other lines of defence fail to solve the problem (for reviews, see Skulachev, 1996a, Skulachev, 1996b, Skulachev, 2000a). This situation represents a particular case of a general biological principle that I called the Samurai law of biology: ‘It is better to die than to be wrong’. According to this principle, a living system insures itself against degradation of genetic and other very complicated programs developed during perhaps more than three billion years of biological evolution. The Samurai law means that a living system is always ready to commit suicide. It kills itself when recognizes that it has become useless or even dangerous for a living system of a higher hierarchical position (Skulachev, 2000a).

Below I shall describe how the programmed death phenomena at various levels of complexity (from intracellular organelles to living organisms) help overcome the oxygen danger and solve some other problems. This analysis will be concluded by an attempt to apply the Samurai law to the processes of aging.

Section snippets

Mitochondrial antioxidant system: initial lines of defence.

Mitochondria, the respiring organelles of the cell, have a large amount of electron transfer enzymes that can be attacked by O2. The one-electron reduction of O2 to O2·− is usually followed by conversion of O2·− to H2O2, which is an immediate precursor of OH·, the most dangerous member of the ROS family. As a rule, mitochondria are responsible for the production of most of the ROS generated in the cell. This occurs in spite of that mitochondria are well equipped to prevent ROS formation and to

Apoptosis induced by massive mitoptosis

As mentioned in the preceding section, the ROS-induced PTP opening leads to swelling of the matrix and, consequently, to the loss of integrity of the outer mitochondrial membrane, thus releasing the intermembrane proteins into the cytosol. Among them, the following four proteins are of interest in this context: cytochrome c, apoptosis-inducing factor (AIF), the second mitochondrial apoptosis-activating protein (Smac; also abbreviated DIABLO) and procaspase 9. All these proteins are somehow

Organoptosis, programmed elimination of unwanted organs.

Massive apoptosis of cells composing an organ should eliminate the organ. This process can be defined as ‘organoptosis’. As an example, consider the disappearance of the tail of a tadpole when it converts to a frog. It was recently reported (Kashiwagi et al., 1999) that addition of thyroxine (a hormone known to cause regression of the tail in tadpole) to severed tails surviving in a special medium caused shortening of the tails that occurred on the time scale of hours. The following chain of

Definition

Obviously, massive apoptosis in an organ of vital importance, resulting in organoptosis, must entail death of the entire organism. On the face of it, such an event should be regarded as a lethal pathology of no biological sense. However, it may not be the case if the organism in question is a member of a kin or community of other individuals. Here, altruistic death of individuals may appear to be useful for a superorganismal unit, being a mechanism for adaptation of the group to a changing

Some general remarks

Weismann's (1889)hypothesis on aging as an adaptive mechanism was strongly criticized by Medawar (1952), who assumed that aging could not have developed during the course of biological evolution. Medawar in fact assumed that, under natural conditions, the majority of organisms die before they become old. This assumption, however, cannot be applied to some periods of evolution of many species (Bowles, 2000).

Moreover, individuals with changes in their genomes can dramatically affect the fate of a

End-under-replication of linear DNA. Role of the telomere

Bowles (1998) suggested that, historically, the living cell invented the first specialized mechanism of aging when linear DNA substituted for the circular DNA inherent in the majority of bacteria and Archae. This event immediately resulted in a specific kind of DNA aging, a process consisting of replication-linked shortening of DNA. Such shortening inevitably accompanies replication of linear DNA, since even now the replication complex operates with linear DNA in the same way as it does with

Specific features of human aging

In many animal species including higher monkeys, the females die soon after their reproductive period is over, a fact that can be regarded as one more example of phenoptosis.

Humans are unique in they have a lifespan that is twice as long as other primates. This is due to the fact that the post-reproductive age life of the female is strongly extended. Lewis (1999) proposed that ‘the transmission of knowledge from grandparents to progeny serves as a driving force for extending human longevity...

Conclusions

In this paper, we started with programmed death of intracellular organelles, then considered similar phenomena on the levels of cells and organs and, moving along this line, came to phenoptosis, programmed death of an organism. The latter for sure takes place in wild nature, being inherent in quite different species from bacteria to higher animals. The possibility has been discussed that phenoptosis also occurs among humans. Here septic shock was regarded as an example of fast phenoptosis

Acknowledgements

The author is very grateful to the Ludwig Institute for Cancer Research (Grant RBO 863) and the Russian Foundation for Basic Research (Grants 95-15-00022 and 00-15-97799) for support.

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