Phenoptosis – Are We Programmed to Die?

In 1999 the Russian biochemist Vladimir Skulachev coined the term Phenoptosis in his paper. In analogy to apoptosis (planned cell death), where cells undergo a death program to protect the organism, he hypothesized that sometimes individual organisms die to protect a population or larger group of organisms. Wikipedia lists numerous examples:

  1. E. coli undergoes programmed death once infected by a phage (a virus that infects bacteria).
  2. Male Antechinus die after their first mating season as their body essentially disintegrates from an overflow of testosterone and cortisol.
  3. Similar to that, Salmon die soon after mating from an increased level of corticosteroids like cortisol. If you take out a salmon’s adrenal glands after spawning they are able to live on happily ever after.
  4. Sepsis – we’ll get to that
  5. Aging in general

The deaths of a single individuals can be understood as serving a  ‘purpose’ for the population as a whole: In the case of E. coli this helps to protect a population from further infection by the phage, while Antechinus and Salmon make room for next generations (See also my post about semelparity, the strategy of only mating once and then dying). This idea can also be extended to the normal aging process: Aging of individuals (and dying from age) increases the overall fitness of the species by leaving more resources to following generations and makes it more likely that the old and not the young fall prey to predators. So far so good. Skulachev, however, goes one step further and suggests that aging and dying may be pre-programmed processes instead of merely random accumulations of damage. When I first heard about this didn’t strike me as a very revolutionary idea. The thought feels somehow intuitive and fits our cozy narrative of ‘everything in nature follows a purpose’. But note that this interpretation of death is indeed quite different from the one we usually have and is able to make strong predictions. Normally, we think of aging as the unintended accumulation of somewhat random damage to cells. This implies that

  • Aging should appear everywhere (maybe with an exception to cases where cell repair mechanisms are exceptionally good).
  • There could be a selection pressure towards better cell repair mechanisms and longer lives (who can live longer can have more offspring). We should maybe see some correlation between age and complexity of an organism.
  • Life can be extended by simply repairing / replacing everything that is broken in an organism.
  • We should presumably see a rather linear relationship between age (i.e. cell damage) and decline in bodily functions
  • We should maybe observe larger outliers in terms of age than we actually do if aging was only due to the random accumulation of damage.

Skulachev’s theory that death and aging are pre-programmed and ‘intended’ has different implications:

  • We should observe species that have lost the aging program (We do. This is called negligible senescence. Some sharks, turtles, jellyfish and maybe even crocodiles don’t seem to necessarily naturally die from age. If this was just a consequence of them having better cell repair mechanisms: why did selection favor this in sharks, but not in other sea predators?
  • Age should hardly be fixable by repairing / replacing individual parts that are damaged. Indeed modern medicine is actually really bad at prolonging the human lifespan. Hygiene, sports and diet have much larger effects.
  • However, aging may be fixable if you are able to change the aging program (soybeans live much longer if you remove their seeds, salmons live if you remove their adrenal glands, animals could live longer by inhibiting pathways responsible for declining cell repair mechanisms)
  • We should see aging to have non-linear effects. Indeed physical decline in humans does not happen linearly, but exponentially (at least mortality increases exponentially with age, this is called the Gompertz law of mortality).
  • We should see individuals die in ways that can be best explained as a way to protect the species.

The last point is where sepsis comes into play as yet another possible program that makes individuals die to protect the species. Sepsis is an ‘over’-reaction of the body to stress and pathogens that leads to a very quick death of the individual. Blood vessels lose their muscular tone and individuals die from circulatory shock and organ failure (usually not from the pathogen itself!). If individuals could in principle survive the pathogen, then this suggests there should be a selection pressure to prevent such overreactions of the body. If however, sepsis is a way to make sure an infected organism dies quickly instead of transmitting the pathogen to other individuals, this starts to make sense.

Conclusion: I find the idea of pre-programmed death very convincing in the cases of E. coli or sepsis (Edit: I found Hbkk’s comment even more convincing). I also find it very convincing to think of death and aging in terms of its contribution to the overall fitness of a species. I am however not quite sure whether aging necessarily needs to be a pre-programmed process in order to serve a secondary purpose. Instead of developing a death program, nature could just as well exert selective pressure not to develop very good cell repair mechanisms. This would also lead to an organism eventually dying out at some point even without programmed death. If there were a a specific program that we could target this would be very good news for modern medicine. I somewhat doubt however, whether there is a single program manageable small number of them) we could target to prevent aging.

2 Comments

  1. Still not convinced about the sepsis story.
    i) I find the ‘textbook story’ of sepsis itself pretty convincing. In the vast majority of infections, the mechanisms responsible for sepsis (i.e. the innate immune system) perform well and in some unfortunate cases the system overshoots. From an evolutionary perspective, this is not terrible because in many of these cases the host would’ve died anyways if you don’t have modern antibiotics to cure the infection.
    ii) Sepsis is usually caused by bacteria and bacterial infections are not usually highly contagious after a successful (adaptive) immune response has been initiated. In contrast, viral infections, of which some show prolonged ‘shedding’ even after symptoms have stopped, do not cause sepsis (even though maladaptive immune response may be the cause for the high death toll of 20-40 year olds during the spanish flu ).
    iii) Sepsis does not seem to be caused by highly virulent agents too often. Things like wound infections or urogenital infections are likely causes of sepsis but unlikely to spread from person to person. So in a lot of sepsis cases, the reaction would still be maladaptive.
    iv) The ‘phenoptosis argument’ would suggest that solitary animals do not need to have this mechanism, because the risk of infecting other members of their species is so small. I did not find any sources claiming absence of sepsis in solitary mammals, but I would be very interested if anybody found some.
    v) Arguments like X does not exist, so there must be a hidden reason, why absence of X is useful irk me. There is probably heavy selection pressure for humans to evolve telepathy. If you could read other people’s mind, it would be much easier for you to find a mate, win fights over resources, cooperate with others, etc. But the fact that the world has not been taken over by mind-reading superhumans doesn’t mean that reading minds would not be useful. This is to say that a powerful regulatory mechanism that stops sepsis but does not impair the immune system in normal function could very well become a positively selected trait, if it existed. I tend to think that such a mechanism would be pretty complex and most traits that would improve sepsis survival would in turn reduce survival in common infections. Mammals could very well just sit at a local optimum and every move toward the global optimum of perfectly calibrated immune response, would just be too deadly.

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