Aging: Reliability Theory and Phenoptosis Concept Leonid A. Gavrilov Natalia S. Gavrilova Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637

Suppose, for the sake of discussion, that the ‘Program’ exists. Then what properties should this ‘Program’ have?

FACT: Genetically identical organisms living in identical conditions do NOT die simultaneously In fact the range (variance) in lifetimes remains quite high. Coefficient of variation =

Implications: The hypothetical ‘Program’ is NOT a program for lifespan (length of life), but rather a program for age-dynamics for probability of death

FACT: Age-related increase in death risk (aging) starts very early. Aging is observed long before post-reproductive age, sometimes as early as at puberty

Stages of Life in Machines and Humans The so-called bathtub curve for technical systems Bathtub curve for human mortality as seen in the U.S. population in 1999 has the same shape as the curve for failure rates of many machines.

Implications: The hypothetical ‘Program’ is not a post-reproductive program based on a principle: “Мавр сделал свое дело, мавр должен уходить” Instead it should be a maturation- related program based on a principle: “Мавр начал свое дело, мавр может начинать потихоньку уходить”

How can this hypothetical ‘Program’ be sustained by Nature (evolution)? If such Program exists then how its accidental switching- off (by random mutations) can be harmful for fitness (number of progeny)?

General Idea: Military equipment designed for combat may have ‘suicidal’ mode of operation (e.g. missiles), sometimes even with programmed self- destruction. This may happen in biology too, if “the struggle for survival” and “biological arms race” are operating literally.

Idea: Programmed death as a way to save progeny from more dangerous, host- adapted “familial” infections. Justification: Over time, infections can evolve within an organism (microevolution), producing vectors well-adapted to a particular host, and his closest relatives. Making parental lifespan shorter saves the progeny from the emergence of such particularly dangerous family-specific infections

Excessive apoptosis and killing of our infected cells by immune system may be advantageous for our progeny (lower risk of family-specific infections), but it results in aging due to cell loss.

Idea: Creating a toxic, self-destructive environment within our own body, in order to control infections. Chronic inflammation including the chemical weapons (ROS, HClO, etc.) Intentional deficits of micronutrients (iron deficiency, etc.) to control infectious growth at the cost of organism’s damage (mutations) High body temperature, even at baseline, even if not good for longevity (depurinization of DNA)

Other Ideas: “Developmental rush –> Developmental noise” hypothesis Selective pressure to complete development sooner rather than later creates opportunities for more ‘mistakes’ introduced during development – “the high initial damage load hypothesis” (HIDL hypothesis).

Consensus between stochastic and programmed aging: Aging is stochastic, because this is a progressive accumulation of random damage Aging may also be considered as programmed, because of specific mechanisms responsible for elevated rates of damage accumulation

Implications for life extension If these ideas are correct, then our bodies are not optimized for a long life, and there are a lot of opportunities for further very significant extension of healthy lifespan