Fundamental concepts linking programmed death to the evolution of multicellularity were advanced as early as 1881 by August Weismann, a zoologist and pioneer of genetic theories designed to explain development and cell differentiation. Weismann proposed that aging and decay are not inherent to life itself but are events that became integral to development only in the course of evolution of multicellular organisms. Only the multicellular organism would inevitably be doomed, through senescence – the process of aging.

A single-celled organism such as an amoeba increases in size when supplied with ample food, and divides into two separate cells. Does division imply the end of individual life? We may debate whether the doubling of an individual means that the original individual’s life has ended. After all, a corpse is not left behind. In a sense, organisms like bacteria or protists are potentially immortal: their lives are ended only being devoured, destroyed by parasites and/or environmental destruction, not aging.

In protists, an amoeba for example, Weismann argued, there is no regular process (we would now say ‘program’) of death in order to terminate the individual life, because every individual cell is simultaneously a generative cell which secures the continuation of the species. By contrast, in the multicellular organism a segregation of generative and somatic cells has evolved. Somatic cells can focus on a few functions and optimize them because they do not need to meet all requirements and accomplish all functions of life, including reproduction. Somatic cells can be fine-tuned to perform their particular task for the benefit of the entire cell community: some cells secrete enzymes and maximize the exploitation of food; other cells optimize sensory functions to exploit the environment and to recognize dangers or opportunities.

This focus on specialized functions to the detriment of cellular reproduction was possible because generative cells took over the task of reproducing the entire organism, standing proxy for the whole community. Gametes focus on the job of reproduction and propagation without being restrained by other occupations. Although both male and female gametes are highly specialized cells, they give rise to a totipotent zygote. The zygote is unable to perform any somatic functions by itself but is able to transmit to its daughter cells the ability to adopt every specialization and to differentiate into every cell type that is provided for by the genetic program of the species. Universal potency and perfection of particular somatic functions are mutually exclusive. A single-celled organism remains bound to compromises.

Death in metazoans is the regular fate of somatic cells. But even in metazoans there are, surprisingly, exceptions to this rule. Cells of metazoans maintained in culture for long periods of time, even human cells, are often immortal just like protists. Because of their immortality such cells can be kept alive and grown for years. And the freshwater polyp Hydra is, as a whole, potentially immortal.

However, cells grown in culture flasks have been subjected to selection: they represent stem cells with the programmed ability to divide, or are cells on the way to becoming cancer cells which have recovered immortality. Hydra is another and peculiar case: all of its terminally differentiated cells in fact die, but every decaying cell is replaced by a substitute generated from immortal stem cells (Sect. 4.​3). Only cells that have preserved the ability to divide are immortal. Apparently, perpetual cell divisions are a prerequisite to immortality, while loss of the capacity for cell division leads to death.

Enzymes and other proteins are not in the energetically lowest conformational state when they are biologically active. Rather, they are in a metastable state created during their synthesis, sometimes with the assistance of chaperones. Many influences such as thermal energy, changing ionic strength and the pH of the solution, or collision with radicals may throw a protein out of its metastable condition into a deeper energetic level: it denatures. The probability of spontaneous renaturation is minimal. Denatured proteins are useless and must be replaced by newly synthesized ones if the cell’s metabolic or developmental programs still require their presence.

A terminally differentiated cell will have difficulties replacing all of its proteins. How could a heart muscle cell replace its contractile apparatus without interrupting its rhythmic beating? How could a nerve cell in the brain repair its numerous dendritic and axonal fibres and hundreds of synaptic connections while staying prepared to fire? And could such a nerve cell even procure all the needed building materials, crowded together with myriads of other competing nerve cells?

Limits set by the stability of genetic information. Above all, limits on the replacement of proteins comes from the condition of the DNA – the source of information needed for the synthesis of proteins.

DNA itself suffers damage by

these factors all cause mutations and irreversible loss of information. Every day a human cell loses about 5,000 purine bases (A or G) by induced depurinization, and 100 cytosine bases are converted into uracil. Cytosine spontaneously deaminates to uracil. After birth, when neuroblasts stop proliferating, the enzymes responsible for repair largely disappear from these cells.

A cell possesses multiple mechanisms of DNA repair. The mechanisms function as long as one of the two DNA strands remains intact and can serve as a template of the correct base sequence. A comprehensive correction of defects is only possible when the entire genome is replicated. This would explain why the only immortal cells are those that divide again and again. In mammals a correlation has been found between the capacity of the DNA repair system and the average lifespan of the species.

In addition, in unicellular organisms and cell communities alike, natural selection eliminates faulty cells. This may be the reason why so many cells undergo cell death in the germline: only cells with (more or less) intact genetic information survive. Thus, sexual reproduction helps to perpetuate a species. On the other hand, positive natural selection of cells with intact DNA presupposes continuing cell multiplication by mitosis. Therefore, the principle is invalid in tissues composed entirely of terminally differentiated cells, such as nervous tissue.

Limits set by the accumulation of damage at the cellular and organismic levels. Numerous age-associated irreversible changes and accumulating deficiencies have been identified. For example,

The two last causes alone restrict the maximum longevity of humans to approximately 120 years. Death is to be expected.

In all eukaryotic organisms and tissues with advancing age disturbed mitochondrial functions are recorded. Over many years this was attributed to irreparable damages caused by toxic oxygen radicals. Highly reactive oxygen species ROS (Reactive Oxygen Species) are the superoxide-ion ^• O _{2 minus} , hydrogen peroxide ^• H ₂ O ₂ ^. and the free hydroxyl radical ^• OH. These can cause oxidative damages to lipids and mitochondrial DNA. When upon abundant food intake and high ATP expenditure the mitochondrial respiratory chain operates at full stretch, inevitably more reactive oxygen species emerge and effect damage to the cells. However, normally these oxygen species are detoxified by catalases and peroxidases. Recent studies suggest that only extreme physical strain would lead to lasting oxidative damages while mild physical activity would induce mechanisms of protection and counteract age-related decrease of the energy-generating metabolism.

Recent studies provide compelling and concurring evidence that an ascetic life style with meagre fare caloric restriction prolongs the average life expectancy, in the round worm Caenorhabditis elegans, in the fly Drosophila and in the mouse, and it is supposed that this applies to humans as well. There are speculations about possible causes, such as the just discussed oxygen radical hypothesis, but assured facts are scarce and no theory is commonly accepted.