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There are two opposite paradigms to explain aging, here precisely defined as "age-related progressive mortality increase, i.e. fitness decline, in the wild". The first maintains that natural selection is unable to maintain fitness as age increases. The second asserts that, in particular ecological conditions, natural selection favors specific mechanisms for limiting the lifespan. The predictions derived from the two paradigms are quite different and often opposing. A series of empirical data and certain theoretical considerations (non-universality of aging; great inter-specific variation of aging rates; effects of caloric restriction on lifespan; damage of aging for the senescing individual but its advantage in terms of supra-individual selection; existence of fitness decline in the wild; proportion of deaths due to intrinsic mortality inversely related to extrinsic mortality, when various species are compared; impossibility of explaining the age-related fitness decline as a consequence of genes that are harmful at a certain age; age-related progressive decline of cell turnover capacities; on/off cell senescence; gradual cell senescence) are compared with the predictions of the two paradigms and their compatibility with each paradigm is considered. The result is that the abovementioned empirical data and theoretical considerations strongly contradict and falsify in many ways all theories belonging to the first paradigm. On the contrary, they are consistent or compatible with the predictions of the second paradigm.

Many species show a significant increase in mortality with increasing chronological age in the wild. For this phenomenon, three possible general hypotheses are proposed, namely that: (1) it has no adaptive meaning; (2) it has an adaptive meaning; (3) the ancestry is the pivotal determinant. These hypotheses are evaluated according to their consistency with the empirical evidence. In particular, (1) the existence of many species with a constant, or almost constant, mortality rate, especially the so-called “animals with negligible senescence”; (2) the inverse correlation, observed in mammals and birds in the wild, between extrinsic mortality and the proportion of deaths due to intrinsic mortality; (3) the existence of highly sophisticated, genetically determined, and regulated mechanisms that limit and modulate cell duplication capacities and overall cell functionality. On the whole, the hypothesis of an adaptive meaning appears to be consistent with the empirical evidence, while the other two hypotheses hardly appear compatible.

A large set of data suggests that progressive reduction of fitness and senile decay in vertebrates are in correlation with the decline of cell replication capacities. However, the limits in such capacities are hardly explained in evolutionarily terms by current gerontological theories that rule out fitness decline as something genetically determined and regulated, and therefore somehow favored by natural selection.Four theories are tested as possible explanations of the “increasing mortality with increasing chronological age in populations in the wild” (“IMICAW”[1]), alias “actuarial senescence in the wild”[2], and of the observed negative correlation between extrinsic mortality and the ratio between deaths due to intrinsic mortality and deaths due to extrinsic mortality. Only the theory attributing an adaptive value to IMICAW allows an evolutionary explanation for it and for the aforesaid inverse correlation, while the other three theories (“mutation accumulation”, “antagonistic pleiotropy”, and “disposable soma” th.) even predict a positive correlation.Afterwards, the same theories are tested as possible explanations for the “state of senility”[3], namely the deteriorated state of individuals in artificially protected conditions (captivity, civilization, etc.) at ages rarely or never observable in the wild. With the distinction between “damage resulting from intrinsic living processes”[4], alias “age changes”[5], and “age-associated diseases”[4,5], the same theory explaining IMICAW allows a rational interpretation of the first category of phenomena while another theory, the “mutation accumulation” hypothesis, gives an immediate interpretation for the second category.The current gerontological paradigm explaining the increasing mortality with increasing chronological age as consequence of insufficient selection should be restricted to the “age-associated diseases”. For IMICAW, it should be substituted with the concept of a physiologic phenomenon genetically determined by a balance of opposite selective pressures — strictly in terms of kin selection — and, for “age changes”, with the action of the same IMICAW-causing mechanisms at ages when selection becomes ineffective.

Phenoptosis is defined as the programmed death of an organism. In a more detailed formulation of the concept, it is the death of an individual caused by its own actions or by actions of close relatives (and not by accidents or age-independent diseases), which is determined by genes that are favored by natural selection and in certain cases increase the evolvability of organisms. This category of phenomena cannot be justified in terms of individual selection and needs always a justification in terms of supra-individual selection. Four types of phenoptosis are proposed (A, obligatory and rapid; B, obligatory and slow; C, optional; D, indirect). Examples of each type and subtype are given. The classification is discussed in its meaning and implications, and compared with another classification of end life types largely based on the classical concept of senescence.

A computer program, which runs on MS-DOS personal computers, is described that assists in the design of synthetic genes coding for proteins. The goal of the program is the design of a gene which (i) contains as many unique restriction sites as possible and (ii) uses a specific codon usage. The gene designed according to the criteria above is (i) suitable for 'modular mutagenesis' experiments and (ii) optimized for expression. The program 'reverse-translates' protein sequences into degenerated DNA sequences, generates a map of potential restriction sites and locates sequence positions where unique restriction sites can be accommodated. The nucleic acid sequence is then 'refined' according to a specific codon usage to remove any degeneration. Unique restriction sites, if potentially present, can be 'forced' into the degenerated nucleic acid sequence by using 'priority codes' assigned to different restriction sequences.

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According to the traditional explanations ("old paradigm"), aging is due to the progressive accumulation of heterogeneous damages that are insufficiently contrasted by natural selection. An opposite interpretation ("new paradigm") sees aging as selectively advantageous in terms of supra-individual natural selection, and this implies the indispensable existence of genetically controlled specific mechanisms that determine it. The aim of this work is to expound synthetically the progressive alterations that mark the aging by showing how these changes are clearly defined and regulated by genes. The possibility of such a description, based on sound evidence, is an essential element for the plausibility of the new paradigm, and a fundamental argument against the tenability of the old paradigm.