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In the first description of evolution, the fundamental mechanism is the natural selection favoring the individuals best suited for survival and reproduction (selection at the individual level or classical Darwinian selection). However, this is a very reductive description of natural selection that does not consider or explain a long series of known phenomena, including those in which an individual sacrifices or jeopardizes his life on the basis of genetically determined mechanisms (i.e., phenoptosis). In fact, in addition to (i) selection at the individual level, it is essential to consider other types of natural selection such as those concerning: (ii) kin selection and some related forms of group selection; (iii) the interactions between the innumerable species that constitute a holobiont; (iv) the origin of the eukaryotic cell from prokaryotic organisms; (v) the origin of multicellular eukaryotic organisms from unicellular organisms; (vi) eusociality (e.g., in many species of ants, bees, termites); (vii) selection at the level of single genes, or groups of genes; (viii) the interactions between individuals (or more precisely their holobionts) of the innumerable species that make up an ecosystem. These forms of natural selection, which are all effects and not violations of the classical Darwinian selection, also show how concepts as life, species, individual, and phenoptosis are somewhat not entirely defined and somehow arbitrary. Furthermore, the idea of organisms selected on the basis of their survival and reproduction capabilities is intertwined with that of organisms also selected on the basis of their ability to cooperate and interact, even by losing their lives or their distinct identities.

A much debated question is whether aging is the cumulative consequence of degenerative factors insufficiently opposed by natural selection, or, on the contrary, an ordered process, genetically determined and regulated, modeled by natural selection, and for which the definition of phenoptotic phenomenon would be entirely appropriate. In this review, theoretical arguments and empirical data about the two hypotheses are exposed, with more evidence in support of the thesis of aging as a form of phenoptosis. However, as the thesis of aging as an adaptive and programmed phenomenon necessarily requires the existence of specific mechanisms that determine to age, such as the subtelomere-telomere theory proposed for this purpose, the evidence supporting the mechanisms described by this theory is reported. In particular, it is highlighted that the recent interpretation of the role of TERRA sequences in the context of subtelomere-telomere theory is a fundamental point in supporting the hypothesized mechanisms. Furthermore, some characteristics of the mechanisms proposed by the theory, such as epigenetic modifications in aging, gradual cell senescence, cell senescence, limits in cell duplications, and fixed size of the telomeric heterochromatin hood, are exposed in their compatibility with both the thesis of aging as phenoptotic phenomenon and the opposite thesis. In short, aging as a form of phenoptosis appears a scientifically sound hypothesis while the opposite thesis should clarify the meaning of various phenomena that appear to invalidate it.

Phenoptosis is a phenomenon that is genetically programmed and favored by natural selection, and that determines death or increased risk of death (fitness reduction) for the individual that manifests it. Aging, here defined as age-related progressive mortality increase in the wild, if programmed and favored by natural selection, falls within the definition of phenoptosis. Sexual reproduction (sex), as for the involved individuals determines fitness reduction and, in some species, even certain death, also falls within the definition of phenoptosis. In this review, sex and aging are analyzed as phenoptotic phenomena, and the similarities between them are investigated. In particular, from a theoretical standpoint, the genes that cause and regulate these phenomena: (i) require analyses that consider both individual and supra-individual selection because they are harmful in terms of individual selection, but advantageous (that is, favored by natural selection) in particular conditions of supra-individual selection; (ii) determine a higher velocity of and greater opportunities for evolution and, therefore, greater evolutionary potential (evolvability); (iii) are advantageous under ecological conditions of K-selection and with finite populations; (iv) are disadvantageous (that is, not favored by natural selection) under ecological conditions of r-selection and with unlimited populations; (v) are not advantageous in all ecological conditions and, so, species that reproduce asexually or species that do not age are predicted and exist.

The programmed aging paradigm interprets aging as a function favored by natural selection at a supra-individual level. This function is implemented, according to the telomere theory, through mechanisms that operate through the subtelomere-telomere-telomerase system. After reviewing some necessary technical and ethical reservations and providing a concise description of aging mechanisms, this work considers interventions that could lead to the control of some highly disabling characteristics of aging, such as Alzheimer's and Parkinson's syndromes and age-related macular degeneration, and afterwards to a full control of aging up to a condition equivalent to that of the species defined as "with negligible senescence". The various steps needed for the development of such interventions are described along general lines.

If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

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 above-mentioned 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.