Phenoptosis and the Various Types of Natural Selection.

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.

Is Human Aging a Form of Phenoptosis?

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.

Is Evidence Supporting the Subtelomere-Telomere Theory of Aging?

The telomere theory tries to explain cellular mechanisms of aging as mainly caused by telomere shortening at each duplication. The subtelomere-telomere theory overcomes various shortcomings of telomere theory by highlighting the essential role of subtelomeric DNA in aging mechanisms. The present work illustrates and deepens the correspondence between assumptions and implications of subtelomere-telomere theory and experimental results. In particular, it is investigated the evidence regarding the relationships between aging and (i) epigenetic modifications; (ii) oxidation and inflammation; (iii) telomere protection; (iv) telomeric heterochromatin hood; (v) gradual cell senescence; (vi) cell senescence; and (vii) organism decline with telomere shortening. The evidence appears broadly in accordance or at least compatible with the description and implications of the subtelomere-telomere theory. In short, phenomena of cellular aging, by which the senescence of the whole organism is determined in various ways, appear substantially dependent on epigenetic modifications regulated by the subtelomere-telomere-telomeric hood-telomerase system. These phenomena appear to be not random, inevitable, and irreversible but rather induced and regulated by genetically determined mechanisms, and modifiable and reversible by appropriate methods. All this supports the thesis that aging is a genetically programmed and regulated phenoptotic phenomenon and is against the opposite thesis of aging as caused by random and inevitable degenerative factors.

Sex and Aging: A Comparison between Two Phenoptotic Phenomena.

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.

Aging of perennial cells and organ parts according to the programmed aging paradigm.

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.

Possible Interventions to Modify Aging.

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.

Non-programmed versus 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 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.

Non-Programmed Versus 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.

The programmed aging paradigm: how we get old.

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.

The concept of phenoptosis and its usefulness for controlling aging.

Aging is generally interpreted according to two opposing paradigms: 1) as a non-adaptive phenomenon, caused by the age-related failure of homeostatic mechanisms; 2) as a specific function, favored by natural selection, which determines the self-destruction of the organism, namely explaining aging as phenoptosis. This interpretation requires genetically determined and regulated age-specific mechanisms, now well documented by an impressive and growing scientific evidence. It follows that, in principle, aging is modifiable even up to the condition, already existing for many species, of "negligible senescence", alias unlimited longevity.

Empirical evidence for various evolutionary hypotheses on species demonstrating increasing mortality with increasing chronological age in the wild.

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.

Evolutionary explanations of the "actuarial senescence in the wild" and of the "state of senility".

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.