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This is the outdated version: Mate-Selection, Scale, And Aging
Kevin L. Brown
Version 6.10, Updated May. 11, 2014
Copy Right: Kevin L. Brown, All rights reserved.
First Published Version August 11, 2009
A theory of aging is proposed challenging the concept that economic trade-offs between body repair and reproduction are the primary drivers of senescence. Instead, it is proposed that dis-economies of scale drive the evolution of growth-termination which caps increases in fitness that typically result from increasing size. Once deprived of growth as a primary method of increasing fitness the individual is unable to mitigate ongoing extrinsic risks to loss of fitness. This limitation drives Mate-Selection processes to more strongly favor the fitness of progeny by discounting the fitness of adults. It is proposed that the discounting of fitness in adults is primarily accomplished by mechanisms that down-regulate autophagy and stem cell differentiation pathways conserving a broad spectrum of resources for potential use by progeny while senescing adults at controlled species specific rates.
Since the publication of the Origin of the Species, many people have attempted to identify the fundamental causes of aging. Prominent theories have proposed that aging is caused by one or more of three basic processes:
In spite of the fact that the high degree of variability in lifespan across species strongly supports the concept that aging is under genetic control, all three of these theories essentially define senescence as beyond direct regulation by natural selection. The continuing support of these theories by evolutionary biologists is in some part due to their inability to square the genetic control of senescence with the idea that selection operates to increase the fitness of the individual and not the group. Relative to aging theory this has remained problematic because It has not been intuitively obvious how senescence can function as a trait that favors the fitness of the individual. This paper presents straight forward mechanisms that overcome the problem of explaining how senescence benefits the individual.
Aging theories built on the foundational logic described above have persisted due to the lack of acceptable explanations as to how aging can be favored across such a wide spectrum of species. Specifically, the question persists, what prevents all species from evolving toward negligible senescence? Stated another way, what stop the proliferation of individuals that cheat the natural order by living too long? Over the last fifty years the dearth of adequate answers to this question has lent indirect support to disposable soma theory which proposes that economic cost to reproduction disfavors body-repair, resulting in senescence. However, in recent years, many experimental results that contradict this concept by demonstrating increased life-span with increased reproductive capacity leaves this question in aging theory unresolved. This paper proposes a solution to this question which is consistent with the experimental evidence and is based the individual as the unit of selection.
In a variety of animal models, manipulations of mechanisms involving TOR and Daf-2 / Daf-16 - FOXO genes and their protein products have demonstrated increases in lifespan that range from 15 percent to 75 percent or more. Though impressive, none of these life extending interventions have transformed senescent species into negligibly senescent species to date. Clearly, important additional mechanisms are involved in the regulation of aging.
This paper, "Mate-Selection Scale And Aging" (MSSA) describes an additional significant mechanism of aging and provides the rational for the species specific rates of senescence that we see across species from the very short lived to the negligibly senescent.
Aging & Negligible Senescence
Theories of Aging And Negligible Senescence
Two decades have past since Caleb Finch in Longevity Senescence and the Genome exhaustively exposed the persistence of negligible senescence in nature and yet the dominant theories of aging continue to lack viable mechanisms or explanations for negligible senescence within their models. This paper presents a mechanism as to how and why negligible senescence persists in select species that is contiguous with the mechanisms I propose for senescence.
Negligible Senescence Across Taxa
Negligible senescence is exhibited by a fraction of animal species found spread throughout the phylogenetic tree as specific species of hydroids, corals, clams, lobsters, turtles, fish, amphibians, lizards, and probably whales. A large percentage of these genetically diverse animals grow continuously and are aquatic. It should be noted that the concept of continuous growth, as used in this paper, represents a fully expressed implementation of a genotype, however the phenotype of the animal may not reflect continuous growth due to external factors acting against growth, such as nutritional limitations and parasitism. The paper "The case for negative senescence" provides evidence of these relationships between continuous growth and negligible senescence.
Some specific examples of negligibly senescent animal species are, the American lobster, the rougheye rockfish, quahog (Arctica islandica) clams, all of which grow continuously throughout life. The only mammal known to exhibit minimal or negligible senescence is the Arctic Bowhead Whale which also appear to grow throughout life.
Hydra exhibit negligible senescence, in some sense without continuous growth. However the somatic cells of the hydra migrate from the center of the body to the periphery where they are sloughed off, preventing growth. Additionally, hydra reproduce asexually via budding. Asexual reproduction applies radically different selective pressure on the evolution of senescence, as I discuss in the section titled "The evolution of Death Mechanisms". Asexual reproduction effectively allows hydra to continue to increase their reproductive capability by increasing the total size of the clone, while terminating the growth of all individuals in the clone. A hydra clone consisting of many individuals can be thought of as a single animal consisting of clusters of autonomous differentiated cells that have simply lost direct physical contact with other differentiated clusters but continues to increase in size and therefor fitness.
Blanding's Turtles also appear to exhibit negligible senescence without continuous growth, this seeming anomaly is discussed in the supplementary materials at the end of the paper.
The Evolution of Death Mechanisms
Asexual Reproduction and Death Mechanisms
It has been proposed by Nick Lane in his book titled "Life Ascending" and others that cellular death mechanisms are required in the creation of complex life forms for the production of differentiated tissue types. But why would this be the case, since cells show great capacity to de-differentiate, re-differentiate and migrate to needed locations to build and grow the complex body form. However, I do agree with Nick that death mechanisms at the cellular level and at the level of the multicellular individual evolved as a way to deal with parasites. Here I go further to propose that death mechanisms evolved specifically in organisms as a direct consequence of the asexual reproduction strategy and as a result, mechanisms of death, senescence and negligible senescence have all been profoundly molded by asexuality.
Many obligately asexual species today are recently derived from sexual species and utilize aspects of the remaining sexual apparatus to accomplish asexual reproduction. These species are not the ones under discussion as they are not the precursors to the evolution of sexual species and do not account for the evolution of mechanisms described here.
It has been propose that the cellular death mechanisms employed by single cellular life were simply modified for use by the very first multicellular organisms to accomplish death of the multicellular individual as there should have been strong selective pressure due to the likelihood that all of the cells constituting the individual were likely infected as well.
Asexual Clones and Death
From the perspective of the selfish gene metaphor, since all member of a clone of asexual individual can stand in for any and all other individuals in in the clone relative to reproduction, the death of any subset of individuals in the clone that prevents the extinction of the entire clone is adaptive and should be selected for. Therefore it is adaptive for any individual in a clone that becomes infected by a parasite to kill itself to stop further spread of the parasite. This I propose is the driving logic behind the evolution and persistence of death mechanisms. Since obligately sexual organisms are not capable of employing this kind of selection logic, I propose that death mechanisms predate evolution of sexual reproduction and that sexually reproducing species have cooped and modified preexisting death mechanisms for there use and in the production of mechanisms of senescence.
Asexual Clones and Negligible Senescence
Individuals of a obligately asexual clone that reproduce by budding for instance can only effectively employee death mechanisms as an effective strategy if other members of the clone do not utilize death mechanisms and do not have finite life spans thus ensuring the continued reproduction of the clone. Therefore I propose that death mechanisms and negligible senescence co-evolved as complementary mechanisms in the same asexual species, as both capabilities must exist in the shared genotype across all the individuals to ensure the rationality of death mechanisms as a way to counter parasitism.
I propose that the initial complementary co-evolution of death mechanisms and unlimited life span or negligible senescence has persisted to this day within the same species and accounts for the high degree of plasticity of lifespan as has been demonstrated over short periods of evolutionary time in nature.
Sexual Species and Death Mechanisms
Within clonal species from cyanobacteria to much more complex forms mass dyings of individuals within the clone are well known and the logic of this can be understood as an effective strategy against predation or parasitism, etc, however In obligately sexual species no individual can represent the complete reproductive interest of the entire phenotype of another individual unless they happen to be an identical twin. For this reason the selection pressure for the maintenance of viable death mechanisms for the purposes of protecting other individuals that can reproductively stand in for the sexual individual does not exist. Therefor other sources of selection pressure must be employed to account for the specific form and persistence of death mechanisms, senescence and negligible senescence exhibited by sexual species and is the next topic considered.
In sexual species which cannot rely on the increasing size of the clone, larger size in the individual often provides a fitness advantage by improving the ability of animals to produce more gametes,and produce larger and more numerous offspring. Larger size improves animals ability to acquire more food and protect self and offspring from predation. These fitness advantages, drive natural selection to favor mechanisms that facilitate non-terminated or continuous growth so as to attain larger size in the individual.
One essential facilitator of continuous growth is negligible senescence because it sustains the vitality of the organism providing more time for growth to take place. The relationship between continuous growth and negligible senescence creates a self-reinforcing process in which fitness and size is always greater in the future than it is in the present, further favoring the future.
This self-reinforcing process drives natural selection to continuously discount some portion of present fitness in favor of the combination of growth, negligible senescence, and future reproductive capability.
In support of this concept, David Reznick et al . (2002) proposed in an article titled: "The evolution of senescence in Fish", "indeterminate growth (non-terminated-growth) is a primary driver to delayed senescence in fish because increased size leads to increases in fecundity." In summation, natural selection favors the evolution of mechanisms that facilitate negligible senescence in species that possess a combination of three attributes consisting of, a low mortality rate in young adults, unlimited iteroparity and non-terminating growth.
The relationship between continuous growth and negligible senescence will be made clearer through the following examination of the relationships between terminated-growth and senescence.
Why Senescence Is Common
Senescence is a common phenotype because few species are able to sustain increasing fitness in adult life. Most species do not sustain increasing fitness because the negative effects of increasing scale (size), when left unchecked, strongly reduce the long term fitness of the individual.
This is not the first theory of Aging to recognize that the cessation of growth was involved in senescence. G. P. Bidder (1932) in a paper titled Senescence, reviewed by Caleb Finch in Longevity, Senescence, and the Genome, proposed that senescence is linked to the cessation of growth. He stated that "weakness inherent in protoplasm of nucleated cells; is the unimportant by-product of regulating mechanisms." He proposed senescence resulted "from the continued action of the regulator after growth was ceased,".
Example of Growth-Termination And Senescence
One particularly instructive example, discussed by Bidder, that reinforces the theory that continuous growth is linked to negligible senescence and the corollary that the cessation of growth is the attribute linked to senescence is found in a species of flatfish Pleuronectes platessa which exhibits continuous growth without signs of senescence in the female. While the males stop growing and experience senescence.
It has long been understood that there is a general positive correlation between size and lifespan. The paradox is that within mammalian species dwarf individuals live significantly longer than non-dwarf individuals. I propose that the understanding of this paradox lies in understanding the effects of scaling on fitness, and more specifically on the secondary effects of the mechanisms that mitigate the negative effects of scale on the individual. I will lay the ground work for this topic next.
Dis-Economies-of-Scale Drive Growth-Termination
Mammals and many non-mammalian species terminate growth in the individual at some point in the life cycle as a way to mitigate the fitness reducing effects resulting from increasing size as described by the square-cube law. See the paper titled "Growth Termination and Scale" for a detailed description of the role of the square-cube law in the evolution of growth deceleration and growth-termination.
Though growth-termination mitigates against a reductions in fitness caused by dis-economies-of-scale (DES's), I propose that second order effects that derive from a state of terminated-growth drive the evolution of senescence. Here I propose answers to the questions of how do these second order effects function and how do they culminate in the near ubiquity of senescence in terrestrial animals.
Growth-Termination Caps Fitness
In many species, growth constitutes the last process operating within the individual that provides continual incremental increases in fitness. Other than senescence itself, growth-termination is the last act of morphological and phenotypic development in most animals and in many species of plants. As a result, growth-termination brings to an end the reasonable probability of additional intrinsically produced fitness increases in the individual. Across many species, growth-termination constitutes a cap on the fitness of the individual.
Extrinsic Risks To Fitness Also Modulates Growth-Termination
Many species terminate growth at sizes that are below the body size necessary to produce a loss of fitness caused by DES. For example, species experiencing increasing mortality rates that are due to predation or parasitism can adapt to the threatened loss of future fitness by initiating reproduction earlier in their life cycle. In many species early growth deceleration drives early sexual maturation and early reproduction.
After defining some terms, I will next describe how the capping of fitness in the adult drives the evolution of mechanisms that favor the fitness of offspring at the expense of the adult.
Definition of Key Terms
"Mate-Selection" is defined as: "Any process implemented by an individual or group of individuals of a species that influences the success or failure of combining a haploid complement of it's own or another individuals genes with the haploid complement of another individuals genes in the production of a diploid offspring through processes that discriminate between potential mates on the basis of phenotypes."
The term "Mate-Selection" has been introduced in order to distinguish a concept that is broader in scope than the conventional meaning ascribed to the term "Sexual Selection" which has come to be associated with the production of sexually dimorphic traits. Mate-Selection on the other hand drives the production of both dimorphic and non-dimorphic traits.
"Trans-Generational Selection" is defined as: "Selection acting on the individual that results from forces that directly or indirectly favor the fitness of juveniles while directly or indirectly disfavoring the fitness of the adult individual."
"Trans-Generational Fitness" is defined as: "The survival and developmental fitness experienced during juvenile development by successive generations of an individuals descendants " .
Trans-Generational Fitness VS. Individual Fitness
Trans-Generational Fitness is distinguished from other concepts of fitness that are also focused on the individual as the object of selection, in that trans-generational fitness is an expression of the effectiveness of genes to survive over multiple generations of progeny. Trans-Generational Fitness is an orientation and focus on the survival of genes through generational time rather than a focus on the increase or decrease in the relative numbers of copies of genes in the next generation. Trans-generational fitness reflects the fact that in nature specific genes and the phenotypes they manifest can in some instances persist for long periods of generational time, avoiding extinction, when populations of the genes fluctuate in both absolute and relative numbers.
Trans-generational fitness can be visualized as one end of what I would call a fitness continuum in which forces that favor the fitness of juvenile progeny are highly influential, while the other end of the fitness continuum represents individuals which are relativistically more influenced by selection forces that favor the fitness of adult individuals. Viewed across the spectrum of mate selecting animal species, the summation of all selection forces that act on the individual define where on the fitness continuum the individual and as a result the species exists, and depicts how strongly the collective effects of all selection forces favors the adult individual and alternatively favors the individuals current and future juvenile progeny.
A more complete description of the implications of trans-generational selection and trans-generational fitness can be found is sister paper titled: The Evolution of Selection.
Favoring The Fitness of Progeny At the Expense Of Adults
Across all organisms time inherently harbors the risk of loss of fitness that results from accidental injury, illness or any cause of death. In many species the inability of the individual to compensate for loss of fitness through continuous growth or through successive bouts of morphological change, favors genes that discount the fitness of parents when the results of this action favors the fitness of existing and future descendants. In other words, extrinsic risks of fitness-loss sometimes favors Trans-Generational fitness by dis-favoring the fitness of the adult individual. This concept is expressed more fully in the sister paper titled: Growth Termination and Scale.
The Paradigm of Trans-Generational Selection
Though sexual reproduction is fundamentally an altruistic act, it is generally considered settled that natural selection acts primarily on the individual to maximize its fitness and not to maximize the fitness of the group and the concepts I express here are in agreement with this conclusion. However, different elements of natural selection impact different aspects of fitness. To extend our understanding of the evolution of senescence it is helpful to distinguish the selection drivers that positively effect the survival of the individual from the Trans-Generational Selection drivers that favor the fitness of progeny.
I propose that relative to senescence and other altruistic traits Natural Selection should be seen as fundamentally bifurcated into the group of drivers that favor individual fitness and the group of drivers that favor Trans-Generational Fitness. I propose that the failure to recognize the primacy of this bifurcation of Natural Selection drivers has been one of the main conceptional obstacles to developing a clearer understanding of senescence and other altruistic traits.
Given the altruistic nature of traits that favor Trans-Generational Fitness, how do we account for the evolution and persistence of these traits across taxa? I propose that the explanation can be found in the effects of Mate-Selection processes.
With the exception of some species of social insects, sperm and eggs contain only half of the chromosomes required to produce a fully functioning reproductive adult. Therefore the production of gametes via meiotic division enforces the need to reconstitute diploidy in offspring via the union of haploid gametes which in turn obligates most animal species to in some way, select mates. The typical existence of a pool of prospective mates provides the common individual with multiple reproductive options. Even when there are equal numbers of both sexes and both sexes are selecting equally, the individual typically has a choice of more than one potential mate, this constitutes a fundamental one-to-many asymmetry of Mate-Selection. The relative number of options available to the selecting individual produces a divergence of interest between the selecting individual and its potential mates and binds the self-interest of the individual to mate discrimination processes enabling greater exploitation of the mating resources and thus improving the individuals ability to compete with other individuals more successfully.
Selection Across Multi-generational Time
Because some mate-selection mechanisms can be implemented with very little effort, very little risk, and very little reduction in future reproductive opportunity, mate-selection can extract a very low cost to the mate-selecting individual. When these low costs to the mate-selecting individual are combined with the asymmetry of mating opportunity this summation affords and enables mate discrimination processes the ability to drive the individual to choose mates with behaviors and genes that improve the fitness of descendants not just in the next generation but also genes that favor the fitness of descendants multiple generations into the future.
Processes and forces that favor mate-selection processes that favor descendants beyond just the next generation I have termed "Trans-generational Selection." It is this attribute of sexual species, in which the individual is influenced by selection forces that favor multi-generational time, that plays a major role in the evolution and persistence of senescence.
Many processes of Mate-Selection affords the individual opportunities to discriminate on the quality of genes as they are expressed in the phenotypes of prospective mates. Predation, competition among individuals of a species, and other conditions, drive the individual to select for altruistic traits in their mates because such traits favor the fitness of their mutual descendants. The flexibility of the processes of Mate-Selection that derives from the effects of diploidy enables and drives the selection of altruistic traits while exacting little cost to the fitness of the selecting individual. The fitness cost that is born by the selecting individual comes in the form of the energy and time required to execute the processes used to discriminate between prospective mates, and this cost is relatively low in the sense that it is not prohibitively high so as to preclude such selection criteria on the part of the selecting individual.
Genes and Self-Interest
Though Trans-Generational Selection favors generations of progeny at the expense of the adult, this is an external or retrospective view of the process. In actuality, both the selecting and selected individuals are acting in their own best-interest. For example, a prospective mate that is being selected by an individual for its complement of altruistic traits, already possesses the altruistic traits and behaviors at the time of mating. Behaviors such as feeding and defending offspring are essentially beyond the individuals control. These traits are largely dictates of genes which resulted from the Mate-Selection processes of its ancestors. From this perspective an animals own phenotype, including all of its altruistic traits, represents part of the total environmental context within which the animal determines, optimizes and executes it self-interest.
Sustaining Reproductive Agendas Trans-Generationally
The active selection of mates that express altruistic, offspring-favoring, phenotypes is one of the most effective mechanisms, available to the individual by which it is capable of preserving traits and behaviors that favor the survival of its genes for generations beyond its own lifespan. Said another way, Mate-Selection may be the best mechanism available to the individual that has the capacity to compel successive generations of descendants to autonomously act in ways that favor its reproductive agendas after it has died. I must emphasize that trans-generational selection represents the action of those forces that favor the persistence of an individuals genes over multi-generational time, not the traditional focus on the number of copies of an individuals genes simply survive to the next generation. The details of the role Mate-Selection plays in the emergence of Trans-Generational Selection and the fitness of progeny are beyond the intended scope of this paper, these mechanisms and processes are elaborated in a sister paper titled: The Evolution of Selection.
Before leaving this topic it should be noted that in species in which both males and females engage in mate selection processes it is in the interest of individuals of both sexes to add another element to its selection criteria of favoring mates with traits that enhance trans-generational fitness. If the individual is to be successful in maintaining its reproductive agendas for an indefinite number of generations into the future the individual must also select mates that show the same behavior of selecting mates that exhibit trans-generationally fitness enhancing traits. Put simply, the selecting individual needs to select mates that also choose mates that use the same selection criteria. Only in this way can the selecting individual maximize the probability of producing descendants that will persist in expressing the trans-generational fitness enhancing trait but also execute this same selection criteria and stabilize these traits and behaviors over generational time. This just constitutes conventional evolutionary logic, to stabilize a sexually selected trait there is often needed an additional trait that drives the individual to select for the primary trait in in its mate.
Resource Conservation Increases Trans-Generational Fitness
Given that Mate-Selection both drives and enables the individual to execute reproductive agendas that favor the fitness of descendants for successive generations beyond its lifetime the question must be asked, specifically what behaviors can an individual engage in that will improve the fitness of its progeny over many generations into the deep future? I propose that to endow progeny with genes for traits and behaviors that preserve future environmental resources, such as food, habitat, and protection from predators, is one of the most effective thing the individual can do to accomplish it reproductive agendas and ensure the fitness of it's future descendants. Since failing to maximally exploit environmental resources to enhance ones own fitness is fundamentally altruistic, these traits and behaviors constitute Trans-Generational Fitness enhancing traits. As previously described DES and other extrinsic risks to fitness provide the selective pressure that drive Mate-Selection processes to favor the evolution of Trans-Generational Fitness enhancing mechanisms that conserve environmental resources.
This paper proposes that two fundamental mechanisms operate in the adult that result in the conservation of environmental resources. Both of these mechanisms conserve a broad spectrum of environmental resources by reducing their use by adults. These mechanisms operates as optimized processes that extracts real costs from the vitality of the adult by manifesting their effects as senescence.
Why Resource Conservation Mechanisms Are Broad Spectrum
Here I propose that generalized resource conservation mechanisms evolved to dominance because any one of many possible environmental factors and circumstances can establish any one of a multitude of environmental resources as a specific and unique fitness limiting resource at a given point in time. Any conservation mechanism that preserves a specific resource will simply shift the fitness limiting resource to the next most scarce resource in line. Any mechanism that evolved to conserve a specific resource or a set of specific resources would over time not compete successfully across multiple generations against a generalized "broad spectrum" resource conservation strategy. Additionally it is easier for evolutionary processes to construct and maintain strong selection for a single mechanism of conservation than to maintain strong selection for a large number of mechanisms most of which are conserving a resource that is non-limiting at any given point in time.
Evidence That Mate-Selection Drives Senescence
Corals, sponges, hydra, and clams, which do not appear to senesce in the conventional sense of the term, are sessile during reproductive stages of life. When reproducing sexually, these sessile animals simply release egg and sperm into the water where fertilization takes place. This method of sexual reproduction precludes the individual from being able to use Mate-Selection mechanisms to discriminate the phenotypes of potential mates. Specifically, without Mate-Selection the individual is not able to differentiate and choose mates that are senescing. As a result, over evolutionary time, individuals are not able to sustain sufficient selective pressure to maintain competence in the genes that are responsible for the senescent phenotype. This erosion of the senescent phenotype is further reinforced as lengthening lifespans directly favor the fitness of the individual over the trans-generational fitness of decedents.
Sea urchins though not truly sessile also reproduce by releasing sperm into the water precluding Mate-Selection, some of these species such as the Red Sea Urchin live over 100 years and do not show signs of senescence. At this time I have not seen data to indicate if shorter lived species of sea urchins senesce or simple die due to high predation rate or due to loss of fitness resulting from dis-economies of scale etc.
Factors Regulating The Strength of Resource Conservation Mechanisms
The existence of non-sessile negligibly senescent animals demonstrates that even though diploidy and Mate-Selection favors Trans-Generational Fitness at the expense of the adult individual, this cost does not have to be so high as to senesce the individual across the spectrum of all animal species. In many species, it appears that a growth-terminating phenotype is required to tip the balance toward strong resource conservation and away from the fitness of the individual far enough to produce the senescent phenotype.
Mate-Selection And Dimorphism's
Sexual Selection has been seen as processes that drive sexually dimorphic traits, I have used the term Mate-Selection in this paper in part to draw the distinction that Mate-Selection is not so constrained. When a female animal selects for senescing mates it is in her interest to pass this trait on to both her male and female progeny. A female that can discern whether a prospective mate's senescence is sex linked will be more successful than a female that does not make such a distinction and as a result selects mates with sex linked senescent traits which will fail to be expressed in the phenotype of it's female offspring leading to negligibly senescent females in the species.
It is a proposition of this paper that Trans-Generational Fitness is implemented primarily through the operation of two fundamental types of mechanisms that conserve resources by withholding them from use by body repair processes in the adult. Both of these types of mechanisms reinforce each other but senesce the organism in distinct ways. I have labeled these mechanisms types as the "Intracellular Depreciation Mechanism" (IDM) and the "Tissue Depreciation Mechanism" (TDM).
The Intracellular Depreciation Mechanism
Entropy And The IDM
The IDM represents a specific down-regulating extension of control on the components of cellular metabolism that are responsible for the effectiveness of entropy mitigation within the cell. The IDM under-mitigates entropy by over conserving resources via the body-wide under-recycling of intracellular components. This attribute establishes the IDM as one of the primary mechanisms by which evolution implements and optimizes species specific rates of senescence. (See Appendix A. in the Supplementary Materials at the end of the paper for a discussion of this topic).
Intracellular Repair And Senescence
Autophagy The Intracellular Recycling Mechanism
Autophagy comprises much of the catabolic half of the intracellular recycling and repair process. Autophagy is a critically important complementary mechanism to growth, antioxidants, and DNA repair enzymes in the regulation of the rate of senescence, and in the realization of negligible senescence. In support of the primacy of autophagy, it has been proposed, by ETTORE BERGAMINI et al. that autophagy is the primary mechanism by which calorie restriction increases lifespan.
The Utilization Of Conserved Resources
I propose that the IDM does not determine how or when conserved resources are exploited, the unique reproductive strategy of each species determines how the conserved resources are utilized to improve Trans-Generational Fitness. It may seem that the generality of this resource conservation mechanism does not provide enough benefit to the organism to drive its persistence across species and niches. However, this paper proposes that this objection is answered by the fact that the individual bares little cost from implementing the processes of selecting a mate on the basis of criteria that include altruistic traits. See the Supplementary Materials sections titled: "The Sensibility Of The IDM And the TDM As The Cause of Senescence", and the section that follows it titled, "Persistence of Senescent & Negligibly Senescent Phenotypes", for an explanation.
Optimal Resource Conservation And Optimal Senescence
The IDM is the regulatory mechanisms that implements intra-cellular resource conservation by down-regulating the intracellular repair mechanisms. The IDM down-regulates intracellular repair until the resultant level of activity produces a species specific rate of accumulation of senescent constituents that is optimal relative to the species specific level of extrinsic risks to the fitness of adults. This "optimal senescence" proposal is supported by the observation that rates of aging is highly species specific and by the long history of failures of antioxidants such as lipoic acid, vitamin E, vitamin C, Acetyl-L-Carnitine, to slow senescence in vivo.
The concept that senescence results from non-incidental, optimized, mechanisms, is also supported by the large body of experimental evidence observed across species that have demonstrated that rates of senescence can be up or down regulated by changes in predation rates and through delayed breeding. This malleability in the rates of senescence points to the existence of these mechanisms of autophagy regulation.
The Dynamics of Autophagy Regulation
Though the IDM is a powerful control mechanism that down-regulates the basal rate of autophagy, some degree of intracellular repair as initiated by autophagy is normally maintained. Cells are not under exclusive regulation by the IDM, other mechanisms such as ones that respond to a shortage of specific amino acids that cannot be synthesized by the organism can cause the up-regulation of autophagy and biosynthesis to levels above the basal rate established by the IDM.
Programmed Cell Death And Senescence
The autophagic component of intracellular repair is not capable of preventing the accumulation of damage to DNA, and so, is not sufficient to prevent deleterious effects over the long term. However Daf -16 type transcription factors are up-regulated along with autophagy driving DNA repair. Unfortunately, DNA repair is not completely effective leaving some types of DNA damage unrepaired. For this reason Programmed Cell Death (PCD) is required to destroy cells that may harbor defective DNA. Though this process is essential to the health of the individual, it is also involved in the production of senescence.
Over time PCD will deplete tissue reserves of parenchymal cells when these cells are no longer being replaced at a sufficient rate to maintain functional tissue mass 20. The depletion of the tissue reserves in one or more essential tissues results in the decline and death of the individual. For example, if pace maker cells in the heart undergo PCD heart failure results. PCD is instrumental to the functioning of both senescent and negligibly senescent phenotypes and constitutes a fundamental element in the second major type of resource conservation mechanism in the organism, this mechanism is called the Tissue Depreciation Mechanism of senescence.
The Tissue Depreciation Mechanism (TDM)
Importance Of The TDM
The TDM could be responsible for the majority of the seemingly intractable aspects of senescence. The TDM represents a down-regulating extension on the body's primary Growth-Termination Mechanisms (GTM). I propose that the TDM constitutes the foundational mechanism that controls age related fibrosis and is one of the primary cause of the progressive degradation of tissue function we observe in aging . The TDM drives processes that define the lifespan of a species independently of the action of the IDM. Note: See, "Growth Termination and Scale" for a detailed description of the evolution of growth deceleration and growth termination.
Second Order Senescence Effects Of The TDM
Though the action of the GTM produces the terminated-growth phenotype, like all other mechanism in the body, it is not exempt from the selection pressures exerted on it by the phenotype it produces. As a result, the second order effects of terminated-growth on the function of the GTM are significant and are factored into the evolution of the total mechanism, this constitutes the second order effect that drives what I call the TDM
Conditions that favor Trans-Generational Fitness, discount the fitness of the individual by driving selection forces to favor the action of the IDM, these same forces also drive optimization of the GTM's rate of tissue growth/repair, the mechanism of this optimization constitutes the TDM. The TDM achieves optimization of resource conservation by down-regulating the production of tissue-specific replacement cells until the quantities produced are insufficient to fully maintain the functional capacity of tissues.
It is proposed that the TDM qualifies as a mechanism of resource conservation because it drives the replacement of tissue specific cells with fibroblasts and extra-cellular matrix (ECM). Because scar tissue or ECM consists of dispersed cells in an extra-cellular protein matrix fewer metabolic resources are required to sustain this tissue than are needed by the equivalent volume of non-fibrotic tissue.
Mechanistically, once deceleration of the cell replacement rate has reached an equilibrium with the rate of tissue cell death, growth-termination occurs. The resulting terminated-growth phenotype produces the second order effects that then drives the further down-regulation of the differentiation of stem and progenitor cells yielding numbers of parenchymal cells that are insufficient to replace dying cells in the target tissue. Over time this process results in the incremental fibrosis of body tissues as fibroblasts and ECM are substituted to replace many of the parenchymal cells that have died due to, injury, the accumulation of senescent cellular components, or due to intrinsically or spontaneously driven apoptosis.
Stem cell differentiation pathways that lead to the production of fibroblasts are not equivalently down-regulated and continues to operate within the phenotypic environment of terminated-growth, sustaining the supply of fibroblast cells and ECM required to maintain the volume and basic structural integrity but not the optimal functionality of the tissues.
Parenchymal Cell Attrition and Senescence
Jeffrey Baron et al, have also proposed a model of the relationship between parenchymal cell attrition, growth termination and senescence in several papers such as "An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues".
Others have recognized the relationship between the processes of fibrosis associated with tissue-damage, repair, and aging, expressing the view that, tissue-damage repair mechanisms contribute to senescence (see "Aging AS A CONSEQUENCE OF MISREPAIR" (2009) ). However the authors conclude that "Misrepair" is ultimately a manifestation of entropy, not the result of a genetically determined mechanism of overt tissue degradation as proposed here.
Senescence And The Regulation of Stem Cell Differentiation
Support for this and other theories of senescence propose that systemic factors control the production rate of many types of parenchymal cells by down-regulating the differentiation pathways of stem and progenitor cells in favor of pathways that increase production of fibroblasts and ECM. See the article in Science titled: Rejuvenation of aged progenitor cells by exposure to a young systemic environment. In this and other similar research, heterochronic parabiotic pairings have been used to demonstrate that it is soluble systemic factors and are regulatorily "upstream" of the cell to cells contact, that are responsible for modulating the stem or progenitor cell differentiation pathways. This research also supports the conclusion that these growth factors are anti-senescent in there action on a variety of stem cell types.
Modification Of The GTM For Senescence Accumulation
The TDM - A Non-Incidental Source of Senescence
The argument has been made in this paper, that the IDM is a non-incidental mechanism of senescence that results as a direct consequence of the favoring of Trans-Generational Fitness which, to a large extent, is driven by terminated-growth. This same logic applies to the TDM, once established in the genome, the terminated-growth phenotype drives second order effects that favor the evolution of a metabolically efficient mechanism of growth-termination, one that conserves resources.
Cell Turnover And The GTM
Other growth-termination mechanisms that are not under the control of the TDM exist and are utilized by specific tissues. For example, the mechanism implemented by the intestinal mucosa achieves terminated-growth via continuous proliferation and differentiation of progenitor cells to produce the cells that compose the lining of the intestinal mucosa. In this mechanism, a high rate of cell proliferation is balanced by an equally high rate of apoptotic activity maintaining static tissue size. Growth-termination mechanisms such as this, with a very high metabolic cost, are appropriate for tissues such as the intestinal mucosa, which has exposure to high levels of carcinogens, viruses, and very high glucose concentrations. It should be noted that this type of growth-termination mechanism is not optimal for other tissues within the context of a growth-terminated phenotype where natural selection is favoring resource conservation and Trans-Generational Fitness.
The IDM Drives the TDM
As it was described, the IDM will senesce cells over time producing incremental disfunction of proteins and organelles such as mitochondria. As mitochondria become senescent they leak more free radicals which can further damage their host cells. As a result, over time, cells will either become senescent or self destruct via apoptosis. The cells eliminated via apoptosis places increasing demands on stem cell differentiation for the production of more replacement cells, just at the time when the TDM is exerting its influence to decelerate the production of tissue specific cells. For these reasons the IDM amplifies the senescence mechanisms of the TDM.
The TDM Drives Senescence Independently of the IDM
Even if an animal is calorie restricted and up-regulated autophagy is preventing the IDM from senescing cells, apoptosis will continue to occur at some rate due to a large number of other drivers. For this reason calorie restriction and other IDM modulating approaches to mitigating senescence are insufficient, intervention at the level of the TDM is required to achieve negligible senescence.
Dwarfism and Senescence
Dwarfism can be viewed as the phenotype that results from mechanisms that knockout the IDM mechanism by driving the continual down-regulation of the anabolic half of metabolism via the insulin-IGF axis and as a result chronically up-regulates the autophagic, catabolic side of metabolism. However I know of no example where dwarfism has resulted in negligible senescence in a species. Instead dwarfisms ability to increase maximal life span by some limited fraction of normal life span is strong evidence for the existence of another senescence mechanism, namely the TDM which is not effectively attenuated by the various causes of dwarfism.
In the context of the above logic, the question still remains, why doesn't dwarfism protect the organism from the effects of the TDM? Dwarfism does prevent the individual from reaching the size threshold at which the GTM / TDM down-regulates the differentiation of stem cells into parenchymal cells, so why are dwarfs not negligibly senescent? One possible answer to this question is embodied in research demonstrating that the proliferation of stem cells which is an anabolic, growth process, is driven by the insulin-IGF-1 axis. Without the initial proliferation step the differentiation step in stem cell morphogenesis does not produce sufficient numbers of parenchymal cells to meet the demands resulting from continuing apoptosis in the tissues.
Juvenile Growth - An Echo of Negligible Senescence
Why do the majority of animals species fail to become reproductive immediately after birth, or put another way, how do we account for the evolution of delayed reproduction in senescent and non-senescent species alike? For example, some whale species produce offspring that are far larger at birth than the size attained by other closely related species over their entire lifetime, yet the majority of species defer reproduction during much of the growth period? The answer to this question is that the period of growth up until sexual maturity is a strong example of the negligibly senescent continuous growth phenotype described earlier.
The mechanisms that determine and favor the reproductive behavior of negligibly senescent growth-non-terminating animals also dis-favors immediate reproduction during growth in the juvenile phase of senescent species. As growth decelerates during puberty, reproductive capacity then begins as it is no longer beneficial to defer reproduction. Additionally, delayed reproduction facilitates the ability of individuals to select mates on the merits of fully mature phenotypes which constitutes a less speculative strategy for mate selection.
Lastly, as individuals of most species select for a senescing phenotype as one of the selection criteria when choosing mates, as this is an indicator of transgenerational fitness enhancing traits, the individual generally need to wait until the end of the growth phase to accurately assess if a potential mate possesses a senescing phenotype. This mate selection process renders early reproductive capability detrimental to the individual as it diverts resources away from growth and its incumbent fitness advantages.
Maturation Signaling Driving Senescence
Just as juvenile growth is an echo of negligible senescence I propose that sexual maturation drives the production of the signaling that drives senescence of both the TDM and IDM types. I propose that at sexual maturity the neural-endocrine system reduces the production of soluble growth/differentiation factors that drives senescence through epigenetic processes. This hypothesis is supported by two animal models a jellyfish and a beetle that have the ability to avoid senescence by repeatedly returning to the juvenile morphology and then back to the mature sexual morphology. It seems reasonable that just as stress is the element in the environment that triggers conversion from asexual reproduction to sexual reproduction in some species that are capable of doing both, physical and physiological stressors seem to play a pivotal role in triggering sexual maturation and senescence in obligately sexual animal species.
Mate-Selection And The Rate-of-Aging
If aging, as I propose, is a mate selected trait then such selection cannot be a binary choice made by mate-selecting individuals on the basis of prospective mates exhibiting markers of senescence or not. Instead I propose that individuals select mates on the basis of the rate of aging that is optimal for the selecting individuals reproductive goals. It seems unlikely that individuals are selecting mates on the basis of the degree of senescence or on the basis of the number of senescent traits as this would not inform the individual as to the expected life span being passed on to its offspring. The rate of aging is the attribute that the selecting individual needs to be selecting on if it is to optimize the life span of its progeny and if it is to pass the same ability to discriminate rate of aging onto its progeny.
Indicators of Aging Rate
So what can an individual use to determine the rate of aging of perspective mates if the accumulation of senescent traits is not indicative of rate of senescence and life-span? I propose that one possibility is that the selecting individual is determining the rate of aging by evaluating the concentration of one or more hormones or hormone like substances which are outwardly expressed and are readably discernible by prospective mates.
It is clear that a life span that is totally determined by genetics is not fully optimal because the environment can change significantly in single a generation dramatically changing the optimal life span of the affected population. Therefore it seem likely that the factors that are determining the rate of aging across species should be subject to some degree of up and down regulation as a result of environmental and epigenetic factors. This conclusion speaks for regulation of aging rates by neurological processes which are the processes most able of aggregating all of the factors that are capable of computing the optimal life span of a species in a given environment.
Chronic Stress and Aging
What does the individual use to accurately assess the rate of aging of prospective mates,? I propose that across animal species, stress hormones that are produced as a response to chronic stress constitute a good proxy for rate of aging as these substances seem to mediate the aging process. Therefore the mate selecting individual should be able to assess the relative aging rate of prospective mates by determining the concentration of stress hormones externally expressed by prospective mates and compare these concentrations to their own.
So what does this accomplish? It can be assumed that stress response and rates of aging vary to some degree in a population in a given environment, so if an individual selects for mates that exhibit hormone concentrations that are indicative of chronic stress that is somewhat higher than it's own levels of the same hormones it will have the effect of producing progeny that terminate growth sooner, mature faster, and age quicker in the next generation. if the individual selects mates that exhibit stress hormone concentrations that are less than its own when environmental stress is low, and hormone concentrations greater than its own when the environmental stress it is experiencing is high then it will be using a simple algorithm to produce offspring that are better adapted to a life that likely to be more or less stress filled at the time the individual executed its mate-selection strategy.
It should be noted that this strategy/algorithm of mate-selection is an evolutionarily stable strategy (ESS) as it invests both the selecting mate and the selected mate to select-on and display these attributes explicitly and honestly as their expression and detection both favor the survival of offspring.
The Island Rule
So lets consider how this applies as an explanation of the Island Rule, which is the phenomena in which small animals grow much larger and live longer on isolated islands and large animals grow much smaller, over generational time. Small animals that are isolated on islands that are devoid of predators experience lower stress through the elimination of threat of predation and as a result have lower stress hormones. So applying my stressed based mate-selecting algorithm the mate selecting individuals will be selecting individual with even lower stress hormone levels , these offspring should on average mature more slowly and as a result grow larger and live longer. For large animals isolated on relatively small islands, food and habitat limitations will leave the population in a chronically stressed state which will drive mate selection toward mates that exhibit higher levels of hormones indicative of chronic stress than the selecting mate and drive the evolution of the population toward faster maturation, smaller size and faster aging.
Death Mechanisms as Implementation of Trans-Generational Fitness Algorithms
Just as the individual is employing mate-selection to obtain the appropriate balance of altruistic traits in prospective mates which enhance the fitness of progeny against the selfish traits that favor the adult survival of prospective mate and progeny,
This strategy also dependent on the selected mate and shared future progeny actually manifests these traits and behavior, whether they be care of the young or the implementation of death mechanisms at the appropriate time and place.
If, as I propose, the implementation of these death mechanisms in modulated neurologically, is there a opportunity to modulate the action of these death mechanisms and senescence in general at the neurological level or must intercession occur at the level of neuro-hormonal interface or is one of these loci of control layered on top of the other?
Death Mechanisms And Their Modulation
To conclude the discussion of the IDM and TDM, just as semelparous animals harbor death mechanisms, once iteroparous animals have senesced to a threshold level, Trans-Generational Selection favors total resource conservation or complete termination of resource consumption. Said another way, I propose that trans-generational selection favors the evolution of death mechanisms that are activated once the individual reaches a threshold level of senescence. I propose that a simple, additional up-regulation of both the IDM and TDM constitute a major portion of these death mechanisms in semelparous and iteroparous animals.
Death mechanisms that are composed of up-regulated versions of the IDM and TDM also makes it feasible for Mate-Selection processes to drive the evolution of death because traits of senescence can function as "tells" for the mate selecting individual alerting them that a prospective mate harbors death mechanisms.
Diseases of Aging As Death Mechanisms
It appears clear that fundamental actions of the IDM and TDM are at the root of many diseases of aging such as cardiovascular disease, immune competence diseases such as cancer, and skeleto-muscular diseases. It has been demonstrated actuarially that senescence is the most important risk factor in the manifestation of these causes of death. Therefore, within the paradigm in which senescence is at its root senescence is genetic and selected for, all of the major causes of death in humans can be seen to be overt death mechanisms.
Digestive System Senescence as Death Mechanism
Consistent with concept that the goal of transgenerational selection constitutes resource conservation by the adult, many animals path to death is mediated by failures of some aspect of the digestive system. Elephants loose the ability to feed after they ware out their last set of molars, pelicans loose the ability to feed when their stomachs fill with fish bones, and octopus are hormonally driven to stop feeding. Now new research reported by Michael Rera, Rebecca I. Clark, and David W. Walker in an article titled Why old flies die, published In the online journal Impact Aging, report that the cells lining the intestinal tract of senesce reducing intestinal permeability and therefor reduce the assimilation of nutrients from food.
Neurological Modulation of Senescence and Death Mechanisms
Though the death mechanisms that I have just described can act to some extent autonomously. I propose that the IDM and TDM based mechanisms of death have evolved under, and in most instances remain under neurological control. The rational for this is that sexually selected traits such as these life-span modulating death mechanisms evolved as a consequence of trans-generational selection pressures and as a result emerge from the processes of mate-selection. At a fundamental level locomotion, the moving toward a selected mate and away from deselected mating options is essential to mate-selection Even though it can be argued that mate-selection can result from following chemical gradients diffused in the environment this system must inform some aspect of the neurological system which is required to integrate the sensing of the chemical gradient with complex muscular actions which are required to bring the individual into proximity with its source. Based on this logic all mate-selection processes including trans-generational selection processes are mediated by neurological processes.
Optimism and Longevity
Centenarian studies demonstrate that populations of very old humans are unusually rich in people with a high degree of optimism, a sense of abundance and other physiological traits that collectively can be viewed as the opposite or at least inconsistent with the modalities of depression. This correlation is further supported by the failure of these same studies to find a strong set of physiological reasons for long life span in humans that is common across the population of individuals in these studies. Additionally, centenarian studies have demonstrated that these individuals share life style habits such as smoking, drinking alcohol, and the consumption of what is believed to be unhealthy diets that is similar in scope and magnitude with the rest of the population of people that experience much shorter lives.
If optimism is a driver of extended life-span, what actually constitutes this attribute, as a physiological phenomenon? For clarification, it has been defined at the conviction of the individual that events will unfold in the future in a favorable or "optimal" way for the same individual. From this it can be seen that an individual that concludes that the adversity it may presently be experiencing will be short lived and that the current circumstances will result in positive events in the future. So when an individual is optimistic and as a result arrives at such a conclusion it is then rational that the individual takes actions to preserve itself for the future. However if an organism is more pessimistic in the same situation it may rationally conclude that adversity will continue and that it makes sense to invoke death mechanisms as part of its trans-generational fitness strategy. I propose that the action taken by an organism that has determined that they cannot be optimistic about the future is to invoke a state of mental depression. I propose that mental depression when left unchecked is the mental state that initiates a cascade events that invoke death mechanisms.
Depression Driven Death Mechanisms
The up-regulation of the IDM and TDM is not the only type of death mechanisms that can evolve under trans-generational selection pressure, the increase in mental depression can both driven by the action of the IDM and TDM but can possibly be driven independently of these mechanism, such as by infectious disease or heavy metals for example. In either case, increasing rates of mental depression which undergoes an initial spike at sexual maturity, seems to have the ability to precipitate a cascade of events that culminates in death in mammals, via a variety of modalities, at a rate that is much faster than would happen in a senescing animal that is not experiencing mental depression. Many in the biomedical community has speculated on the how mental depression could be an adaptive or beneficial trait in the individual. If depression is as I propose, a trans-generationally selected trait, this line of reasoning is misguided in that this adaptation favors progeny and disfavors the adult individual. The biomedical community needs to rethink the casual foundation of the diseases of aging, including all diseases that increase at sexual maturity, and rethink how these diseases as a result may be most effectively treated.
Senescence Modulation, A Network Or Hierarchy
As described, there are overt death mechanisms which can be invoked by extrinsic factors or by senescence. So the question remains in the quest for the complete understanding and remediation of aging, is there a single foundational cause or physiological driver of aging or is there a network of multiple causes which can not be separated and redefined as a hierarchy? I propose that the malleability of rates of aging as has been demonstrated in breeding experiments across the phylogenetic landscape points to a hierarchy. I would argue that a true network of controls would not allow the flexibility and rapidity of change in length of lifespan as has been demonstrated in worms, flies, fish and possums and dogs etc.
If we are dealing with a true hierarchy then I feel we should be looking for a single mediator that communicates information from a mechanism that integrates, time, animal vigor and trans-generational fitness, in its modulation of the rate of senescence. As I have previously expressed, experimental evidence supports the idea that this mediator is a soluble evolutionarily highly conserved morphogenic type substance that when expressed at high concentrations prevents senescence.
Biological Clocks and Aging
At this writing I know of no natural or experimental intervention that transforms an individual of a senescing species into a non-senescing individual, instead anti-aging interventions only extend lifespan some percentage beyond an average within a species specific genetically defined range of lifespans. So it seems very likely that one or more aging biological clocks exist which define the range of lifespans individuals of a given species experience. Recent research by Steve Horvath has pointed to the possibility that a highly accurate epigenetic clock which consists of DNA methylation at specific sites exists in most cells of the body which tracks and determines age of the cell. This research has been described in a Nature News article and the research paper reported in Genome Biology, opens potentially significant new vistas for aging research.
Recently, supercentenarian research points to the possibility that exhaustion of blood stem cell reserves may play a significant role in aging pointing to another potential example of a significant clock of aging.
The Nature of the Clock
So, we are left with a significant set of unanswered questions. If aging is fundamentally driven by a clock, is this clock defined genetically, recording time epigenetically as possibly exemplified by the work of M Horvath and acting neurologically via the hypothalamus? How do we tell the difference between the clock with its actual cogs and gears and the closest downstream effects of the clock where it simply logs time? And finally is the fundamental clock we are seeking systemic or highly localized in the body? There are still more significant questions, for example, in animals is there fundamentally one systemic clock and only one way this clock logs the passage of time, and are all systems that have a temporal element to them, utilized this time log to initiate and terminate actions in the body? If this is the case we may not want to change the intrinsic rate at which this clock logs time or for that matter we may not want to zero the time log due to its effect on other aspects of body regulation. Clearly if there is a fundamentally independent clock of aging then this would not be the case and it might be possible to intercede at the level of the clocks initial logging or even change the rate the clock "ticks" later in life.
As a result of this characterization of the nature of the clock I think it is useful to differentiate the "aging-clock" from other biological clocks or a fundamental systemic clock even if the aging-clock utilizes the time log of a more fundamental clock as its temporal cadence to initiate and regulate the rate of senescence and the activation of death mechanisms.
The Aging-Clock & the Rate of Senescence
Because the rate of aging is so species specific and has proved only incrementally malleable over generational time I propose that the fundamental aging clock is genetically defined. However I have attempted to make the case in this paper for the idea that epigenetic and neuro-hormonal mechanisms exist that allow the individual to up or down regulate their rate of senescence to more fully optimize their rate of development, maturation and senescence. I have propose that individuals select for mates that attempt to optimize their rate of senescence to make it consistent with changes in the relative strength of individual selection pressure to trans-generational selection pressure to which they are exposed in real time.
The Hypothalamic Clock and Senescence as developmental stage
Thyrotropin Releasing hormone which is produced by the hypothalamus has been shown to have a role in growth and development and in senescence. via its regulation of the production of Thyroid Stimulating Hormone (TSH).
I wish to note that we have truly come full circle in our conception of the logic of aging, Alfred Russel Wallace , one of the first to speak on the evolution of aging, proposed that aging and subsequent dying occurs to the benefit of the species namely because of the death of old individuals would free up resources for subsequent generations. This idea though well thought of in the past has declined in popularity because it seemed to require a mechanism based on group selection. It is now clear that group selection is not necessary, Mate-Selection in conjunction with dis-economies of scale is sufficient to drive the evolution and persistence of aging via mechanisms that conserve resources.
It gives us pause to accept that aging is a direct result of the selfish interest of the individual as expressed through our Mate-Selection biases. The evolutionary pressure to senesce the individual must be viewed as high considering that this is a trait that we share with a vast number of divergent species through evolutionary time. Fortunately it may not have to be this way as we are now poised at the moment in time when it becomes feasible to forestall and possibly reverse senescence in humans through a modification of the TDM.
It is plausible that Negligible Senescence can be achieved in growth-terminating vertebrates through interventions that up-regulate the rates of autophagy in such a manner as to maintain static size while maintaining the rate of intracellular repair above the threshold of senescence. ( See Appendix A. ) This component of negligible senescence should be feasible as there are many methods such as CR, rapamycin, protein restriction, etc, that can be employed to up-regulate autophagy and intracellular repair in general.
It will also be necessary to supplement the production of parenchymal replacement cells in great enough numbers to compensate for PCD so as to sustain tissue functions at youthful levels throughout the body. Blanding's turtles may be an example of this strategy, implemented in nature. ( See Appendix B. ) Once this result has been achieved it may be necessary to address potential deleterious genetic conditions that result from the effects of antagonistic pleiotrophy or other presently unknown mechanisms.
It is reasonably probable that we will soon identify and synthesize the regulatory factors of stem and progenitor cell differentiation, if researchers have not already done so by the time of this writing. As described earlier, recent studies utilizing heterochronic parabiotic pairings seem to be making great strides in closing on the mechanism and structure of these factors giving us reason for optimism.
Consistent with my earlier optimism, on 5-09-13 Lee and Wagers have reported in Cell the identification the highly conserved soluble factor called Growth Differentiation Factor 11 (GDF-11) that regulates an aspect of adult morphogenesis in heart and in other complex tissues of mice. This appears to be the soluble blood factor that Wagers and her team illuminated the existence of, in their heterochronic parabiotic pairing experiments described earlier. They demonstrated that GDF-11 regresses age associated cardiac hypertrophy in as little as four weeks restoring the heart to youthful form and function. This appears to be a highly significant stride toward understanding and mitigating aging and should dramatic enough to provide a strong impetus for shifting funding away from calorie restriction and toward stem cell and growth differentiation factor investigations as the primary focus of aging research.
Finch, Caleb E.; "Senescence, Longevity, and the Genome" (1990). The University of Chicago Press, Chicago and London.
Adamson L, Walum E, (2007). Insulin and IGF-1 mediated inhibition of apoptosis in CHO cells grown in suspension in a protein-free medium. Altern Lab Anim. 2007 Jun;35(3):349-52.
Rick Lane, Bill Martin, (2010). Why Complex life probably evolved only once; NEW SCIENTIST 12:52 21 October 2010 by Michael Le PageGabriela P. Finkielstain, Patricia Forcinito, Julian C. K. Lui, Kevin M. Barnes, Rose Marino, Sami Makaroun, Vina Nguyen, Jacob E. Lazarus, Ola Nilsson, and Jeffrey Baron, (2009). An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues.
Endocrinology. 2009 April; 150(4): 1791–1800. Published online 2008 November 26. doi: 10.1210/en.2008-0868.
Irina M. Conboy, Michael J. Conboy, Amy J. Wagers, Eric R. Girma, Irving L. Weissman & Thomas A. Rando (2005), Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760-764
Andrew S. Brack, Michael J. Conboy, Sudeep Roy, Mark Lee, Calvin J. Kuo, Charles Keller, Thomas A. Rando, (2007). Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis. Science 317 (5839): 807-810
Reznick, D., C. Ghalambor, and L. Nunney. The evolution of senescence in fish. Mechanisms of Aging and development. 123: 773-789.Finch, Caleb E.; "Senescence, Longevity, and the Genome" (1990). The University of Chicago Press, Chicago and London. Page 240 4.5.2Mitteldorf, J. (2004). "Ageing selected for its own sake" (PDF). Evol. Ecol. Res. 6: 937–53. On the tension between experimental data and evolutionary theory. Bredesen DE (October 2004). "The non-existent aging program: how does it work?". Aging Cell 3 (5): 255–9. doi:10.1111/j.1474-9728.2004.00121.x. PMID 15379848. More on the tension between experiment and theory.http://www.ncbi.nlm.nih.gov/pubmed/3549508
http://www.tortoisetrust.org/articles/snappers.htm Speaks to evolution of delayed reproduction in snapping turtles.
20. Norman E. Sharpless1 and Ronald A. DePinho2 Telomeres, stem cells, senescence, and cancer J Clin Invest. 2004;113(2):160–168. doi:10.1172/JCI20761.
Who-Seung Lee, Pat Monaghan and Neil B. Metcalfe, Experimental demonstration of the growth rate–lifespan trade-off,Proceedings of the Royal Society B, 2012, DOI: 10.1098/rspb.2012.2370 (open access)
I elected to self publish this paper and its two sister papers, Growth Termination and Scale, and The Evolution of Selection , for several reasons. Firstly I wanted the ability to update and refine the paper and its concepts frequently within a medium that can document all of the changes that have occurred over time. Secondly I wanted a medium in which I could utilized hyperlinks as a way to provide references that are more convenient to the reader than traditional references. Thirdly I published on the internet because I wanted a medium in which search engines can be leveraged to provide ever improving indexing capabilities over time as the concepts expressed in the papers evolve. Google and other search engines are employing ever more effective artificial intelligence technologies to improve their search results. So, it is my expectation that the concepts expressed in these three papers will be continually more differentiated from the corpus of evolution and aging theory papers as search technology advance. Search technologies in the near future I expect will go substantially beyond basic keyword indexing and begin to map and contrast the conceptual meaning of content even when different papers are using dispirit language and different metaphor with which to describe similar concepts, As this technological change occurs I am confident, that individuals looking for fresh new conceptions of evolution and aging theory will be served these papers. And lastly because the concepts presented in this paper deviate greatly from conventional evolutionary thought at this time, I have elected to self publish to be free myself of editorial review that can and often results in considerable publication delay and sometimes de facto censorship. I am prepared instead to allow the reader and the passage of time to judge the merits of the ideas I have presented.
Note: Supplementary Material is still in draft and under active edit.
Most perennial plants species do not employ growth-termination as a strategy to avoid a reduction in fitness. As a result many plants appear to express negligible senescence until they exceed a specific size. Perennial plants tend to grow until they die and unlike animals many plants die as a direct consequence of growing past their optimal size. Tree core rotting, uprooting, lightning strikes, desiccation of the upper-most branches etc, are examples where large size can negatively effect fitness. In support of this observation, it has been demonstrated in a paper found in Exp Gerontol. 2001 Apr;36(4-6):651-73. titled "The paradox of great longevity in a short-lived tree species." that even in species considered to be short lived individual trees can live to extraordinary ages of more than 1600 years when their growth rate is slowed and their size remains smaller than that of standard trees of the species.
The prevalence of negligible senescence in plants also supports the primacy of the role of Mate-Selection in senescence. As with sessile animals, the sessile nature of plants limit interaction with mates to contact and selection of gametes. As a result, plants are unable to employ Mate-Selection mechanisms in the evaluation of the phenotype of their prospective mates to determine if they are senescing, however mate-selection is to some extent provided indirectly via insect and animal pollinators though they do not share the same evolutionary agendas for the plant species. As a result, sufficient selective pressure is not brought to bare on iteroparous plants leaving them unable to evolve or maintain the genes capable of producing a senescing phenotype.
Depicting Metabolism And Senescence
Figures A, B, C, E, F, and H, found here in the supplementary material are used to diagrammatically represent the relationships between the anabolic processes of biosynthesis and growth the catabolic processes of autophagy and senescence across various conditions and life histories.
Figure A. The Meaning of Cell Repair
Figure A, depicts the mutually exclusive relationship between anabolic cell growth and the catabolic processes of autophagy and apoptosis. When a cell is engaged in the anabolic process of protein synthesis it is being primarily driven by the insulin/IGF-1 axis, when insulin/IGF-1 concentration is low the cell will be experiencing a greater amount of autophagic activity. Point A. in the figure above represents the average metabolic state when the cell is involved in anabolic operations, and point C. represent the Cell in its average catabolic state of autophagy.
Point B above represents the combination of the two states and illustrates the average state of the cell by combining the anabolic and catabolic processes of one complete cycle. The location of the point relative to the boarder of constant size indicates whether the cell is, growing, shrinking or remaining the same size. In this specific case point B. depicts a cell that is growing.
Figure B. Biosynthesis Autophagy & Senescence
The blue line that bisects Figure B. designates the Boarder of Constant Cell Size, this line depicts the plot of possible equilibrium points that represent a balance between the various levels of anabolic and catabolic activity associated with autophagy and biosynthesis that results in no change in size of the cell over time. This blue line also depicts increasing metabolism and increasing resource utilization as you move away from the origin.
The red asymptotic line defines the upper boundary of the "Zone of Senescence" which is the various ratios of anabolic to catabolic activity that defines the threshold or boarder for the accumulation of senescent traits. The Zone of Senescence reflects the fitness discounting activity of the IDM, where as above and to the right of this line represents cell that will not be accumulating senescent intracellular components.
Located as shown, the red dot illustrates an average state in which metabolic resources are being conserved by reducing the catabolic and anabolic functions that constitute intracellular repair, driving metabolism into the zone of senescence. The location of the red dot within the graph also illustrates a state of "metabolically discounting the future". Shown below the blue line, the Red Dot also depicts a state in which a slight reduction in cell size is occurring over time.
B. Optimized Senescence
The Discount Rate of Senescence
The "Discount Rate of Senescence" is a term intended to connote that a mechanism exists within the IDM and TDM that establishes a species specific rate of accumulation of senescent traits or generally this concept can be thought of as the species specific rate of aging. Experimental verification will be required to determine the complete list of parameters that control the rate that natural selection and more directly Trans-Generational Selection discounts future fitness of the individual. Until such time here is a short list of items that potentially could calibrate the Discount Rate of Senescence: This list consists of, mortality rate of young adults, the length of the reproductive cycle, and the productivity of the average individuals reproductive cycle.
Figure C. illustrates graphically the effects on intracellular repair as the organisms growth phase is terminated and replaced by an equilibrium of the anabolic (biosynthetic) and the catabolic (autophagic) rate of cellular repair which results from the action of an IDM that is insufficient to prevent the accumulation of senescent traits.
Figure C. Example of Senescent Iteroparous Animals
Figure C. above provides an example of the metabolic shift undertaken by a growth terminating iteroparous animal. The upper red dot depicts the growth phase of the animal and the lower red dot represents the process of growth-termination within the Zone of Senescence. The distance the red dot moves down into the zone of senescence, relative to its position during growth defines the quantity of resources that are being conserved for potential use to support the Trans-Generational Fitness or the present and future fitness of progeny. The (x,y) distance that the metabolism of the animal resides below the boundary of the zone of senescence along the blue line indicates how strongly a species discounts individual fitness in favor of Trans-Generational Fitness, as growth decelerates to the point of growth-termination.
Figure H. Negligible Senescence And The Allocation of Resources
The two yellow points in Figure H above represent the metabolic growth and repair characteristics exhibited by a negligibly senescent continuously growing animal that is iteroparous. The point labeled POIR is the point of optimal iteroparous reproduction. In this example, the animal will, during a reproductive period, exist physiologically just above the zone of senescence on the line of equilibrium between growth and repair processes in order to optimize reproductive capacity as this is the point that maintains negligible senescence while exploiting a minimum of resources. During non-reproductive times the animal will exist at the higher point favoring anabolic processes driving growth through the utilization of the stem cell derived parenchymal cell proliferation. Growth and repair position cycling depicted by the double headed arrow above the Zone of Senescence optimizes current reproductive capability while preserving future reproductive capability.
Figure F. Simultaneous Growth And Senescence
Figure F. The movement of the Red Dot over evolutionary time towards the upper left position depicts natural selection favoring a mechanism by which a species evolves toward faster growth and early sexual maturation by lowering the rate of autophagy and up-regulating biosynthesis. Note that faster growth is achieved without any increase in energy demand, however the animal is subjected to faster rates of senescence. It has been reported that this does occur in guppies and it could occur in other short lived fast growing vertebrates such as opossums. Under different conditions, when the mortality rate of young adults is lower, nature selection can favor mechanisms the drive the ratio of biosynthesis to autophagy towards the ratio expressed by the lower Red dot, which in this example produces slow growth without accumulation of senescent cellular constituents.
The concepts illustrated in Figure F are also supported by the research of
Appendix B. General Considerations
Programmed Cell Death and Negligible Senescence
It is conventional thought that apoptotic and autophagic based forms of Programmed Cell Death (PCD) play a significant role in the generation of senescence. However, evidence is often overlooked that PCD can be both positively and negatively modulated through a broad variety of initiating events, some of these initiating events has the effect of applying PCD as a critically important component in anti-senescence mechanisms as proposed in this paper. In support of this idea, it has been demonstrated that IGF-1 levels are inversely correlated with life span in many organisms, while it has also been demonstrated that IGF-1 inhibits autophagic and apoptotic activity.
Negligible Senescence cannot be achieved in complex organisms through growth alone because the "mutational ratchet" will incrementally compromise the fitness of the individual with the continuous cell division that is required for non-terminating growth . The elimination of genetically defective cells is required to maintain the integrity of the organism over extended periods of time. Random mutational events, free radical damage, viral infection and other assaults, drives the tissues of organisms to perform PCD to eliminate cells with altered DNA. Apoptosis and some forms of autophagy provide this function. The cells eliminated through PCD are replaced by the same feed-stocks of cells that are used in tissue growth as described previously.
Evidence For Stem Cell Regulation Via Systemic Factors
Stem Cell Differentiation in Growth-Terminated Animals
Once the growth period in animals is terminated, populations of stem cells have been shown to differentiate into fibroblasts at a higher rate than normal, which is consistent with our lifelong anecdotal observations of senescence. Due to the body's attempt to maintain tissue size, the continuing intrinsic apoptotic activity sustains the demand for new functional cells within tissues. However, even a slight reallocation of stem cells away from the functional tissue-specific cell types and toward the fibroblast differentiation pathways results in a progressive fibrosis of tissues.
This concept is supported by the laboratory of Edden Heber-Katz which as demonstrated that p21 gene knockout enables tissue regeneration is mammals such as the MRL mouse. Blood factors that result from the elimination of the functioning of this gene have been shown to elicit the same regenerative capability in non-p21-knockout mice.
Why A Non-Senescing GTM Is Rare
Why isn't it common to find that a non-senescing GTM has evolved in growth-terminating species which experience a very low mortality rate in young adults? Ultimately the answer to this question comes down to the need to mitigate the trans-generational selective advantage of discounting the fitness of the individual. The only way to marginally dis-favor Trans-Generational Fitness is to ensure that future fitness of the individual is greater than present fitness of the individual, or said another way, that the fitness of the individual increases with time.
Since all genomes are finite morphological change within the individual cannot be relied on for continued increases in fitness over time, the only obvious way for growth-terminating species to tip the balance in favor of future fitness is through building up resources that can be used to produce continued incremental improvement in fitness over time. The organisms that might possibly be performing this increase in fitness of the individual over time, via the accumulation of resources and without continued growth, are humans and some social insects.
Social insects have achieved significant extensions of life-span within the constraints of growth-termination, however this may have been achieved through very slow non-terminated-growth as the long lived reproductive individuals are much larger than the shorter lived non-reproductive individuals. With respect to humans, sufficient time may not have passed since the beginning of, the agricultural revolution, education, and culture, to have facilitated the accumulation of resources sufficient to drive a mechanism that discounts present fitness and as a result favor the evolution of a non-senescing GTM. Few if any other animal species accumulate enough resources over time sufficient to demonstrate continued improvement in individual fitness. This is what we would expect based on the rarity of negligibly senescent growth-terminating species. Growth-termination is a high evolutionary barrier to the achievement of negligible senescence.
The Persistence And Regulation of Senescence
To describe the role of the IDM and the TDM as the primary mechanisms of senescence does not provide a complete explanation of the phenomena. This section provides possible additional mechanisms for the persistence of senescence and describes factors and potential mechanisms for the species specific regulation of the rate of senescence.
Theories of Aging have long struggled in their attempt to provide a viable explanation as to how and why individuals do not "cheat" by evolving life-spans that significantly exceed the species specific life span. This has been a persistent problem in aging theory given that it has been shown repeatedly that point mutations in single genes that render some specific proteins ineffective results in significant increases in life span in many species.
This paper makes clear that this problem is based on the false assumption that the self interest of the individual is the controlling metric. It is the self interest of the individual to ensure that future generations of its species continue to senesce. Toward this end the individual applies mate selection criteria to select for longevity traits in mates that do not exceed their own longevity. When point mutations occur that increase life span in the individual, the trait is breed out of the population through the application of Mate-Selection criteria that favor Trans-Generational Fitness and as a result select against greater longevity.
Overtly Senescent Traits Are Indicators of Trans-Generational Fitness
In support of the concept that Mate-Selection effectively removes point mutations that increase longevity, it is proposed that overt markers such as graying hair have evolved to act as accurate indicators of the existence, rate and strength of senescence, and as such act as a metric that guides Mate-Selection processes to efficiently select mates with traits that favor Trans-Generational Fitness. In support of this it has been demonstrated that skin stem cell lines associated with hair follicle are know to senesce while other skin stem cell lines do not show replicative senescence.
Self Reinforcing Longevity Phenotypes
The Sensibility Of The IDM And The TDM As The Cause of Senescence
Why is it not obvious that growth-termination is a primary cause of senescence and why has it taken so long to arrive at this conclusion? One reason could be the coexistence of similar species some which demonstrate negligible senescence while others demonstrate senescence and still others demonstrate semelparity, seemingly within similar niche. This picture is confused further by the variability of lifespan in similar species, and by the observation that many closely related species can differ greatly in size.
Though it is not possible to define the conditions under which each species evolved, this paper provides an explanation as to why convergent evolution has not eliminated the diversity of these, persistent, yet seemingly opposite phenotypes. MSSA proposes that convergent evolution does not occur among these species because these phenotypes are composed of synergistic trait pairs which endow the species with the capability to resist selective pressure to change.
Persistence of Senescent and Negligibly Senescent Phenotypes
Synergistic trait pairs illustrated in Figure F. below, provides an explanation for the persistence of these disparate phenotypes to resist selective pressure for convergence. For a species to convert it's phenotype from the trait pair consisting of continuous growth and negligible senescence to one that exhibits the trait pair of terminated growth and senescence, the species has to assume a trait pair of continuous growth and senescence as a transitional phenotype. This trait pair effectively dedicates excess resources to vegetative growth without increasing the fitness of the individual. This phenotype disfavors Trans-Generational Fitness without greatly improving individual fitness. Therefore, this transitional trait pair confers less fitness than either of the other two trait pairs and as a result it is negatively selected for.
The same logic applies to the transitioning of a species from a growth-terminating senescent phenotype to a continuously growing negligibly senescent phenotype, the species must pass through the transitional trait pair phenotype. On a population basis negative selection of the transitional phenotype constitutes a "Transition Barrier" stabilizing the non-transitory phenotypes as depicted in Figure D below. The magnitude of this transition barrier accounts for phenotypic persistence in similar species across the spectrum of phenotypes from negligibly senescent, to senescent, to semelparous.
The other possible transitional trait pair, growth-terminating and negligibly senescent, does not mitigate future risk as well as the continuous growth phenotype and it does not maximize Trans-Generational Fitness as effectively as the growth-terminating senescent phenotype.
In Figure D. below, the transitional trait pair are negatively selected-for relative to the other trait pairs as shown in the boxes labeled A and B. In the non-transitional trait pair each trait drives natural selection to favor their partner trait in the pair. The curved arrows in the green shaded boxes below depict the reinforcing aspect of the phenotypic trait pairs. The figure also depicts the role DES plays in determining which phenotype is utilized by a given species.
Figure D. DES Actuated Self-Stabilizing Phenotypes
Figure D, illustrates how changes in the magnitude of the DES's (bottom arrow) imposed on the organism by modification of their niches represents the specific type of selective pressure that can drive the evolution of the species enabling it to transition across the phenotypic barrier to the alternate self-stabilizing state. Morphological change also can cause increases or decreases in the DES's acting on the organism. The MSSA proposes that morphogenic change can also cause organisms to repetitively transition between the two stable states over evolutionary time. These transitions can be driven by morphological change just as it can be driven by environmental change. Multiple transitions between these two stable phenotypes will have the effect of cleansing the genome of "disposable soma" and antagonistic pleiotrophic type mutations.
The Semelparity Hole
Another example of self-stabilizing phenotypes is semelparity which is a more extreme example of a growth-terminating senescent phenotype. This trait confines reproductive opportunity to a single event and as a result drives natural selection to minimize cellular repair to the point that large reductions in predation and large reductions in DES cannot tip the balance toward another phenotype. Such a phenotype is essentially a self-reinforcing lock-step, since once established, the organism essentially incorporates into its genome a very high mortality rate in young adults. This will permit the inclusion of many disposable soma and antagonistic pleiotrophy type deleterious changes to the genome that further precludes improved fitness via increasing cellular repair. Any improvements in cellular repair will detract from the resources that can be dedicated to the only reproductive event that can occur and so will be strongly selected-against. Semelparity represents a very strong bias towards Trans-Generational Fitness at the cost of individual fitness.
Figure E. Metabolic Characteristics of Semelparity
Figure E, provides an example of the semelparous animal such as the pacific salmon. At sexual maturation the metabolic parameters change migrating along the trajectory of the arrow which depicts the animal strongly conserving both the anabolic and catabolic activity of cellular repair. It should be noted that the organism maintains some overall bias to growth which accounts for the continued morphological changes such as the hooked jaw and humped back etc. The pacific salmon drives its metabolism deep into the zone of senescence conserving large energy resources to power the migration to up stream spawning grounds but eliminates the option of iteroparity due to programmed death.
MSSA proposes that filial cannibalism is an attribute of the negligibly senescent non-terminating-growth phenotype. By consuming its offspring this phenotype continues to favor its own growth and future reproductive capability. Of course, the fact that any given cannibalized offspring will carry only half of the parents genes contributes greatly to the logic of this mechanism. In this model, offspring represents competition for available food supplies that could be used by the parent to increase their own future fitness. Additionally, offspring produced early in the reproductive life of the parent will compete with the parent in the future.
CR and Senescence
As described earlier, Calorie Restriction (CR) results in life extension in vertibrates by preventing the suppression of autophagy via the insulin-IGF-1 axis. CR up-regulates autophagy above the basal level that has been down-regulated by the effects of the IDM. Modulators of anabolic biosynthesis other than the insulin-IGF-1 axis that do not suppress the up-regulation of autophagy, sustain cellular repair at levels that prevent the accumulation of senescent cellular constituents in CR. However under CR the TDM is still active and is not strongly suppressed by these mechanisms and as a result, vital parenchymal cells will still be lost and not replaced due to intrinsically driven apoptosis. Fibrosis and decrepitude will continue to occur though at a some what slower rate. This, I propose, is the reason that CR does not produce negligible senescence only species specific increases in lifespan.
Senescence and the Colonization of Land
As fish colonized the land they gave up the bouncy of water and subjected themselves to a very large and abrupt increase in the DES effects that are the by-product of gravity. If the fish progenitor of land vertebrates was a species that executed a continuous-growth phenotype it is probable that growth-terminating regulatory genes were again released from constraints of inhibition concurrent with other major changes in form and function that were needed to survive on land.
Water was a very competitive place containing many large and evolved predators, as a result, natural selection strongly favored the adaptions to a land existence. However, leaving the water subjected these species to large amounts of DES resulting in the adoption of a growth-terminating, senescent, phenotype. Because this adaptation afforded great protection from predation, it dramatically and immediately lowering the mortality rate of young adults. Until large differentiated populations of animals emerged on the land and predation resumed, natural selection strongly favored the rapid increases in life-span in such growth-terminated species.Cleansing the Genome
The Disposable Soma and Antagonistic Pleiotrophy theories illuminate the experimentally demonstrable reason why deleterious mutations will accumulate in the genome of post reproductive individuals. However, growth-terminating species do not commonly possess a multitude of genetic diseases similar to Huntington's Disease, which expresses a deleterious phenotype some period of time after sexual maturity.
The rarity of genetic diseases that display antagonistic pleiotroyph effects supports the idea that a growth-non-terminating, negligibly senescent species recently existed in the ancestry of mammals. The existence of such an ancestor species would have had the effect of cleansing the genome of these type mutations as they would negatively effect fecundity in animals that exhibit iteroparity, continuous growth and and a low mortality rate in young adults. The existence of a recent ancestor that was growth-non-terminating again supports the idea that the controlling mechanism of growth-termination is fundamental and highly conserved in trans-species evolution.
Basal Metabolic Rate and Autophagic Down-Regulation
Speculating, it seems plausible that the basal metabolic rate that is regulated by the "Hypothalamus > Pituitary > Thyroid > T3,T4" mechanism, could be involved in regulating the basal rate of autophagy and through it, the rate of intracellular repair.
The question arises as to whether turtles and tortoises are growth-terminating negligibly senescent species, the evidence may show that these animals like snakes and other reptiles implement slow, perhaps in-perceptively slow growth throughout life. However many of these animals experience a low mortality rate in young adults which could also provide some selective pressure toward delayed senescence. Growth-termination cycling is another option that could exist somewhere between growth-terminating phenotypes and continuous growth phenotypes. In this scenario, turtles would have growth-terminating regulatory genes that cycle within the course of a year between varying degrees of activity and inactivity. This cycling could account for the annualized markers of age that are present in species that exhibit what appears to be continuous growth.
Growth-Termination Without Attenuated Stem Cell Differentiation
Blanding's Turtles appear to stop growing at some point in life while seemingly remaining negligibly senescent. This species may maintain negligible senescence by establishing a permanent equilibrium between cell replacement and apoptotic processes. This, like the hydra, would constitute growth-termination with negligible senescence. If the Blanding's turtle does effectively terminate-growth in this manor, then this species could stand as an excellent example in nature for our scrutiny of the capability of achieving negligible senescence under terminated-growth. However, its applicability to the human condition may be limited as it may be a very recent split from a growth-non-terminating ancestor. If this is the case, then evolution may simply have not optimized the resource conservation mechanism to drive the species into a slightly senescing state. This speculation seems reasonable since the Blanding's turtles mortality rate and reproductive capability may drive selective forces to only weekly discount the fitness of adults.
It has been reported that older females are better at locating and securing superior nesting places, their brains in effect may be providing these turtles with a way to continue to increase fitness over time without maintaining growth.
From the perspective of evolutionary theory, menopause has been seen as perplexing. For this reason much has been written speculating on the evolutionary sensibility for the persistence of menopause across mammalian species. I would like to propose another alternative, within the context of this theory. Menopause can simply represent a cessation of reproductive capability that has been overtly shutdown to prevent risky pregnancy because the body has determined the degree of senescence has compromised the health state to the point that there is a low probability that pregnancy will result in offspring that live long enough to reproduce. If this is the case, then in theory, fertility could be reinstated if the senescent condition could be reversed to some degree.
This idea unifies the menopause that results from aging with the temporary menopause that results in elite athletes and anorexics which is triggered by insufficient fat stores and is reversible. In this case menopause is just a senescence induced example of the same mechanism.
Proposed experiment to test hypothesis that Mate-Selection drives the persistence of the aging phenotype in Drosophila melanogaster.
Significant experimental evidence exists that supports that both male and female Drosophila melanogaster (DM) engage in sexual selection of mates, for this and other practical reasons this species could be an ideal experimental animal to investigate the proposal that the rate of senescence is a sexually selected trait. M Rose and others have bread files for many years that senesce at varying rates, it seems reasonable to employ these lines to see if flies preferentially select mates on the basis of rate of aging and not not absolute age of its potential mates age for example.
If flies have a mate-selection preference for young or older flies the following experiment might address this question. However this will not shed light on the question of how senescence comes to presist in the population.
The first step in this process is to demonstrate the hypothesis that a population of young adults will preferentially mate with older flies.
A preference for Senescing mates may be restricted to females, males may have a preference for virgin females as a way to maximize reproduction, however if female selection is stronger senescence will still remain a sexually selected trait in this species.
By using larger population of sterile older flies mixed in with a newly mature population of fertile flies it should be possible to demonstrate by the number of hatching eggs if a preference for older mates exist in the younger and older flies. The logic here is, if a preference exists for selecting mates that show signs of senescence there should be fewer viable offspring produced than would be expected based on the simple numeric ratio of young to old, that is if young flies are preferentially mating with older flies and the older flies are preferentially mating with older flies we should see fewer offspring than the simple ratio of old steriles to young fertile would predict.
Introduce a small mixed sex population of newly mature virginto a X times larger population of old (in the last quarter of reproductive life ) males and females that are tetracycline dependent sterile.
Compare the reproductive yield to the theoretically expected yield when no mate-selection bias against senescence has been established in the species via selection caused by the experiment itself. This will be used as a base line for the study.
Repeat step 1 utilizing successive generations of offspring, until the reproductive yield per generation significantly exceeds the offspring yield derived from step 1.
Note: If the hypothesis is correct this process should eliminate the preference for senescence and install a mate-selection preference for non-senescence , in the population.
Introduce a population of newly mature virgin female flies, that are progeny of step 2, to a small population of young tetracycline sterile males and a large population of old senescing males ( in their last quarter of reproductive life ) and compare the progeny yield to the expected yield to test for a bias for youth in mate-selection and to account for the possibility that the females can detect tetracycline dependence.
Note: This step should test for the complement to the selective pressure of step 1.
Introduce successive virgin female populations constituting progeny of step 2 to successive populations of tetracycline sterile old males and fertile males of the same age that constituting progeny for step 2.
Note: This experimental design may not differentiate young flies interest in senescing mates from the preference of senescing individuals for non-senescing individuals. This could be tested by utilizing flightless senescent sterile populations in such a way as to require the non-senescent fertile males and females to actively do the selecting by flying to achieve mating contacts with the sterile senescent flies. This result can then be compared with the matings where both populations are flightless and where both populations can fly and where the non-senescent population is paired with a flighted sterile senescent population.
Note: If we have successfully removed the female preference for senescence in step 1 the populations should evolve longer life spans over time. Repeat steps 1, 2 and 4 to fix and enhance the phenotypes.
End of Supplementary Material
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Article 2004 -Senescence as a sexually selected trait.