Current Aging Science (v.8, #1)

Aging is Neither a Failure nor an Achievement of Natural Selection by Juan Carlos Aledo, Jose Maria Blanco (4-10).
In contraposition to the view of aging as a stochastic time-dependent accumulation of damage, phenoptotic theories of aging postulate that senescence may provide supra-individual advantages, and therefore it might have been promoted by natural selection. We reason that although programmed aging theories are subjectively appealing because they convey a cure for aging, they also raise a number of objections that need to be dealt with, before we may be entitled to contemplate aging as an adaptive function evolved through natural selection. As an alternative view, we present metabolism as an endless source of by-products and errors causing cellular damage. Although this damage accumulation event is a spontaneous entropy-driven process, its kinetics can be genetically and environmentally modulated, giving place to the wide range of lifespans we observe. Mild forms of damage may be accumulating during a long enough period of time to allow reproduction before the fatal failure happens. Hence, aging would be a stochastic process out of the reach of natural selection. However, those genetic pathways influencing the rate of aging and consequently determining longevity may be targets of natural selection and may contribute to shaping the optimal strategy according to the ecological context. In this sense, short- and long-lived organisms represent two extreme strategies that, in terms of biological fitness, can perform equally well, each within its own niche.

There is increasing evidence that nutritional and hormonal signals during development can influence longevity. It was reported that mice subjected to mild calorie restriction only during the preweaning period live longer than control animals. In long-lived hypopituitary dwarf mice, longevity can be reduced by growth hormone replacement therapy during pre- and peri-pubertal period. These findings suggest that trajectory of aging is importantly influenced by the availability of nutrients and the levels of anabolic hormones during development.

The longstanding debate about whether aging may have evolved for some adaptive reason is generally considered to pit evolutionary theory against empirical observations consistent with aging as a programmed aspect of organismal biology, in particular conserved aging genes. Here I argue that the empirical evidence on aging mechanisms does not support a view of aging as a programmed phenomenon, but rather supports a view of aging as the dysregulation of complex networks that maintain organismal homeostasis. The appearance of programming is due largely to the inadvertent activation of existing pathways during the process of dysregulation. It is argued that aging differs markedly from known programmed biological phenomena such as apoptosis in that it is (a) very heterogeneous in how it proceeds, and (b) much slower than it would need to be. Furthermore, the taxonomic distribution of aging across species does not support any proposed adaptive theories of aging, which would predict that aging rate would vary on a finer taxonomic scale depending on factors such as population density. Thus, while there are problems with the longstanding non-adaptive paradigm, current evidence does not support the notion that aging is programmed or that it may have evolved for adaptive reasons.

In the 60 years since Medawar questioned the assumption that aging is a selected trait with a fitness benefit, mainstream biogerontology has overwhelmingly adopted the view that aging is a product of evolutionary neglect rather than evolutionary intent. Recently, however, this question has come to merit further scrutiny, for three reasons: a variety of new ways in which aging could indeed be 'programmed' have been proposed, several phenomena with superficial similarities to programmed aging have been suggested to offer evidence for it and against the mainstream consensus, and above all it has become appreciated that the existence or otherwise of 'pro-aging genes' has enormous implications for determining our optimal strategy for the medical postponement of age-related ill-health. Accordingly, it is timely to revisit the arguments and data on this topic. In this article I discuss difficulties in reconciling the programmed-aging concept with existing data, flaws in various arguments given by others that existing data prove aging to be programmed, and extensions of these considerations to various phenomena that in one or another way resemble programmed aging. I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, and thus that our only option for substantial extension of healthspan is a divide-and-conquer panel of interventions to repair the damage that the body inflicts upon itself throughout life as side-effects of its normal operation. I explicitly avoid arguments that rely on unnecessarily abstruse evolutionary theory, in order to render my line of reasoning accessible to the broadest possible audience.

Solving the Programmed/Non-Programmed Aging Conundrum by Theodore C. Goldsmith (34-40).
For more than 150 years there has been some level of scientific argument regarding whether aging in humans and other mammals is purposely genetically programmed because living too long produces an evolutionary disadvantage, or whether aging in mammals is non-programmed because there is no such disadvantage. Although for many decades it was very widely thought that programmed aging in mammals was theoretically impossible, new evolutionary mechanics theories and new discoveries support programmed mammal aging as well as programmed lifespan limitation in non-mammals. The emergence of modern programmed aging theories has created a schism in the bioscience community regarding the programmed/ non-programmed issue. Because the two theories have radically different predictions regarding the fundamental nature of aging and consequently the nature of highly age-related diseases like cancer, stroke, and heart disease, resolving this issue is critical to medical research.
This article summarizes the evolutionary mechanics basis of modern programmed and non-programmed aging theories, describes some of the many ancillary circumstances that continue to prevent resolution of this issue, and recommends steps that could be taken to rapidly resolve the programmed/ non-programmed conundrum.


There are two modern evolutionary theories of mammal senescence: Programmed theories contend that mammals purposely limit their lifespans because doing so creates an evolutionary advantage. Non-programmed theories contend that each mammal specie only needs a particular lifespan and therefore only evolved and retained the capability for attaining that lifespan. Arguments over the evolutionary nature of aging have now existed for more than 150 years and for reasons described here may never be definitively resolved.
The programmed/ non-programmed question is critical to medical research because the theories have grossly different predictions regarding the biological mechanisms associated with the aging process and therefore, the nature of age-related diseases and conditions.
This article describes and compares two approaches for avoiding the need to obtain resolution on the evolutionary basis of senescence in order to identify and characterize the biological mechanisms responsible for aging and therefore the nature of highly age-related diseases.


Towards an Evidence-based Model of Aging by Harold L. Katcher (46-55).
The modern synthesis or evolutionary theory of aging assumes that aging results from the accumulation of errors or damages at the cellular level through the inadequacies of an organism's repair and maintenance machinery. The demonstration of cellular and organic rejuvenation requires the hypothesis that aging is the result of irreparable damage to be rejected. I will propose basic principles of mammalian aging based only on experimental data, without imposing the constraints of evolutionary theory. Consideration of the results of experiment suggests that fundamental assumptions about cell and organ aging being autonomous process, and about the centrality of cellular aging in organismic aging are wrong. The derived principles indicate that exogenous control of age-phenotype at cellular and higher levels of biological organization is possible.

Non-programmed Versus Programmed Aging Paradigm by Giacinto Libertini (56-68).
There are two opposite paradigms to explain aging, here precisely defined as 'age-related progressive mortality increase, i.e. fitness decline, in the wild'. The first maintains that natural selection is unable to maintain fitness as age increases. The second asserts that, in particular ecological conditions, natural selection favors specific mechanisms for limiting the lifespan. The predictions derived from the two paradigms are quite different and often opposing. A series of empirical data and certain theoretical considerations (non-universality of aging; great inter-specific variation of aging rates; effects of caloric restriction on lifespan; damage of aging for the senescing individual but its advantage in terms of supra-individual selection; existence of fitness decline in the wild; proportion of deaths due to intrinsic mortality inversely related to extrinsic mortality, when various species are compared; impossibility of explaining the age-related fitness decline as a consequence of genes that are harmful at a certain age; age-related progressive decline of cell turnover capacities; on/off cell senescence; gradual cell senescence) are compared with the predictions of the two paradigms and their compatibility with each paradigm is considered. The result is that the abovementioned empirical data and theoretical considerations strongly contradict and falsify in many ways all theories belonging to the first paradigm. On the contrary, they are consistent or compatible with the predictions of the second paradigm.

Is Programmed Aging a Cause for Optimism? by Josh Mitteldorf (69-75).
Aging is now viewed as programmed under genetic control by a growing minority of evolutionary biologists, and a larger proportion of researchers in gerontology. The hypothesis of programmed aging has been regarded as encouraging for anti-aging science. Some mechanisms of programmed aging may present ready targets for medical interference [mitigation alleviation attenuation], while other kinds of programmed mechanism may yet prove to be refractory. The most promising possibility is that the machinery responsible for maintenance of the vibrant and youthful state of the body is never really lost, but de-commissioned by hormonal signals in the aging body; restoring a youthful signaling environment should then be sufficient to prompt the body to restore itself. But it is also possible that aging may be programmed in a way that does not facilitate anti-aging interventions. We identify two possible cases: In the first, the body is programmed to age via neglect rather than by affirmative self-destruction, so that damage is accumulating that the body is beyond the body's power to repair. In the second, aging is controlled by an epigenetic clock whose workings are so intricate as to be intractable for human mastery in the foreseeable future. There is substantial evidence that first of these is not a likely scenario, but the jury is still out on the second.

It is supposed that the development and aging of multicellular animals and humans are controlled by a special form of the clock mechanism - a chronograph. The development of animals and their aging are interconnected by the program of the species lifespan that has been selected in the evolution of each species to fit the resources of its ecological niche. The theory is based on the idea about a controlled loss by the neurons in the brain of hypothetical organelles – chronomeres that represent themselves small DNA molecules, which are amplificates of the segments of chromosomal DNA. A regular mode of the process of chronomere losses by neurons is provided by a pacemaker localized in the pineal gland and activated at least once per lunar month. Neurons, consecutively losing their chronomeres, are organized in the brain in the temporal relay race. Analogues of chronomeres, namely printomeres, are supposed to exist in dividing non-neuronal cells. Printomeres are not involved in a performance of temporal function, instead they are responsible for the maintenance in dividing cells of their memory about the state of differentiation. A critical shortening or loss of a printomere in a dividing cell leads to a cellular senescence, whereas telomere shortening is a bystander of this process. Thus, aging of a multicellular organism is associated with the loss of chronomeres, whereas senescence of dividing cells is associated with the loss of regulatory RNAs encoded by printomeres. If the cells that have lost their printomeres are environmentally forced to divide, they can transform into cancer cells.

Ageing is generally viewed as a detrimental phenotype; with age comes increasing susceptibility to disease and frailty. Recent data also suggests that disease can result in an increase in ageing phenotypes suggesting a positive feedback loop. It is clear that lifespan can be modified genetically and by interventions in certain organisms but the mechanisms by which this is achieved have not yet been fully elucidated, as indeed is the case for the ageing process itself. Because of the intimate relationship between disease, ageing and ultimately lifespan it is difficult to dissect the effects of individual changes. As we learn more about individual pathways and allelic variants influencing ageing and disease we can begin to unravel the influence of natural selection on these processes.

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned. (1) Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no agerelated diseases. (2) In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified. (3) In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event). (4) Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies. (5) In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions.
In this review, we consider point (5) in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging – to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life.


During the last decade, our understanding of the molecular mechanisms regulating the cellular environment has made significant advances. With the new dynamical description of the functionalities of the cell, several processes known to play a crucial role in the onset of aging such as cell senescence, the increase of ROS level and telomere shortening appear to be a consequence of the disruption of a systemic dynamical equilibrium established within the cellular environment. In this short review, I discuss how these new features provide us with a way to improve the current evolutionary theory of aging and help to clarify the role played by aging within the context of the evolution.