Evolutionary theories of aging. 2. The need not to close the debate

BACKGROUND: Keller and Genoud [Gerontology 1999;45: 336-338] consider that a previous article of Le Bourg [Gerontology 1998;44:345-348] is an inappropriate criticism of evolutionary theories of aging and offer a refutation of this article. OBJECTIVE: We answer that the article was not devoted to the criticism of evolutionary theories of aging but, rather, to the sometimes fast tackling of these theories on what is observed in the wild. Furthermore, we answer to the specific points contained in the Keller and Genoud's article (longevity of ants, reproduction in mammals, and the case of the human species). CONCLUSION: The debate about evolutionary theories of aging is not closed: it would be an error to try to do it before a consensus has been reached.     

A test of Fisher''s theory of dominance.

One of the first patterns noticed by geneticists was that mutations are almost always recessive to their wild-type alleles. Several explanations of this striking pattern have been offered. The two most influential are Fisher's theory--which argues that dominance results from natural selection against recurring deleterious mutations--and Wright's theory--which argues that dominance results from the physiology of gene action. The debate over which of these theories is correct represents one of the most protracted controversies in the history of evolutionary biology. Here I test Fisher's theory by assessing the dominance of mutations in an organism that is typically haploid, the alga Chlamydomonas reinhardtii. The results show that mutations are recessive just as often among haploid as among diploid species. This result falsifies Fisher's theory of dominance and provides strong support for the alternative physiological theory.     

Evolution: questions for the modern theory.

The blind spot of the present generation of evolutionists is failure to see the consequences and limits of natural selection. Darwinian natural selection is a costly process of differential elimination of individuals. The widely accepted misdefinition of natural selection as differential reproduction mistakenly hides the Darwinian process and its cost. And current theories of selfish genes, inclusive fitness, and kin selection are incompatible with Darwinian selection. Implicitly, if not explicitly, they postulate genes that favor themselves but reduce the Darwinian fitness of the individuals carrying them. Such genes would not survive; they would eliminate themselves by causing the selective elimination of their carriers. Critical questions that evolutionists should be asked are suggested. My own "unhappy conclusion" is that, because most biologists have forgotten what natural selection is, much current evolutionary and sociobiological theory presented by the most influential evolutionists is mistaken and dangerous. Anthropologists and sociologists are wise to distrust it.     

From the stress theory of aging to energetic and evolutionary expectations for longevity

Stress targets energy carriers. Genes for stress resistance are selected that convey high metabolic efficiency enabling adaptation to the energetically restrictive and hence stressful environments of natural populations. Data from experimental organisms and from humans are consistent with a primary role for stress resistance underlying life span, which provides a hitherto neglected procedure for assaying longevity in natural populations. Taking into account the metabolic consequences of stressful environments, the free-radical theory of aging becomes a general stress theory of aging. A recent derivative, the deprivation-syndrome theory of aging, highlights resource and hence energy shortages. Energy balances under the stress theory of aging are primary for an understanding of the evolutionary limits of longevity of organisms in their habitats. In contrast, well-nourished humans of the modern era, and laboratory, domesticated and island populations are exposed to more benign conditions which appear to provide the background for other evolutionary theories of aging, especially the mutation accumulation and antagonistic pleiotropy theories. In modern human populations where selection for stress resistance is relaxed compared with earlier harsher conditions, substantial future evolutionary extensions to maximum life span may be difficult to attain because of the mutation accumulation process. However there is an urgent need for comparative empirical studies of life-history traits including longevity under benign and harsh environments. This revised version was published online in July 2006 with corrections to the Cover Date.     

The effects of nutritional manipulation and laboratory selection on lifespan in Drosophila melanogaster.

There are parallels between the effects of laboratory selection and nutritional manipulation on the expression of lifespan and other fitness-related characters in Drosophila melanogaster. However, little is known about the effects of laboratory selection and nutritional manipulation when applied simultaneously. Given that D. melanogaster is one of the major model organisms for testing theories of aging, simultaneous application of laboratory selection and nutritional manipulation is of considerable interest. To that end we developed six groups of five fold replicated populations selected for either early or late fertility. Each of these groups was maintained on either high- or low-nutrition diets. Comparisons among the groups showed that nutrition is neutral in selecting for lifespan. Moreover, the dietary-restriction response can be broken by simultaneous selection and nutritional manipulation. Finally, characters that respond in a parallel manner under selection or nutritional manipulation may not when the two are applied simultaneously.     

The ecological stress theory of aging and hormesis: an energetic evolutionary model

Free-living organisms normally struggle to exist in harsh environments that are nutritionally and energetically inadequate, where evolutionary adaptation is challenged by internal stresses within organisms and external stresses from the environment. The incorporation of environmental variables into aging theories such as the free-radical and metabolic rate/oxidative stress theories, is the basis of the ecological stress theory of aging and hormesis. Environmental variation from optimum to lethal extremes gives a fitness-stress continuum, where energetic efficiency, or fitness, is inversely related to stress level; in the evolutionary context survival is a more direct measure of fitness for assessing aging than is lifespan. On this continuum, the hormetic zone is in the optimum region, while aging emphasizes survival towards lethal extremes. At the limits of survival, a convergence of physiological and genetical processes is expected under accumulating stress from Reactive Oxygen Species, ROS. Limited ecologically-oriented studies imply that major genes are important towards limits of survival compared with the hormetic zone. Future investigations could usefully explore outlier populations physiologically and genetically, since there is the likelihood that genetic variability may be lower in those cohorts managing to survive to extremely advanced ages as found in highly stressed ecological outlier populations. If so, an evolutionary explanation of the mortality-rate decline typical of cohorts of the extremely old emerges. In summary, an energetic evolutionary approach produces a general aging theory which automatically incorporates hormesis, since the theory is based on a fitness-stress continuum covering the whole range of possible abiotic environments of natural populations.     

What evolutionary biology can do for gerontology

Evolutionary biologists have shown mathematically that aging is an inevitable consequence of age-specific natural selection acting on species with somata separate from germ lines. Two specific genetic mechanisms are known which could underlie the evolution of aging under these conditions: age-specificity of gene effects and antagonistic pleiotropy between early and late ages. Comparative evidence indicates that senescence occurs only when the stipulations of the evolutionary theory are met. Laboratory experiments with Drosophila indicate that prolonging the action of natural selection leads to the evolution of postponed senescence. The genetic variation involved in such postponed senescence exhibits both age-specificity and antagonistic pleiotropy. These theories and empirical findings together suggest that the best general theory of aging now available is the evolutionary theory. In addition, this work has yielded Drosophila stocks with postponed senescence that are being used to unravel physiological mechanisms of senescence.     

The normative dimensions of extending the human lifespan by age-related biomedical innovations

The current normative debate on age-related biomedical innovations and the extension of the human lifespan has important shortcomings. Mainly, the complexity of the different normative dimensions relevant for ethical and/or juridicial norms is not fully developed and the normative quality of teleological and deontological arguments is not properly distinguished. This article addresses some of these shortcomings and develops the outline of a more comprehensive normative framework covering all relevant dimensions. Such a frame necessarily has to include conceptions of a good life on the individual and societal levels. Furthermore, as a third dimension, a model for the access to and the just distribution of age-related biomedical innovations and technologies extending the human lifespan will be developed. It is argued that such a model has to include the different levels of the general philosophical theories of distributive justice, including social rights and theories of just health care. Furthermore, it has to show how these theories can be applied to the problem area of aging and extending the human lifespan.     

Thermodynamics and information in aging: why aging is not a mystery and how we will be able to make rational interventions

Currently, the aging research field lacks consensus in its focus and methodology. Foundational principles, such as the evolutionary origins and physiological definition of aging, remain controversial. The aim of this paper is to resolve these issues. By applying the concepts of thermodynamics and information in an evolutionary context, the aging phenotype can be derived from first principles. Life uses information storage to maintain its distance from thermodynamic equilibrium. Since it is impossible to make any process 100% efficient, a selective force (i.e., natural selection) is needed to maintain the information's viability. Natural selection operates upon generations, and for reasons discussed subsequently, the somatic body cannot implement an analogous selective process. The aging phenotype we see can be derived from this model along with a number of insights that will enhance our ability to make intelligent and rational interventions.     

The maintenance gap: a new theoretical perspective on the evolution of aging

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation. Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms. This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.     

The evolution of aging phenotypes in snakes: a review and synthesis with new data

Reptiles are underutilized vertebrate models in the study of the evolution and persistence of senescence. Their unique physiology, indeterminate growth, and increasing fecundity across the adult female lifespan motivate the study of how physiology at the mechanistic level, life history at the organismal level, and natural selection at the evolutionary timescale define lifespan in this diverse taxonomic group. Reviewed here are, first, comparative results of cellular metabolic studies conducted across a range of colubrid snake species with variable lifespan. New results on the efficiency of DNA repair in these species are synthesized with the cellular studies. Second, detailed studies of the ecology, life history, and cellular physiology are reviewed for one colubrid species with either short or long lifespan (Thamnophis elegans). New results on the rate of telomere shortening with age in this species are synthesized with previous research. The comparative and intraspecific studies both yield results that species with longer lifespans have underlying cellular physiologies support the free-radical/repair mechanistic hypothesis for aging. As well, both underscore the importance of mortality environment for the evolution of aging rate.     

The stress of aging

Although the evolutionary theories of aging are quite well established, our knowledge about how we age is still very limited. The abundance and heterogeneity of available mechanistic theories of aging implicitly suggest that this phenomenon is overly complex and unlikely to be explained by a single pathway. Moreover, although aging remains a unique process, it is characterized by heterogeneous manifestations, not only determining inter-individual variations, but even intra-individual diversities. Such heterogeneity renders the inner nature of the aging process of difficult evaluation in older persons due to the potential biases introduced by multiple age-related social, biological, and clinical factors (and responsible for the evidence-based issue in geriatrics). Moving from the difficulties in translating anti-aging preclinical interventions into clinical trials, an alternative approach is illustrated. We encourage moving to a holistic evaluation of aging by adopting specific and consequent modifications in the design and conduction of clinical research. Such approach is today commonly applied in the clinical setting where the complexity of older patients often requires multidimensional interventions to adequately target the geriatric syndromes. Consistently, interventions targeting the aging process may result ineffective if too focused on a single underlying causal mechanism and/or failing to capture the complexity of the phenomenon. In this context, frailty (a geriatric syndrome characterized by age-related declines occurring across multiple physiologic systems) may indeed represent a clinically relevant threshold throughout the continuum of the aging process and a promising benchmark to test multidomain interventions against age-related conditions.     

Theories and mechanisms of aging

This article discusses various theories of aging and their relative plausibility related to the human aging process. Structural and physiologic changes of aging are discussed in detail by organ system. Each of the organ systems is discussed when applicable to the various theories of aging. Normal versus abnormal aging is discussed in the context of specific aging processes, with atypical presentations of disease and general links to life expectancy. Life expectancy and lifespan are discussed in the context of advances in medical science and the potential ultimate link to human life span.     

Innateness and culture in the evolution of language

Human language arises from biological evolution, individual learning, and cultural transmission, but the interaction of these three processes has not been widely studied. We set out a formal framework for analyzing cultural transmission, which allows us to investigate how innate learning biases are related to universal properties of language. We show that cultural transmission can magnify weak biases into strong linguistic universals, undermining one of the arguments for strong innate constraints on language learning. As a consequence, the strength of innate biases can be shielded from natural selection, allowing these genes to drift. Furthermore, even when there is no natural selection, cultural transmission can produce apparent adaptations. Cultural transmission thus provides an alternative to traditional nativist and adaptationist explanations for the properties of human languages.     

Biology of longevity: role of the innate immune system

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy. In fact, by neutralizing infectious agents the immune system plays a beneficial role until reproduction and parenting. However, by determining chronic inflammation, it can be detrimental later in life, a period largely unforeseen by evolution. In particular, the data coming from the long-lived male population under study show that genetic polymorphisms responsible for a low inflammatory response might result in an increased chance of long lifespan in an environment with a reduced pathogen burden. Such a modern and healthy environment also permits a lower grade of survivable atherogenic inflammatory response.     

How evolutionary thinking affects people's ideas about aging interventions

Evolutionary theory has guided the development of antiaging interventions in some conscious and some unconscious ways. It is a standard assumption that the body's health has been optimized by natural selection, and that the most benign and promising medical strategies should support the body's efforts to maintain itself. The very concept of natural healing is a reflection of evolutionary thinking about health. Meanwhile, a developing body of experimental evidence points to the startling hypothesis that aging is a metabolic program, under genetic control we are programmed for death. Evolution has provided that the aging program can be abated in times of stress, e.g., caloric restriction. CR mimetics are already recognized as a promising avenue for antiaging research. Beyond this, there are two ancient mechanisms of programmed death in protists that have survived half a billion years of evolution, and still figure in the aging of vertebrates today. These are apoptosis and replicative senescence via telomere truncation. Most researchers have been wary of modifying these mechanisms because they are known to play a stopgap role in cancer prevention. But intriguing evidence suggests that, despite some counter-carcinogenic function, the net result of both these mechanisms may be to shorten lifespan. Thus, interventions that suppress apoptosis and that preserve telomeres may be promising avenues for life extension research. A third element of the body's self-destruction program co-opts the inflammation response. Epidemiological evidence suggests that NSAIDs including aspirin protect against atherosclerosis, arthritis, and some forms of cancer. It may be that aging engages an autoimmune response that can be modified by drugs acting more narrowly on this same pathway. The existence of an evolutionary program that controls aging from the top down supports a new optimism concerning the types of antiaging interventions that are possible, and the likelihood that simple strategies may have dramatic results without dramatic side-effects.     

Making SENSE: strategies for engineering negligible senescence evolutionarily

Thirty years ago, in 1977, few biologists thought that it would be possible to increase the maximum life span characteristic of each species over the variety of environmental conditions in which they live, whether in nature or in the laboratory. But the evolutionary theory of aging suggested otherwise. Accordingly, experiments were performed with fruit flies, Drosophila melanogaster, which showed that manipulation of the forces of natural selection over a number of generations could substantially slow the rate of aging, both demographically and physiologically. After this first transgression of the supposedly absolute limits to life extension, it was suggested that mammals too could be experimentally evolved to have greater life spans and slower aging. And further, it was argued that such postponed-aging mammals could be used to reverse-engineer a slowing of human aging. The subsequent discovery and theoretical explanation of mortality-rate plateaus revealed that aging was not due to the progressive physiological accumulation of damage. Instead, aging is now understood by evolutionary biologists to arise from a transient fall in age-specific adaptation, a fall that does not necessarily proceed toward ineluctable death. This implies that SENS must be based on re-tuning adaptation, not repairing damage. As evolutionary manipulation of model organisms shows us how adaptation can be focused on engineering negligible senescence, there are thus both scientific and practical reasons for making SENS evolutionary; that is making SENSE.     

Pharmacology of delayed aging and extended lifespan of Caenorhabditis elegans

The identification and analysis of compounds that delay aging and extend lifespan is an important aspect of gerontology research; these studies can test theories of aging, lead to the discovery of endogenous systems that influence aging, and establish the foundation for treatments that might delay normal human aging. Here we review studies using the nematode Caenorhabditis elegans to identify and characterize compounds that delay aging and extend lifespan. These studies are considered in four groups: (1) Studies that address the free-radical theory of aging by analyzing candidate compounds with antioxidant activities including vitamin E, tocotrienols, coenzyme Q, and Eukarion-8/134. (2) Studies that analyze plant extracts (blueberry and Ginko biloba) that contain a mixture of compounds. (3) Studies of resveratrol, which was identified in a screen for compounds that affect the activity of the Sir2 protein that influences lifespan. (4) Studies based on screening compound libraries using C. elegans aging as a bioassay, which led to the identification of the anticonvulsant medicines ethosuximide and trimethadione. There has been exciting progress in the analysis of compounds that influence C. elegans aging, and important challenges and opportunities remain in determining the mechanisms of action of these compounds and the relevance of these observations to aging of other animals.