Evolution of aging theories: Why modern programmed aging concepts are transforming medical research

Programmed aging refers to the idea that senescence in humans and other organisms is purposely caused by evolved biological mechanisms to obtain an evolutionary advantage. Until recently, programmed aging was considered theoretically impossible because of the mechanics of the evolution process, and medical research was based on the idea that aging was not programmed. Theorists struggled for more than a century in efforts to develop non-programmed theories that fit observations, without obtaining a consensus supporting any non-programmed theory. Empirical evidence of programmed lifespan limitations continued to accumulate. More recently, developments, especially in our understanding of biological inheritance, have exposed major issues and complexities regarding the process of evolution, some of which explicitly enable programmed aging of mammals. Consequently, science-based opposition to programmed aging has dramatically declined. This progression has major implications for medical research, because the theories suggest that very different biological mechanisms are ultimately responsible for highly age-related diseases that now represent most research efforts and health costs. Most particularly, programmed theories suggest that aging per se is a treatable condition and suggest a second path toward treating and preventing age-related diseases that can be exploited in addition to the traditional disease-specific approaches. The theories also make predictions regarding the nature of biological aging mechanisms and therefore suggest research directions. This article discusses developments of evolutionary mechanics, the consequent programmed aging theories, and logical inferences concerning biological aging mechanisms. It concludes that major medical research organizations cannot afford to ignore programmed aging concepts in assigning research resources and directions.     

Melatonin receptors: current status, facts, and hypotheses

Great progress has been made in the identification of melatonin binding sites, commonly identified as melatonin receptors by many authors, in recent years. The bulk of these studies have investigated the sites using either autoradiographic and biochemical techniques with the majority of the experiments being done on the rat, Djungarian and Syrian hamster, and sheep, although human tissue has also been employed. Many of the studies have identified melatonin binding in the central nervous system with either tritium- or iodine-labelled ligands. The latter ligand seems to provide the most reproducible and consistent data. Of the central neural tissues examined, the suprachiasmatic nuclei are most frequently mentioned as a location for melatonin binding sites although binding seems to be widespread in the brain. The other tissue that has been prominently mentioned as a site for melatonin binding is the pars tuberalis of the anterior pituitary gland. There may be time-dependent variations in melatonin binding densities in both neural and pituitary gland tissue. Very few attempts have been made to identify melatonin binding outside of the central nervous system despite the widespread actions of melatonin. Preliminary experiments have been carried out on the intracellular second messengers which mediate the actions of melatonin.     

Rotifers in aging research: use of rotifers to test various theories of aging

Four theories of aging are discussed to examine how effectively they might explain the aging process in rotifers. One of the early theories, the rate of living theory of aging can perhaps be discounted. Although the theory predicts that increased biological energy expenditure, in the form of increased activity or reproduction, would lead to a shorter lifespan, these predictions are not born out by experimental evidence. At the whole animal level, a case can be made for a theory of programmed aging, where the end of reproduction signals the end of the lifespan. Support for this view comes from the observation that lifespan is positively correlated with reproductive parameters, that treatments that extend lifespan usually act to extend the reproductive period, and that the end of reproduction is associated with high mortality and senescent biochemical changes. Two molecular theories of aging are also discussed; the free radical theory of aging and the calcium theory of aging. These theories point to the fact that molecular damage accumulates and that calcium influx increases in the course of aging. When free radical buildup or calcium homeostasis is reduced, lifespan is extended. A molecular explanation of aging does not necessarily exclude the idea of programmed aging. It is probable that an eventual understanding of the aging process will rest on both a physiological and molecular basis.     

Testing predictions of the programmed and stochastic theories of aging: Comparison of variation in age at death,menopause, and sexual maturation

One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8–13% for age at menarche, 7–11% for age at menopause, and 16–21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.     

Genetic instability and aging: theories, facts, and future perspectives

The fundamental mechanisms involved in the physiological deterioration observed with age in mammalian organisms have not yet been elucidated. It appears that random alterations in informational biomolecules and in their synthesis could be the basis of such physiological changes. There is, however, a lack of knowledge with respect to the frequency and characteristics of changes introduced in the cellular molecular machinery. Moreover, the driving force initiating the generation of such alterations and the order of events in which they occur are unknown at present. In this article, data concerning the hypothesis that the aging process is associated with widespread genetic instability are reviewed in the context of the complex interactions between the three major informational biomolecules, DNA, RNA, and protein. We conclude that the results obtained to date do not rule out the possibility that genetic instability in a wide sense is a major causal factor in a number of age-related phenomena. However, it appears that new strategies based on a new technology are ultimately necessary to elucidate the alterations in the intricately interwoven patterns of molecular control that could underlie the various aspects of the aging process. A first attempt is made to formulate the problems in this field and to provide some solutions.     

Ambiquities of aging: Japanese experience and perceptions of menopause

The initial findings of this study indicate that menopause is regarded as a natural life-cycle transition in Japan in which the biological marker of cessation of menstruation is not considered to be of great importance. Symptom reporting among all respondents is generally low regardless of menopausal status, and symptoms such as shoulder stiffness and headaches, which are reported frequently, are not linked specifically to menopausal status (even though individual informants may perceive them to be so). Symptoms of hot flashes and sudden perspiration are higher among peri- and post-menopausal women, but their prevalence appears to be much lower than research findings from other areas to date. Reports by Japanese gynecologists emphasize that menopausal women are liable to present with numerous non-specific somatic complaints. This may well be an accurate representation of a clinical population, but the findings of this present study indicate that such a picture is by no means representative of the average middle-aged female population in Japan. While occupational differences do not contribute to variation in reported symptomatology (with the exception of lumbago and shoulder stiffness), there are nevertheless considerable differences in the subjective meaning of menopause, many of which can be accounted for by class and occupational differences. Presentation of these differences awaits a future publication, but there is one topic which is of concern to the majority of the respondents from each of the sub-samples. The present generation of women entering their 50's are the first where the majority must face later middle age in a nuclear family, along with their husbands, although both they and their husbands have been socialized for the more distant male/female relationships of an extended family. Japanese women cannot look forward, as they did in the past, to the power and comforts derived from running an extended family; on the contrary many can expect a late middle age of looking after bed-ridden parents or parents-in-law, and a lonely, isolated and often poverty-stricken old age (Steslicke 1984), since many pension programs are by no means adequate. Some of their fears about aging are expressed in their views on menopause, but these fears do not appear to be manifested at all prominently as either psychological or somatic representations. When asked to compare their lives with that of their own mothers, stories of incredible hardships from pre- and immediately post-war Japan are vividly portrayed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genomic outlier profile analysis: mixture models, null hypotheses, and nonparametric estimation

In most analyses of large-scale genomic data sets, differentialexpression analysis is typically assessed by testing for differencesin the mean of the distributions between 2 groups. A recentfinding by Tomlins and others (2005) is of a different typeof pattern of differential expression in which a fraction ofsamples in one group have overexpression relative to samplesin the other group. In this work, we describe a general mixturemodel framework for the assessment of this type of expression,called outlier profile analysis. We start by considering thesingle-gene situation and establishing results on identifiability.We propose 2 nonparametric estimation procedures that have naturallinks to familiar multiple testing procedures. We then developmultivariate extensions of this methodology to handle genome-widemeasurements. The proposed methodologies are compared usingsimulation studies as well as data from a prostate cancer geneexpression study.     

The development of small primate models for aging research

Nonhuman primate (NHP) aging research has traditionally relied mainly on the rhesus macaque. But the long lifespan, low reproductive rate, and relatively large body size of macaques and related Old World monkeys make them less than ideal models for aging research. Manifold advantages would attend the use of smaller, more rapidly developing, shorter-lived NHP species in aging studies, not the least of which are lower cost and the ability to do shorter research projects. Arbitrarily defining "small" primates as those weighing less than 500 g, we assess small, relatively short-lived species among the prosimians and callitrichids for suitability as models for human aging research. Using the criteria of availability, knowledge about (and ease of) maintenance, the possibility of genetic manipulation (a hallmark of 21st century biology), and similarities to humans in the physiology of age-related changes, we suggest three species--two prosimians (Microcebus murinus and Galago senegalensis) and one New World monkey (Callithrix jacchus)--that deserve scrutiny for development as major NHP models for aging studies. We discuss one other New World monkey group, Cebus spp., that might also be an effective NHP model of aging as these species are longer-lived for their body size than any primate except humans.     

Understanding ecological community succession: Causal models and theories,a review

Critical review of explanations for patterns of natural succession suggests a strong, common basis for theoretical understanding, but also suggests that several well known models are incomplete as explanations of succession. A universal, general cause for succession is unlikely, since numerous aspects of historical and environmental circumstances will impinge on the process in a unique manner. However, after disturbance, occupation of a site by any species causes changes in the conditions at the site. Sorting of species may result, since different species are adapted to different regions of environmental gradients. Such sorting can generate several patterns of species abundance in time, but commonly results in sequential replacements of species adapted to the varying conditions. This may be due to constraints on species' strategies, or life history traits, placed by the limited resources available to the organism. These constraints often result in inverse correlation between traits which confer success during early and late stages of succession. Facilitatory or inhibitory effects of species on each other are best understood in terms of these life history interactions, perhaps as restrictions on, or as moderation of, these processes.Strong support for the importance of correlations in life history traits stems from comparisons of simulated succession with and without these correlations. These simulations are reviewed in some detail, and followed by brief reviews of other prominent models for succession. Several aspects of the confusion and controversies in the successional literature are then discussed, with a view to a more optimistic synthesis and direction for successional ecology.     

Cancer,aging and immunotherapy: lessons learned from animal models

Aging of the immune system is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age is associated with an increased incidence of cancer. Although there is a plethora of reports evaluating the effect of immunotherapy in stimulating antitumor immune responses, the majority of these studies do not pay attention to the effect aging has on the immune system. Studies from our group and others indicate that immunotherapies could be effective in the young, are not necessarily effective in the old. To optimally stimulate an antitumor immune response in the old, it is necessary to (1) identify and understand the intrinsic defects of the old immune system and (2) use relevant models that closely reflect those of cancer patients, where self-tolerance and aging are present simultaneously. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate stronger antitumor immune response in the old and the use of a tolerant animal tumor model to target a self-tumor antigen for the optimization of immunotherapeutic interventions in the old.     

Alzheimer's disease: current knowledge,management and research

Alzheimer''s disease is a common neurological condition, appearing as early as age 40 but increasing dramatically in incidence over age 85. Different genetic factors are at play, modified by events over a lifetime. Clinical diagnosis is possible through careful history taking with a reliable informant and a minimum number of laboratory tests. A relatively predictable natural history can be observed, with progression through stages of cognitive loss, functional impairment and behavioural disinhibition or apathy. New medications such as donepezil offer hope for improving or stabilizing symptoms. Such treatment can be administered by primary care physicians with experience in the diagnosis and management of Alzheimer''s disease. Disease stabilization, or even prevention, may be possible in the future.     

Integral projections models,their construction and use in posing hypotheses in ecology

Replicated experiments at the level of the population are often not feasible for field systems. Despite this, population‐level observational studies play a critical role in biology. For example, they have revealed how environmental change generates ecological and evolutionary change in free‐living populations. When replicated experiments are impossible, constructing models and using these to conduct in silico experiments is the next best thing. Recent advances in the construction and analysis of integral projection models (IPMs) mean they offer a remarkably powerful tool to study ecological and evolutionary dynamics. IPMs can be parameterised using data frequently collected by ecologists, but the ease with which they can be constructed and analysed is perhaps not as widely appreciated as it could be. In this paper, which is loosely related to the talk I gave when receiving the Per Brinck Oikos Award in 2012, I show how easily IPMs can be constructed and analysed, and I argue they play an important role in posing and testing hypotheses in population biology.