Mitochondrial Changes in Ageing Caenorhabditis elegans – What Do We Learn from Superoxide Dismutase Knockouts?

One of the most popular damage accumulation theories of ageing is the mitochondrial free radical theory of ageing (mFRTA). The mFRTA proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular damage to mitochondrial DNA (mtDNA). Within the mFRTA, the "vicious cycle" theory further proposes that reactive oxygen species (ROS) promote mtDNA mutations, which then lead to a further increase in ROS production. Recently, data have been published on Caenorhabditis elegans mutants deficient in one or both forms of mitochondrial superoxide dismutase (SOD). Surprisingly, even double mutants, lacking both mitochondrial forms of SOD, show no reduction in lifespan. This has been interpreted as evidence against the mFRTA because it is assumed that these mutants suffer from significantly elevated oxidative damage to their mitochondria. Here, using a novel mtDNA damage assay in conjunction with related, well established damage and metabolic markers, we first investigate the age-dependent mitochondrial decline in a cohort of ageing wild-type nematodes, in particular testing the plausibility of the "vicious cycle" theory. We then apply the methods and insights gained from this investigation to a mutant strain for C. elegans that lacks both forms of mitochondrial SOD. While we show a clear age-dependent, linear increase in oxidative damage in WT nematodes, we find no evidence for autocatalytic damage amplification as proposed by the "vicious cycle" theory. Comparing the SOD mutants with wild-type animals, we further show that oxidative damage levels in the mtDNA of SOD mutants are not significantly different from those in wild-type animals, i.e. even the total loss of mitochondrial SOD did not significantly increase oxidative damage to mtDNA. Possible reasons for this unexpected result and some implications for the mFRTA are discussed.     

Expression of genetic and environmental variation during ageing

Summary A selection experiment with Drosophila melanogaster was carried out to test some theories of ageing by calculating genetic parameters for a reproductive fitness trait at different ages. Successful selection for increased lifespan showed that longevity is a trait under genetic control. Positive genetic correlations between early and late fitness were found. These results do not support the pleiotropy theory of ageing which predicts a negative genetic correlation. Both environmental and additive genetic variation clearly increased with age. Increased environmental variation probably reflects the individuals' difficulties in coping with environmental stress. The increase in additive genetic variation supports the mutation accumulation theory of ageing, as well as other theories that postulate increased additive genetic variation with age.     

Physiological ageing of potato tubers: A Review

Numerous theories have been proposed to describe the complex process of ageing in biological systems. Two general groups of ageing theories currently exist: 1) stochastic where the accumulation of random molecular damage leads to loss of information vital to the cell; and, 2) systemic where an organised, genetically based sequence of metabolic activities leads to programmed ageing. Whether these are acceptable models of ageing in potato tubers is unknown although the tuber could provide a useful experimental system for studying ageing. An initial requirement for advancing the concept of ageing in potato tubers must centre on the development of a suitable ageing index. A review of the literature suggests that a modified approach to ‘sprouting capacity’ and ‘incubation period’ may allow tuber ageing to be described in mathematical terms that would, in turn, facilitate the development of a physiological ageing index as well as temperature sensitive predictive models. Although a number of biochemical studies of ageing have been pursued, the development of adequate biomarkers has yet to achieve a coordinated level of development as found in a range of organisms. For example, ageing in other biological systems may be viewed as an outcome of an accumulation of random molecular damage and may be primarily caused by a changing balance between reactive oxygen species and diminishing levels of protective agents such as superoxide dismutase, alpha‐tocopherol or vitamin C. The exploration of these and similar problems in the context of appropriate modelling approaches should allow a better understanding of physiological ageing in potato tubers.     

Reproductive effort accelerates actuarial senescence in wild birds: an experimental study

Optimality theories of ageing predict that the balance between reproductive effort and somatic maintenance determines the rate of ageing. Laboratory studies find that increased reproductive effort shortens lifespan, but through increased short‐term mortality rather than ageing. In contrast, high fecundity in early life is associated with accelerated senescence in free‐living vertebrates, but these studies are non‐experimental. We performed lifelong brood size manipulation in free‐living jackdaws. Actuarial senescence – the increase in mortality rate with age – was threefold higher in birds rearing enlarged‐ compared to reduced broods, confirming a key prediction of the optimality theory of ageing. Our findings contrast with the results of single‐year brood size manipulation studies carried out in many species, in which there was no overall discernible manipulation effect on mortality. We suggest that our and previous findings are in agreement with predictions based on the reliability theory of ageing and propose further tests of this proposition.     

Ageing free radicals and cellular stress

A number of theories have attempted to account for ageing processes in various species. Following the < rate of living > theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with ageing. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxidize surrounding molecules such as DNA, proteins and lipids. As a consequence various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation and accumulation of lipid byproducts. Oxidative stress is an adaptive process which is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions. Experimental evidence suggests that the ageing organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed ; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species. While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of ageing appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by an increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length ; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in ageing is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth or fertility, and despite its negative effect on somatic functions and ageing. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule.     

Immunological markers of ageing

Ageing is a process involving morphological and physiological modifications that gradually appear with time and lead to death. Given the heterogeneous nature of the process among individuals and among the different organs, tissues, and systems in the same individual, the concept of has been developed. The search for parameters that enable us to evaluate biological age--and therefore longevity--and the analysis of the efficacy of strategies to retard the ageing process are the objectives of gerontology. At present, one of the most important theories of ageing is the theory. Given that immune cell function is an excellent marker of health, we review the concepts that enable different functional and oxidative stress parameters in immune cells to be identified as markers of biological age and longevity. None of these parameters is universally accepted as a biomarker of ageing, although they are becoming increasingly important.     

Evidence for Evolution Versus Evidence for Intelligent Design: Parallel Confusions

The popular defense of intelligent design/creationism (ID) theories, as well as theories in evolutionary biology, especially from the perspective that both are worthy of scientific consideration, is that empirical evidence has been presented that supports both. Both schools of thought have had a tendency to rely on the same class of evidence, namely, the observations of organisms that are in need of being explained by those theories. The result is conflation of the evidence that prompts one to infer hypotheses applying ID or evolutionary theories with the evidence that would be required to critically test those theories. Evidence is discussed in the contexts of inferring theories/hypotheses, suggesting what would be possible tests, and actual testing. These three classes of inference being abduction, deduction, and induction, respectively. Identifying these different inferential processes in evolutionary biology and ID allow for showing that the evidence to which theories and hypotheses provide understanding cannot be the same evidence supporting those theories and hypotheses. This clarification provides a strong criterion for showing the inability of an ID theory to be of utility in the ongoing process of acquiring causal understanding, that is the hallmark of science.     

Dynamic energy budget approaches for modelling organismal ageing

Ageing is a complex multifactorial process involving a progressive physiological decline that, ultimately, leads to the death of an organism. It involves multiple changes in many components that play fundamental roles under healthy and pathological conditions. Simultaneously, every organism undergoes accumulative 'wear and tear' during its lifespan, which confounds the effects of the ageing process. The scenario is complicated even further by the presence of both age-dependent and age-independent competing causes of death. Various manipulations have been shown to interfere with the ageing process. Calorie restriction, for example, has been reported to increase the lifespan of a wide range of organisms, which suggests a strong relation between energy metabolism and ageing. Such a link is also supported within the main theories for ageing: the free radical hypothesis, for instance, links oxidative damage production directly to energy metabolism. The Dynamic Energy Budgets (DEB) theory, which characterizes the uptake and use of energy by living organisms, therefore constitutes a useful tool for gaining insight into the ageing process. Here we compare the existing DEB-based modelling approaches and, then, discuss how new biological evidence could be incorporated within a DEB framework.     

Ageing and immortality

The concept of the force of natural selection was developed to explain the evolution of ageing. After ageing, however, comes a period in which mortality rates plateau and some individual organisms could, in theory, live forever. This late-life immortality has no presently agreed upon explanation. Two main theories have been offered. The first is heterogeneity within ageing cohorts, such that only extremely robust individuals survive ageing. This theory can be tested by comparisons of more and less robust cohorts. It can also be tested by fitting survival data to its models. The second theory is that late-life plateaus in mortality reflect the inevitable late-life plateau in the force of natural selection. This theory can be tested by changing the force of natural selection in evolving laboratory populations, particularly the age at which the force plateaus. This area of research has great potential for elucidating the overall structure of life-history evolution, particularly the interrelationship between the three life-history phases of development, ageing and immortality.     

Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology

Although the etiology of autoimmune diseases remains largely unknown, a prevailing theory concerns the infection-induced activation of self-reactive lymphocytes via the process of molecular mimicry. Here, we discuss the theory of molecular mimicry and its continued evolution from the initial basic considerations of sequence similarity to the current theories of structural homology. Such findings serve to further our understanding of T-cell receptor degeneracy and might one day provide a direct link between infection and autoimmune disease.     

Sex differences in nutrient-dependent reproductive ageing

Evolutionary theories of aging predict that fitness-related traits, including reproductive performance, will senesce because the strength of selection declines with age. Sexual selection theory predicts, however, that male reproductive performance (especially sexual advertisement) will increase with age. In both bodies of theory, diet should mediate age-dependent changes in reproductive performance. In this study, we show that the sexes exhibit dramatic, qualitative differences in age-dependent reproductive performance trajectories and patterns of reproductive ageing in the cricket Teleogryllus commodus. In females, fecundity peaked early in adulthood and then declined. In contrast, male sexual advertisement increased across the natural lifespan and only declined well beyond the maximum field lifespan. These sex differences were robust to deviations from sex-specific dietary requirements. Our results demonstrate that sexual selection can be at least as important as sex-dependent mortality in shaping the signal of reproductive ageing.     

Genetic basis of limited cell proliferation.

Knowledge about the changes that occur as cells traverse their replicative lifespans grows apace, as evidenced by the articles in this issue. Controversy over the interpretation of this knowledge continues, however, and is indeed fuelled by new discoveries (e.g., see Cristofalo, 1990; Holliday, 1990; Smith, 1990). This paper makes a brief commentary on the problems of cellular ageing, with particular emphasis on the unfolding picture of the genetic control of ageing and longevity which derives from evolutionary theory (Kirkwood and Rose, 1991). The case is argued for a synthetic view which recognizes that the immediate causes of limited cell proliferation probably involve some form of active genetic control, but that the ultimate reason for cell ageing is found in evolutionary theories which suggest that the ageing process is not actively programmed and that senescence may be due to the accumulation of damage.     

The metal ion theory of ageing: dietary target hazard quotients beyond radicals

Numerous theories of ageing exist and many are interconnected when viewed through a modern integrative biology perspective. Diet provides a link to a large number of the theories that prevail at the molecular levels. In particular, metal ions form key elements of the radical theory along with having established roles in several age-related neurodegenerative disorders. Lifetime exposure to metals has been linked to ageing by contributions to oxidative stress and neurodegenerative disorders. As many foodstuffs contain high levels and diverse profiles of metals, their cumulative effect on ageing warrants investigation. The cumulative level of concern from environmental exposure can be expressed as a dimensionless index of target hazard quotient (THQ) or for known carcinogens, the target cancer risk (TR). This paper posits that a quantifiable relationship exists between ageing and level of concern resulting from cumulated metal exposure; and that this relationship can be used to develop an ageing-related index of concern from chronic metal ion exposure. As individual differences may facilitate or moderate this cumulated exposure, the potential influence on ageing or on the development of neurodegenerative disorders should be included into the model.     

A comparison of variant theories of intact biochemical systems. I. Enzyme-enzyme interactions and biochemical systems theory

The need for a well-structured theory of intact biochemical systems becomes increasingly evident as one attempts to integrate the vast knowledge of individual molecular constituents, which has been expanding for several decades. In recent years, several apparently different approaches to the development of such a theory have been proposed. Unfortunately, the resulting theories have not been distinguished from each other, and this has led to considerable confusion with numerous duplications and rediscoveries. Detailed comparisons and critical tests of alternative theories are badly needed to reverse these unfortunate developments. In this paper we (1) characterize a specific system involving enzyme-enzyme interactions for reference in comparing alternative theories, and (2) analyze the reference system by applying the explicit S-system variant within biochemical systems theory (BST), which represents a fundamental framework based upon the power-law formalism and includes several variants. The results provide the first complete and rigorous numerical analysis within the power-law formalism of a specific biochemical system and further evidence for the accuracy of the explicit S-system variant within BST. This theory is shown to represent enzyme-enzyme interactions in a systematically structured fashion that facilitates analysis of complex biochemical systems in which these interactions play a prominent role. This representation also captures the essential character of the underlying nonlinear processes over a wide range of variation (on average 20-fold) in the independent variables of the system. In the companion paper in this issue the same reference system is analyzed by other variants within BST as well as by two additional theories within the same power-law formalism--flux-oriented and metabolic control theories. The results show how all these theories are related to one another.     

The impact of the cardiovascular component and somatic mutations on ageing

Mechanistic insight into ageing may empower prolonging the lifespan of humans; however, a complete understanding of this process is still lacking despite a plethora of ageing theories. In order to address this, we investigated the association of lifespan with eight phenotypic traits, that is, litter size, body mass, female and male sexual maturity, somatic mutation, heart, respiratory, and metabolic rate. In support of the somatic mutation theory, we analysed 15 mammalian species and their whole-genome sequencing deriving somatic mutation rate, which displayed the strongest negative correlation with lifespan. All remaining phenotypic traits showed almost equivalent strong associations across this mammalian cohort, however, resting heart rate explained additional variance in lifespan. Integrating somatic mutation and resting heart rate boosted the prediction of lifespan, thus highlighting that resting heart rate may either directly influence lifespan, or represents an epiphenomenon for additional lower-level mechanisms, for example, metabolic rate, that are associated with lifespan.     

Towards an integrative understanding of soil biodiversity

Soil is one of the most biodiverse terrestrial habitats. Yet, we lack an integrative conceptual framework for understanding the patterns and mechanisms driving soil biodiversity. One of the underlying reasons for our poor understanding of soil biodiversity patterns relates to whether key biodiversity theories (historically developed for aboveground and aquatic organisms) are applicable to patterns of soil biodiversity. Here, we present a systematic literature review to investigate whether and how key biodiversity theories (species–energy relationship, theory of island biogeography, metacommunity theory, niche theory and neutral theory) can explain observed patterns of soil biodiversity. We then discuss two spatial compartments nested within soil at which biodiversity theories can be applied to acknowledge the scale‐dependent nature of soil biodiversity.     

Development of DNA methylation-based epigenetic age predictors in loblolly pine (Pinus taeda)

Biological ageing is connected to life history variation across ecological scales and informs a basic understanding of age-related declines in organismal function. Altered DNA methylation dynamics are a conserved aspect of biological ageing and have recently been modelled to predict chronological age among vertebrate species. In addition to their utility in estimating individual age, differences between chronological and predicted ages arise due to acceleration or deceleration of epigenetic ageing, and these discrepancies are linked to disease risk and multiple life history traits. Although evidence suggests that patterns of DNA methylation can describe ageing in plants, predictions with epigenetic clocks have yet to be performed. Here, we resolve the DNA methylome across CpG, CHG, and CHH-methylation contexts in the loblolly pine tree (Pinus taeda) and construct epigenetic clocks capable of predicting ages in this species within 6% of its maximum lifespan. Although patterns of CHH-methylation showed little association with age, both CpG and CHG-methylation contexts were strongly associated with ageing, largely becoming hypomethylated with age. Among age-associated loci were those in close proximity to malate dehydrogenase, NADH dehydrogenase, and 18S and 26S ribosomal RNA genes. This study reports one of the first epigenetic clocks in plants and demonstrates the universality of age-associated DNA methylation dynamics which can inform conservation and management practices, as well as our ecological and evolutionary understanding of biological ageing in plants.     

A review and appraisal of the DNA damage theory of ageing

Given the central role of DNA in life, and how ageing can be seen as the gradual and irreversible breakdown of living systems, the idea that damage to the DNA is the crucial cause of ageing remains a powerful one. DNA damage and mutations of different types clearly accumulate with age in mammalian tissues. Human progeroid syndromes resulting in what appears to be accelerated ageing have been linked to defects in DNA repair or processing, suggesting that elevated levels of DNA damage can accelerate physiological decline and the development of age-related diseases not limited to cancer. Higher DNA damage may trigger cellular signalling pathways, such as apoptosis, that result in a faster depletion of stem cells, which in turn contributes to accelerated ageing. Genetic manipulations of DNA repair pathways in mice further strengthen this view and also indicate that disruption of specific pathways, such as nucleotide excision repair and non-homologous end joining, is more strongly associated with premature ageing phenotypes. Delaying ageing in mice by decreasing levels of DNA damage, however, has not been achieved yet, perhaps due to the complexity inherent to DNA repair and DNA damage response pathways. Another open question is whether DNA repair optimization is involved in the evolution of species longevity, and we suggest that the way cells from different organisms respond to DNA damage may be crucial in species differences in ageing. Taken together, the data suggest a major role of DNA damage in the modulation of longevity, possibly through effects on cell dysfunction and loss, although understanding how to modify DNA damage repair and response systems to delay ageing remains a crucial challenge.     

Tissue engineering strategies to bioengineer the ageing skin phenotype in vitro

Human skin ageing is a complex and heterogeneous process, which is influenced by genetically determined intrinsic factors and accelerated by cumulative exposure to extrinsic stressors. In the current world ageing demographic, there is a requirement for a bioengineered ageing skin model, to further the understanding of the intricate molecular mechanisms of skin ageing, and provide a distinct and biologically relevant platform for testing actives and formulations. There have been many recent advances in the development of skin models that recapitulate aspects of the ageing phenotype in vitro. This review encompasses the features of skin ageing, the molecular mechanisms that drive the ageing phenotype, and tissue engineering strategies that have been utilised to bioengineer ageing skin in vitro.