LINK-AGE: coordination and consolidation of European biogerontology: en route towards formation of a European college of biogerontology.
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Aging↗
Biomedical subjects
Thomas B L Kirkwood
Publications and source records attributed to Thomas B L Kirkwood.
Trade-off mediated effects on the genetics of human survival caused by increasingly benign living conditions.
It is sometimes suggested that modern life, with its planned fertility and medically assisted compensation for genetic disadvantage, has greatly reduced the power of natural selection to produce significant further human evolution. However, this overlooks the very recent and dramatic changes that have occurred in the patterns of human mortality, driven by the development of increasingly benign living conditions. Where the genetics of survival are significantly influenced by life history trade-offs, as is now thought to be the case for ageing and longevity, a change in the environment can shift the optimal balance that was established through natural selection under previous conditions. We examine this possibility in the context of the dramatic recent change in the mortality pressure exerted by infectious disease using a model of a hypothetical immunogenetic trade-off that weighs survival against fecundity. Our results predict that such a change might have a significant effect on population genetics over relatively short-timescales, and they may also resolve the paradox of genes that impair fertility in present-day populations by showing how such genes might be a legacy from a powerful trade-off that has acted until very recently.
Biological Evolution↗
Tools for the SBML Community.
MOTIVATION: SBML is quickly becoming the standard format to exchange biochemical models. The tools presented in this paper are loosely-coupled, and are intended to be incorporated into SBML aware applications. The rationale for this is to reduce the amount of repeated work carried out within the community and to create tools that offer a greater number of features to the end-user. AVAILABILITY: All tools described are available from http://www.basis.ncl.ac.uk/software and are licensed under GNU General Public License.
Biochemistry↗
Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans.
Calorie restriction is known to increase lifespan in many but not all species and may perhaps not do so in humans. Exceptions to life extension have been identified in the laboratory and others are known in nature. Given the variety of physiological responses to variation in food supply that are possible, evolutionary life history theory indicates that an increased investment in maintenance in response to resource shortage will not always be the strategy that maximises Darwinian fitness. Additionally, for the well-studied species in which life extension is observed, there is considerable variation in the response. This suggests that it is not an ancient ancestral response, which has been conserved across the species range. Although calorie restriction does not increase lifespan in all species, it remains a fascinating and valuable tool to study ageing at the whole organism level.
Aging↗
Understanding the odd science of aging.
Evolutionary considerations suggest aging is caused not by active gene programming but by evolved limitations in somatic maintenance, resulting in a build-up of damage. Ecological factors such as hazard rates and food availability influence the trade-offs between investing in growth, reproduction, and somatic survival, explaining why species evolved different life spans and why aging rate can sometimes be altered, for example, by dietary restriction. To understand the cell and molecular basis of aging is to unravel the multiplicity of mechanisms causing damage to accumulate and the complex array of systems working to keep damage at bay.
Aging↗
What accounts for the wide variation in life span of genetically identical organisms reared in a constant environment?
Individual organisms show marked variability in life span, even when they are of the same genotype and are raised in a common environment protected from extrinsic hazards. This intrinsic variability of life span is thought to arise from the stochastic nature of the cellular and molecular mechanisms controlling development and ageing. In this article we review what is currently understood about the factors underlying the variability of life span and consider the implications for research that aims to improve the predictability of health in old age.
Animals↗
Modelling the disposable soma theory of ageing.
We describe a mathematical model, developed using the Mathematica programming system of the disposable soma theory of ageing. The model makes explicit predictions about the optimal strategies for investment in somatic maintenance versus investments in growth and reproduction and confirms the central prediction of the disposable soma theory that the optimum investment in somatic maintenance is less than what would be required for indefinite longevity. We also describe how the optimal investment in maintenance is affected by varying the parameters that specify the schedules of reproduction and mortality.
Animals↗
Modelling the actions of chaperones and their role in ageing.
Many molecular chaperones are also known as heat shock proteins because they are synthesised in increased amounts after brief exposure of cells to elevated temperatures. They have many cellular functions and are involved in the folding of nascent proteins, the re-folding of denatured proteins, the prevention of protein aggregation, and assisting the targeting of proteins for degradation by the proteasome and lysosomes. They also have a role in apoptosis and are involved in modulating signals for immune and inflammatory responses. Stress-induced transcription of heat shock proteins requires the activation of heat shock factor (HSF). Under normal conditions, HSF is bound to heat shock proteins resulting in feedback repression. During stress, cellular proteins undergo denaturation and sequester heat shock proteins bound to HSF, which is then able to become transcriptionally active. The induction of heat shock proteins is impaired with age and there is also a decline in chaperone function. Aberrant/damaged proteins accumulate with age and are implicated in several important age-related conditions (e.g. Alzheimer's disease, Parkinson's disease, and cataract). Therefore, the balance between damaged proteins and available free chaperones may be greatly disturbed during ageing. We have developed a mathematical model to describe the heat shock system. The aim of the model is two-fold: to explore the heat shock system and its implications in ageing; and to demonstrate how to build a model of a biological system using our simulation system (biology of ageing e-science integration and simulation (BASIS)).
Animals↗
Asymmetry and the origins of ageing.
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Aging↗
Food restriction, evolution and ageing.
The food restriction model for life extension is nearing "three-score and 10" years of age and remains in good shape, preserving much of the mystique of its youth. Although originally described for laboratory rodents, recent work shows that food restriction also appears to slow ageing processes in a range of other animal species, raising the question of whether this response represents some generalised evolutionary adaptation, perhaps a strategy to cope with periods of famine. If the food restriction response does have an adaptive basis, this would suggest that specific gene regulatory processes have evolved to shape the organism's physiological response to food restriction. It will then be important to investigate how these are organised and whether the same or different factors are at play in the various species in which food restriction extends life span.
Aging↗
Time of our lives. What controls the length of life?
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Aging↗
A mathematical model of ageing in yeast.
Budding yeast, Saccharomyces cerevisiae, is commonly used as a system to study cellular ageing. Yeast mother cells are capable of only a limited number of divisions before they undergo senescence, whereas newly formed daughters usually have their replicative age "reset" to zero. Accumulation of extrachromosomal ribosomal DNA circles (ERCs) appears to be an important contributor to ageing in yeast, and we describe a mathematical model that we developed to examine this process. We show that an age-related accumulation of ERCs readily explains the observed features of yeast ageing but that in order to match the experimental survival curves quantitatively, it is necessary that the probability of ERC formation increases with the age of the cell. This implies that some other mechanism(s), in addition to ERC accumulation, must underlie yeast ageing. We also demonstrate that the model can be used to gain insight into how an extra copy of the Sir2 gene might extend lifespan and we show how the model makes novel, testable predictions about patterns of age-specific mortality in yeast populations.
Aging↗
Hormonal control of the yolk precursor vitellogenin regulates immune function and longevity in honeybees.
A striking example of plasticity in life span is seen in social insects such as ants and bees, where different castes may display distinct ageing patterns. In particular, the honeybee offers an intriguing illustration of environmental control on ageing rate. Honeybee workers display a temporal division of labour where young bees (or 'hive bees') perform tasks within the brood nest, and older bees forage for nectar, pollen propolis and water. When bees switch from the hive bee to the forager stage, their cellular defence machinery is down-regulated by a dramatic reduction in the number of functioning haemocytes (immunocytes). This study documents that the yolk precursor vitellogenin is likely to be involved in a regulatory pathway that controls the observed decline in somatic maintenance function of honeybee foragers. An association between the glyco-lipoprotein vitellogenin and immune function has not previously been reported for any organism. Honeybee workers are functionally sterile, and via the expression of juvenile hormone, a key gonotrophic hormone in adult insects, their vitellogenin levels are influenced by social interactions with other bees. Our results therefore suggest that in terms of maintenance of the cellular immune system, senescence of the honeybee worker is under social control.
Animals↗
Intrinsic ageing of gut epithelial stem cells.
The maintenance of integrity of gut epithelium is essential for the well being of the organism throughout life. Gut epithelium is maintained through a carefully controlled balance between cell loss and renewal, which is sustained by the proliferation of the epithelial stem cells. Although these stem cells show no intrinsic limit to their proliferative capacity, recent evidence indicates that they suffer important functional impairments during the course of ageing. This paper reviews what is currently known about intrinsic ageing of gut epithelial stem cells and its functional consequences.
Aging↗
Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme mediating the cellular response to DNA strand breaks. It plays a critical role in genomic stability and survival of proliferating cells in culture undergoing DNA damage. Intestinal epithelium is the most proliferative tissue in the mammalian body and its stem cells show extreme sensitivity to low-level genotoxic stress. We investigated the role of PARP-1 in the in vivo damage response of intestinal stem cells in crypts of PARP-1-/- and control mice following whole-body gamma-irradiation (1 Gy). In the PARP-1-/- mice there was a significant delay during the first 6 h in the transient p53 accumulation in stem cells whereas an increased number of cells were positive for p21(CIP1/WAF1). Either no or only marginal differences were noted in MDM2 expression, apoptosis, induction of or recovery from mitotic blockage, or inhibition of DNA synthesis. We further observed a dose-dependent reduction in crypt survival measured at 4 days post-irradiation in control mice, and this crypt-killing effect was significantly potentiated in PARP-1-/- mice. Our results thus establish that PARP-1 acts as a survival factor for intestinal stem cells in vivo and suggest a functional link with early p53 and p21(CIP1/WAF1) responses.
Animals↗
The most pressing problem of our age.
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Aged↗
Genes that shape the course of ageing.
Recent discoveries have placed the insulin signalling pathways at the heart of the genetic control of longevity. An elegant new study of genes acting downstream of these signals in the nematode worm Caenorhabditis elegans reveals a plethora of information about the complex network of mechanisms that modulate the ageing process.
Aging↗
Somatic mutations and ageing in silico.
Considerable evidence points to an accumulation of somatic mutations in older cells and organisms but the causal role of mutations in the ageing process is still unclear. In addition to demonstrating that mutations accumulate, it is important to address the question of whether they do so at a sufficient rate and with a dynamic profile that is consistent with them playing a causative role. We describe the development of in silico models that can be used to explore the role of somatic mutations in ageing and which form a part of a growing effort to build predictive mathematical and computer models that can help unravel the complexity of the functional genomics of ageing. Our models address, in particular, how mutations affect populations of dividing cells like human fibroblasts, in which the challenge to the somatic mutation theory is greatest, since selection at the cellular level will tend to suppress the accumulation of mutations.
Aging↗