Summary
Dietary restriction (DR) extends lifespan in an impressively wide array of species spanning three eukaryotic kingdoms. In sharp contrast, relatively little is known about the effects of DR on ...functional senescence, with most of the work having been done on mice and rats. Here we used Drosophila melanogaster to test the assumption that lifespan extension through DR slows down age‐related functional deterioration. Adult virgin females were kept on one of three diets, with sucrose and yeast concentrations ranging from 7% to 11% to 16% (w/v). Besides age‐specific survival and fecundity, we measured starvation resistance, oxidative stress resistance, immunity, and cold‐stress resilience at ages 1, 3, 5, and 7 weeks. We confirmed that DR extends lifespan: median lifespans ranged from 38 days (16% diet) to 46 days (11% diet) to 54 days (7% diet). We also confirmed that DR reduces fecundity, although the shortest‐lived flies only had the highest fecundity when males were infrequently available. The most striking result was that DR initially increased starvation resistance, but strongly decreased starvation resistance later in life. Generally, the effects of DR varied across traits and were age dependent. We conclude that DR does not universally slow down functional deterioration in Drosophila. The effects of DR on physiological function might not be as evolutionarily conserved as its effect on lifespan. Given the age‐specific effects of DR on functional state, imposing DR late in life might not provide the same functional benefits as when applied at early ages.
Researchers must understand how mutations affect survival at various ages to understand how ageing evolves. Many models linking mutation to age-specific survival have been proposed but there is ...little evidence to indicate which model is most appropriate. This is a serious problem because the predicted evolutionary endpoints of ageing depend upon the details of the specific model. We apply an explicitly quantitative genetic perspective to the problem. To determine the inheritance of dichotomous traits (such as survival), quantitative genetics has long employed a threshold model. Beginning from first principles, we show how this is the most defensible mutational model for age-specific survival and how this, relative to the standard model, predicts delayed senescence and mortality deceleration at late age. These are commonly observed patterns of ageing that heretofore have required more complicated survival models. We also show how this model can be developed further to unify quantitative genetics and evolutionary demography into a more complete conceptual framework for understanding the evolution of ageing.
The proportion of men and women surviving over 65 years has been steadily increasing over the last century. In their later years, many of these individuals are afflicted with multiple chronic ...conditions, placing increasing pressure on healthcare systems. The accumulation of multiple health problems with advanced age is well documented, yet the causes are poorly understood. Animal models have long been employed in attempts to elucidate these complex mechanisms with limited success. Recently, the domestic dog has been proposed as a promising model of human aging for several reasons. Mean lifespan shows twofold variation across dog breeds. In addition, dogs closely share the environments of their owners, and substantial veterinary resources are dedicated to comprehensive diagnosis of conditions in dogs. However, while dogs are therefore useful for studying multimorbidity, little is known about how aging influences the accumulation of multiple concurrent disease conditions across dog breeds. The current study examines how age, body weight, and breed contribute to variation in multimorbidity in over 2,000 companion dogs visiting private veterinary clinics in England. In common with humans, we find that the number of diagnoses increases significantly with age in dogs. However, we find no significant weight or breed effects on morbidity number. This surprising result reveals that while breeds may vary in their average longevity and causes of death, their age-related trajectories of morbidities differ little, suggesting that age of onset of disease may be the source of variation in lifespan across breeds. Future studies with increased sample sizes and longitudinal monitoring may help us discern more breed-specific patterns in morbidity. Overall, the large increase in multimorbidity seen with age in dogs mirrors that seen in humans and lends even more credence to the value of companion dogs as models for human morbidity and mortality.
Background:
Biobanks have been supporting longitudinal prospective and retrospective studies by providing standardized services for the acquisition, transport, processing, storage, and distribution ...of high-quality biological material and associated data. Here, we describe how the Dog Aging Project (DAP), a large-scale longitudinal study of the domestic dog (Canis familiaris) with translational applications for humans, developed a biobank of canine biospecimens and associated data.
Design and methods:
This was accomplished by working with the Cornell Veterinary Biobank, the first biobank in the world to receive accreditation to ISO 20387:2018—General Requirements for Biobanking. The biobank research team was involved in the early collection stages of the DAP, contributing to the development of appropriate workflows and processing fit-for-purpose biospecimens. In support of a dynamic strategy for real-time adjustment of processes, a pilot phase was implemented to develop, test, and optimize the biospecimen workflows, followed by an early phase of collection, processing, and banking of specimens from DAP participants.
Results:
During the pilot and early phases of collection, the DAP Biobank stored 164 aliquots of whole blood, 273 aliquots of peripheral blood mononuclear cells, 130 aliquots of plasma, and 70 aliquots of serum, and extracted high molecular weight genomic DNA suitable for whole-genome sequencing from 109 whole blood specimens. These specimens, along with their associated preanalytical data, have been made available for distribution to researchers.
Conclusion:
We discuss the challenges and opportunities encountered during the implementation of the DAP Biobank, along with novel strategies for promoting biobanking sustainability such as partnering with a DAP quality assurance manager and a DAP marketing and communication specialist and developing a pilot grant structure to fund small innovative research projects.
Metabolomic responses to extreme thermal stress have recently been investigated in Drosophila melanogaster. However, a network level understanding of metabolomic responses to longer and less drastic ...temperature changes, which more closely reflect variation in natural ambient temperatures experienced during development and adulthood, is currently lacking. Here we use high-resolution, non-targeted metabolomics to dissect metabolomic changes in D. melanogaster elicited by moderately cool (18degreesC) or warm (27degreesC) developmental and adult temperature exposures. We find that temperature at which larvae are reared has a dramatic effect on metabolomic network structure measured in adults. Using network analysis, we are able to identify modules that are highly differentially expressed in response to changing developmental temperature, as well as modules whose correlation structure is strongly preserved across temperature. Our results suggest that the effect of temperature on the metabolome provides an easily studied and powerful model for understanding the forces that influence invariance and plasticity in biological networks.
Two evolutionary genetic models-mutation accumulation and antagonistic pleiotropy-have been proposed to explain the origin and maintenance of senescence. In this paper, we focus our attention on the ...mutation accumulation model. We re-examine previous evidence for mutation accumulation in light of new information from large-scale demographic experiments. After discussing evidence for the predictions that have been put forth from models of mutation accumulation, we discuss two critical issues at length. First, we discuss the possibility that classical fruit fly stock maintenance regimes may give rise to spurious results in selection studies of aging. Second, we consider evidence for the assumptions underlying evolutionary models of aging. These models assume that mutations act additively on age-specific survival rate, that there exist mutations whose effects are confined to late age-classes, and that all mutations have equal effects. Recent empirical evidence suggests that each of these three assumptions is unlikely to be true. On the basis of these results, we do not conclude that mutation accumulation is no longer a valid explanation for the evolution of aging. Rather, we suggest that we now need to begin developing more biologically realistic genetic models for the evolution of aging.
Experiments with fruitflies have shown that those with fewer offspring generally live longer. A study on 1,200 years of genealogical data from British aristocrats suggests that this relationship ...extends to humans as well.
Theories for the evolution of aging rest on the assumption that at least some deleterious mutations have effects that are limited to certain ages. Many mutation accumulation studies have tried to ...measure the number and magnitude of deleterious mutations, but few studies have tried to determine the extent to which the effects of mutations are limited to particular ages. Here we estimate the age-specific effect of deleterious mutations on mortality rate in an outbred population of the fruit fly, Drosophila melanogaster. We used the 'middle class neighborhood' approach to accumulation mutations in populations of flies that had recently been obtained from the wild. There are mutations that increase mortality rates, but whose effects are limited to specific ages. The age-specificity of mutational effects differs between the sexes, between virgin and mated flies, and over time. After 10 and 20 generations of mutation accumulation, there were clear age-specific effects of mutations. After 30 generations, however, the degree of age-specificity decreased. In addition, mutation accumulation led to a steady increase in larval mortality and a small but significant increase in the sex ratio of eclosing flies. We discuss the implications of these results for models of aging, and suggest approaches that future studies should take to obtain accurate information on the age-specificity of novel mutations.
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