Jessica M. Hoffman

Effects of age, sex, and genotype on high-sensitivity metabolomic profiles in the fruit fly, Drosophila melanogaster.

Researchers have used whole‐genome sequencing and gene expression profiling to identify genes associated with age, in the hope of understanding the underlying mechanisms of senescence. But there is a substantial gap from variation in gene sequences and expression levels to variation in age or life expectancy. In an attempt to bridge this gap, here we describe the effects of age, sex, genotype, and their interactions on high‐sensitivity metabolomic profiles in the fruit fly, Drosophila melanogaster. Among the 6800 features analyzed, we found that over one‐quarter of all metabolites were significantly associated with age, sex, genotype, or their interactions, and multivariate analysis shows that individual metabolomic profiles are highly predictive of these traits. Using a metabolomic equivalent of gene set enrichment analysis, we identified numerous metabolic pathways that were enriched among metabolites associated with age, sex, and genotype, including pathways involving sugar and glycerophospholipid metabolism, neurotransmitters, amino acids, and the carnitine shuttle. Our results suggest that high‐sensitivity metabolomic studies have excellent potential not only to reveal mechanisms that lead to senescence, but also to help us understand differences in patterns of aging among genotypes and between males and females.

The Companion Dog as a Model for the Longevity Dividend

The companion dog is the most phenotypically diverse species on the planet. This enormous variability between breeds extends not only to morphology and behavior but also to longevity and the disorders that affect dogs. There are remarkable overlaps and similarities between the human and canine species. Dogs closely share our human environment, including its many risk factors, and the veterinary infrastructure to manage health in dogs is second only to the medical infrastructure for humans. Distinct breed-based health profiles, along with their well-developed health record system and high overlap with the human environment, make the companion dog an exceptional model to improve understanding of the physiological, social, and economic impacts of the longevity dividend (LD). In this review, we describe what is already known about age-specific patterns of morbidity and mortality in companion dogs, and then explore whether this existing evidence supports the LD. We also discuss some potential limitations to using dogs as models of aging, including the fact that many dogs are euthanized before they have lived out their natural life span. Overall, we conclude that the companion dog offers high potential as a model system that will enable deeper research into the LD than is otherwise possible.

Invariance and plasticity in the Drosophila melanogaster metabolomic network in response to temperature

BackgroundMetabolomic 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 (18°C) or warm (27°C) developmental and adult temperature exposures.ResultsWe 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.ConclusionsOur 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.

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

Primates tend to be long-lived for their size with humans being the longest lived of all primates. There are compelling reasons to understand the underlying age-related processes that shape human lifespan. But the very fact of our long lifespan that makes it so compelling, also makes it especially difficult to study. Thus, in studies of aging, researchers have turned to non-human primate models, including chimpanzees, baboons, and rhesus macaques. More recently, the common marmoset, Callithrix jacchus, has been recognized as a particularly valuable model in studies of aging, given its small size, ease of housing in captivity, and relatively short lifespan. However, little is known about the physiological changes that occur as marmosets age. To begin to fill in this gap, we utilized high sensitivity metabolomics to define the longitudinal biochemical changes associated with age in the common marmoset. We measured 2104 metabolites from blood plasma at three separate time points over a 17-month period, and we completed both a cross-sectional and longitudinal analysis of the metabolome. We discovered hundreds of metabolites associated with age and body weight in both male and female animals. Our longitudinal analysis identified age-associated metabolic pathways that were not found in our cross-sectional analysis. Pathways enriched for age-associated metabolites included tryptophan, nucleotide, and xenobiotic metabolism, suggesting these biochemical pathways might play an important role in the basic mechanisms of aging in primates. Moreover, we found that many metabolic pathways associated with age were sex specific. Our work illustrates the power of longitudinal approaches, even in a short time frame, to discover novel biochemical changes that occur with age.

Multiple morbidities in companion dogs: a novel model for investigating age-related disease

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.

A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated

Lifespan provides a discrete metric that is intuitively appealing and the assumption has been that healthspan is extended concomitant with lifespan. Medicine has been more successful at extending life than preserving health during aging. Interventions that extend lifespan in model organisms do not always result in a corresponding increase in healthspan, suggesting that lifespan and healthspan may be uncoupled. To understand how interventions that extend life affect healthspan, we need measures that distinguish between young and old animals. Here we measured age-related changes in healthspan in male and female C57BL/6JNia mice assessed at 4 distinct ages (4 months, 20 months, 28 months and 32 months). Correlations between health parameters and age varied. Some parameters show consistent patterns with age across studies and in both sexes, others changed in one sex only and others showed no significant differences in mice of different ages. Few correlations existed among health assays, suggesting that physiological function in domains we assessed change independently in aging mice. With one exception, health parameters were not significantly associated with an increased probability of premature death. Our results show the need for more robust measures of murine health and suggest a potential disconnect between health and lifespan in mice.

Do Female Dogs Age Differently Than Male Dogs

Humans, as well as their closest ancestors, the higher African primates, exhibit female-biased survival and multiple sex differences in causes of death. However, the effects of sex on aging and longevity in an excellent model of human health, the companion dog, have not been well explored. Using two large independent databases on companion dog longevity and causes of death, we performed the most extensive analysis of sex differences in dog aging to date. Unlike the findings in humans, we observed only a small effect of sex on canine longevity. When broken down by neutering status, we discovered a small male advantage in survival among intact dogs but a clear female survival advantage among neutered dogs. Overall, the effect of neutering on life span was greater than the effect of sex. However, we found few sex differences in causes of death in either intact or neutered dogs. The results of this study suggest limited sex effects on either longevity or causes of death in the companion dog. Our analysis suggests that the majority of apparent sex differences in the wider canine populations may be due to the effects of neutering.

The companion dog as a model for human aging and mortality

Around the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influence aging, morbidity, and longevity. However, the most commonly studied animal species, laboratory mice and rats, do not experience environmental conditions similar to those to which humans are exposed, nor do we often diagnose them with many of the naturally occurring pathologies seen in humans. Recently, the companion dog has been proposed as a powerful model to better understand the genetic and environmental determinants of morbidity and mortality in humans. However, it is not known to what extent the age‐related dynamics of morbidity, comorbidity, and mortality are shared between humans and dogs. Here, we present the first large‐scale comparison of human and canine patterns of age‐specific morbidity and mortality. We find that many chronic conditions that commonly occur in human populations (obesity, arthritis, hypothyroidism, and diabetes), and which are associated with comorbidities, are also associated with similarly high levels of comorbidity in companion dogs. We also find significant similarities in the effect of age on disease risk in humans and dogs, with neoplastic, congenital, and metabolic causes of death showing similar age trajectories between the two species. Overall, our study suggests that the companion dog may be an ideal translational model to study the many complex facets of human morbidity and mortality.

Canine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals: Sex, breed and comorbidity in canine HAC

OBJECTIVE To describe a large population of dogs with a diagnosis of hyperadrenocorticism at the time of death in North American veterinary teaching hospitals, and to identify comorbid conditions associated with hyperadrenocorticism. MATERIALS AND METHODS Retrospective cohort study of 1519 dogs with hyperadrenocorticism from a population of 70,574 dogs reported to the Veterinary Medical Database. Signalment, presence or absence of hyperadrenocorticism, aetiology of hyperadrenocorticism (if described), frequency of select comorbidities and causes of death were evaluated in dogs with and without hyperadrenocorticism. RESULTS Hyperadrenocorticism was more frequent in females. Neutering was associated with a minor, but significant, increase in the odds of hyperadrenocorticism. Hyperadrenocorticism was the presumed cause of death of 393 (25∙9%) of affected dogs. When aetiology was specified (527 dogs, corresponding to 34∙7% of the cases), pituitary-dependent hyperadrenocorticism [387 (73∙4%) out of 527 dogs] was more common than functional adrenocortical tumour [136 (25∙8%) out of 527 dogs). Hyperadrenocorticism was over-represented in certain expected (miniature poodle, dachshund) and unexpected (Irish setter, bassett hound) breeds compared with the population at large. Of the select comorbidities investigated, dogs with hyperadrenocorticism were at increased risk for concurrent diabetes mellitus, urinary tract infection, urolithiasis, hypertension, gall bladder mucocoele and thromboembolic disease compared with dogs without hyperadrenocorticism. CLINICAL SIGNIFICANCE Hyperadrenocorticism is significantly associated with certain comorbid conditions but is not a major cause of mortality in affected dogs. Documented patterns now provide targets for prospective clinical research.

Is Antagonistic Pleiotropy Ubiquitous in Aging Biology

Abstract Lay Summary: An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams’ 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge. No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams’ hypothesis? What are the implications of Williams’ hypothesis for the modern goal of medically intervening to enhance and prolong human health? Here we briefly review the current state of knowledge on antagonistic pleiotropy both under wild and laboratory conditions. Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.