Papers by Véronique Legault
Innovation in Aging
Defined as, “stereotype, prejudice, and discrimination directly towards people because of their a... more Defined as, “stereotype, prejudice, and discrimination directly towards people because of their age”, ageism may contribute to adverse health outcomes, accelerate aging process, and increase the burden on health and social services. Little is known about the ageism impact on biological aging. Secondary analysis of the American Health and Retirement Study (2012 and 2016 waves) was carried out. Participants were asked: the self-perception of aging (SPA), the causes of receiving discrimination, including ageism as one of the causes, and the frequency of receiving such discrimination. The aging rate was measured using two distinct measurements: homeostatic dysregulation (using Mahalanobis distance on 44 biomarkers, n= 9934, 2016 wave) and epigenetic aging clocks (n=4018, 2016 wave). The influence of perceived ageism (current or previous waves) on the aging rate was modelled with linear models using biological aging (aka. homeostatic dysregulation and epigenetic age) as the dependent var...
BMC Biology
Background Little is known about how normal variation in dietary patterns in humans affects the a... more Background Little is known about how normal variation in dietary patterns in humans affects the ageing process. To date, most analyses of the problem have used a unidimensional paradigm, being concerned with the effects of a single nutrient on a single outcome. Perhaps then, our ability to understand the problem has been complicated by the fact that both nutrition and the physiology of ageing are highly complex and multidimensional, involving a high number of functional interactions. Here we apply the multidimensional geometric framework for nutrition to data on biological ageing from 1560 older adults followed over four years to assess on a large-scale how nutrient intake associates with the ageing process. Results Ageing and age-related loss of homeostasis (physiological dysregulation) were quantified via the integration of blood biomarkers. The effects of diet were modelled using the geometric framework for nutrition, applied to macronutrients and 19 micronutrients/nutrient subcl...
Little is known about how normal variation in dietary patterns in humans affects the aging proces... more Little is known about how normal variation in dietary patterns in humans affects the aging process, largely because both nutrition and the physiology of aging are highly complex and multidimensional. Here, we apply the nutritional geometry framework to data from 1560 older adults followed over four years to assess how nutrient intake patterns affect the aging process. Aging was quantified via blood biomarkers integrated to measure loss of homeostasis. Additionally, we extend nutritional geometry to 19 micronutrients. Salient results include benefits of intermediate protein and vitamin E intake. Broadly, we show that there are few simple answers of “good” or “bad” nutrients – optimal levels are generally intermediate, but dependent on other nutrients. Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results, and our approach presents a roadmap for future studies to explore the full complexity ...
Aging, 2022
Old age is a crucial risk factor for severe coronavirus disease 2019 (COVID-19), with serious or ... more Old age is a crucial risk factor for severe coronavirus disease 2019 (COVID-19), with serious or fatal outcomes disproportionately affecting older adults compared with the rest of the population. We proposed that the physiological health status and biological age, beyond the chronological age itself, could be the driving trends affecting COVID-19 severity and mortality. A total of 155 participants hospitalized with confirmed COVID-19 aged 26-94 years were recruited for the study. Four different physiological summary indices were calculated: Klemera and Doubal's biological age, PhenoAge, physiological dysregulation (PD; globally and in specific systems), and integrated albunemia. All of these indices significantly predicted the risk of death (p < 0.01) after adjusting for chronological age and sex. In all models, men were 2.4-4.4-times more likely to die than women. The global PD was shown to be a good predictor of deterioration, with the odds of deterioration increasing by 41.7% per 0.5-unit increase in the global PD. As for death, the odds also increased by 68.3% per 0.5-unit increase in the global PD. Our results are partly attributed to common chronic diseases that aggravate COVID-19, but they also suggest that the underlying physiological state could capture vulnerability to severe COVID-19 and serve as a tool for prognosis that would, in turn, help inpatient management.
Data on 14 physiological variables and measures of workload, current productivity, future fecundi... more Data on 14 physiological variables and measures of workload, current productivity, future fecundity, and survival measured in 93 female European starlings (Sturnus vulgaris) at two breeding stages (incubation, chick-rearing), for first-and second-broods over two years (152 observations)
Innovation in Aging, 2021
Despite its widespread presence in older adults, frailty etiology is still unclear, being associa... more Despite its widespread presence in older adults, frailty etiology is still unclear, being associated with dysregulation in diverse physiological systems. Here, we show evidence that frailty emerges from broad loss of homeostasis integrated through complex systems dynamics. Using the NuAge and WHAS cohorts, we calculated Mahalanobis distance-based physiological dysregulation in six systems and tested the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We found clear support for breadth of associations, but only partial support for diffuseness and nonlinearity: 1) physiological dysregulation is positively associated with frailty in many or all systems, depending on analyses; 2) the number of dysregulated systems or the total amount of dysregulation are more predictive than individual systems, but results only partially replicated across cohorts; 3) dysregulation trends are exponential, but not always significant. These results ...
Critical transition theory suggests that complex systems should experience increased temporal var... more Critical transition theory suggests that complex systems should experience increased temporal variability just before abrupt change, such as increases in clinical biomarker variability before mortality. We tested this in the context of hemodialysis using 11 clinical biomarkers measured every two weeks in 763 patients over 2496 patient-years. We show that variability – measured by coefficients of variation – is more strongly predictive of mortality than biomarker levels. Further, variability is highly synchronized across all biomarkers, even those from unrelated systems: the first axis of a principal component analysis explains 49% of the variance. This axis then generates powerful predictions of all-cause mortality (HR95=9.7, p<0.0001, where HR95 is a scale-invariant metric of hazard ratio across the predictor range; AUC up to 0.82) and starts to increase markedly ∼3 months prior to death. Such an indicator could provide an early warning sign of physiological collapse and serve t...
Frontiers in Physiology, 2021
There is an increasingly widespread use of biomarkers in network physiology to evaluate an organi... more There is an increasingly widespread use of biomarkers in network physiology to evaluate an organism’s physiological state. A recent study showed that albumin variability increases before death in chronic hemodialysis patients. We hypothesized that a multivariate statistical approach would better allow us to capture signals of impending physiological collapse/death. We proposed a Moving Multivariate Distance (MMD), based on the Mahalanobis distance, to quantify the variability of the multivariate biomarker profile as a whole from one visit to the next. Biomarker profiles from a visit were used as the reference to calculate MMD at the subsequent visit. We selected 16 biomarkers (of which 11 are measured every 2 weeks) from blood samples of 763 chronic kidney disease patients hemodialyzed at the CHUS hospital in Quebec, who visited the hospital regularly (∼every 2 weeks) to perform routine blood tests. MMD tended to increase markedly preceding death, indicating an increasing intraindiv...
Biogerontology, 2020
w) contains supplementary material, which is available to authorized users.. Conflict of interest... more w) contains supplementary material, which is available to authorized users.. Conflict of interest AAC is Founder and CSO at Oken Health. Consent for publication Not applicable. Ethical approval Both studies were approved by their Local Ethics Committee, in terms of study protocol and consent procedure. The NuAge Database and Biobank and secondary analysis for this project were approved by the Comité d' éthique de la recherche du CIUSSS de l'Estrie-CHUS (Projects 2019-2832 and 14-059, respectively). Informed consent All participants recruited in both studies signed informed consent.
Background: Generalized, biomarker-based metrics of health status have numerous applications in f... more Background: Generalized, biomarker-based metrics of health status have numerous applications in fields ranging from sociology and economics to clinical research. We recently proposed a novel metric of health status based on physiological dysregulation measured as a Mahalanobis distance (DM) among clinical biomarkers. While DM was not particularly sensitive to the choice of biomarkers, it required calibration when used in different populations, making it difficult to compare findings across studies. To facilitate its use, here we aimed to identify and validate a standard version of DM that would be highly stable across populations, while using fewer biomarkers drawn exclusively from common blood panels. Methods: Using three datasets, we identified nine-biomarker (DM9) and seventeen-biomarker (DM17) versions of DM, choosing biomarkers based on their consistent levels across populations. We validated them in a fourth dataset. We assessed DM stability within and across populations by lo...
Mechanisms of Ageing and Development, 2020
Are diseases caused by aging? What are the mechanisms of aging? Do all species age? These hotly d... more Are diseases caused by aging? What are the mechanisms of aging? Do all species age? These hotly debated questions revolve around a unitary definition of aging. Because we use the word "aging" so frequently, both colloquially and scientifically, we rarely pause to consider whether this word maps to an underlying biological phenomenon, or whether it is simply a grab-bag of diverse phenomena linked more by our mental associations than by any underlying biology. Here, we consider how the presence of the colloquial word "aging" generates a cognitive bias towards supposing there is a unitary biological phenomenon. We ask what kind of evidence would support or refute that idea, and subsequently show clear evidence at multiple levels that aging is not a unitary phenomenon. In particular, the known aging pathways lead to heterogeneous outputs, not a single coordinated phenomenon. From levels ranging from cellular/molecular to clinical to demographic to evolutionary, we show how the supposition that aging is a unitary phenomenon can mislead and distract us from asking the best questions. For major sub-disciplines of aging biology, we show how going beyond the notion of unitary aging can hone the paradigm and help advance the pace of discovery.
Mechanisms of Ageing and Development, 2020
Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree,... more Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework.
Innovation in Aging, 2020
The geometric framework for nutrition has largely been applied to macronutrients in experimental ... more The geometric framework for nutrition has largely been applied to macronutrients in experimental settings. Here, we utilize the framework to examine both macro and micronutrient intake patterns in observational human data. We used nutritional intake patterns (3x 24h recall per visit) of 1754 older Quebecers from the NuAge cohort to predict multi-system homeostatic dysregulation scores calculated from 30 biomarkers. Intermediate intake of both macro- and micronutrients was generally associated with lower dysregulation scores (i.e., better health). Furthermore, there were often nutrient-nutrient interactions, such that the optimal level of one nutrient depends on the intake level of others. However, higher protein intake was generally associated with better health, and results varied substantially across different dysregulation systems. Accordingly, even though nutrition does have important effects on health trajectories during aging, it will be challenging to arrive at population-lev...
Innovation in Aging, 2019
Increased variability in levels of several individual biomarkers has been shown to predict advers... more Increased variability in levels of several individual biomarkers has been shown to predict adverse outcomes, particularly in hemodialysis patients, for whom time series data is often available. Here, we evaluate the feasibility of using multivariate approaches to quantify global physiological variability as a potential predictor of adverse outcomes. We used data on 588 deaths and 1196 hospitalisations across ~38,000 visits of 591 hemodialysis patients at a Quebec hospital, as well as data on frailty and mortality in 580 patients assessed 20+ times within a one-year period at a hospital in Saitama, Japan. We use two approaches: principal components analysis (PCA) of the coefficients of variation (CVs) of the individual biomarkers over the previous year, and Mahalanobis distance (MD) of the biomarker profile relative to the same profile at the previous time point. We show that both methods provide substantial prediction of both impending mortality and impending hospitalisation, with h...
Innovation in Aging, 2019
Physiological dysregulation (PD) and integrated albunemia (IA) are organism-level aging mechanism... more Physiological dysregulation (PD) and integrated albunemia (IA) are organism-level aging mechanisms that can be measured using standard biomarkers, and in humans they have been shown to increase with age and predict health outcomes. Here, we use 10 species from the Internet Primate Aging Database (iPAD), a longitudinal database of biomarkers and mortality in captive primates, to analyze the generalizability of the role of PD and IA in aging, as well as the conservation of the underlying physiology. Human patterns are broadly but not universally replicated in primates. For example, PD increases with age in nine of eleven species, and predicts mortality in three of four. Both IA and PD can to some extent be cross-calibrated across species, indicating surprising conservation of underlying homeostatic norms; in the case of PD, the calibration weakens with phylogenetic distance.
Aging Cell, 2019
Two major goals in the current biology of aging are to identify general mechanisms underlying the... more Two major goals in the current biology of aging are to identify general mechanisms underlying the aging process and to explain species differences in aging. Recent research in humans suggests that one important driver of aging is dysregulation, the progressive loss of homeostasis in complex biological networks. Yet, there is a lack of comparative data for this hypothesis, and we do not know whether dysregulation is widely associated with aging or how well signals of homeostasis are conserved. To address this knowledge gap, we use unusually detailed longitudinal biomarker data from 10 species of nonhuman primates housed in research centers and data from two human populations to test the hypotheses that (a) greater dysregulation is associated with aging across primates and (b) physiological states characterizing homeostasis are conserved across primates to degrees associated with phylogenetic proximity. To evaluate dysregulation, we employed a multivariate distance measure, calculated from sets of biomarkers, that is associated with aging and mortality in human populations. Dysregulation scores positively correlated with age and risk of mortality in most nonhuman primates studied, and signals of homeostatic state were significantly conserved across species, declining with phylogenetic distance. Our study provides the first broad demonstration of physiological dysregulation associated with aging and mortality risk in multiple nonhuman primates. Our results also imply that emergent signals of homeostasis are evolutionarily conserved, although with notable variation among species, and suggest promising directions for future comparative studies on dysregulation and the aging process.
Frontiers in Zoology, 2018
Background: It is widely assumed that variation in fitness components has a physiological basis t... more Background: It is widely assumed that variation in fitness components has a physiological basis that might underlie selection on trade-offs, but the mechanisms driving decreased survival and future fecundity remain elusive. Here, we assessed whether physiological variables are related to workload ability or immediate fitness consequences and if they mediate future survival or reproductive success. We used data on 13 physiological variables measured in 93 female European starlings (Sturnus vulgaris) at two breeding stages (incubation, chickrearing), for first-and second-broods over two years (152 observations). Results: There was little co-variation among the physiological variables, either in incubating or chick-rearing birds, but some systematic physiological differences between the two stages. Chick-rearing birds had lower hematocrit and plasma creatine kinase but higher hemoglobin, triglyceride and uric acid levels. Only plasma corticosterone was repeatable between incubation and chick-rearing. We assessed relationships between incubation or chick-rearing physiology and measures of workload, current productivity, future fecundity or survival in a univariate manner, and found very few significant relationships. Thus, we next explored the utility of multivariate analysis (principal components analysis, Mahalanobis distance) to account for potentially complex physiological integration, but still found no clear associations. Conclusions: This implies either that a) birds maintained physiological variables within a homeostatic range that did not affect their performance, b) there are relatively few links between physiology and performance, or, more likely, c) that the complexity of these relationships exceeds our ability to measure it. Variability in ecological context may complicate the relationship between physiology and behavior. We thus urge caution regarding the overinterpretation of isolated significant findings, based on single traits in single years, in the literature.
The Journals of Gerontology: Series A, 2017
The aging process differs in important ways between the sexes, with women living longer but at hi... more The aging process differs in important ways between the sexes, with women living longer but at higher risk for frailty (the male-female health-survival paradox). The underlying biological mechanisms remain poorly understood, but may relate to sex differences in physiological dysregulation patterns. Here, using biomarkers from two longitudinal cohort studies (InCHIANTI and BLSA) and one cross-sectional survey (NHANES), we assess sex differences in trajectories of dysregulation globally and for five physiological systems: oxygen transport, electrolytes, hematopoiesis, lipids, and liver/kidney function. We found higher dysregulation levels in men, both globally and in the oxygen transport and hematopoietic systems (p < .001 for all), though differences for other systems were mixed (electrolytes) or absent (lipids and liver/kidney). There was no clear evidence for sex differences in rates of change in dysregulation with age. Although risk of frailty and mortality increase with dysregulation, there was no evidence for differences in these effects between sexes. These findings imply that the greater susceptibility of women to frailty is not simply due to a tolerance for higher dysregulation; rather, it may actually be men that have a greater tolerance for dysregulation, creating a male-female dysregulation-frailty paradox. However, the precise physiological mechanisms underlying the sex differences appear to be diffuse and hard to pin down.
Experimental gerontology, Jan 16, 2017
Recent studies have shown contradictory associations between calcium levels and health outcomes. ... more Recent studies have shown contradictory associations between calcium levels and health outcomes. We suspected these conflicting results were the consequence of more general issues with how biomarkers are analyzed in epidemiological studies, particularly in the context of aging. To demonstrate the risks of typical analyses, we used three longitudinal aging cohort studies and their demographic subsets to analyze how calcium levels change with age and predict risk of mortality and frailty. We show that calcium levels either increase or decrease with age depending on the population, and positively or negatively predict frailty depending on the population; both age and frailty results showed substantial heterogeneity. Mortality analyses revealed few significant associations but were likely underpowered. Variation in population composition (demographics, diseases, diet, etc.) leads to contradictory findings in the literature for calcium and likely for other biomarkers. Epidemiological stu...
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Papers by Véronique Legault