Papers by Alexandre Dal-Pan
A life-long follow-up of physiological and behavioural functions was initiated in 38-month-old mo... more A life-long follow-up of physiological and behavioural functions was initiated in 38-month-old mouse lemurs (Microcebus murinus) to test whether caloric restriction (CR) or a potential mimetic compound, resveratrol (RSV), can delay the ageing process and the onset of age-related diseases. Based on their potential survival of 12 years, mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake and a RSV group (200 mg/kg.day–1) fed ad libitum. Since this prosimian primate exhibits a marked annual rhythm in body mass gain during winter, animals were tested throughout the year to assess body composition, daily energy expenditure (DEE), resting metabolic rate (RMR), physical activity and hormonal levels. After 1 year, all mouse lemurs seemed in good health. CR animals showed a significantly decreased body mass compared with the other groups during long day period only. CR or RSV treatments did not affect body c...
PLoS ONE, 2014
The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process... more The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 mg.kg 21 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MS E mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo-and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo-and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism.
AGE, 2011
A lifelong follow-up of physiological and behavioural functions was initiated in 38-month-old mou... more A lifelong follow-up of physiological and behavioural functions was initiated in 38-month-old mouse lemurs (Microcebus murinus) to test whether caloric restriction (CR) or a potential mimetic compound, resveratrol (RSV), can delay the ageing process and the onset of age-related diseases. Based on their potential survival of 12 years, mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake and a RSV group (200 mg/kg.day-1) fed ad libitum. Since this prosimian primate exhibits a marked annual rhythm in body mass gain during winter, animals were tested throughout the year to assess body composition, daily energy expenditure (DEE), resting metabolic rate (RMR), physical activity and hormonal levels. After 1 year, all mouse lemurs seemed in good health. CR animals showed a significantly decreased body mass compared with the other groups during long day period only. CR or RSV treatments did not affect body composition. CR induced a decrease in DEE without changes in RMR, whereas RSV induced a concomitant increase in DEE and RMR without any obvious modification of locomotor activity in both groups. Hormonal levels remained similar in each group. In summary, after 1 year of treatment CR and RSV induced differential metabolic responses but animals successfully acclimated to their imposed diets. The RESTRIKAL study can now be safely undertaken on a long-term basis to determine whether ageassociated alterations in mouse lemurs are delayed with
Communications Biology, Apr 5, 2018
The health benefits of chronic caloric restriction resulting in lifespan extension are well estab... more The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species, but the effects in humans and other primates remain controversial. Here we report the most advanced survival data and the associated follow-up to our knowledge of age-related alterations in a cohort of grey mouse lemurs (Microcebus murinus, lemurid primate) exposed to a chronic moderate (30%) caloric restriction. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases and preserved loss of brain white matter in several brain regions. However, caloric restriction accelerated loss of grey matter throughout much of the cerebrum. Cognitive and behavioural performances were, however, not modulated by caloric restriction. Thus chronic moderate caloric restriction can extend lifespan and enhance health of a primate, but it affects brain grey matter integrity without affecting cognitive performances.
Journal of Alzheimer's Disease, Nov 1, 2016
No effective preventive treatment is available for age-related cognitive decline and Alzheimer's ... more No effective preventive treatment is available for age-related cognitive decline and Alzheimer's disease (AD). Epidemiological studies indicate that a diet rich in fruit is associated with cognitive improvement. It was thus proposed that high polyphenol concentrations found in berries can prevent cognitive impairment associated with aging and AD. Therefore, the Neurophenols project aimed at investigating the effects of a polyphenolic extract from blueberries and grapes (PEBG) in the triple-transgenic (3xTg-AD) mouse model of AD, which develops AD neuropathological markers, including amyloid- plaques and neurofibrillary tangles, leading to memory deficits. In this study, 12-month-old 3xTg-AD and NonTg mice were fed a diet supplemented with standardized PEBG (500 or 2500 mg/kg) for 4 months (n = 15-20/group). A cognitive evaluation with the novel object recognition test was performed at 15 months of age and mice were sacrificed at 16 months of age. We observed that PEBG supplementation with doses of 500 or 2500 mg/kg prevented the decrease in novel object recognition observed in both 15-month-old 3xTg-AD mice and NonTg mice fed a control diet. Although PEBG treatment did not reduce A and tau pathologies, it prevented the decrease in mature BDNF observed in 16-month-old 3xTg-AD mice. Finally, plasma concentrations of phenolic metabolites, such as dihydroxyphenyl valerolactone, a microbial metabolite of epicatechin, positively correlated with memory performances in supplemented mice. The improvement in object recognition observed in 3xTg-AD mice after PEBG administration supports the consumption of polyphenols-rich extracts to prevent memory impairment associated with age-related disease, without significant effects on classical AD neuropathology.
Food & function, Jan 22, 2016
The low bioavailability of dietary phenolic compounds, resulting from poor absorption and high ra... more The low bioavailability of dietary phenolic compounds, resulting from poor absorption and high rates of metabolism and excretion, is a concern as it can limit their potential beneficial effects on health. Targeted metabolomic profiling in plasma and feces of mice supplemented for 15 days with a blueberry extract, a grape extract or their combination revealed significantly increased plasma concentrations (3-5 fold) of blueberry phenolic metabolites in the presence of a co-ingested grape extract, associated with an equivalent decrease in their appearance in feces. Additionally, the repeated daily administration of the blueberry-grape combination significantly increased plasma phenolic concentrations (2-3-fold) compared to animals receiving only a single acute dose, with no such increase being observed with individual extracts. These findings highlight a positive interaction between blueberry and grape constituents, in which the grape extract enhanced the absorption of blueberry phenol...
Nutrition and Aging, 2016
A growing body of evidence suggests that dietary interventions may delay or halt the progression ... more A growing body of evidence suggests that dietary interventions may delay or halt the progression of age-related health disorders and cognitive decline. Among the components of the human diet, polyphenols from berries are essential micronutrients that have been particularly studied for improving cognitive functions. In the present review, we highlight the health impact of major polyphenolic classes found in berries: flavanols, anthocyanins and stilbenes, focusing on resveratrol. The reports of beneficial effects of berry consumption on age-related cognitive decline and associated neurobiological processes in animals and human are underscored. We then discuss the potential benefit of each category of polyphenols on memory impairment and in neurodegenerative diseases. Berry polyphenols improve several types of memory and have a global effect on brain plasticity, partly through their antioxidant activity and/or their effect on neuronal signal transduction and neuroinflammation. Interestingly, accumulated bioavailability data suggest that most polyphenols, or at least key metabolites, can access the brain in sufficient concentrations. Collectively, the data accumulated so far suggest that dietary polyphenols can modulate brain health and function, and strengthen the importance of fruit consumption for a healthy brain aging and the prevention of age-related diseases. However, further preclinical work is needed to determine the most neuroactive nutraceutical formulations, whether through the diet or supplement, to subsequently design and perform informative clinical trials.
PLoS ONE
Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral sup... more Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus). Thirty-three adult male mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake, and an RSV group (RSV supplementation of 200 mg.kg−1.day−1) fed ad libitum. Three different cognitive tests, two motor tests, one emotional test and an analysis of cortisol level were performed in each group. Compared to CTL animals, CR or RSV animals did not show any change in motor performances evaluated by rotarod and jump tests, but an increase in spontaneous locomotor activity was observed in both groups. Working memory was improved by both treatments in the spontaneous alternation task. Despite a trend for CR group, only RSV supplementation increased sp...
Oxidative Medicine and Cellular Longevity
In several species, resveratrol, a polyphenolic compound, activates sirtuin proteins implicated i... more In several species, resveratrol, a polyphenolic compound, activates sirtuin proteins implicated in the regulation of energy balance and biological clock processes. To demonstrate the effect of resveratrol on clock function in an aged primate, young and aged mouse lemurs (Microcebus murinus) were studied over a 4-week dietary supplementation with resveratrol. Spontaneous locomotor activity and daily variations in body temperature were continuously recorded. Reduction in locomotor activity onset and changes in body temperature rhythm in resveratrol-supplemented aged animals suggest an improved synchronisation on the light-dark cycle. Resveratrol could be a good candidate to restore the circadian rhythms in the elderly.
Journal of Biological Rhythms
Resveratrol (RSV) is a dietary polyphenolic compound with several positive effects on metabolic f... more Resveratrol (RSV) is a dietary polyphenolic compound with several positive effects on metabolic functions and longevity. We tested the effect of RSV on the circadian clock in a nonhuman primate, the gray mouse lemur. The impact of a 2-week dietary supplementation of RSV on the rhythms of locomotor activity and body temperature in constant dark conditions (DD) was investigated in young (n = 7) and old (n = 6) animals. RSV supplementation followed 2 weeks in DD under normal diet (CTL). In both young and old animals receiving RSV, we observed a shortening of the free-running period compared to those under CTL (-15 minutes in young animals and -45 minutes in old animals), accompanied by a lower mean body temperature in both age groups and decreased locomotor activity in young animals. Thus, RSV is a food component capable of influencing a primate's circadian clock. This property may be of interest clinically in the context of the treatment of circadian disruption and in the context ...
RMR and aerobic capacity. The large degree of individual variation in traits such as metabolic ra... more RMR and aerobic capacity. The large degree of individual variation in traits such as metabolic rate, aerobic capacity, starvation tolerance and risk-taking behaviour suggests that there are trade-offs between these traits whichdepending on environmental factors such as food availability and predator abundancecould have an important influence on which individuals survive in wild populations.
Background: Resveratrol, a natural polyphenolic compound, was shown to protect rodents against hi... more Background: Resveratrol, a natural polyphenolic compound, was shown to protect rodents against high-fat-diet induced diabesity by boosting energy metabolism. To the best of our knowledge, no data is yet available on the effects of resveratrol in non-human primates. Six non-human heterotherm primates (grey mouse lemurs, Microcebus murinus) were studied during four weeks of dietary supplementation with resveratrol (200 mg/kg/day) during their winter bodymass gain period. Body mass, spontaneous energy intake, resting metabolic rate, spontaneous locomotor activity and daily variations in body temperature were measured. In addition, the plasma levels of several gut hormones involved in satiety control were evaluated. Results: Resveratrol reduced the seasonal body-mass gain by concomitantly decreasing energy intake by 13% and increasing resting metabolic rate by 29%. Resveratrol supplementation inhibited the depth of daily torpor, an important energy-saving process in this primate. The daily amount of locomotor activity remained unchanged. Except for an increase in the glucose-dependent insulinotropic polypeptide, a gut hormone known to promote mobilization of fat stores, no major change in satiety hormone plasma levels was observed under resveratrol supplementation. Conclusions: These results suggest that in a non-human primate, resveratrol reduces body-mass gain by increasing satiety and resting metabolic rate, and by inhibiting torpor expression. The measured anorectic gut hormones did not seem to play a major role in these observations.
Background: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely rel... more Background: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with autosomal dominant inheritance in which members affected by FTD, ALS or both; showing genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as a massively expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). Methods: Review of published and unpublished data. Results: Studies from many centers have now shown the C9ORF72 mutation to be the most common genetic cause of familial and sporadic forms of both FTD and of ALS and the basis of most families in which both conditions occur. The associated phenotype is heterogeneous with wide variation in age of onset and survival. FTD is more often the behavioral variant than progressive non-fluent aphasia and the motor features are usually typical of ALS but with more frequent bulbar onset. Memory problems, psychosis and a wide range of other motor symptoms have also been reported. There may be striking clinical variability within families and some evidence for genetic anticipation. The underlying neuropathology is a characterized by TDP-43 immunoreactive inclusions in a wide range of neuroanatomical regions including the cerebral cortex (FTLD-TDP) and lower motor neurons (ALS-TDP). In addition, the presence of ubiquitin-positive, TDP-43-negative inclusions in the cerebellum and hippocampus is a consistent and unique feature that indicates abnormal metabolism of some unidentified protein(s). The hexanucleotide repeat is located between two alternately spliced first exons and abnormal expansion results in loss of one alternatively spliced C9ORF72 transcript and the formation of nuclear RNA foci, suggesting multiple pathogenic mechanisms. Conclusions: The C9ORF72 mutation is a major cause of familial and sporadic FTD and ALS, and likely accounts for the majority of families with combined FTD and ALS. This further supports the concept that FTD and ALS represent a clinicopathological spectrum of disease and highlights the role of RNA mis-metabolism in the pathogenesis of these conditions.
The use of non-human primate models is required to understand the ageing process and evaluate new... more The use of non-human primate models is required to understand the ageing process and evaluate new therapies against age-associated pathologies. The present article summarizes all the contributions of the grey mouse lemur Microcebus murinus, a small nocturnal prosimian primate, to the understanding of the mechanisms of ageing. Results from studies of both healthy and pathological ageing research on the grey mouse lemur demonstrated that this animal is a unique model to study age-dependent changes in endocrine systems, biological rhythms, thermoregulation, sensorial, cerebral and cognitive functions.
Journal of Neuroscience, 2013
Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzhe... more Defects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n ϭ 12), mild cognitive impairment (n ϭ 12), or AD (n ϭ 12). A loss of total PAK, detected in the cortex of AD patients (Ϫ39% versus controls), was correlated with cognitive impairment (r 2 ϭ 0.148, p ϭ 0.027) and deposition of total and phosphorylated tau (r 2 ϭ 0.235 and r 2 ϭ 0.206, respectively), but not with A42 (r 2 ϭ 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12-and 20-month-old 3xTg-AD mice, an animal model of AD-like A and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (Ϫ25%), but without enhancement of A/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function.
Experimental Gerontology, 2013
Oxidative stress is a key factor in the aging process and in the development of age-related disea... more Oxidative stress is a key factor in the aging process and in the development of age-related diseases. Because nutritional interventions such as caloric restriction (CR) delay the onset of age-related diseases and increase the lifespan of many species, the impact of a moderate CR was tested on male grey mouse lemur (Microcebus murinus), which have a median survival time of 5.7 years in captivity. The effects of CR on these lemurs were compared with a potential mimetic, resveratrol (RSV), a polyphenol naturally found in grapes. We hypothesized that both CR and RSV impact oxidative DNA and RNA damage compared to standard-fed control (CTL) animals. Adult (3-4 years old) male mouse lemurs were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Oxidative stress was estimated after 3, 9, 15 and 21 months of treatment using the measurement of oxidized nucleosides in urine samples by mass spectrometry. The resting metabolic rate, adjusted for changes in body composition, was also measured to assess the potential relationship between oxygen consumption and oxidative damage markers. This study provides evidence for oxidative stress accumulation with age in grey mouse lemur. Dietary interventions resulted in a short-term increase in oxidative stress levels followed by reduced levels with increasing age. Moreover, in this photoperiod-dependent heterotherm primate, seasonal variations in oxidative stress were observed, which was likely due to a season-dependent, cost-benefit trade-off between torpor use and oxidative stress.
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Papers by Alexandre Dal-Pan