A vegetable fat-based diet delays psychomotor and cognitive development compared with maternal dairy fat intake in infant gray mouse lemurs.

Dairy fat has a unique lipid profile; it is rich in short- and medium-chain saturated fatty acids that induce ketone production and has a balanced ω6/ω3 ratio that promotes cognitive development in early life. Moreover, the high consumption of vegetable oils in pregnant and lactating women raises concerns regarding the quality of lipids provided to offspring. Here, we investigate maternal dairy fat intake during gestation and lactation in a highly valuable primate model for infant nutritional studies, the gray mouse lemur (Microcebus murinus). Two experimental diets are provided to gestant mouse lemurs: a dairy fat-based (DF) or vegetable fat-based diet (VF). The psychomotor performance of neonates is tested during their first 30 days. Across all tasks, we observe more successful neonates born to mothers fed a DF diet. A greater rate of falls is observed in 8-day-old VF neonates, which is associated with delayed psychomotor development. Our findings suggest the potential benefits of lipids originating from a lactovegetarian diet compared with those originating from a vegan diet for the psychomotor development of neonates.

Characterization of sinoatrial automaticity in Microcebus murinus to study the effect of aging on cardiac activity and the correlation with longevity.

Microcebus murinus, or gray mouse lemur (GML), is one of the smallest primates known, with a size in between mice and rats. The small size, genetic proximity to humans and prolonged senescence, make this lemur an emerging model for neurodegenerative diseases. For the same reasons, it could help understand how aging affects cardiac activity. Here, we provide the first characterization of sinoatrial (SAN) pacemaker activity and of the effect of aging on GML heart rate (HR). According to GML size, its heartbeat and intrinsic pacemaker frequencies lie in between those of mice and rats. To sustain this fast automaticity the GML SAN expresses funny and Ca2+ currents (If, ICa,L and ICa,T) at densities similar to that of small rodents. SAN automaticity was also responsive to ß-adrenergic and cholinergic pharmacological stimulation, showing a consequent shift in the localization of the origin of pacemaker activity. We found that aging causes decrease of basal HR and atrial remodeling in GML. We also estimated that, over 12 years of a lifetime, GML generates about 3 billion heartbeats, thus, as many as humans and three times more than rodents of equivalent size. In addition, we estimated that the high number of heartbeats per lifetime is a characteristic that distinguishes primates from rodents or other eutherian mammals, independently from body size. Thus, cardiac endurance could contribute to the exceptional longevity of GML and other primates, suggesting that GML's heart sustains a workload comparable to that of humans in a lifetime. In conclusion, despite the fast HR, GML replicates some of the cardiac deficiencies reported in old people, providing a suitable model to study heart rhythm impairment in aging. Moreover, we estimated that, along with humans and other primates, GML presents a remarkable cardiac longevity, enabling longer life span than other mammals of equivalent size.

Increased oligodendrogenesis and myelination in the subventricular zone of aged mice and gray mouse lemurs.

The adult rodent subventricular zone (SVZ) generates neural stem cells (NSCs) throughout life that migrate to the olfactory bulbs (OBs) and differentiate into olfactory interneurons. Few SVZ NSCs generate oligodendrocyte precursor cells (OPCs). We investigated how neurogliogenesis is regulated during aging in mice and in a non-human primate (NHP) model, the gray mouse lemur. In both species, neuronal commitment decreased with age, while OPC generation and myelin content unexpectedly increased. In the OBs, more tyrosine hydroxylase interneurons in old mice, but fewer in lemurs, marked a surprising interspecies difference that could relate to our observation of a continuous ventricle in lemurs. In the corpus callosum, aging promoted maturation of OPCs into mature oligodendrocytes in mice but blocked it in lemurs. The present study highlights similarities and dissimilarities between rodents and NHPs, revealing that NHPs are a more relevant model than mice to study the evolution of biomarkers of aging.

Relationships between endogenous circadian period, physiological and cognitive parameters and sex in aged gray mouse lemurs (Microcebus murinus).

The biological clock generates circadian rhythms, with an endogenous period tau close to 24 h. The circadian resonance theory proposes that lifespan is reduced when endogenous period goes far from 24 h. It has been suggested that daily resetting of the circadian clock to the 24 h external photoperiod might induce marginal costs that would accumulate over time and forward accelerate aging and affect fitness. In this study, we aimed to evaluate the link between the endogenous period and biomarkers of aging in order to investigate the mechanisms of the circadian resonance theory. We studied 39 middle-aged and aged Microcebus murinus, a nocturnal non-human primate whose endogenous period is about 23.1 h, measuring the endogenous period of locomotor activity, as well as several physiological and behavioral parameters (rhythm fragmentation and amplitude, energetic expenditure, oxidative stress, insulin-like growth factor-1 (IGF-1) concentrations and cognitive performances) in both males and females. We found that aged males with tau far from 24 h displayed increased oxidative stress. We also demonstrated a positive correlation between tau and IGF-1 concentrations, as well as learning performances, in males and females. Together these results suggest that a great deviation of tau from 24 h leads to increased biomarkers of age-related impairments.

Overview of age-related changes in psychomotor and cognitive functions in a prosimian primate, the gray mouse lemur (Microcebus murinus): Recent advances in risk factors and antiaging interventions.

Aging is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. Impaired glucose homeostasis is a major risk factor for cognitive decline in middle-aged humans, pointing at the existence of early markers of unhealthy aging. The gray mouse lemur (Microcebus murinus), a small lemuriform Malagasy primate, shows relatively slow aging with decreased psychomotor capacities at middle-age (around 5-year old). In some cases (∼10%), it spontaneously leads to pathological aging. In this case, some age-related deficits, such as severe cognitive decline, brain atrophy, amyloidosis, and glucoregulatory imbalance are congruent with what is observed in humans. In the present review, we inventory the changes occurring in psychomotor and cognitive functions during healthy and pathological aging in mouse lemur. It includes a summary of the cerebral, metabolic, and cellular alterations that occur during aging and their relation to cognitive decline. As nutrition is one of the major nonpharmacological antiaging strategies with major potential effects on cognitive performances, we also discuss its role in brain functions and cognitive decline in this species. We show that the overall approach of aging studies in the gray mouse lemur offers promising ways of investigation for understanding, prevention, and treatments of pathological aging in humans.

Oscillatory Activity in Mouse Lemur Primary Motor Cortex During Natural Locomotor Behavior.

In arboreal environments, substrate orientation determines the biomechanical strategy for postural maintenance and locomotion. In this study, we investigated possible neuronal correlates of these mechanisms in an ancestral primate model, the gray mouse lemur. We conducted telemetric recordings of electrocorticographic activity in left primary motor cortex of two mouse lemurs moving on a branch-like small-diameter pole, fixed horizontally, or vertically. Analysis of cortical oscillations in high ß (25-35 Hz) and low γ (35-50 Hz) bands showed stronger resting power on horizontal than vertical substrate, potentially illustrating sensorimotor processes for postural maintenance. Locomotion on horizontal substrate was associated with stronger event-related desynchronization than vertical substrate, which could relate to locomotor adjustments and/or derive from differences in baseline activity. Spectrograms of cortical activity showed modulation throughout individual locomotor cycles, with higher values in the first than second half cycle. However, substrate orientation did not significantly influence these variations. Overall, these results confirm that specific cortical mechanisms are solicited during arboreal locomotion, whereby mouse lemurs adjust cortical activity to substrate orientation during static posture and locomotion, and modulate this activity throughout locomotor cycles.

Repurposing beta-3 adrenergic receptor agonists for Alzheimer's disease: beneficial effects in a mouse model.

BACKGROUND: Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through ß3 adrenergic receptor (ß3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits, and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a ß3AR agonist could exert benefits in AD as well. METHODS: CL-316,243, a specific ß3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p. RESULTS: Here, we show that ß3AR agonist administration decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a ß3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety, and tau pathology were not modified. Finally, insoluble Aß42/Aß40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice. CONCLUSIONS: Overall, our results indicate that ß3AR stimulation reverses memory deficits and shifts downward the insoluble Aß42/Aß40 ratio in 16-month-old 3xTg-AD mice. As ß3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.

Lipid Transport and Metabolism at the Blood-Brain Interface: Implications in Health and Disease.

Many prospective studies have shown that a diet enriched in omega-3 polyunsaturated fatty acids (n-3 PUFAs) can improve cognitive function during normal aging and prevent the development of neurocognitive diseases. However, researchers have not elucidated how n-3 PUFAs are transferred from the blood to the brain or how they relate to cognitive scores. Transport into and out of the central nervous system depends on two main sets of barriers: the blood-brain barrier (BBB) between peripheral blood and brain tissue and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) between the blood and the CSF. In this review, the current knowledge of how lipids cross these barriers to reach the CNS is presented and discussed. Implications of these processes in health and disease, particularly during aging and neurodegenerative diseases, are also addressed. An assessment provided here is that the current knowledge of how lipids cross these barriers in humans is limited, which hence potentially restrains our capacity to intervene in and prevent neurodegenerative diseases.

Orientation Preference Maps in Microcebus murinus Reveal Size-Invariant Design Principles in Primate Visual Cortex.

Orientation preference maps (OPMs) are a prominent feature of primary visual cortex (V1) organization in many primates and carnivores. In rodents, neurons are not organized in OPMs but are instead interspersed in a "salt and pepper" fashion, although clusters of orientation-selective neurons have been reported. Does this fundamental difference reflect the existence of a lower size limit for orientation columns (OCs) below which they cannot be scaled down with decreasing V1 size? To address this question, we examined V1 of one of the smallest living primates, the 60-g prosimian mouse lemur (Microcebus murinus). Using chronic intrinsic signal imaging, we found that mouse lemur V1 contains robust OCs, which are arranged in a pinwheel-like fashion. OC size in mouse lemurs was found to be only marginally smaller compared to the macaque, suggesting that these circuit elements are nearly incompressible. The spatial arrangement of pinwheels is well described by a common mathematical design of primate V1 circuit organization. In order to accommodate OPMs, we found that the mouse lemur V1 covers one-fifth of the cortical surface, which is one of the largest V1-to-cortex ratios found in primates. These results indicate that the primate-type visual cortical circuit organization is constrained by a size limitation and raises the possibility that its emergence might have evolved by disruptive innovation rather than gradual change.

Survival is reduced when endogenous period deviates from 24 h in a non-human primate, supporting the circadian resonance theory.

Circadian rhythms are ubiquitous attributes across living organisms and allow the coordination of internal biological functions with optimal phases of the environment, suggesting a significant adaptive advantage. The endogenous period called tau lies close to 24 h and is thought to be implicated in individuals' fitness: according to the circadian resonance theory, fitness is reduced when tau gets far from 24 h. In this study, we measured the endogenous period of 142 mouse lemurs (Microcebus murinus), and analyzed how it is related to their survival. We found different effects according to sex and season. No impact of tau on mortality was found in females. However, in males, the deviation of tau from 24 h substantially correlates with an increase in mortality, particularly during the inactive season (winter). These results, comparable to other observations in mice or drosophila, show that captive gray mouse lemurs enjoy better fitness when their circadian period closely matches the environmental periodicity. In addition to their deep implications in health and aging research, these results raise further ecological and evolutionary issues regarding the relationships between fitness and circadian clock.

EthoLoop: automated closed-loop neuroethology in naturalistic environments.

Accurate tracking and analysis of animal behavior is crucial for modern systems neuroscience. However, following freely moving animals in naturalistic, three-dimensional (3D) or nocturnal environments remains a major challenge. Here, we present EthoLoop, a framework for studying the neuroethology of freely roaming animals. Combining real-time optical tracking and behavioral analysis with remote-controlled stimulus-reward boxes, this system allows direct interactions with animals in their habitat. EthoLoop continuously provides close-up views of the tracked individuals and thus allows high-resolution behavioral analysis using deep-learning methods. The behaviors detected on the fly can be automatically reinforced either by classical conditioning or by optogenetic stimulation via wirelessly controlled portable devices. Finally, by combining 3D tracking with wireless neurophysiology we demonstrate the existence of place-cell-like activity in the hippocampus of freely moving primates. Taken together, we show that the EthoLoop framework enables interactive, well-controlled and reproducible neuroethological studies in large-field naturalistic settings.

Physiological and cognitive consequences of a daily 26 h photoperiod in a primate: exploring the underlying mechanisms of the circadian resonance theory.

The biological clock expresses circadian rhythms, whose endogenous period (tau) is close to 24 h. Daily resetting of the circadian clock to the 24 h natural photoperiod might induce marginal costs that would accumulate over time and forward affect fitness. It was proposed as the circadian resonance theory. For the first time, we aimed to evaluate these physiological and cognitive costs that would partially explain the mechanisms of the circadian resonance hypothesis. We evaluated the potential costs of imposing a 26 h photoperiodic regimen compared to the classical 24 h entrainment measuring several physiological and cognitive parameters (body temperature, energetic expenditure, oxidative stress, cognitive performances) in males of a non-human primate (Microcebus murinus), a nocturnal species whose endogenous period is about 23.5 h. We found significant higher resting body temperature and energy expenditure and lower cognitive performances when the photoperiodic cycle length was 26 h. Together these results suggest that a great deviation of external cycles from tau leads to daily greater energetic expenditure, and lower cognitive capacities. To our knowledge, this study is the first to highlight potential mechanisms of circadian resonance theory.

Evidence of the Role of Omega-3 Polyunsaturated Fatty Acids in Brain Glucose Metabolism.

In mammals, brain function, particularly neuronal activity, has high energy needs. When glucose is supplemented by alternative oxidative substrates under different physiological conditions, these fuels do not fully replace the functions fulfilled by glucose. Thus, it is of major importance that the brain is almost continuously supplied with glucose from the circulation. Numerous studies describe the decrease in brain glucose metabolism during healthy or pathological ageing, but little is known about the mechanisms that cause such impairment. Although it appears difficult to determine the exact role of brain glucose hypometabolism during healthy ageing or during age-related neurodegenerative diseases such as Alzheimer's disease, uninterrupted glucose supply to the brain is still of major importance for proper brain function. Interestingly, a body of evidence suggests that dietary n-3 polyunsaturated fatty acids (PUFAs) might play significant roles in brain glucose regulation. Thus, the goal of the present review is to summarize this evidence and address the role of n-3 PUFAs in brain energy metabolism. Taken together, these data suggest that ensuring an adequate dietary supply of n-3 PUFAs could constitute an essential aspect of a promising strategy to promote optimal brain function during both healthy and pathological ageing.

Profiling torpor-responsive microRNAs in muscles of the hibernating primate Microcebus murinus.

When food scarcity is coupled with decreased temperatures, gray mouse lemurs (Microcebus murinus) depress their metabolic rates and retreat into bouts of either daily torpor or multi-day hibernation, without dramatically dropping body temperatures like other 'traditional hibernators'. Rapid and reversible mechanisms are required to coordinate the simultaneous suppression of energetically expensive processes and activation of pro-survival pathways critical for successful torpor-arousal cycling. MicroRNAs, a class of endogenous non-coding small RNAs, are effective post-transcriptional regulators that modulate all aspects of cellular function. The present study hypothesizes that miRNAs are intimately involved in facilitating the molecular reorganization events necessary for lemur skeletal muscle torpor. Small RNA-Sequencing was used to compare miRNA profiles from skeletal muscles of torpid and control primates. We characterized 234 conserved miRNAs, of which 20 were differentially expressed during torpor, relative to control. Examples included downregulation of key muscle-specific (myomiR) members, miR-1 and miR-133, suggesting a switch to muscle-specific energy-saving strategies. In silico target mapping and logistic regression-based gene set analysis indicated the inhibition of energy costly pathways such as oxidative phosphorylation and muscle proliferation. The suppression of these metabolic pathways was balanced with a lack of miRNA inhibition of various signaling pathways, such as MAPK, mTOR, focal adhesion, and ErbB. This study identifies unique miRNA signatures and 'biomarkers of torpor' that provide us with primate-specific insights on torpor at high body temperatures that can be exploited for human biomedical concerns.

The age-performance relationship in the general population and strategies to delay age related decline in performance.

The age-performance relationship describes changes in the organism's structural and functional capabilities over the course of the lifespan. The typical, empirical pattern is an asymmetrical inverted-U shape association with peak capacity occurring early in life. This process is well described in the literature, with an increasing interest in features that characterize this pattern, such as the rate of growth, age of peak performance, and rate of decline with aging. This is usually examined in cohorts of individuals followed over time with repeat assessments of physical or cognitive abilities. This framework ought to be integrated into public health programs, embedding the beneficial (such as physical or cognitive training) or adverse effects (such as chronic diseases or injuries) that respectively sustain or limit capabilities. The maintenance of physical or cognitive performances at older ages would result in both optimal health and promote resistance to disabling conditions and chronic diseases, such as obesity and type 2 diabetes. The causes of accelerated degeneration of health optima are mainly: sedentary and unhealthy lifestyles -including poor nutrition-, exposure to environmental pollutants, and heterogeneity in aging. Better knowledge of optima, compatible with or required for good health, should also allow for establishing ideal conditions for longevity.

Strengths and Weaknesses of the Gray Mouse Lemur (Microcebus murinus) as a Model for the Behavioral and Psychological Symptoms and Neuropsychiatric Symptoms of Dementia.

To face the load of the prevalence of Alzheimer's disease in the aging population, there is an urgent need to develop more translatable animal models with similarities to humans in both the symptomatology and physiopathology of dementia. Due to their close evolutionary similarity to humans, non-human primates (NHPs) are of primary interest. Of the NHPs, to date, the gray mouse lemur (Microcebus murinus) has shown promising evidence of its translatability to humans. The present review reports the known advantages and limitations of using this species at all levels of investigation in the context of neuropsychiatric conditions. In this easily bred Malagasy primate with a relatively short life span (approximately 12 years), age-related cognitive decline, amyloid angiopathy, and risk factors (i.e., glucoregulatory imbalance) are congruent with those observed in humans. More specifically, analogous behavioral and psychological symptoms and neuropsychiatric symptoms of dementia (BPSD/NPS) to those in humans can be found in the aging mouse lemur. Aged mouse lemurs show typical age-related alterations of locomotor activity daily rhythms such as decreased rhythm amplitude, increased fragmentation, and increased activity during the resting-sleeping phase of the day and desynchronization with the light-dark cycle. In addition, sleep deprivation successfully induces cognitive deficits in adult mouse lemurs, and the effectiveness of approved cognitive enhancers such as acetylcholinesterase inhibitors or N-methyl-D-aspartate antagonists is demonstrated in sleep-deprived animals. This result supports the translational potential of this animal model, especially for unraveling the mechanisms underlying dementia and for developing novel therapeutics to prevent age-associated cognitive decline. In conclusion, actual knowledge of BPSD/NPS-like symptoms of age-related cognitive deficits in the gray mouse lemur and the recent demonstration of the similarity of these symptoms with those seen in humans offer promising new ways of investigating both the prevention and treatment of pathological aging.

Daily Torpor and Sleep in a Non-human Primate, the Gray Mouse Lemur (Microcebus murinus).

Daily torpor is an energy-saving process that evolved as an extension of non-rapid eye movement (NREM) sleep mechanisms. In many heterothermic species there is a relation between torpor expression and the repartition of the different behavioral states of sleep. Despite the presence of sleep during this period of hypothermia, torpor induces an accumulation of sleep debt which results in a rebound of sleep in mammals. We aimed to investigate the expression of sleep-wake rhythms and delta waves during daily torpor at various ambient temperatures in a non-human primate model, the gray mouse lemur (Microcebus murinus). Cortical activity was measured with telemetric electroencephalography (EEG) recordings in the prefrontal cortex (PFC) during the torpor episode and the next 24 h following hypothermia. Gray mouse lemurs were divided into two groups: the first group was subjected to normal ambient temperatures (25°C) whereas the second group was placed at lower ambient temperatures (10°C). Contrary to normal ambient temperatures, sleep-wake rhythms were maintained during torpor until body temperature (Tb) of the animals reached 21°C. Below this temperature, NREM and REM sleep strongly decreased or were absent whereas the EEG became isoelectric. The different states of sleep were proportional to Tbmin during prior torpor in contrast to active phases. Delta waves increased after torpor but low Tb did not induce greater delta power compared to higher temperatures. Our results showed that Tb was a determining factor for the quality and quantity of sleep. Low Tb might be inconsistent with the recovery function of sleep. Heterothermy caused a sleep debt thus there was a rebound of sleep at the beginning of euthermia to compensate for the lack of sleep.

Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated ß-amyloid peptides (Aß) and tau proteins. Iatrogenic induction of Aß is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aß. Induction of Aß and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aß or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aß depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.

The Biological Clock in Gray Mouse Lemur: Adaptive, Evolutionary and Aging Considerations in an Emerging Non-human Primate Model.

Circadian rhythms, which measure time on a scale of 24 h, are genetically generated by the circadian clock, which plays a crucial role in the regulation of almost every physiological and metabolic process in most organisms. This review gathers all the available information about the circadian clock in a small Malagasy primate, the gray mouse lemur (Microcebus murinus), and reports 30 years data from the historical colony at Brunoy (France). Although the mouse lemur has long been seen as a "primitive" species, its clock displays high phenotypic plasticity, allowing perfect adaptation of its biological rhythms to environmental challenges (seasonality, food availability). The alterations of the circadian timing system in M. murinus during aging show many similarities with those in human aging. Comparisons are drawn with other mammalian species (more specifically, with rodents, other non-human primates and humans) to demonstrate that the gray mouse lemur is a good complementary and alternative model for studying the circadian clock and, more broadly, brain aging and pathologies.

Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies.

The health benefits of chronic caloric restriction (CR) resulting in lifespan extension are well established in many species and has been recently demonstrated also in non-human primates, but its effects in humans remain to be proven on a long-term basis. CR might be a very efficient anti-aging strategy but its definition and limits must be well understood before envisaging to apply it to human. In this review, we first report and compare the recently issued CR studies in non-human primates and humans and then try to understand what an optimal caloric intake is. In a last part, we will discuss the pertinence of using CR as an anti-aging strategy with respect to the risks of frailty and obesity.