Effects of age on thermoregulatory responses during cold exposure in a nonhuman primate, Microcebus murinus

Cold resistance appears altered with aging. Among existing hypotheses, the impaired capacity in response to cold could be related to an altered regulation of plasma IGF-1 concentration. The combined effects of age and cold exposure were studied in a short-living primate, the gray mouse lemur (Microcebus murinus), which adjusts its energy balance using a daily torpor phase, to avoid high energy cost of normothermia maintenance. Changes in body mass, core temperature, locomotor activity, and caloric intake were monitored under 9-day exposures to 25 degrees C and 12 degrees C in captive animals in winter conditions. Short-term (after 2 days) and long-term (after 9 days) cold-induced changes in IGF-1 levels were also evaluated. In thermoneutral conditions (25 degrees C), general characteristics of the daily rhythm of core temperature were preserved with age. At 12 degrees C, age-related changes were mainly characterized by a deeper hypothermia and an increased frequency of torpor phases, associated with a loss of body mass. A short-term cold-induced decrease in plasma IGF-1 levels was observed. IGF-1 levels returned to basal values after 9 days of cold exposure. No significant effect of age could be evidenced on IGF-1 response. However, IGF-1 levels of cold-exposed aged animals were negatively correlated with the frequency of daily torpor. Responses exhibited by aged mouse lemurs exposed to cold revealed difficulties in the maintenance of normothermia and energy balance and might involve modulations of IGF-1 levels.     

Personality and performance are affected by age and early life parameters in a small primate

A whole suite of parameters is likely to influence the behavior and performance of individuals as adults, including correlations between phenotypic traits or an individual's developmental context. Here, we ask the question whether behavior and physical performance traits are correlated and how early life parameters such as birth weight, litter size, and growth can influence these traits as measured during adulthood. We studied 486 captive gray mouse lemurs (Microcebus murinus) and measured two behavioral traits and two performance traits potentially involved in two functions: exploration behavior with pull strength and agitation score with bite force. We checked for the existence of behavioral consistency in behaviors and explored correlations between behavior, performance, morphology. We analyzed the effect of birth weight, growth, and litter size, while controlling for age, sex, and body weight. Behavior and performance were not correlated with one another, but were both influenced by age. Growth rate had a positive effect on adult morphology, and birth weight significantly affected emergence latency and bite force. Grip strength was not directly affected by early life traits, but bite performance and exploration behavior were impacted by birth weight. This study shows how early life parameters impact personality and performance.     

Tridemethylisovelleral, a potent cytotoxic agent

The synthesis and in vitro cytotoxicity toward various tumor cell lines of (+/-)-tridemethylisovelleral, an analogue of the bioactive fungal sesquiterpene (+)-isovelleral retaining the bicyclo[4,1,0]hept-2-en-1,2-dicarbaldehyde system but lacking the three methyl groups, is reported. The cytotoxicity of tridemethylisovelleral toward several tumor cell lines was found to be comparable with those of established antitumor drugs, and significantly higher than that of isovelleral.     

Age-related effects on the biological clock and its behavioral output in a primate

In humans, activity rhythms become fragmented and attenuated in the elderly. This suggests an alteration of the circadian system per se that could in turn affect the expression of biological rhythms. In primates, very few studies have analyzed the effect of aging on the circadian system. The mouse lemur provides a unique model of aging in non-human primates. To assess the effect of aging on the circadian system of this primate, we recorded the circadian and daily rhythms of locomotor activity of mouse lemurs of various ages. We also examined age-related changes in the daily rhythm of immunoreactivities for vasoactive intestinal polypeptide (VIP) and arginine-vasopressin (AVP) in suprachiasmatic nucleus neurons (SCN), two major peptides of the biological clock. Compared to adult animals, aged mouse lemurs showed a significant increase in daytime activity and an advanced activity onset. Moreover, when maintained in constant dim red light, aged animals exhibited a shortening of the free-running period compared to adult animals. In adults, AVP immunoreactivity (ir) peaked during the second part of the day, and VIP ir peaked during the night. In aged mouse lemurs, the peaks of AVP ir and VIP ir were significantly shifted with no change in amplitude. AVP ir was most intense at the beginning of the night; whereas, VIP ir peaked at the beginning of the daytime. A weakened oscillator could account for the rhythmic disorders often observed in the elderly. Changes in the daily rhythms of AVP ir and VIP ir may affect the ability of the SCN to transmit rhythmic information to other neural target sites, and thereby modify the expression of some biological rhythms.     

Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate,the grey mouse lemur

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months’ supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety.     

Impaired Control of Body Cooling during Heterothermia Represents the Major Energetic Constraint in an Aging Non-Human Primate Exposed to Cold

Daily heterothermia is used by small mammals for energy and water savings, and seems to be preferentially exhibited during winter rather than during summer. This feature induces a trade-off between the energy saved during daily heterothermia and the energy cost of arousal, which can impact energy balance and survival under harsh environmental conditions. Especially, aging may significantly affect such trade off during cold-induced energy stress, but direct evidences are still lacking. We hypothesized that aging could alter the energetics of daily heterothermia, and that the effects could differ according to season. In the gray mouse lemur (Microcebus murinus), a non-human primate species which exhibits daily heterothermia, we investigated the effects of exposures to 25 and 12°C on body composition, energy balance, patterns of heterothermia and water turnover in adult (N = 8) and aged animals (N = 7) acclimated to winter-like or summer-like photoperiods.Acclimation to summer prevented animals from deep heterothermia, even during aging. During winter, adult animals at 12°C and aged animals at 25°C exhibited low levels of energy expenditure with minor modulations of heterothermia. The major effects of cold were observed during winter, and were particularly pronounced in aged mouse lemurs which exhibited deep heterothermia phases. Body composition was not significantly affected by age and could not explain the age-related differences in heterothermia patterns. However, aging was associated with increased levels of energy expenditure during cold exposure, in concomitance with impaired energy balance. Interestingly, increased energy expenditure and depth of heterothermia phases were strongly correlated.In conclusion, it appeared that the exhibition of shallow heterothermia allowed energy savings during winter in adult animals only. Aged animals exhibited deep heterothermia and increased levels of energy expenditure, impairing energy balance. Thus, an impaired control of the heterothermic process induced high energy costs in the aging mouse lemur exposed to cold.     

The effects of N-methyl-N'-nitro-N-nitrosoguanidine on KB cells. II. Cell sensitivity to the lethal effect of the drug as a function of the cell age and of the nature of the culture medium

We have tested the sensitivity of KB cells to the lethal effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), measured as cell loss within the 20-h period following a 1-h drug treatment, as a function of culture age and of the medium in which treated cells were incubated after elimination of MNNG. We showed that KB cell sensitivity to the lethal effect of the drug decreased with time after seeding when the treated cells were post-incubated in drug-free medium conditioned by untreated cells of the same age as treated ones but not when they were post-incubated in fresh drug-free medium. This difference was due in part to the fact that the conditioned medium had acquired with time a protective activity for treated cells and in part to an increased competence of aging cells to be protected by this medium. By post-incubating treated stationary cells sequentially in both media, we showed that a brief (15 min) post-incubation of the cells in fresh medium was sufficient to trigger cell death even if the cells were afterwards transferred to conditioned medium. In contrast, long post-incubation in fresh medium did not cause cell death if the cells were first post-incubated in conditioned medium for about 3 h. We conclude that: the medium acted on cell sensitivity to the lethal effect of MNNG through its growth regulatory ability; quiescent cells were less sensitive to the drug than growing cells; the sensitive phase of the cell was located before S; cell hypersensitivity might be due to deficient repair of cellular lesions rather than to increased lesion formation.     

Micro-MRI Study of Cerebral Aging: Ex Vivo Detection of Hippocampal Subfield Reorganization,Microhemorrhages and Amyloid Plaques in Mouse Lemur Primates

Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon''s horn. We show that both dentate gyrus and Ammon''s horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon''s horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.     

Are Cytochrome P450 CYP2C8 and CYP2C9 Polymorphisms Associated with Ibuprofen Response in Very Preterm Infants?

Background

Patent ductus arteriosus (PDA) in extremely preterm infants remains a challenging condition with conflicting treatment strategies. Ibuprofen is currently used to treat PDA with ductal closure failure rate up to 40%. We test the hypothesis that cytochrome P450 CYP2C8/2C9 polymorphisms may predict ibuprofen response.

Methodology/Principal Findings

We studied extremely preterm neonates with haemodynamically significant PDA and treated with ibuprofen. One or two variant CYP2C8 and/or 2C9 alleles were found in 17% of the population, most of them were from Caucasian ethnicity (67–74%). Response to ibuprofen and clinical course of infants carrying variants CYP2C8 and CYP2C9 were similar. Comparing infants with wild type or variant CYP2C8 and CYP2C9 genotypes, response rate to ibuprofen was significantly higher in wild type than in mutated carriers in univariate analysis (73% versus 52%, p = 0.04). Comparing responders (ductus closure; n = 75) and non-responders (surgical ligation; n = 36), the only two factors significantly associated with the response to ibuprofen using multivariate analysis were higher gestational age and non Caucasian ethnicity but not CYP2C polymorphism.

Conclusions

CYP2C polymorphism was not associated with PDA response to ibuprofen and this factor appears not appropriate to optimize the ductal closure rate by modulating ibuprofen dosing strategy. This study points out the role for ethnicity in the interindividual variability of response to ibuprofen in extremely preterm infants.     

Aging and biological rhythms in primates

All living organisms exhibit rhythmic activities in a wide variety of endocrine and behavioural parameters. These biological rhythms are endogenously generated by a circadian clock, and they are entrained by cyclic variations of environmental factors called synchronizers. Aging is associated with changes in amplitude and temporal organization of many daily and seasonal rhythms. In humans, daily rhythms of sleep, thermoregulation and hormonal secretion are severely altered with aging. Except in humans, studies on primates are scarce. However, age-related effects on biological rhythms are relatively consistent among primate species studied to date, including humans. Therefore, non human primates are of valuable use for such investigations. Most studies have been performed on the Rhesus macaque (longevity 35-40 years) and on the gray mouse lemur (longevity 10-12 years). Like in humans, the rest-activity rhythm becomes fragmented in aged primates, and shows an increased activity during the resting period. Aging induces a decrease in amplitude of the body temperature rhythm and an increase in energy consumption. Various hormonal secretions exhibit a decrease with aging, but the rhythmic components of these declines have not always been depicted. Moreover, changes (amplitude or phase) in daily variations depended of the hormonal secretion tested. Taken together, these results suggest that the biological clock in the brain would be a primary target of aging. The main central clock is located in the suprachiasmatic nucleus of the hypothalamus whose endogenous oscillations are entrained by light. In this brain structure, cellular function and sensitivity to light show drastic changes with age in the mouse lemur. The precise knowledge of age-related alterations of biological rhythms in primates can have important consequences on the development of new treatments to maintain or restore biological rhythmicity in the elderly.