Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus

Abstract

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 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 age-associated alterations in mouse lemurs are delayed with CR and if RSV can mimic these effects.

Fig. 1

Experimental schedule during the first year of the RESTRIKAL study. Daily energy expenditure (DEE), water turnover (WTO), fat mass (FM) and fat-free mass (FFM) were assessed twice a year. Measurement of insulin-like growth factor type 1 (IGF-1) level and resting metabolic rate (RMR) were performed four times a year. Testosterone level analysis was performed three times a year, once in SD and twice in long days (LD) period. Locomotor activity was tested once a year at the end of the LD period during which the animals remain relatively active (w week)

Fig. 2

Effects of caloric restriction (CR) or resveratrol supplementation (RSV) on seasonal variations in percentage of calories ingested (CI) (a), body mass gain (b) and body mass plateaus (c). Data of the comparison of mean body mass gain during the short days (SD) and long days (LD) plateaus were log-transformed. Plateaus were calculated from weeks 13 to 19 for the SD period and weeks 38 to 44 for the LD period. ANOVA results are reported on the right side of the graphs, for treatment (Tr), photoperiod (P) or crossed effects (C) on the percentage of CI and body mass changes during the first year of CR or RSV supplementation compared to control feeding (CTL) in SD and LD animals (n = 13 for CTL group, n = 14 for CR group, n = 14 for RSV group). p in bold means value is significant and p in italic means value is not significant but shows a trend. Values are expressed as mean ± SEM

Fig. 3

Effects of photoperiod and treatment on body mass at the time of the experiment (a), fat-free mass (b), fat mass (c), total body water (d), water turnover (e), daily energy expenditure (f) and daily energy expenditure adjusted to body mass (g). ANOVA results are reported on the right side of the graphs, for treatment (Tr), photoperiod (P) or crossed effects (C) on body mass, fat-free mass, fat mass, total body water, water turnover and daily energy expenditure adjusted or not to body mass during the first year of caloric restriction (CR) or resveratrol (RSV) supplementation compared to control feeding (CTL) in short days (SD) and long days (LD) animals (n = 12 for each group). p in bold means value is significant and p in italic means value is not significant but shows a slight trend. Values of body mass, fat-free mass and fat mass are expressed in g; values of total body water are expressed in %; values of water turnover are expressed in g.day^–1.g^–1 of animal; values of daily energy expenditure are expressed in kJ.day^–1. All parameters are expressed as mean ± SEM

Fig. 4

Effects of photoperiod and treatment on resting metabolic rate. ANOVA results are reported on the graph, for treatment (Tr), photoperiod (P) or crossed effects (C) on resting metabolic rate changes during the first year of caloric restriction (CR) or resveratrol (RSV) supplementation compared to control feeding (CTL) in short days (SD) and long days (LD) animals (n = 13 for CTL group, n = 14 for CR group, n = 14 for RSV group). p in bold means value is significant. Values are expressed in ml O₂.h^–1.g^–0.67 as mean ± SEM

Fig. 5

Effects of treatment on daily spontaneous locomotor activity. ANOVA results are reported on the graph, for treatment (Tr) during the first year of caloric restriction (CR) or resveratrol (RSV) supplementation compared to control feeding (CTL) in long days (LD) animals only (n = 5 for CTL group, n = 9 for CR group, n = 7 for RSV group). Values are expressed in a.u. as mean ± SEM

Fig. 6

Effects of photoperiod and treatment on plasma insulin-like growth factor type 1 (IGF-1) level. Data were log-transformed for statistical analysis. ANOVA results are reported on the right side of the graph, for treatment (Tr), photoperiod (P) or crossed effects (C) on IGF-1 level changes during the first year of caloric restriction (CR) or resveratrol (RSV) supplementation compared to control feeding (CTL) in short days (SD) and long days (LD) animals (n = 11 for each group). p in bold means value is significant and p in italic means value is not significant but shows a slight trend. Values are expressed in ng/ml as mean ± SEM

Fig. 7

Effects of photoperiod and treatment on testis size (a) and testosterone level (b). ANOVA results are reported on the right side of the graphs, for treatment (Tr), photoperiod (P) or crossed effects (C) on testis size and plasma testosterone level during the first year of caloric restriction (CR) or resveratrol (RSV) supplementation compared to control feeding (CTL) in short days (SD) and long days (LD) animals (n = 12 for CTL group, n = 11 for CR group, n = 11 for RSV group). p in bold means value is significant. Values of testis size are expressed in a.u. and values of testosterone level are expressed in ng/ml. Both parameters are expressed as mean ± SEM