Nutraceuticals have sex-dependent positive effects on healthy ageing in murine models

Introduction Human lifespan has been rising in developed countries however this phenomenon has not been paralleled by an increase in disease-free life expectancy (healthspan). In this context, although great efforts are constantly put through to develop novel target-specific drugs, aimed at alleviating age-related frailty, the occurrence of multiple side effects do not render them the best choice to improve overall healthspan. The use of nutraceutical compounds show many advantages in terms of biosafety, acceptance by the patients and economy. Thus, the interest of scientific community is growing in this field of research with the main aim to characterize the anti-ageing properties and to shed light to the mechanisms of action of natural compounds. Aim The present study was aimed at investigating the effects of a nutraceutical compound, the ACD-0503, on the health phenotype in a murine model of physiological ageing. Methods Two different doses of ACD-0503 (low dose - 50 mg/Kg - and high dose - 500 mg/Kg) were administered to 3- and 24-month-old mice through drinking water for 52 days. Following 2 weeks on the nutraceutical treatment a thorough characterization of motor functions and physical strength, metabolic as well as cognitive and emotional profile was carried out. Results ACD-0503 improved several aspects that are important for the promotion of healthy ageing, acting in an age-, sex- and dose-dependent fashion. More in detail, ACD-0503 high dose was effective in buffering the age-related decline in old male mice since it improved motor function (Beam Walking) and glucose homeostasis (Insulin Sensitivity Test) in addition to the HDL/LDL cholesterol ratio, an index of lower cardiovascular risk. By contrast, aged females treated with both doses of ACD-0503 showed a trend to spend more time in the target zone during the Morris Water Maze Test, suggesting improved memory retention compared to controls. By contrast, only ACD-0503 low dose improved muscle strength (Grip Strength Test) while worsening glucose homeostasis, as assessed both in the Insulin Sensitivity and in the Glucose Tolerance tests. Currently, metabolomic and transcriptomic analysis are in progress on central and peripheral tissues to assess potential underlying mechanisms. Conclusions Overall, these findings indicate that ACD-0503 exerts promising pro-healthspan effects, probably via its anti-oxidant activity, although further data are required to characterise the most important pathways affected by ACD-0503 and to better understand the age, dose and sex differences observed in this study. In particular, one important conclusion is that data obtained in males cannot be immediately extrapolated to female subjects, raising a note of caution for the use of nutraceutical compounds in the general population. - Support: H2020 AwE (grant N. 633589).