D-Galactose Affects Ageing Male and Female Brains Differently

A research study demonstrated in mice the biological relevance of gender in the effects of accelerated ageing caused by a chronic treatment of D-galactose, a sugar found abundantly in milk and to a lesser extent in fruits and vegetables.

The research study by the Universitat Autònoma de Barcelona (UAB) in collaboration with the University of La Laguna (ULL) demonstrates in mice the biological relevance of gender in the effects of accelerated ageing caused by a chronic treatment of D-galactose, a sugar found abundantly in milk and to a lesser extent in fruits and vegetables. At high doses, this substance accelerates ageing in males, affecting them at sensory and motor level and in their neuro-immuno-endocrine system, while females experience alterations in learning and their ability to register information about their surroundings and orientation. However, at low doses the treatment has positive effects, especially in males.

For almost two decades, chronic treatments with D-galactose have been used as a tool to create animal models of accelerated ageing. Their neurotoxicity is due to abnormal ROS accumulation, molecules proper of oxidative stress and AGEs, proteins or lipids which become glycated because of exposure to sugars, both related to the acceleration of the multisystem functional decline occurring during ageing. These D-galactose induced biological products are also involved in the development or deterioration of many degenerative diseases such as diabetes, arteriosclerosis, kidney diseases, infections and Alzheimer's disease.

"The difficulty in research with accelerated ageing models using D-galactose lies in the fact that its neurotoxicity effects at biochemical level do not always translate into or are observable as pathological symptoms at behavioral level. In the study we found convincing evidence of some of them and observed important differences between the males and females," says Dr. Lydia Giménez-Llort, lead researcher of the project.

Through a complete and multifunctional behavioral analysis, researchers examined the chronic effects of low (50 mg/kg) and high (100 mg/kg) doses of D-galactose in male and female mice aged 6 months -- the equivalent of 40 human years. Based on the results of twelve tests they assessed the sensory, motor, emotional and cognitive fields and also explored the effects on the neuro-immuno-endocrine system, decisive in pinpointing the vital capacity or biological age of individuals.

The results point to the existence of different sensitivity thresholds depending on the sex of the animal with regards to their functional capacity to meet the performance level required for certain tasks: D-galactose had pro-ageing effects at sensory and motor level and on the immuno-endocrine system in males, while in females it altered their motor performance and some learning processes as well as their spatial memory -- the ability to register information about their surroundings and orientation, which depends on the hippocampus and cerebellum.

"The most surprising results are found in the low doses of D-galactose, which seem to trigger positive effects in males, such as improved learning and memory, while in females the expected dose-response ratio continues, with deteriorated motor and spatial learning, although there are improvements in some aspects such as memory. These results point to the complexity of the effects at functional level, and therefore all of these observations open the door to new lines of research which can clarify all these underlying neuronal mechanisms and help to understand the vulnerability and differential protection observed," explains Dr. Rafael Castro, ULL researcher and co-author of the study.

"In the past few years, what is known as Gender-specific Medicine warns about the need and importance to research into sex and gender-specific aspects, as well as consider the age factor, having more knowledge in biology throughout a person's life and creating more personalized medicines. Our study demonstrates this need and reinforces the idea that the male and female genders must be considered two exceptional natural scenarios in which to study the biological, psychological, social and environmental roles, their functional interactions and their impact on the intercommunication of homeostatic networks, which guarantee a balance in health and are affected by diseases throughout their life cycle," Dr. Giménez-Llort highlights.

The research also contributes to gaining more in-depth knowledge in the study of biological and environmental determinants, as well as different lifestyles and habits at specific moments such as in mid-life, in which the ageing process gains speed and gradually reduces the organism's functional capacities, which begin to see a limitation in their biological anti-oxidant capacity to counteract imbalances caused by age.

Illustration: Rafael Castro Fuentes (ULL) and the UAB's researchers Lydia Giménez-Llort –left- and Raquel Baeta Corral.


Universitat Autònoma de Barcelona News Release (02/19/18)

Science Daily (02/19/18)

Abstract (The Journals of Gerontology: Series A, 2018.)