Physiological Consequences of Aging

Malgorzata Oklejewicz (Erasmus MC) 
Yvonne Rijksen (Erasmus MC) 

The increase in life span in Western societies is accompanied with an increased incidence of age-related diseases (e.g. diabetes, atherosclerosis, neurodegeneration) that affect quality of life and impinges on health care demands. Evidently, the development of potential pharmaceutical and lifestyle intervention strategies that allow “healthy aging” require insight in the mechanism of aging and etiology of age-related disorders.

Aging has been defined as the progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death and, as portrayed in the Free Radical Theory of Aging, is caused by reactive oxygen species molecules (e.g. metabolic byproducts) that damage cellular components. Since DNA is a target for oxidants, it is not surprising that DNA damage and repair mechanisms have recently emerged as important factors in the process of aging. As energy metabolism (generating ROS) and detoxification processes (neutralizing ROS) are adjusted to the light-dark cycle by an internal body clock it also may not come as a surprise that a defective circadian clock results in accelerated aging, suggesting that, like DNA repair, the circadian system can be considered as an anti-aging factor. On the other hand, circadian behavior and molecular clock performance loses robustness with progressing age.

Thus far, the effect of aging on the circadian core oscillator and its ability to entrain to light on the one hand, and aging-associated changes in the robustness of circadian output parameters on the other hand, have not been examined in a systematic fashion. We are analyzing the spatio-temporal clock gene and protein expression in the SCN and peripheral tissues of young and old wild type and prematurely aging DNA repair deficient mice. Particularly, we are using SCN-specific DNA repair-deficient animals to study the effect of accelerated aging of the master clock in time and the consequence for organismal performance. Biological endpoints investigated include behavioral parameters (wheel running activity, light resetting), hormonal signaling (including the DNA damage induced survival response), aging markers, along with a detailed histopathological analysis. Studies also include transcriptome profiling of the SCN and liver at various ages. The results obtained will elucidate the vulnerability of the circadian system to ageing, as well as its involvement in the ageing process itself, and might provide a novel therapeutic approach to healthy ageing via manipulation of the circadian timing system.