Geroprotection By Synergistic Anti-Aging Interventions

The western world we know is subject to a demographic shift towards overaging. Senescence is closely linked to physiological decline and an increase in the prevalence of age-related diseases, including diabetes type II, cardiovascular and neurodegenerative disorders, which all result in chronic illness and frailty in our seniorities. In recent years considerable effort has been undertaken to expand lifespan e.g. through elaborate dietary regimens, but likewise promotion of well-being during that extra lifetime has largely been neglected. Therefore it is of utmost socio-economic interest to develop strategies that enhance healthspan and combat senescence in a convenient way. Surprisingly, combinatory treatment strategies to extend healthspan have not been systematically investigated so far. Therefore we propose the screening for synergistic geroprotectors - substances that slow or delay aging, repair age-associated damage, and therefore extend healthspan. We will focus on already known inducers of autophagy, a cellular self- cleaning process that is activated upon fasting as an anti-aging regimen, and combine them to achieve surplus benefit. When administered alone, many of these substances display undesirable adverse effects due to their relatively high dosage. However, when applied in combination with a second autophagy- inducer, we expect reduced dosage and increased efficacy via their influence on parallel, compensatory cellular pathways. We will strive for a potent combinatory approach by screening fruit flies for age-related healthspan parameters, such as mobility, sleep and memory performance. Major influences on cellular pathways at protein- and metabolism-levels will be determined by targeted mass spectrometry and confirmed for their causality with the help of specific genetically engineered fruit flies. The most prominent combinatory intervention will be further tested in a pre-clinical mouse model, and its beneficial impact as geroprotector will be evaluated using different behavioral assays (muscle strength, coordination and memory). We plan to decipher systemic and organ-specific changes (e.g. inflammation and stress response) in order to find so far unidentified molecular key players of synergistic healthspan extension. With our approach, we expect to achieve three goals: (i) determining subcellular changes and conserved hallmarks of aging, (ii) finding synergistic treatments that improve the current efficacy of health- promoting interventions and (iii) reducing the effective dose for the most common anti-aging compounds to limit unwanted side-effects. Within the scope of this proposed project we will be able to extend our in- depth knowledge about aging and senescence, and at the same time will provide great opportunity for unrestricted quality of life into advanced old age.