Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic GDF11 triggers a calorie restriction-like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, GDF11 could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders. K E Y W O R D Sadiponectin, aging, calorie restriction, GDF11, heterochronic parabiosis, rejuvenation | 9 of 11 KATSIMPARDI eT Al. GDF11 (Peprotech, was dissolved in water, further diluted according to the manufacturer's instructions, and injected at a concentration of 1 mg/kg. Control mice (young or aged) were injected with equivalent volumes of saline. Injection concentration was chosen based on a pilot study with three different concentrations (0.1, 0.5, and 1.0 mg/kg) where consistent weight loss and brain rejuvenation were observed upon 1 mg/kg GDF11 administration. The half-life of GDF11 at these concentrations was found to be of 12 hr. | GDF11 administration

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