Research over the last couple of decades has shown that aging is not an irreversible process as once thought, but instead is subject to manipulation. This plasticity of aging extends to a different degree for each organ, but we now know that there are ways to slow down and even reverse aging.

Genetic manipulation of well-studied pathways such as Sirtuins, mTOR and Insulin/IGF-1/FoxO, proves that a single gene can have a crucial role in determining lifespan and healthspan. Interestingly, it is also possible to increase lifespan and reverse aging by systemic manipulations, where changes in organismal physiology involve activation of metabolic and endocrine pathways. Calorie restriction (CR) is the most efficient systemic manipulation known to date to delay aging, increase longevity, improve metabolic fitness and rejuvenate the aged brain across species. Mechanistically, CR involves organismal metabolic changes and acts through all the aforementioned pathways, mTOR, Sirtuin1 and IGF-1 signaling.

Previously, we and others showed that infusion of young systemic factors in the aged organism can rejuvenate several organs, including those with low regenerative capacity, such as the brain. Muscle progenitor activity in aged mice was increased after exposure to young blood, leading to enhanced regeneration and reduced fibrotic responses. Age-related cardiac hypertrophy was decreased and the decline in pancreatic beta cell replication was reversed upon heterochronic parabiosis, suggesting that rejuvenation is possible regardless of the organ's regenerative capacity.

The fact that both young systemic factors and calorie restriction have very similar effects raised the interesting possibility that these two systemic manipulations could be interconnected and that some young systemic factors could act as CR mimetics. Indeed, we recently identified GDF11 as a CR-mimetic acting through stimulation of the white adipose tissue to trigger secretion of adiponectin.

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Moreover, we recently demonstrated that GDF11 has yet another beneficial role as it attenuates depression-like behavior and improves memory in aged mice via neuronal autophagy. Serum levels of GDF11 are inversely associated with depression in patients. 

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Our current projects focus on identifying pro- and anti-aging blood and CSF factors in human physiological and pathological aging, and deciphering their specific mechanisms of action in the brain.