Research
Human blood and CSF factors provoking accelerated brain aging
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. 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 (Science, 2014). 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 and its blood levels are linked to a healthy or disease status: increase of GDF11 via systemic injections provokes multiple beneficial effects and at the same time, calorie-restricted mice show increased levels of GDF11 together with a multitude of beneficial effects, as it is well known (Aging Cell, 2020). In addition, circulating levels of GDF11 were found to be lower in patients with major depressive disorder (MDD) compared to healthy individuals, and fluctuations in GDF11 levels mirrored changes in disease status (Nature Aging, 2023).
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​Current focus: We are now using large-scale proteomics and aptamer screens to identify blood and CSF factors responsible for aging and age-related diseases in humans.
Brain health and longevity pathways in the naked mole rat
The naked mole rat is a unique model of exceptional longevity and resistance to age-related diseases. Despite its small size, it can live over 30 years—far longer than other rodents—while maintaining high physiological function throughout its lifespan. Remarkably, naked mole rats show a near absence of cancer, minimal cognitive decline with age, and sustained proteostasis and DNA repair mechanisms. Their resistance to hypoxia, low incidence of cardiovascular and neurodegenerative diseases, and stable metabolic function make them a valuable model for studying mechanisms of healthy aging and disease resistance.
Current focus: We are investigating genetic and molecular pathways that are unique in this animal model in order to identify targets for brain health and longevity.
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GDF11 biotherapy
GDF11 is a circulating blood factor recently implicated in the aging process. Our previous work identified novel and pleiotropic roles for this factor in aged organisms. At the organismal level, we demonstrated that GDF11 acts as a calorie-restriction mimetic, inducing weight loss independently of anorexia. Mechanistically, this effect is mediated by the stimulation of adiponectin secretion in white adipose tissue (Aging Cell, 2020). At the central nervous system (CNS) level, we showed that GDF11 treatment can attenuate depressive-like behaviors and improve memory deficits in aged mice via autophagy- and mTOR-dependent pathways. In a preclinical model of depression—using chronic corticosterone treatment in young mice—GDF11 administration also reduced depression-like symptoms. In patients with major depressive disorder (MDD), circulating levels of GDF11 were found to be lower than in healthy individuals, and fluctuations in GDF11 levels mirrored changes in disease status (Nature Aging, 2023).
Current focus: We are currently investigating the potential of GDF11, a naturally occurring protein, as a biotherapeutic agent, while also exploring the molecular mechanisms underlying its action.
Aging-like mechanisms in brain disorders
Brain aging and depression share several common features at the molecular, cellular, and functional levels. Both are associated with increased inflammation, impaired neurogenesis, and synaptic dysfunction, particularly in regions such as the hippocampus and prefrontal cortex. Dysregulation of stress-response systems, including the HPA axis, and alterations in neurotransmitter signaling—especially serotonin and dopamine—are also frequently observed. Additionally, reduced neuroplasticity and changes in energy metabolism contribute to cognitive decline and mood disturbances seen in both conditions. We previously showed that GDF11 can restore both of these impairments. These overlapping mechanisms suggest that aging and depression may reinforce one another and share therapeutic targets.
Current focus: We are investigating these shared molecular pathways at the cellular, molecular and behavioral level, as well as possible common therapeutic targets.