Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

Abstract

Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

“…The fact that systemic administration of GDF11 induced healthy weight loss as early as 1 week after treatment and subsequently reached a plateau comes to accordance with previous reports (Ozek et al, ; Poggioli et al, ). During and after the treatment, all mice were healthy and displayed no signs of cachexia or frailty contrary to previous reports (Egerman et al, ).…”

“…Subsequently, other reports argued that GDF11 was positively associated with aging, cachexia, and inhibition of muscle regeneration in aged mice (Egerman et al, ; Harper et al, ; Jones et al, ), while different studies showed a beneficial role for GDF11 in the periphery (Poggioli et al, ; Su et al, ; Walker et al, ). In the central nervous system, GDF11 was also shown to be neuroprotective for neurovascular recovery and neurogenesis (Anqi, Ruiqi, Yanming, & Chao, ; Ma et al, ; Ozek, Krolewski, Buchanan, & Rubin, ; Schafer & LeBrasseur, ; Zhang et al, ).…”

“…While systemic administration of recombinant GDF11 protein induced a rejuvenating effect on the brain by increasing neurogenesis and vascular remodeling, GDF11‐injected aged mice also became lean (Katsimpardi et al, ; Ozek et al, ; Poggioli et al, ). This led us to hypothesize that the rejuvenation effect of GDF11 may result from a concerted action of this molecule on whole‐organismal physiology and that this interesting protein may be a rejuvenation mechanism coupling CR and heterochronic parabiosis.…”

Rejuvenating the blood and bone marrow to slow aging-associated cognitive decline and Alzheimer’s disease

“…Plasma transfer experiments demonstrating rejuvenation following intravenous delivery of a relatively small volume of young plasma or serum into old mice (100-175 μl, 6-10 times over 2-4 weeks) 5,6,11,12 suggest that supplementation with youthful factors may be sufficient to promote cognitive health, both during healthy aging and in neurodegenerative disease. Systemic administration of Growth Differentiation Factor 11 (GDF11) increased the number of neural stem cells and improved vascular remodeling in the subventricular zone and hippocampus of aged mice 14,15 . GDF11 may not cross the blood-brain barrier but instead impact the brain parenchyma by enhancing vascular endothelial growth factor (VEGF) secretion by brain vascular endothelial cells 15 , thereby stimulating both angiogenesis and neurogenesis 16 .…”

“…Systemic administration of Growth Differentiation Factor 11 (GDF11) increased the number of neural stem cells and improved vascular remodeling in the subventricular zone and hippocampus of aged mice 14,15 . GDF11 may not cross the blood-brain barrier but instead impact the brain parenchyma by enhancing vascular endothelial growth factor (VEGF) secretion by brain vascular endothelial cells 15 , thereby stimulating both angiogenesis and neurogenesis 16 . THBS4 and SPARCL1 may also be beneficial 9 if these factors are capable of crossing the blood-brain barrier to promote synapse formation and function.…”