Research Paper|Volume 12, Issue 9|pp 8049—8066

Growth differentiation factor-11 supplementation improves survival and promotes recovery after ischemic stroke in aged mice

Jacob Hudobenko¹, Bhanu Priya Ganesh¹, Jianjun Jiang², Eric C. Mohan³, Songmi Lee¹, Sunil Sheth¹, Diego Morales¹, Liang Zhu⁴, Julia K. Kofler⁵, Robia G. Pautler², Louise D. McCullough^1,⁶, Anjali Chauhan¹

¹Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
²Baylor College of Medicine, Houston, TX 77030, USA
³University of Connecticut Health Science Center, Farmington, CT 06030, USA
⁴Biostatistics and Epidemiology Research Design Core, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
⁵Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
⁶Memorial Hermann Hospital, Texas Medical Center, Houston, TX 77030, USA

Received: September 16, 2019Accepted: March 24, 2020Published: May 4, 2020

https://doi.org/10.18632/aging.103122

Copyright © 2020 Hudobenko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Growth differentiation factor (GDF) 11 levels decline with aging. The age-related loss of GDF 11 has been implicated in the pathogenesis of a variety of age-related diseases. GDF11 supplementation reversed cardiac hypertrophy, bone loss, and pulmonary dysfunction in old mice, suggesting that GDF11 has a rejuvenating effect. Less is known about the potential of GDF11 to improve recovery after an acute injury, such as stroke, in aged mice. GDF11/8 levels were assessed in young and aged male mice and in postmortem human brain samples. Aged mice were subjected to a transient middle cerebral artery occlusion (MCAo). Five days after MCAo, mice received and bromodeoxyuridine / 5-Bromo-2'-deoxyuridine (BrdU) and either recombinant GDF11 or vehicle for five days and were assessed for recovery for one month following stroke. MRI was used to determine cerebrospinal fluid (CSF) volume, corpus callosum (CC) area, and brain atrophy at 30 days post-stroke. Immunohistochemistry was used to assess gliosis, neurogenesis, angiogenesis and synaptic density. Lower GDF11/8 levels were found with age in both mice and humans (p<0.05). GDF11 supplementation reduced mortality and improved sensorimotor deficits after stroke. Treatment also reduced brain atrophy and gliosis, increased angiogenesis, improved white matter integrity, and reduced inflammation after stroke. GDF11 may have a role in brain repair after ischemic injury.