Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

// Hanadie Yousef 2, 5 , Michael J. Conboy 1 , Adam Morgenthaler 1 , Christina Schlesinger 1 , Lukasz Bugaj 1 , Preeti Paliwal 1 , Christopher Greer 1 , Irina M. Conboy 1 , David Schaffer 1, 3, 4 1 Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA 2 Department of Molecular and Cellular Biology, UC Berkeley, Berkeley, CA, USA 3 Department of Chemical and Biomolecular Engineering, UC Berkeley, Berkeley, CA, USA 4 Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, CA, USA 5 Current address Stanford University, Department of Neurology and Neurological Sciences Correspondence to: David Schaffer, e-mail: [email protected] Irina M. Conboy, e-mail: [email protected] Keywords: aging, stem cell microenvironment, neurogenesis, TGF-β signaling, myogenesis Received: March 03, 2015      Accepted: April 24, 2015      Published: May 06, 2015 ABSTRACT Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.