title: Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal.
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.
authors.affiliation: Department of Molecular and Cellular Biology, UC Berkeley, Berkeley, CA, USA.|Current address: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: Hanadie
authors.initials: H
authors.lastname: Yousef
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Conboy
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Morgenthaler
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Schlesinger
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Bugaj
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Paliwal
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Greer
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.
authors.forename: Irina M
authors.initials: IM
authors.lastname: Conboy
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), UC Berkeley, Berkeley, CA, USA.|Department of Chemical and Biomolecular Engineering, UC Berkeley, Berkeley, CA, USA.|Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schaffer
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000187:drug effects*; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D016212:Transforming Growth Factor beta
keywords: Gerotarget; TGF-β signaling; aging; myogenesis; neurogenesis; stem cell microenvironment