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2015 ; 6
(14
): 11959-78
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Systemic attenuation of the TGF-? pathway by a single drug simultaneously
rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal
#MMPMID26003168
Yousef H
; Conboy MJ
; Morgenthaler A
; Schlesinger C
; Bugaj L
; Paliwal P
; Greer C
; Conboy IM
; Schaffer D
Oncotarget
2015[May]; 6
(14
): 11959-78
PMID26003168
show ga
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 ? (TGF-?) 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-? 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-?1 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 ?2 microglobulin (B2M), a component of MHC class I
molecules. These findings suggest that at high levels typical of aged tissues,
TGF-?1 promotes inflammation instead of its canonical role in attenuating immune
responses. In agreement with this conclusion, inhibition of TGF-?1 signaling
normalized B2M to young levels in both studied tissues.
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