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.

TGF-β and NF-κB signaling pathway crosstalk potentiates corneal epithelial senescence through an RNA stress response

“…Cellular senescence can be induced by various stimuli and stress, including oxidative stress, DNA damage, metabolic insults, oncogene activation, and epigenetic changes [13–17]. Cumulative findings suggest that transforming growth factor-β (TGF-β) is also capable of inducing cellular senescence [17–21]. For instance, TGF-β has been shown to induce both replicative and premature senescence in epithelial cells and to suppress hTERT expression via a Smad3-mediated signaling pathway [22].…”

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood

“…The numbers of Ki67+ proliferating subgranular zone (SGZ) cells were quantified throughout the entire dentate gyrus (DG) of the hippocampus, as in ref. 8, where based on co-immunodetection of Sox-2, these Ki67+ SGZ cells are virtually all-neural stem cells. As shown in Fig.…”

“…One way to increase healthy longevity would be to rejuvenate the regenerative and repair capacity of aged tissues. Published work suggests restoring the circulatory environment of aged tissues back to a productive, young, composition may help to rapidly and broadly enhance the maintenance and repair of multiple old organs, combat degeneration and extend health span12345678.…”

“…Thus far, only heterochronic parabiosis has been shown to enhance myogenesis, hepatogenesis, bone regrowth, neurogenesis, cognition and the numbers of dendritic spines in old mice. Most importantly, the positive effects of heterochronic parabiosis are robust for muscle, lesser for liver and marginal for neurogenesis; and a significant inhibition of even young tissue stem cells by the aged circulatory milieu takes place24581115.…”

The Impact of Aging on Mechanisms of Mammalian Epimorphic Regeneration

“…Systemic pharmacological inhibition of TGF-β signaling improves neurogenesis and muscle regeneration in old mammals [20], suggesting a general age-related overactivation of TGF-β/BMP signaling. In contrast, growth differentiation factor GDF11/BMP11 has been identified as a rejuvenating factor for neuronal tissue, vasculature, cardiac and skeletal muscle; however, due to the high similarity of GDF11 to myostatin/GDF8, there are doubts about the specificity of these data [21].…”