Systemic factors mediate reversible age-associated brain dysfunction.
Brain function declines in aging mammals. Recent work has identified dysregulation of key blood-borne factors whose altered expression during aging diminishes brain function in mice. Increased C-C motif chemokine 11 (CCL11) expression with aging is detrimental to brain function. On the other hand, plasma levels of the trophic factor growth/differentiation factor 11 (GDF11) decrease with aging. Restoration of youthful levels of GDF11 by injection partially restores brain function and neurogenesis by improving endothelial cell function and vasculature. Moreover, GDF11 has a rejuvenative effect on cardiac and skeletal muscle. Decreased type II interferon (IFN-II) and increased type I interferon (IFN-I) signaling during aging at the choroid plexus (CP), which constitutes the brain-cerebrospinal fluid barrier (B-CSF-B), negatively effects brain function. Blood from young mice contains factors that restore IFN-II levels. IFN-II is required for maintenance of the CP, and low IFN-II levels are associated with decreased cognitive abilities. IFN-I levels appear to drive increased CCL11 expression through the CSF. Blood from young animals does not restore IFN-I levels. However, injecting anti-interferon-α/β receptor (IFNAR) antibodies into the CSF inhibits downstream IFN-I gene and protein expression and decreases expression of CCL11, partially restoring neurogenesis and cognitive function. These results suggest that IFN-I plays a critical role in increasing CCL11 during aging of the brain. An emerging theme is that aging-associated loss of function in mammals may involve a set of defined, potentially reversible changes in many tissues and organs, including the brain, permitting development of potential rejuvenative therapies.
Panorama Research Institute and Regenerative Sciences Institute , Sunnyvale, California.
Andrew R
AR
Mendelsohn
James W
JW
Larrick
D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D054413:Chemokine CCL11 / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism; D003071:Cognition; D016207:Cytokines / Q000378:metabolism; D055412:Growth Differentiation Factors / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal; D055495:Neurogenesis; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction
D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D016207:Cytokines; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma