Open AccessMolecular aging and rejuvenation of human muscle stem cells
Author(s) -
Carlson Morgan E.,
Suetta Charlotte,
Conboy Michael J.,
Aagaard Per,
Mackey Abigail,
Kjaer Michael,
Conboy Irina
Publication year - 2009
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.200900045
Subject(s) - rejuvenation , stem cell , microbiology and biotechnology , biology , chemistry , medicine , gerontology
Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short‐lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF‐β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen‐activated protein kinase (MAPK)/phosphate extracellular signal‐regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70‐year‐old humans, rendering them similar to cells from 20‐year‐old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways.