Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Abstract

SummaryBone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

“…To study the role of Ash1l in MSCs regulation, we start with exploring whether it participates in bone loss diseases and the relationship between bone mass and Ash1l as well as H3K4me3. We used animal models of aging and OVX to induce age-related osteoporosis and estrogen deficiency-mediated postmenopausal osteoporosis respectively, both of which have been widely used to mimic the molecular pathogenesis of osteoporotic bone loss [27][28][29]. We compared the bone mass of femurs in 2-and 24-months-old mice with micro-CT analysis.…”

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

“…On the other hand, positive effects of rapamycin have been found in cancellous bone of old rats and mice. (95,96) Rapamycin also attenuates alveolar bone loss in old female C57BL6/JNia mice. (97) Administration of everolimus, another mTOR inhibitor, reduces the loss of bone mass in the ovariectomy model due to an inhibitory effect on bone resorption.…”

“…These findings implicate a decline in mTORC2 activity in age‐related osteoporosis. On the other hand, positive effects of rapamycin have been found in cancellous bone of old rats and mice . Rapamycin also attenuates alveolar bone loss in old female C57BL6/JNia mice .…”

“…Unknown Mice with deficient autophagy in the osteoblast lineage have low bone mass turnover (58,60) Unknown Deregulated nutrient sensing Skeletal content of IGF1 and IGFBP-5 declines after the second decade of life (66)(67)(68) Rictor, a specific component of mTORC2, decreases with aging in murine osteoblasts (93,94) Reductions in serum IGF1 after 5 months of age in mice decrease cancellous bone mass (74)(75)(76) Mice lacking Sirt1 in different bone cell populations exhibit low bone mass (81) Pharmacological or genetic inhibition of mTORC1 attenuates the loss of bone with age (95,96,100) Caloric restriction or Sirt1 stimulation attenuates skeletal aging (110,113,114,(117)(118)(119) Deletion of FoxO1, FoxO3, and FoxO4 in the osteoblast lineage increases bone mass throughout life (82) Mitochondrial dysfunction ROS increases in murine bone (127,128) Sod1 -/mice have low bone mass (137) Deletion of Sod2 in osteoblasts/osteocytes decreases bone mass (138) Inhibition of mitochondrial ROS production in cells of the mesenchymal lineage attenuates skeletal aging (140) Cellular senescence Cellular senescence increases in myeloid cells, osteoprogenitors, and osteocytes (35,174,175) Unknown Genetic ablation of p16 Ink4a -expressing cells or pharmacological approaches using senolytics or senomorphics in old mice improves bone mass (176)…”

Save your gut save your age: The role of the microbiome in stem cell ageing

“…In human mammary epithelial cells (HMEC), old progenitors demonstrated the reduced tendency of differentiation from HMEC to myoepithelial cells owing to impairment of Hippo pathway transducers Yes‐associated protein (YAP) and transcriptional co‐activator with a PDZ‐binding domain (TAZ) . In agreement with HMEC, dysfunctions of autophagy in bone marrow‐derived mesenchymal stem cells result in accelerating ageing as exemplified by diminishing osteogenic differentiation and proliferation capacity, whereas autophagy activator rapamycin antagonizes the autophagy malfunction‐provoked senescence …”