Autophagy Upregulation in Bone Marrow Stromal Cells Extends Life in Mice – Fight Aging!
Autophagy is the name given to the collection of processes that recycle damaged and excess proteins and structures in the cell. It encompasses mechanisms by which these recycling targets are first identified, then flagged, and finally transported to a lysosome where they are broken down. Upregulation of autophagy has been demonstrated to improve health and slow aging in a range of laboratory species, using a range of different strategies. Mild stress such as that provided by calorie restriction is known to upregulate autophagy, and many of the approaches discovered to date mimic some aspect of the calorie restriction response. Administration of rapamycin, for example, inhibits mTOR signaling to manipulate nutrient sensing in a favorable way.
In today’s open access paper, researchers show that targeted upregulation of autophagy in bone marrow progenitor cell populations in aged mice can improve health very broadly, including reductions in inflammation. The actual intent was to slow the loss of bone mineral density that occurs with age, and the intervention achieves this goal as well. Further, the mice lived longer, but when this outcome occurs as a result of manipulating stress response mechanisms there is good reason to think that the degree of extended life in humans will be much smaller than that demonstrated in mice. Plasticity of longevity in response to low calorie intake is an adaptation to reduce the impact of seasonal famine, so only short-lived species exhibit relatively large changes in life span.
Bone marrow stromal/stem cells (BMSCs) are generally considered as the common progenitors for both osteoblasts and adipocytes in bone marrow, and have been shown to have great potential for clinical application. However, their number and function decline with aging, especially the preferential differentiation of aged BMSCs into adipocytes rather than osteoblasts is reasonably accepted as a leading cause of senile osteoporosis (SOP), which is characterized by increased bone marrow fat accumulation and decreased bone loss. Thus, the balance between osteogenic and adipogenic lineage commitment of BMSCs is essential for bone homeostasis.
Despite the fact that the mechanisms under which the lineage shift occurs in aged BMSCs are not fully clear, accumulated studies have showed that diversity strategies for BMSCs rejuvenation are of benefits for bone quality and even healthspan improvement. For example, modification of transcription factors, epigenetics, and autophagy that enhanced osteogenesis and decreased adipogenesis of BMSCs alleviated SOP in mice. The latest evidence uncovered that premature aging of skeletal stem/progenitor cells caused bone loss. Therefore, it is assumed that stimulation of bone formation by BMSCs rejuvenation in vivo is an effective and attractive strategy for age-associated bone loss.
Transcription factor EB (TFEB) is a key transcriptional regulator of autophagy and lysosomal biogenesis. Emerging discoveries demonstrated that TFEB overexpression promoted longevity and reduced the burden of diseases, holding great promise as a therapeutic strategy for multiple age-associated diseases. Regulation of TFEB has been shown to control the activities of osteoblasts and osteoclasts, the two main cells playing in the coupling of bone remodeling for homeostasis, implying its potential use in osteoporosis prevention. However, little is known about the relationship between TFEB activities and osteoporosis. As precursors of bone lineage cells, BMSCs directly contribute to bone remodeling by differentiating into osteoblasts, but how and to what extend TFEB regulates fate decision of aged BMSCs in bone marrow is still unclear.
In this study, we synthesized a novel small molecule compound (named “CXM102”) that could promote autophagy activities in aged BMSCs via enhancement of TFEB nuclear translocation, leading to senescence rejuvenation and bone anabolic effects in middle age mice. Additionally, low dose and long-term administration of CXM102 showed better benefits for healthspan than rapamycin in mice, including extended lifespan, reduced serum levels of inflammation, less lipid droplets and fibrosis in organs. Our results demonstrated that CXM102 could significantly counteract aberrant lineage allocations of aged BMSCs, alleviate osteoporotic bone loss, increase healthspan and longevity of middle age mice.
