Researchers here provide evidence for increased autophagy, achieved via targeting mTOR to mimic some of the response to calorie restriction, to improve stem cell function in old mice. As a result some of the loss of bone mass and strength that occurs with age was reversed. Autophagy is the collection of maintenance processes responsible for clearing out broken proteins and structures in the cell, but like most of our biochemistry it declines in effectiveness with age. Increased levels of autophagy have been shown to be necessary for the gains in health and longevity provided by calorie restriction in short-lived species, and mTOR is one of the regulatory genes through which the calorie restriction response works. It is not surprising to find that inhibiting mTOR improves autophagy, and thus also improves the function of many systems in the body that benefit from having less garbage and breakage in their cells.
The overall slowing of aging produced by calorie restriction touches on all aspects and measures of aging, and that includes a reduction in the usual rate of decline in stem cell activity in old age. So the study here illustrates that calorie restriction, stem cell activity, autophagy, and mTOR all link together nicely. Unfortunately, we should not expect the same size of effect in humans as is observed in mice: calorie restriction is very good for health, but it certainly doesn't extend human life span by 40%, as is the case in mouse studies. This is generally the case for all longer-lived species, as the size of the life span increase produced by calorie restriction and its mechanisms under the hood scales down as life span scales up.
Mesenchymal stem cells (MSCs) are pluripotent cells that play crucial roles in tissue maintenance, repair, and regeneration. However, data suggest that beneficial functions of MSCs may become compromised with age; this is closely associated with age-related loss of repair and regenerative capacity of different tissues. Bone marrow-derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging.
Autophagy is a process in which cellular components such as proteins and damaged mitochondria are engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled in order to maintain cellular homeostasis. Autophagy has been widely studied as a mechanism for anti-aging effects and in alleviating age-related diseases. Recent studies have indicated that autophagy is required for maintaining the stemness and differentiation capacity of stem cells. It has been reported that autophagy is a crucial mechanism in the maintenance of the young state of satellite cells, and failure of autophagy causes declines in the number and function of satellite cells. Autophagy can protect BMMSCs from oxidative stress, which indicates that autophagy plays a protective role in cell aging. Conversely, autophagy also has been proven to be a requirement for maintenance of replicative senescence of MSCs. Therefore, whether and how autophagy regulates MSC aging remains unclear.
Bone marrow-derived mesenchymal stem cells have been regarded as the main source of osteoblasts for skeletal repair. It has been reported that degenerative changes of BMMSCs in humans and rodents during aging are associated with bone aging. Bone marrow-derived mesenchymal stem cells tend to partially lose their self-renewal capacity and differentiate into adipocytes instead of osteocytes with aging, which causes bone loss and fat accumulation. Our findings showed that aged BMMSCs had decreased osteogenesis, elevated adipogenesis and decreased proliferation compared with young BMMSCs; these results are in line with the previous findings.
We speculate that decreased autophagy in aged BMMSCs might be one of the causes of degenerative changes of aged BMMSCs, and bone loss by decreased autophagy could be a potential new mechanism of bone aging. The results of the manipulation of autophagy in both young BMMSCs and aged BMMSCs confirmed our speculations. As an autophagy inhibitor, 3-MA was used on young BMMSCs; the results showed that inhibition of autophagy not only reduced osteogenesis and promoted adipogenesis but also inhibited proliferation of young BMMSCs, which indicated that decreased autophagy could turn young cells into an aged state with degenerative properties. Meanwhile, the autophagy inducer rapamycin could partially convert aged BMMSCs to a young state by increasing osteogenesis, reducing adipogenesis and promoting proliferation. In summary, we conclude that activation of autophagy can restore degenerative properties of aged BMMSCs via regulating oxidative stress and p53 expression.