Today's open access paper links a number of different areas of research and development of interest. Firstly, that senescent cells accumulate with age to disrupt tissue structure and function with their inflammatory secretions. Secondly, that the innate immune cells known as microglia become overly active and inflammatory in the aging brain, and a growing body of evidence supports a significant role for these inflammatory microglia in the development of neurodegenerative conditions. Some of these inflammatory microglia are senescent. Thirdly, the stem cell therapies pioneered over the last thirty years, and the more modern use of extracellular vesicles such as exosomes derived from stem cell cultures, appear to largely produce benefits via a sustained reduction in chronic inflammation in older individuals. The transplanted cells do not tend to survive in large numbers, and it is a short burst of signaling following transplantation that produces months-long changes in immune behavior via its effect on native cells.
Because stem cell transplants work via a brief period of signaling, they also tend to work when human cells are transplanted into animals. Here, researchers show that one source of human stem cells for transplantation has positive effects on cognitive function in old mice. Using cell culture experiments, the researchers demonstrate that the signaling generated by stem cells has a senomorphic effect on harmful senescent microglia, meaning that it dampens the worst aspects of the senescent state and thereby improves cognitive function by reducing the ongoing harm done to the function of the brain. We might expect that extracellular vesicles derived from the same source as the stem cells used in this study to produce similar outcomes. The results reported here are in line with other studies in which senescent cells are removed, or their signaling is reduced via other means; senescent cells clearly actively maintain dysfunction in tissues, and matters improve when their are restrained or removed.
Microglia, the resident immune cells of the central nervous system (CNS), play a critical role in maintaining neural homeostasis by monitoring the CNS microenvironment, remodeling and pruning synapses, and clearing cellular debris through phagocytosis. Recent studies have identified a distinct subpopulation of microglia termed lipid droplet-accumulating microglia (LDAM), which exhibit a unique phenotype characterized by metabolic reprogramming, elevated oxidative stress, and heightened pro-inflammatory responses. These alterations disrupt microglial homeostasis, impair their ability to clear amyloid-beta plaques and tau protein aggregates, and contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD).
Lipid droplets (LDs) are lipid-rich organelles enveloped by a phospholipid monolayer, primarily composed of triglycerides and cholesterol esters. Under physiological conditions, the homeostasis of intracellular LDs is tightly regulated. However, under pathological conditions, this balance is disrupted, leading to lipid droplet accumulation and subsequent cellular dysfunction. Accumulating evidence shows that LD content in microglia and neurons increases with age. In microglia, LD enrichment is linked with a pro-inflammatory phenotype and exhibits reduced phagocytic capacity toward cellular debris and protein aggregates.
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons.
View the full article at FightAging
