Research Roundup: Metformin and Healthy Aging and More

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Metformin’s Implications for Healthy Aging

Metformin is the most widely prescribed drug for type 2 diabetes and pre-diabetes. But how the drug works in controlling blood sugar levels isn’t completely understood. Researchers from the Salk InstituteThe Scripps Research Institute and Weill Cornell Medical College found that the way the drug “switches” on or off various cellular processes may explain why the drug seems to extend health span and life span. The research was published in the journal Cell Reports.

“These results provide us with new avenues to explore in order to understand how metformin works as a diabetes drug, along with its health-span-extending effects,” said Reuben Shaw, co-corresponding author and director of Salk’s NCI-designated Cancer Center. “These are pathways that neither we, nor anyone else, would have imagined.”

Earlier research showed that metformin activated the AMPK pathway, which can stall cell growth and change metabolism in nutrient-scarce environments, which occurs in some cancers. Using a novel screening platform to study kinases, Shaw and his team found that metformin turns on many other kinases and pathways, many independent of AMPK. Two are Protein Kinase D and MAPKAPK2. They aren’t well understood, but are related to cellular stress, would may be associated with the health-span- and life-span-extending aspects of metformin.

“We never imagined these two kinases would have anything to do with metformin,” Shaw said. “The results broaden our understanding of how metformin induces a mild stress that triggers sensors to restore metabolic balance, explaining some of the benefits previously reported such as extended healthy aging in model organisms taking metformin. The big question now are what targets of metformin can benefit the health of all individuals, not just type 2 diabetics.”

How Your Cells Stay in Shape

Researchers have found that the health of cells is maintained by two types of movement. Some cellular compartments don’t have membranes, which wasn’t well understood, because those membranes were viewed as essential to holding a cell together. What recent research found was these compartments act as liquid droplets made of material that don’t mix. And in the nucleolus, inside the cell nucleus, they found that this kind of non-mixing tension causes movement that is involved in a kind of dance that helps maintain cellular health.

How Cancer Cells Grow and Spread in the Colon

Duke Cancer Institute investigators developed a technique to observe how stem cell mutations begin and metastasize throughout the colon. They utilized a molecular dyeing technique in a new way, tagging common colon cancer mutations in the stem cells to create what they are calling a “fluorescent barcode.” This allowed the stem cells to be visually tracked and provided insight into the dynamics of pre-cancerous behavior of the mutated cells.

Group of Prostate Cancer “Super Responders” Identified

Researchers discovered that a small number of men with advanced prostate cancer who had exhausted all other treatment options were “super responders,” and lived for two years longer than expected. The patients were being treated with Merck’s checkpoint inhibitor Keytruda (pembrolizumab). Although many patients responded well to the therapy, the study found that a small subpopulation that had mutations in genes involved in DNA repair appeared to be particularly responsive to the therapy. The study suggests that testing for PD-L1 alone wasn’t sufficient to determine which patients would respond best to checkpoint inhibitor therapy.

Possible Stem Cell Fix for Damaged Tendons

Tendon damage—tears and ruptures of the rotator cuffs, Achilles’ tendon or knee injuries—are notoriously slow to heal, if ever. This is largely because a buildup of scar tissue, but also because tendons have little blood flow. Researchers have identified tendon stem cell that may improve healing of tendon tissues. Both tendon stem cells and scar tissue precursor cells are stimulated by platelet-derived growth factor-A. But when tendon stem cells were engineered so they didn’t respond to the growth factor, only scar tissue and no new tendon cells form after injury. It’s possible that drugs could be developed that block the scar-forming cells and stimulate the tendon stem cells.

Possible New Approach to Treating Cystic Fibrosis

Although there are several approved drugs to treat cystic fibrosis (CF), there are not many effective anti-inflammatory and anti-infective treatments for CF patients. The main cause of death in CF is lung disease, driven by severe inflammation and chronic infection in the airways. One of the most aggressive bacterial infections in CF lungs also causes some immune cells to change their metabolism. This causes the cells to produce a protein that stimulates more inflammation. The research group used a small molecule called MCC950 to decrease levels of the protein in a CF laboratory model. It not only decreased inflammation but helped clear the lungs of bacteria.

New Insights into How the Brain Removes Waste Substances

Investigators identified a new pathway in the central nervous system that removes waste substances from the brain. It does so by creating corpora amylacea (CA), which are aggregates made by glycose polymerase. This has implications for neurodegenerative diseases. CA was first described in 1837 and are abundant in the brains of the elderly and in patients with Alzheimer’s, Parkinson’s, and Huntington’s diseases. The study concluded that some waste substances in the brain are removed by astrocytes, which store them as corpora amylacea. The CA appear to act as waste containers that are later removed from the nervous system.

 

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