A three-drug combination extended lifespan in a group of nine old mice
A three-drug combination extended lifespan in a group of nine old mice
On 17 July, Irina Conboy's group published a study of DMA, a combination of dichloroacetate, metformin, and navitoclax. Treatment began at approximately 18 months of age. Median lifespan was 1002 days in the nine mice treated with DMA and 815 days in the nine control mice.
After injury or another form of stress, some cells stop dividing, remain in the tissue, and release inflammatory signals. These cells are called senescent cells. Navitoclax inhibits BCL-XL, a protein that supports the survival of both senescent cells and platelets. Platelets help stop bleeding by forming clots. The same protein is required for the survival of both senescent cells and platelets. At 18 hours after administration of 50 mg of navitoclax per kilogram of body weight, the platelet count was approximately one quarter of the control level.
The authors reduced the navitoclax dose to 5 mg per kilogram and added metformin and dichloroacetate. Metformin inhibits mitochondrial complex I, which is part of the cellular energy production system. Dichloroacetate helps direct pyruvate, a product of glucose breakdown, into the mitochondria. The authors tested the hypothesis that senescent and cancer cells are less able to switch between energy-producing pathways. If so, the two metabolic drugs would place these cells under stress and make them more sensitive to a low dose of navitoclax.
In cell cultures, DMA reduced ATP, the molecule that transfers energy within cells, almost to background levels in senescent connective tissue cells and MCF-7 breast cancer cells. Healthy connective tissue cells maintained their ATP levels. Adding ATP from an external source partially restored the survival of senescent cells. This partial restoration of survival supports a link between ATP depletion and cell death.
Viability did not decrease in human neural progenitor cells. It decreased by approximately 20% in human muscle cells and by 5% in liver cells. These cultures do not show which cells DMA affects in mouse organs.
Median lifespan was 187 days longer in the DMA group, and mean overall lifespan was 12% longer. Separate analyses of males and females could not reliably distinguish the effect of DMA from random variation because each subgroup contained only three to six animals. In the survival experiment, the authors tested the effect of the complete DMA combination. Control mice received a drug-free solution, and the experiment did not include separate groups for each component. The mice were followed until natural death. This differs from the Immorta Bio study, which measured survival after a toxic doxorubicin regimen in young mice. The authors did not measure the number of senescent cells in the organs of these mice. A single protein marker cannot provide such a map. The SenNet atlas showed that the set of senescence features varies with cell type and the cause of cellular aging. The survival data therefore apply to the DMA combination as a whole.
After DMA treatment, the platelet count was approximately 70% of the control level, but the authors could not distinguish this difference from random variation. This short test measured only platelet counts. In several animal models of pulmonary hypertension, which is elevated pressure in the blood vessels of the lungs, ABT-263 treatment was associated with the loss of senescence-marked cells lining the blood vessels and with impaired pulmonary vascular function. In the DMA study, the authors did not measure which cells the combination affected in mouse organs or how those effects changed organ function.