Five dissimilar ways to extend mouse lifespan (two drugs, a diet, and two genetic disruptions) converge on the same metabolic switch in the liver: it stops burning glucose and starts breaking down three amino acids, with glucagon giving the command
Five dissimilar ways to extend mouse lifespan (two drugs, a diet, and two genetic disruptions) converge on the same metabolic switch in the liver: it stops burning glucose and starts breaking down three amino acids, with glucagon giving the command
On September 19, the journal npj Aging published a paper by a University of Michigan group comparing the livers of mice whose lifespans are extended by acarbose and canagliflozin (diabetes drugs), caloric restriction, and two genetic disruptions: Snell dwarf mice and growth hormone receptor knockout mice (GHRKO). In all five models, the liver reduces the activity of glucose-degrading enzymes and increases the activity of enzymes that break down alanine, glutamine, and asparagine, with the hormone glucagon acting as the switch.
Before this work, the only known common feature of these five lifespan-extending methods was that all five suppress two intracellular pathways driving cell growth and division (MEK1-ERK and mTOR) and activate chaperone-mediated autophagy, the cell's mechanism for clearing damaged proteins. What happens further downstream was unknown: approaches that search for a signal across all genes and proteins of the liver had not found this connection, because stringent statistical filters discarded a weak but real signal together with the noise.
Richard Miller, one of the authors, recalled a similar trace in his own earlier data from these same mice: a hint of increased amino acid catabolism that had not passed the same filter. Rather than running another proteome-wide search, he and his colleagues directly measured the activity of specific liver enzymes: those that break down glucose and those that degrade alanine, glutamine, and asparagine into Krebs cycle intermediates, the cell's energy source.
The result was consistent across all five models. Enzymes that export glucose from the liver into the bloodstream were unchanged, meaning the liver switches only its own fuel without increasing sugar release into the blood. The authors reproduced the same enzymatic shift in ordinary mice with trametinib, a melanoma drug that blocks the MEK1-ERK pathway and has already added roughly a third to mouse lifespan when combined with rapamycin.
The authors tested this in liver cells in a dish: trametinib alone was not sufficient, and the enzymes did not shift. This means the liver receives the command from an external, hormonal signal. Glucagon emerged as the candidate: a hormone that normally drives the liver to release energy during fasting and low insulin. The authors administered a glucagon analogue both to cultured liver cells and to live mice over a 30-day course, and in both cases the enzymatic shift was reproduced. In Snell dwarf mice and GHRKO mice, the pancreas produces considerably more glucagon than in normal mice: in Snell dwarfs, its precursor rises 40- to 60-fold in both sexes, and this increase coincides with their longer lifespan. Canagliflozin extends mouse lifespan by 14%, but only in males, and the glucagon response to it is also stronger in males. This may explain why the effect is limited to one sex.
"Based on these experimental models, we propose that components of the insulin-glucagon axis are among the fundamental regulators of the metabolic shift observed across different lifespan-extending interventions in mice."
A direct test, disabling the glucagon receptor in mice and checking whether aging accelerates, is not feasible: such mice already have shorter lifespans for a different reason. The authors therefore propose the reverse: administering this hormone to healthy mice and testing whether it extends lifespan on its own. In humans, such drugs already exist; for example, mazdutide acts both as glucagon and as the hormone GLP-1.