Stress on the proteasome, the cellular complex that breaks down damaged and surplus proteins, has a shared molecular fingerprint: it activates on its own in aging mouse tissues and is detectable in the blood of older people
Stress on the proteasome, the cellular complex that breaks down damaged and surplus proteins, has a shared molecular fingerprint: it activates on its own in aging mouse tissues and is detectable in the blood of older people
A team at St. Jude Children's Research Hospital suppressed the proteasome, both chemically and by targeted genetic knockdown, in human cells, mouse muscle, and brain organoids, and identified 121 genes that respond consistently across all three systems. When the team mapped this gene list onto mouse tissue aging data and human plasma data, the same program turned out to activate on its own with age.
When the proteasome is inhibited, the cell mounts an emergency response: it upregulates chaperones (proteins that refold or disassemble damaged molecules) and builds new proteasomes to replace the disabled ones. This response was first described in yeast in the 1990s, but since then it had been studied piecemeal, in separate cell models, and whether it had a shared, reproducible profile across systems was unknown.
The motivation came from an earlier finding by the same laboratory, led by Fabio Demontis at St. Jude. In 2021, the group showed in Drosophila that moderate proteasome stress in skeletal muscle triggers a protective signal across the whole organism: the muscle secretes an enzyme that produces the sugar maltose, and maltose, acting through chaperones, protects the fly's brain and retina from aging. This implied that secreted proteins could serve as a measurable molecular trace of the same systemic response. That trace is what the team set out to find in a paper published on September 16.
The team tested the idea in three systems at once: human cells, mouse muscle cells (continuing the laboratory's focus on muscle), and human brain organoids, the tissue counterpart of the target reached by the same signal in flies. The proteasome was inhibited in two independent ways: with MG132, a chemical relative of bortezomib used to treat multiple myeloma, and with targeted knockdown of proteasome subunit genes, to rule out off-target drug effects.
Proteasome genes themselves were upregulated as expected, but to varying degrees across cell types, which made them poor universal markers. Three other categories, however, behaved identically in every system: chaperones and secreted signaling factors rose, while cell-cycle regulators fell. The genes shared across all systems were compiled into a single list of 121 genes (67 upregulated, 54 downregulated). Some of these genes carry DNA-binding sites for Nrf1, a known transcriptional activator of proteasome genes, and the upregulated subset additionally carries binding sites for Hsf1, the heat-shock factor that drives chaperone expression.
When the 121 genes were mapped onto a public atlas of mouse tissue aging, the upregulated portion of the signature increased with age in adipose tissue, heart, kidney, muscle, lung, and other organs, while the downregulated portion declined in bone, brain, and muscle. In muscle, both shifts tracked together and began early. Of the six secreted proteins in the signature for which data existed in a plasma aging atlas covering nearly 3000 proteins in 4263 people aged 18 to 95, the direction of change with age matched in every case: the metalloproteinases MMP10 and MMP12, inhibin INHBA, nerve growth factor NGF, and the already established stress hormone GDF15 all rise with both proteasome stress and aging, while the receptor IL17RD falls in both contexts.
Until now, proteasome stress had only been studied artificially, by switching it on and off in vitro. There is now a defined set of genes and circulating blood proteins that can be used to measure this program in living tissues and to test whether a geroprotective intervention reduces specifically this axis of damage. The signature was derived mainly under strong proteasome inhibition, so for the time being it detects pronounced disruption more reliably than subtle age-related shifts, as the authors themselves acknowledge.