Muscle aging and early Alzheimer’s disease activate the same inflammatory program in vascular and immune cells, with two candidate genes identified as potential shared off switches
Muscle aging and early Alzheimer’s disease activate the same inflammatory program in vascular and immune cells, with two candidate genes identified as potential shared off switches
A team from Zhejiang University and Amsterdam University Medical Center compared gene activity in young and old muscle with data from the brains of people with early Alzheimer’s disease. They found overlapping sets of inflammatory genes in vascular and immune cells in both tissues, and a similar signal in blood from living participants. A computational model identified two genes whose simulated inactivation reduced inflammation in both tissues.
For years, the idea that weakening muscles and declining brain function reflect a shared process rested on proteins that muscle releases into the blood, such as irisin. This preprint from October 8, a research paper shared before journal publication, examines the idea at the cellular level by comparing which genes are active in muscle and brain tissue.
In a muscle tissue atlas containing nearly 300 thousand cells from young and older donors, older donors showed increased inflammatory gene activity in 11 of 15 cell types and 77% more signals between cells.
For the brain analysis, the researchers used an Allen Institute atlas containing 1,1 million cell nuclei from 84 donors, with tissue damage graded on a continuous scale based on autopsy findings rather than a binary classification of healthy or diseased. At the early end of this scale, brain immune and vascular cells showed the same increase in inflammatory programs. As the disease progressed, signaling between brain cells weakened: its total strength fell by almost 20%, and activity declined in 38 of 39 inflammatory pathways, groups of genes that become active together. The comparison with muscle therefore focused on the early stage.
The authors then compared genes in vascular and immune cells, the only cells with comparable roles in muscle and brain tissue. They found overlap in six of eight inflammatory pathways in vascular cells (109 shared genes) and four of eight in immune cells (51 genes). A similar inflammatory cell subset consistently found across species had already been identified in another tissue: in mice, baboons, and humans, the same proinflammatory subset of lung alveolar macrophages increased more than tenfold with age.
The strength of the blood signal varied by condition. In physical frailty, characterized by weakness and slow walking, the same pathways were active in 30 of 36 pathway and cell type combinations tested. In mild cognitive impairment, they were active in only one combination, and in Alzheimer’s disease, in five. Across two independent groups of blood donors, 23 of 30 tests confirmed the same direction of change.
Using a computational model of gene regulatory interactions, the authors simulated switching off 18 candidate genes one at a time and compared the effects across both tissues for 13 of them. Only ETS2 and BHLHE40 consistently and predictably reduced inflammatory programs across all donors and passed every model robustness check. The authors present this pair as a hypothesis for laboratory testing: the effect did not remain statistically significant after correction, and the muscle and brain samples came from different people. Experiments are still needed to establish a “muscle → brain” link.
ETS2 has also been studied in another context. In June 2024, researchers at the Francis Crick Institute showed in Nature that excessive ETS2 activity reproduces inflammation associated with Crohn’s disease and ulcerative colitis, and that MEK inhibitors, which block its activation, suppress inflammation in cell experiments. BHLHE40 is known for other functions: in T-cells, it regulates the balance between inflammatory and anti-inflammatory signals, while in macrophages, it controls proliferation.
This preprint gives the proposed connection between muscle and brain aging a concrete basis in shared genes and identifies molecules that could be tested as targets for disrupting that connection.