Integrative multi-omics analyses identified dysregulation of the endosome-lysosome-autophagy axis and immune-inflammatory imbalance as characteristic pathophysiological features of elderly sepsis, distinguished from both young sepsis and healthy aging.
Key Findings
Results
Two characteristic metabolites were identified as distinctive to elderly sepsis: D-aspartic acid and LysoPC (18:1/0:0).
These metabolites were identified using a three-step screening pipeline applied to untargeted metabolomics data.
D-aspartic acid is associated with D-Amino acid metabolism, and alanine, aspartate, and glutamate metabolism pathways.
LysoPC (18:1/0:0) is associated with glycerophospholipid metabolism.
The study compared four groups: young healthy controls, elderly healthy controls, young sepsis patients, and elderly sepsis patients.
Results
Seven proteins were identified as characteristic to elderly sepsis: SCGB3A2, ATP6V1E1, APOA1, AP1G1, INHBC, CRYZL1, and CXCL14.
Proteins were identified through the same three-step screening pipeline applied to proteomics data.
Pairwise correlation analyses were conducted on screened molecules, retaining those with |rs| ≥ 0.4 for subsequent enrichment analyses.
These proteins were subjected to KEGG and/or GO functional enrichment analyses.
Enriched protein-centric functional terms were linked to the endocytic vesicle lumen, proton-translocating V-type ATPase, receptor ligand activity, and signaling receptor activator activity.
Results
Enriched metabolic pathways in elderly sepsis included D-Amino acid metabolism, alanine/aspartate/glutamate metabolism, and glycerophospholipid metabolism.
These pathways were identified through KEGG functional enrichment analyses of the characteristic metabolites.
The pathways reflect perturbations distinct to the combination of aging and sepsis insults.
Glycerophospholipid metabolism is relevant to membrane dynamics and inflammatory signaling.
Results
Protein-centric functional enrichment analysis implicated the endosome-lysosome-autophagy axis as dysregulated in elderly sepsis.
GO enrichment terms were linked to the endocytic vesicle lumen and proton-translocating V-type ATPase, key components of lysosomal function.
ATP6V1E1, one of the seven characteristic proteins, is a subunit of the vacuolar-type H+-ATPase (V-type ATPase) critical for lysosomal acidification.
AP1G1 is involved in vesicle trafficking and endosomal sorting.
These findings collectively support a hypothesis of endosome-lysosome-autophagy axis dysregulation as a distinguishing feature of elderly sepsis.
Results
Immune-inflammatory imbalance was identified as a characteristic feature of elderly sepsis through enriched functional terms related to receptor ligand activity and signaling receptor activator activity.
CXCL14, a chemokine, was among the seven characteristic proteins, supporting immune dysregulation.
INHBC (inhibin subunit beta C) and APOA1 (apolipoprotein A-I) were also among the characteristic proteins with known immune-modulatory roles.
SCGB3A2 has known anti-inflammatory properties and was identified as a characteristic protein.
The dual insults of aging and sepsis were highlighted as producing distinct pathophysiological features compared to sepsis in younger individuals.
Methods
Elderly sepsis was characterized using an integrative multi-omics approach combining untargeted metabolomics and proteomics across four comparison groups.
Four groups were studied: young healthy controls, elderly healthy controls, young patients with sepsis, and elderly patients with sepsis.
A three-step screening pipeline was used to identify molecules characteristic specifically of elderly sepsis.
Pairwise correlation analyses retained molecule pairs with |rs| ≥ 0.4 for downstream pathway enrichment.
Both KEGG and GO functional enrichment analyses were applied to the correlated molecules.
What This Means
This research suggests that sepsis in elderly patients involves specific biological disruptions that are distinct from sepsis in younger patients and from normal aging alone. Using a combined approach that simultaneously measured hundreds of small molecules (metabolomics) and proteins (proteomics) in blood samples from four groups — young healthy people, elderly healthy people, young sepsis patients, and elderly sepsis patients — the researchers identified two metabolites and seven proteins that are uniquely altered in elderly sepsis. These molecules are associated with abnormal amino acid processing and fat metabolism, as well as disrupted immune signaling.
A key finding is that elderly sepsis appears to involve dysfunction of the cell's internal waste disposal and recycling system, known as the endosome-lysosome-autophagy axis. This system normally breaks down and recycles cellular debris and pathogens, and its failure could impair how elderly patients with sepsis clear infections and damaged cellular components. Additionally, several of the identified proteins are involved in immune regulation, suggesting that elderly sepsis is characterized by an imbalanced immune-inflammatory response that differs from what is seen in younger sepsis patients.
This research suggests that the combination of aging and sepsis creates a unique biological state that may require targeted treatment strategies different from those used in younger patients. By identifying specific molecular signatures of elderly sepsis, this study provides a foundation for future research into new therapies tailored to this high-risk population, which currently faces substantially higher rates of illness and death from sepsis compared to younger individuals.
Gou Y, Xia Z, Haireti N, Aikepaer A, Yang J, Li D. (2026). Multi-Omics Reveals Dysregulation of the Endosome-Lysosome-Autophagy Axis and Immune-Inflammatory Imbalance in Elderly Sepsis.. Clinical interventions in aging. https://doi.org/10.2147/CIA.S613629