A review in Cell proposes a unifying process for aging: Mesenchymal Drift.
Mesenchymal Drift: A New Lens on Aging
A review published in the journal Cell introduces Mesenchymal Drift (MD) as a central process that integrates multiple hallmarks of aging. MD is described as a progressive loss of cell identity, where cells acquire mesenchymal characteristics. While this drift is initially adaptive, chronic activation becomes maladaptive.
Connecting the Hallmarks of Aging
The review details how MD interacts with established aging mechanisms, forming self-reinforcing loops:
- Genomic Instability: DNA damage can trigger MD, and MD may exacerbate genomic instability in a vicious cycle.
- Mitochondrial Dysfunction: Excessive mitochondrial reactive oxygen species promote MD-related processes like epithelial-mesenchymal transition (EMT) and fibrosis. Impaired mitophagy sustains pro-fibrotic signaling, while its restoration mitigates fibrosis.
- Chronic Inflammation: Inflammatory cytokines (IL-1β, TNF-α, IL-6) induce MD, while cells undergoing MD secrete cytokines that maintain inflammation.
Therapeutic Implications
The authors outline two key avenues for intervention:
- Early Detection: Quantifying MD in tissues could enable early detection of maladaptive cell states and provide biomarkers for monitoring treatment.
- Partial Reprogramming: Approaches like partial Yamanaka factor reprogramming may counteract MD by inducing mesenchymal-epithelial transition (MET). In animal models, this has restored cellular functions and reversed some aging phenotypes. However, these approaches are preclinical and carry risks, including tumorigenesis.
Conclusion
The authors conclude that MD represents a mechanistic trajectory where multiple hallmarks of aging converge. Viewing aging through this lens may inform future interventions by targeting this central process.