Cellular Identity Collapse: From Specialization to "Drift"
In biology, "drift" isn’t a romantic race on Mount Akina. A groundbreaking Cell study by Altos Labs scientists reveals: Aging cells undergo mesenchymal drift (MD) systemically. Once-specialized cells—alveolar cells for gas exchange, hepatocytes for detoxification, neurons for signaling—gradually lose identity markers, uniformly shifting toward a "mesenchymal state." Instead of performing specialized functions, they secrete fibrotic matrix (hardening organs), release inflammatory factors, and accelerate tissue damage.
This drift is systemic: In idiopathic pulmonary fibrosis (IPF) patients, the highest MD group had a median survival of 294 days vs. 1027 days in the lowest group—a >3-fold difference. Blood-borne senescence factors (e.g., GDF15, TGF-β) act as "drift catalysts," spreading aging signals via circulation.
Partial Reprogramming: Halting Drift Before "Reset"
Traditional approaches (e.g., inhibiting ZEB1, a key drift gene) only address symptoms. The team turned to partial reprogramming: transiently activating Yamanaka factors (OSKM) to reverse drift within a "safety window" before full cellular dedifferentiation.
- Human proof: Skin cells from a 96-year-old showed dramatic reversal after 3 days of reprogramming—drift-driving genes (SNAI1, TWIST1) plummeted, and senescence profiles shifted younger. Pro-fibrotic myofibroblasts even regained multilineage differentiation potential.
- Mouse validation: 7 months of periodic partial reprogramming reduced MD in kidneys/livers, decreased fibrosis markers, and improved tissue function—without inducing pluripotency. This proves inhibiting drift alone rejuvenates cells.
Mechanism: Correcting Cellular Identity
Aging cells’ MD is an "incomplete reversion"—stuck between specialization and stemness. Partial reprogramming reactivates mesenchymal-epithelial transition (MET) early, clearing drift imprints while preserving identity.
Single-cell sequencing uncovered: Reprogramming reconstructs pseudopodial adhesion structures, suppresses pro-fibrotic TGF-β signaling, and reanchors cells to their "professional roles." Notably, senescent cells respond more sensitively—aged cells’ drift traits are prioritized for correction, while young cells risk over-reprogramming.
Significance & Future
This study identifies mesenchymal drift as a unifying mechanism for aging and >10 chronic diseases (pulmonary fibrosis, Alzheimer’s, chronic kidney disease, etc.), usable as a disease progression biomarker. Partial reprogramming rejuvenates tissues via "identity correction"—no stem cell conversion needed, opening safe anti-aging avenues.
Future interventions (e.g., TGF-β pathway modulation, optimized reprogramming cycles) could delay aging and treat fibrosis. As corresponding author Belmonte noted: "Maintaining cells’ 'professional integrity' may hold the key to healthy aging."
References
[1] Lu JY, Tu WB, Li R, et al. Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming. Cell. 2025.
[2] Sharma R. iPS Cells—The Triumphs and Tribulations. Dent J. 2016.
[3] Qiao Y, et al. Tumorigenic and Immunogenic Properties of Induced Pluripotent Stem Cells. Stem Cell Rev Rep. 2020.
[2] Sharma R. iPS Cells—The Triumphs and Tribulations. Dent J. 2016.
[3] Qiao Y, et al. Tumorigenic and Immunogenic Properties of Induced Pluripotent Stem Cells. Stem Cell Rev Rep. 2020.