Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming

Area of Science:

• Cellular Biology
• Aging Research
• Genomics

Background:

• Loss of cellular and tissue identity is a key feature of aging and disease.
• Mechanisms driving this identity loss remain largely unknown.

Purpose of the Study:

• To investigate the molecular mechanisms underlying cellular identity loss in aging and disease.
• To explore the potential of partial reprogramming as a therapeutic strategy.

Main Methods:

• Analysis of gene expression data from over 40 human tissues and 20 diseases.
• Investigation of "mesenchymal drift" (MD) and its correlation with disease progression.
• Experimental suppression of key MD transcription factors.
• Yamanaka factor-induced partial reprogramming to assess its impact on MD and epigenetic rejuvenation.

Main Results:

• A pervasive upregulation of mesenchymal genes and altered stromal cell composition, termed "mesenchymal drift" (MD), was identified across multiple tissues and diseases.
• Increased MD correlates with disease severity, reduced patient survival, and higher mortality risk.
• Suppression of MD transcription factors induced epigenetic rejuvenation.
• Partial reprogramming significantly reduced MD and rejuvenated the aging transcriptome without dedifferentiation.

Conclusions:

• Mesenchymal drift is a significant factor in aging and disease progression.
• Partial reprogramming offers a promising approach to reverse age-related cellular and tissue dysfunction by reducing MD.
• These findings provide a mechanistic understanding of partial reprogramming's benefits and a framework for developing novel interventions.