Researchers demonstrate that p62 protein depletion drives skin cell senescence through USP7 pathway dysregulation and show that replenishing p62 delays senescence markers in fibroblasts and keratinocytes, offering a novel target for anti-aging skin therapies.
Key points
p62 directly binds USP7, preserving autophagic degradation and preventing p53/p21/p16-mediated senescence in dermal fibroblasts and keratinocytes.
p62 knockout in keratinocytes accelerates skin thinning and increases inflammatory SASP markers (interleukins, TNF-α) in a mouse model.
p62 overexpression halves UV-induced senescence rates in skin cells and reduces expression of USP7 and senescence biomarkers.
Why it matters:
Targeting p62 replenishment offers a novel senomorphic strategy to maintain skin health and delay visible signs of aging.
Q&A
What role does p62 play in cellular maintenance?
How does p62 interaction with USP7 affect skin aging?
What are senescence-associated secretory phenotype (SASP) factors?
Why is restoring p62 considered safer than inhibiting other senescence pathways?
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Academy
p62 and Autophagy in Skin Aging
Introduction: Maintaining clear and functional skin cells is vital for healthy skin. One of the key players in this process is p62, a protein that acts as a bridge between damaged cellular components and the autophagy machinery, the cell’s cleanup system. Understanding p62’s role helps explain why skin ages and how scientists might slow the process.
What Is p62?
p62, or Sequestosome1: p62 is an autophagy receptor that recognizes and binds to proteins tagged for degradation. By attaching to ubiquitinated proteins and organelles, p62 escorts these materials into lysosomes—cellular structures that break down and recycle waste. This function keeps cells healthy by preventing toxic buildup.
How Autophagy Works
- Tagging: Damaged proteins or organelles are marked with ubiquitin tags.
- Recognition: p62 binds these tagged components via specific binding domains.
- Sequestration: p62-protein complexes are enveloped within autophagosomes, double-membrane vesicles.
- Degradation: Autophagosomes fuse with lysosomes, whose enzymes digest the contents into reusable building blocks.
Decline with Age
Over time, p62 levels naturally decrease. As a result, cells lose autophagy efficiency, leading to accumulation of damaged proteins, increased cellular stress, and activation of senescence pathways. In skin, this manifests as thinning, sagging, and reduced barrier function.
p62 and Senescence
- Senescence Pathways: Without adequate p62, the deubiquitinase USP7 accumulates, stabilizing p53 and p21 proteins that halt cell division and trigger inflammatory secretions.
- SASP Factors: Senescent cells release pro-inflammatory factors (e.g., interleukins and TNF-α) that damage nearby cells and degrade tissue structure.
Implications for Skin Health
By restoring or boosting p62 levels, researchers aim to reestablish effective autophagy. This approach could reduce USP7 accumulation, limit p53/p21 activation, and lower inflammatory signals. The goal is a senomorphic therapy—one that prevents or delays senescence—rather than killing cells outright.
Broader Significance in Longevity Science
While this research focuses on skin, p62’s role in autophagy is universal. Similar strategies may apply to other tissues affected by aging, such as the brain, liver, and cardiovascular system. Enhancing autophagy through p62 could become a cornerstone of future longevity interventions, promoting healthspan by maintaining cellular resilience.