A key molecule, p62, orchestrates skin aging via USP7 degradation

#1

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Open Access Paper:

SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation

Skin aging is a complex process driven by intrinsic genetic factors and extrinsic environmental influences. In this study, sequestosome1 (SQSTM1/p62) was identified as a key regulator of senescence, the senescence-associated secretory phenotype (SASP), and skin aging. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of ubiquitin-specific protease 7 (USP7) during senescence induction by orchestrating its degradation through specific binding interactions. In particular, the Tyr-67 residue within the PB1 domain or Gln-418 within the UBA domain of p62 forms a hydrogen bond with Ala-993 in the Ubl5 domain of USP7. Mutations in either Tyr-67 or Gln-418 of p62, or Ala-993 of USP7, resulted in the induction of cellular senescence, highlighting the critical role of these molecular interactions in the regulation of aging processes.

https://onlinelibrary.wiley.com/doi/10.1111/acel.70078

#2

My ChatGPT query:

how is it possible to increase P62 levels in skin?

ChatGPT response:

Increasing p62 (also known as SQSTM1) levels in the skin is a complex but increasingly studied topic, especially because p62 plays a critical role in autophagy, oxidative stress response, and skin aging. The goal of increasing p62 in the skin is typically tied to improving cellular cleanup (proteostasis), reducing age-related degeneration, or enhancing resistance to UV and pollution stressors.

Here are the main strategies based on current research:

:microscope: 1. Topical Compounds That Stimulate p62 Expression

Some compounds and extracts can upregulate p62 in skin cells:

  • Retinoids (e.g., retinoic acid, retinol): These have been shown to modulate autophagy and may increase p62 as part of skin rejuvenation.

  • Polyphenols and Flavonoids:

    • Resveratrol, EGCG (from green tea), and curcumin have been reported to modulate autophagy and potentially increase p62 expression under stress.

  • Botanical extracts:

    • Certain marine algae (e.g., Ascophyllum nodosum), fermented ingredients, and plant stem cell extracts (e.g., from Malus domestica) are included in cosmeceuticals and have been linked to increased autophagy markers including p62.

  • Nrf2 activators:

    • p62 is upregulated in response to oxidative stress, and Nrf2 pathway activators (like sulforaphane from broccoli) may induce it.

:pill: 2. Hormonal & Metabolic Modulation

  • mTORC1 Inhibition:
    Drugs or compounds that mildly inhibit mTORC1 (e.g., rapamycin) can induce autophagy and increase p62 accumulation in a context-dependent manner.
  • Caloric restriction or mimetics:
    These metabolic changes may enhance autophagy processes and indirectly raise p62 levels.

:lotion_bottle: 3. Cosmetic Technologies and Peptides

  • Some cosmetic brands now target proteostasis and autophagy via peptides, liposomal delivery systems, and biofermented ingredients aimed at increasing p62 levels.
  • Clinical-grade serums or formulations using technologies licensed from autophagy research (e.g., BASF, Mibelle Biochemistry) may reference p62 increase as a target.

:test_tube: 4. Genetic and Experimental Methods (Research stage)

  • Gene editing or transfection: In lab models, overexpression of SQSTM1/p62 can be induced via transfected vectors.
  • siRNA silencing of inhibitors: Inhibiting p62 repressors via RNA silencing is used in research to elevate its levels.
  • 3D skin models have shown p62 upregulation with UV and stress exposure, and targeted delivery systems (like nanoparticles) are being tested for this.

:warning: Important Considerations

  • Too much p62 accumulation is not always beneficial. In some diseases (like cancer or neurodegeneration), p62 overaccumulation is problematic.
  • A balanced autophagy response is more important than simply increasing p62.
  • Always consider that topical delivery into viable skin layers (epidermis/dermis) is challenging and requires good formulation.

:white_check_mark: Summary: How to potentially increase p62 in skin

Method Example Notes
Topical agents Retinoids, EGCG, curcumin Stimulate autophagy and antioxidant responses
Nrf2 activators Sulforaphane Boosts oxidative defense, may increase p62
mTOR inhibitors Rapamycin (experimental) Boosts autophagy, increases p62 in certain contexts
Metabolic strategies Caloric restriction Systemic effects; may influence skin indirectly
Cosmetic actives Peptides, stem cell extracts Used in anti-aging skincare targeting p62
Gene therapies Research-only Used in lab models to modulate p62 directly

Would you like recommendations for actual skincare products or ingredients currently on the market that are claimed to influence p62 or autophagy?

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