What is the role of secretome (a set of signaling molecules) in skin aging?

The Role of Secretome in Skin Aging

The secretome—a collection of bioactive molecules secreted by cells, particularly from senescent cells—plays a dual and critical role in skin aging: it drives tissue degeneration through chronic inflammation and matrix degradation while simultaneously offering therapeutic potential when derived from mesenchymal stem cells for skin rejuvenation.

The Detrimental Role: Senescence-Associated Secretory Phenotype (SASP)

Mechanism of Aging Through SASP

Senescent cells accumulate in aging skin and secrete pro-inflammatory cytokines, chemokines, growth factors, and matrix proteases that collectively form the SASP, which directly causes tissue degeneration and dysfunction. 1

The pathophysiology unfolds through this sequence:

• Cellular senescence is triggered by genomic instability, telomere shortening, metabolic stress, reactive oxygen species, oncogene activation, and mitochondrial dysfunction. 1

• These triggers activate tumor suppressor genes (p53, p16Ink4a, p21) that induce permanent cell cycle arrest. 1

• Arrested senescent cells develop SASP and become resistant to apoptosis, persisting in tissues for years unless cleared by the immune system. 1

• SASP proteins spill into the extracellular matrix and circulation, damaging neighboring cells through paracrine effects and interfering with tissue repair and regeneration. 1

Specific Impact on Skin Tissue

In skin, senescent keratinocytes and fibroblasts accumulate with aging and exhibit multiple senescence markers including p21, γ-H2A.X, and TAF/TIF. 1

The burden of senescence increases measurably in:

• Human CD4+ lymphocytes 1
• Kidney epithelia 1
• Skin tissue, where different cell subtypes (papillary vs. reticular fibroblasts, keratinocytes across epidermal strata) display heterogeneous senescent phenotypes 1

The accumulation of senescent cells and negative effects of SASP proteins on the intercellular matrix and progenitor cells represent a primary cause of tissue degeneration in age-related degenerative diseases, including skin aging. 1, 2

Clinical Manifestations

SASP-driven skin aging manifests as:

• Wrinkle formation through collagen degradation by matrix proteases 3
• Loss of skin elasticity from elastin breakdown 3
• Chronic low-grade inflammation (inflammaging) 1
• Impaired wound healing capacity 1
• Reduced barrier function 4

The Therapeutic Role: MSC-Derived Secretome

Composition and Mechanism

Mesenchymal stem cell (MSC)-derived secretomes contain growth factors, cytokines, chemokines, angiogenic factors, extracellular matrix proteins, antimicrobial peptides, and extracellular vesicles (microvesicles and exosomes) that promote tissue rejuvenation, regeneration, homeostasis, and immunomodulation. 5, 6

The therapeutic secretome works through distinct mechanisms:

• Anti-inflammatory effects by modulating inflammatory signaling pathways and reducing chronic inflammation 5, 6, 4

• Antioxidant activity that neutralizes reactive oxygen species 6

• Enhanced cell proliferation and migration to facilitate skin regeneration 5

• Replenishment of collagen, fibronectin, and elastin in the dermal matrix 3

• Modulation of aging signaling pathways to reverse cellular senescence 3

• Restoration of skin barrier function through regulation of physiological processes including cell apoptosis, detoxification, and anti-aging mechanisms 4

Evidence for Clinical Efficacy

In vitro and in vivo studies consistently demonstrate that MSC secretome reverses the aging process and achieves skin rejuvenation superior to available conventional treatments. 3

Specific applications with documented efficacy include:

• Wound healing acceleration 5
• Photoprotection against UV damage 5
• Hair growth promotion 5
• Treatment of inflammatory conditions (psoriasis, atopic dermatitis, acne) 5, 4
• Reduction of wrinkles and improvement in photoaging scores 7

Delivery Methods

Both microneedling and fractional CO2 laser delivery of adipose-derived MSC secretome produce comparable improvements in skin aging parameters, including total dermoscopy photoaging scale scores and wrinkle reduction. 7

Fractional CO2 laser achieves higher patient satisfaction and preference but lower comfort scores compared to microneedling. 7

Common adverse effects include pain, burning sensation, pruritus, and transient erythema (more prolonged with fractional CO2 laser). 7

Critical Distinctions and Clinical Implications

The Paradox of Secretomes

The secretome concept encompasses two opposing biological phenomena:

1. Pathological SASP from senescent cells that accelerates aging 1
2. Therapeutic secretome from healthy MSCs that reverses aging 5, 3, 6

This distinction is crucial: targeting senescent cell clearance (senolytics) addresses the harmful secretome, while applying MSC-derived secretome provides regenerative factors. 1

Measurement Challenges

Quantification of senescence burden in human skin remains complex because:

• No single biomarker is specific to senescence (p53, p21, SA-β-galactosidase, SASP factors can appear in non-senescent contexts) 1
• p16Ink4a is not always present in senescent cells 1
• Heterogeneous forms of senescence develop according to different triggers and tissue types 1
• Autofluorescent extracellular matrix components in dermis interfere with detection 1

Common Pitfalls to Avoid

Do not conflate the harmful SASP from senescent cells with the therapeutic secretome from MSCs—these represent opposite biological processes requiring different interventions. 1, 5, 3

Avoid relying on single senescence markers in skin; multiple markers (p16, p21, γ-H2A.X, SA-β-galactosidase) should be assessed together given their lack of individual specificity. 1

When using far-red or near-infrared detection methods to overcome autofluorescence in skin sections, particularly when detecting low-expression proteins in the dermal compartment. 1

Recognize that keratinocytes and fibroblasts differ dramatically in replication dynamics and lifespan in vivo, requiring cell-type-specific validation of senescence markers. 1

For therapeutic applications, ensure MSC secretome products have appropriate safety standards and quality control, as the field currently lacks standardized regulations. 6