The MIRACLE study aims to investigate age-related mitochondrial dysfunction, mitochondrial RNA (mtRNA) release, inflammation, and cellular senescence in adult participants across three age groups. Skin-derived fibroblasts and peripheral blood mononuclear cells (PBMCs) will be isolated from skin biopsy and blood samples to characterize age-related cellular and molecular changes and to test experimental therapeutic strategies identified in preclinical studies. Serum, plasma, and whole-blood RNA will be used for protocol-defined analyses of circulating inflammatory mediators and systemic transcriptional signatures related to inflammation, type I interferon activation, mitochondrial stress response, immune aging, and senescence-associated pathways.
Male and female
Age between 18 and 90 years (stratified in three groups: young, middle-aged, elderly)
Written informed consent
Inability to understand the potential risk and benefits of the study
Legal incapacity
Subjects who have taken antibiotics, anti-inflammatory drugs, or antihistamines within the past 7 days
Diagnosis of diabetes mellitus
Parallel
Skin biopsy and venous blood sampling
Procedure/SurgeryA single 3-4 mm punch biopsy of forearm skin is performed under local anesthesia (lidocaine 1% with epinephrine 1:100,000) for primary dermal fibroblast isolation. Venous blood is collected by standard phlebotomy from the antecubital fossa (43 mL total volume per participant): 5 mL in SST tube for serum separation, 3 mL in EDTA tube for plasma separation, 32 mL in EDTA tubes for PBMC isolation by density gradient centrifugation, and 3 mL in Tempus Blood RNA tube for whole-blood RNA stabilization. All procedures are performed at a single visit at enrollment. Samples are processed for biospecimen-based ex vivo molecular and cellular analyses; no investigational product is administered to participants.
Age-dependent differences in cytosolic release of mitochondrial RNA (mtRNA) in primary human fibroblasts
Assessment of release of mtRNA in the cytosol of primary fibroblasts isolated from study participants across age groups. Cytosolic mtRNA levels assessed through analysis of the mean fluorescence intensity (MFI) per cell by immunofluorescence.
Age-dependent differences in mitochondrial function in primary human fibroblasts
Characterization of mitochondrial function parameters in primary fibroblasts isolated from study participants across age groups. Mitochondrial function assessed through analysis of mitochondrial Complex I activity in nmol/min/mg protein by functional ELISA.
Activation of inflammatory pathways in primary human fibroblasts
Assessment of inflammatory pathway activation markers in fibroblasts isolated from participants across age groups. Inflammatory pathway activation assessed through Interleukin-6 concentration in skin-derived fibroblast culture supernatant in pg/mL
Activation of senescence pathways in primary human fibroblasts
Assessment of cellular senescence markers and senescence-associated pathway activation in fibroblasts isolated from participants across age groups. Senescence pathway activation assessed as percentage (%) of Senescence-associated β-galactosidase (SA-β-gal)-positive cells per microscopic field.
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