AgingMIRACLENCT07596615
Mitigating Mitochondrial RNA Release During Aging to Control Inflammation and Senescence
A study testing Skin biopsy and venous blood sampling in people with Aging and Inflammation, run by Mario Negri Institute for Pharmacological Research at 2 sites in Italy.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- Aging, Inflammation, Healthy Ageing
- What is being tested?
- Skin biopsy and venous blood sampling
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 2 sitesItaly
- Study dates
- Sep 2026to Sep 2031
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male and female
- Age between 18 and 90 years (stratified in three groups: young, middle-aged, elderly)
- Written informed consent
Who cannot join
- 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
- Use of anticoagulant medications
- Any subject with a contraindication to the mini-invasive biopsy procedure
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy2 sites
Laboratory for Targeted Therapy in Autoimmune Diseases
Bergamo, BG, 24126
Luca Perico, PhD, +3003542131, luca.perico@marionegri.it
Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"
Ranica, BG, 24020
Miriam Rigoldi, MD, +390354535327, miriam.rigoldi@marionegri.it
About this study
Official title: Mitigating Mitochondrial RNA Release During Aging to Control Inflammation and Senescence, Preserving Organ Function and Enhancing Healthspan
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.
Read the detailed description
Mitochondria are crucial for ATP production and intracellular signaling in higher eukaryotic cells. These organelles contain genetic material that reflects their bacterial ancestry, including mitochondrial RNA (mtRNA). Under normal conditions, mtRNA is tightly confined and processed within mitochondria, ensuring the proper synthesis of proteins required for oxidative phosphorylation. Recent evidence suggests that mitochondrial stress may promote the leakage of mitochondrial components, including mtRNA. Once released into the cytosol, mtRNA can be sensed by cytosolic pattern recognition receptors (PRRs), thereby activating signaling pathways that promote the production of pro-inflammatory cytokines.
Although these mechanisms have been investigated mainly under conditions of acute stress, the specific contribution of mitochondrial dysfunction and mtRNA release to chronic low-grade inflammation and cellular senescence during physiological aging remains incompletely understood. This represents an important knowledge gap in the understanding of molecular processes that may contribute to age-related inflammation and functional decline.
The MIRACLE project includes a broade series of preclinical in vitro and in vivo experiments aimed at clarifying the mechanisms linking mitochondrial dysfunction, mtRNA release, inflammatory pathway activation, and cellular senescence during aging. These experimental activities are designed to define the biological pathways involved and to identify potential strategies capable of modulating mtRNA-associated inflammatory and senescence responses.
Within this broader framework, the present human study is intended to corroborate and extend the preclinical findings in humans. To this aim, adult participants across different age groups will be enrolled, and skin biopsy and blood samples will be collected to obtain skin-derived fibroblasts, peripheral blood mononuclear cells (PBMCs), serum, plasma, and whole-blood RNA.
Skin-derived fibroblasts will provide an accessible primary cell model for the investigation of age-related cellular and molecular changes. Fibroblasts isolated from participants of different ages will be used to assess mitochondrial function, mtRNA release, inflammatory signaling, and markers of cellular senescence. PBMCs collected from the same participants will be analyzed as a complementary blood-derived cellular model to evaluate systemic immune and inflammatory features, including immunosenescence-related signatures. Serum and plasma samples will be used to measure circulating inflammatory mediators and senescence-associated factors, while whole-blood RNA will be used to assess systemic transcriptional signatures related to inflammation, type I interferon activation, mitochondrial stress response, immune aging, and senescence-associated pathways.
- Conditions
- Aging, Inflammation, Healthy Ageing
- Being tested
- Skin biopsy and venous blood sampling
- Keywords
- mitochondrial dysfunction, skin-derived fibroblasts, mtRNA, PBMCs, senescence, inflammaging
- Medical subject headings
- Inflammation, Mitochondrial Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Skin biopsy and venous blood samplingProcedure or surgery
A 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.
| Study group | Role | What they receive |
|---|---|---|
| Young adults | Experimental | Female and male volunteers aged 18-40 years Receives: Procedure: Skin biopsy and venous blood sampling |
| Middle-aged adults | Experimental | Female and male volunteers aged 40-60 years Receives: Procedure: Skin biopsy and venous blood sampling |
| Elderly adults | Experimental | Female and male volunteers aged 60-90 years Receives: Procedure: Skin biopsy and venous blood sampling |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Day 1 (at enrollment)
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.
Measured: Day 1 (at enrollment)
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
Measured: Day 1 (at enrollment)
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.
Measured: Day 1 (at enrollment)
Comparison of fibroblast findings with PBMC-derived parameters from the same participants
Integration and comparison of fibroblast-derived molecular data with corresponding PBMC-derived measurements obtained from the same participants as described above.
Measured: Day 1 (at enrollment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2026
- Study startSep 2026 (estimated)
- Primary completionSep 2031 (estimated)
- Study completionSep 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for AgingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Cohort, cross-sectional
- Masking
- None (open label)
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mario Negri Institute for Pharmacological Research
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Giuseppe Remuzzi, Study director, Istituto Di Ricerche Farmacologiche Mario Negri
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07596615
- Sponsor's protocol ID
- MIRACLE
- Other IDs
- FIS-2024-00858
- Acronym
- MIRACLE
- Status last verified
- May 2026
- First submitted
- 29 Apr 2026
- Last updated
- 19 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Zuber TJ. Punch biopsy of the skin. Am Fam Physician. 2002 Mar 15;65(6):1155-8, 1161-2, 1164.
PubMed 11925094Nischal U, Nischal Kc, Khopkar U. Techniques of skin biopsy and practical considerations. J Cutan Aesthet Surg. 2008 Jul;1(2):107-11. doi: 10.4103/0974-2077.44174.
PubMed 20300359Yasui Y, Kato H, Oda T, Nakamura M, Morita A. Complications and risk factors of punch biopsy: A retrospective large-scale study. J Dermatol. 2023 Jan;50(1):98-101. doi: 10.1111/1346-8138.16585. Epub 2022 Sep 24.
PubMed 36151785Akiyama Y, Norimatsu Y, Ohno Y. Prophylactic antimicrobials may not be needed to prevent surgical site infection after skin biopsy: a retrospective study. Antimicrob Resist Infect Control. 2022 Feb 16;11(1):35. doi: 10.1186/s13756-022-01077-z.
PubMed 35172906
Study at a glance
From the registry record, last updated by the sponsor on 19 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mitigating Mitochondrial RNA Release During Aging to Control Inflammation and Senescence, Preserving Organ Function and Enhancing Healthspan
- ClinicalTrials.gov ID
- NCT07596615
- Acronym / sponsor ID
- MIRACLE / MIRACLE
- Conditions
- Aging, Inflammation, Healthy Ageing
- Keywords
- mitochondrial dysfunction, skin-derived fibroblasts, mtRNA, PBMCs, senescence, inflammaging
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Study start
- Sep 2026 (estimated)
- Primary completion
- Sep 2031 (estimated)
- Study completion
- Sep 2031 (estimated)
- First posted
- 19 May 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Mitochondria are crucial for ATP production and intracellular signaling in higher eukaryotic cells. These organelles contain genetic material that reflects their bacterial ancestry, including mitochondrial RNA (mtRNA). Under normal conditions, mtRNA is tightly confined and processed within mitochondria, ensuring the proper synthesis of proteins required for oxidative phosphorylation. Recent evidence suggests that mitochondrial stress may promote the leakage of mitochondrial components, including mtRNA. Once released into the cytosol, mtRNA can be sensed by cytosolic pattern recognition receptors (PRRs), thereby activating signaling pathways that promote the production of pro-inflammatory cytokines.
Although these mechanisms have been investigated mainly under conditions of acute stress, the specific contribution of mitochondrial dysfunction and mtRNA release to chronic low-grade inflammation and cellular senescence during physiological aging remains incompletely understood. This represents an important knowledge gap in the understanding of molecular processes that may contribute to age-related inflammation and functional decline.
The MIRACLE project includes a broade series of preclinical in vitro and in vivo experiments aimed at clarifying the mechanisms linking mitochondrial dysfunction, mtRNA release, inflammatory pathway activation, and cellular senescence during aging. These experimental activities are designed to define the biological pathways involved and to identify potential strategies capable of modulating mtRNA-associated inflammatory and senescence responses.
Within this broader framework, the present human study is intended to corroborate and extend the preclinical findings in humans. To this aim, adult participants across different age groups will be enrolled, and skin biopsy and blood samples will be collected to obtain skin-derived fibroblasts, peripheral blood mononuclear cells (PBMCs), serum, plasma, and whole-blood RNA.
Skin-derived fibroblasts will provide an accessible primary cell model for the investigation of age-related cellular and molecular changes. Fibroblasts isolated from participants of different ages will be used to assess mitochondrial function, mtRNA release, inflammatory signaling, and markers of cellular senescence. PBMCs collected from the same participants will be analyzed as a complementary blood-derived cellular model to evaluate systemic immune and inflammatory features, including immunosenescence-related signatures. Serum and plasma samples will be used to measure circulating inflammatory mediators and senescence-associated factors, while whole-blood RNA will be used to assess systemic transcriptional signatures related to inflammation, type I interferon activation, mitochondrial stress response, immune aging, and senescence-associated pathways.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Cohort, cross-sectional
| Arm | Type | Receives |
|---|---|---|
| Young adults | Experimental | Procedure: Skin biopsy and venous blood samplingFemale and male volunteers aged 18-40 years |
| Middle-aged adults | Experimental | Procedure: Skin biopsy and venous blood samplingFemale and male volunteers aged 40-60 years |
| Elderly adults | Experimental | Procedure: Skin biopsy and venous blood samplingFemale and male volunteers aged 60-90 years |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Male and female
- Age between 18 and 90 years (stratified in three groups: young, middle-aged, elderly)
- Written informed consent
Key exclusion criteria (6 listed)
- 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
- Use of anticoagulant medications
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Skin biopsy and venous blood samplingA 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. | Procedure or surgery | Elderly adults, Middle-aged adults, Young adults |
Primary outcome
Age-dependent differences in cytosolic release of mitochondrial RNA (mtRNA) in primary human fibroblasts
Time frame: Day 1 (at enrollment)
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
Time frame: Day 1 (at enrollment)
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
Time frame: Day 1 (at enrollment)
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
Time frame: Day 1 (at enrollment)
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.
Comparison of fibroblast findings with PBMC-derived parameters from the same participants
Time frame: Day 1 (at enrollment)
Integration and comparison of fibroblast-derived molecular data with corresponding PBMC-derived measurements obtained from the same participants as described above.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 May 2026.
- Background: PubMed 11925094Zuber TJ. Punch biopsy of the skin. Am Fam Physician. 2002 Mar 15;65(6):1155-8, 1161-2, 1164.
- Background: PubMed 20300359Nischal U, Nischal Kc, Khopkar U. Techniques of skin biopsy and practical considerations. J Cutan Aesthet Surg. 2008 Jul;1(2):107-11. doi: 10.4103/0974-2077.44174.
- Background: PubMed 36151785Yasui Y, Kato H, Oda T, Nakamura M, Morita A. Complications and risk factors of punch biopsy: A retrospective large-scale study. J Dermatol. 2023 Jan;50(1):98-101. doi: 10.1111/1346-8138.16585. Epub 2022 Sep 24.
- Background: PubMed 35172906Akiyama Y, Norimatsu Y, Ohno Y. Prophylactic antimicrobials may not be needed to prevent surgical site infection after skin biopsy: a retrospective study. Antimicrob Resist Infect Control. 2022 Feb 16;11(1):35. doi: 10.1186/s13756-022-01077-z.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Giuseppe Remuzzi study director
Istituto Di Ricerche Farmacologiche Mario Negri
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Skin biopsy and venous blood sampling in people with Aging and Inflammation, run by Mario Negri Institute for Pharmacological Research at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 19 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Luca Perico, PhD (+3903542131, luca.perico@marionegri.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Age-dependent differences in cytosolic release of mitochondrial RNA (mtRNA) in primary human fibroblasts (time frame: Day 1 (at enrollment)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07596615, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2026.