The Role of Sirolimus in Preventing Functional Decline in Older Adults

Aging is associated with progressive impairment of tissue and organ function, resulting in increased susceptibility to chronic disease, frailty and disability. Currently there are limited treatment options to alter this inevitable process. The proposed work has the potential to identify a new therapeutic intervention to decrease aging-related degenerative processes.

Rapamycin or sirolimus is a macrocyclic immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR). The mammalian target of rapamycin (mTOR) pathway is part of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway which is a fundamentally linked to cell metabolism, proliferation, differentiation, and survival. This pathway is altered in a variety of diseases, including cancers, immunosuppressed states, and fibroproliferative diseases. The mTOR kinase is considered one of the leading regulators of this pathway. Changes in mTOR signaling are closely associated with inflammation, cell growth and survival, leading to the development of chronic diseases. Recent evidence also suggests that mTOR inhibitors are promising modulators of the aging process by slowing the mechanisms of aging at the cellular level. There is a growing appreciation of the potential impact of sirolimus in slowing aging processes and in prolonging healthy lifespan.

The proposed study addresses critical gaps in our understanding of the safety and efficacy of sirolimus in delaying aging processes and is based on findings in animal studies and incidental clinical observations. The investigators will overcome potential biases with a randomized control trial. The proposed intervention study is intended to improve our insight into clinical outcomes leading to prevention of chronic diseases such as skin cancer and mortality. Our overarching hypothesis is that sirolimus is one of the first pharmacological agents that will impact the aging process and chronic disease development. Specifically, the investigators aim to investigate whether sirolimus can reduce the occurrence or increase in biomarkers of aging processes.

Study Overview

• Status: Not yet recruiting
• Conditions: Aging
• Intervention / Treatment: Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Irina Timofte; Phone Number: 2163347534; Email: Irina.Timofte@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• patients 55 years or older

Exclusion Criteria:

• Creatinine clearance <30 mL/min
• Underlying chronic liver disease
• Other investigational therapy received within 1 month prior to screening visit
• Pulmonary Arterial Hypertension (PAH), mean Pulmonary Arterial Presure(mPAP)>30 mm Hg
• Extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)

• Cardiovascular diseases, any of the following: Myocardial infarction within 6 months, planned coronary artery disease intervention , left ventricular EF <45%

  • History of haemorrhagic central nervous system (CNS) event within 1 year from screening visit.
  • Any of the following within 3 months of screening visit :Haemoptysis or haematuria;Active gastro-intestinal (GI) bleeding or GI - ulcers; Major injury or surgery
• History of thrombotic event (including, DVT, PE, stroke and transient ischemic attack) within 1 year from screening visit.
• Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
• Planned major surgical procedures.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
• Concurrent active alcohol or drug abuse.
• Clinically significant cognitive impairment
• Functional impairment (defined by ADL status)
• Patients not able to understand or follow trial procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention; Patients randomized to the intervention will initially take 0.5 mg sirolimus. The dose will be adjusted weekly to obtain a sirolimus levels of 5-7 ng/ml whole blood in the first months. After the first month, the patient will have monthly blood work and will be followed in clinic every 3 months. Functional assessment and aging biomarkers will be obtained at baseline and 1 year follow up. Completion of the 1-year treatment period will be followed by a follow-up visit 4 weeks later.	Drug: Sirolimus; Patients will be randomly assigned to sirolimus or standard of care
No Intervention: Control; Interventions: standard of care Patients are not going to receive any additional intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by walking speed	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by chair stand	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by standing balance	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by grip strength	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by body mass index	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by muscle mass	1 year
Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging as measured by waist circumference	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating biomarkers of aging as measured by ESR	We are going to check circulating biomarkers of aging as measured by erythrocyte sedimentation rate(ESR)	1 year
Circulating biomarkers of aging as measured by C-reactive protein(CRP)	We are going to check circulating biomarkers of aging as measured by C-reactive protein(CRP)	1 year
Circulating biomarkers of aging as measured by levels of Hemoglobin(Hb)	We are going to check circulating biomarkers of aging as measured by levels of Hemoglobin(Hb)	1 year

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center

Publications and helpful links

General Publications

• Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013 Mar;123(3):980-9. doi: 10.1172/JCI64099. Epub 2013 Mar 1.
• Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep. 2017 Oct 27;7(1):14272. doi: 10.1038/s41598-017-14612-5.
• Lawrence J, Nho R. The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis. Int J Mol Sci. 2018 Mar 8;19(3):778. doi: 10.3390/ijms19030778.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: January 19, 2022
• First Submitted That Met QC Criteria: February 2, 2022
• First Posted (Actual): February 14, 2022

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: prevention; aging; sirolimus
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: STU-2022-0060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No