Reversing Epigenetic & Other Markers of Senescence by Transfusing Young Plasma To Older Human Subjects

Study Overview
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Brief Summary
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This trial is designed to study the effects of monthly transfusions of young healthy male donor plasma on biological age as assessed by DNA methylation levels, and changes in cognitive, renal, and pulmonary function, muscle strength, telomere length, testosterone, estrogen, DHEAS, IGF-1, high resolution C-Reactive protein, and expression of P16INK4a in peripheral blood T lymphocytes and skin biopsies.

Detailed Description
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Aging is a process for which there is no cure. Plasma transfusions, based on extensive animal studies, have the potential to reverse many, systemic age-related changes in the human body as well as age related chronic diseases. This is a non-randomized, uncontrolled phase I/II study to study the effects of monthly transfusions of young healthy male donor plasma on biological age as assessed by DNA methylation levels, and changes in cognitive, renal, and pulmonary function, muscle strength, telomere length, testosterone, estrogen, DHEAS, IGF-1, high resolution C-Reactive protein, and expression of p16INK4a in peripheral blood T lymphocytes and skin biopsies. To determine the safety and tolerability of monthly, 2-unit transfusions of young (<25 years of age) healthy male donor plasma for 6 months in patients older then 40 years of age.

Official Title
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Reversing Epigenetic & Other Markers of Senescence by Transfusing Young Plasma To Older Human Subjects

Conditions
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Aging

Intervention / Treatment
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* Biological: Plasma Transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 40. Stable medications for 2 months prior to Screening. Signed and dated written informed consent obtained from the subject in accordance with local Institutional Review Board regulations. Males and all Women of Child Bearing Potential agree to abstain from sex or use an adequate method of contraception for the duration of the study and for 30 days after the last dose of study drug. Adequate contraceptive methods include those with a low failure rate, i.e., less than 1% per year, when used consistently and correctly), and , a woman who has been surgically sterilized or who has been in a state of amenorrhea. Exclusion Criteria: Dementia of any etiology. Any medical condition other than dementia that could account for cognitive deficits (e.g., active seizure disorder, stroke, Central Nervous System diseases); History of significant cardiovascular, hematologic, renal, or advanced hepatic disease (or laboratory evidence thereof); History of major psychiatric illness or untreated depression; Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5x upper limit of normal (ULN), total bilirubin >1.5 x ULN, Alanine Transaminase >3 x ULN, Aspartate Transaminase >3 x ULN, or International Normalized Ratio (INR) >1.2 at Screening evaluations; Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of study data; Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection; Current clinically significant viral infection; Major surgery within four weeks prior to Screening; Any contraindication to monthly plasma transfusions, including but not limited to: History of significant transfusion complications; Compatible plasma units not available; Prior intolerance to intravenous (IV) fluids; Immunoglobulin A deficiency by history or laboratory evidence at Screening; Bleeding; Any concurrent use of an anti-coagulant therapy. Daily administration of Aspirin 81mg will be allowed as long as the dose is stable for 30 days prior to Screening. Anti-platelet drugs are acceptable. Treatment with another investigational drug or participation in another interventional clinical trial within 3 months of Screening; Treatment with any human blood product, including IV immunoglobulin, during the 6 months prior to Screening or during the trial; Pregnant or lactating; Positive pregnancy test at Screening or Baseline (Day 1); Cancer within 5 years of Screening, except for nonmetastatic skin cancer or non-metastatic prostate cancer not expected to cause significant morbidity or mortality within one year of Baseline. AB blood type.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasma Transfusion<br>Plasma Transfusions with 2 units of plasma per dose, for a total of 6 doses | Biological: Plasma Transfusion<br>* All subjects will receive monthly, 2-unit transfusions of young healthy male donor plasma for total of 6 treatments. The plasma will be administered at a transfusion services facility in a manner consistent with generally accepted and standard guidelines for plasma transfusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological age as assessed by DNA methylation levels, to calculate the Epigenetic age. | The epigenetic clock, as assessed by DNA methylation levels, which has been shown to be highly correlated with biologic age, longevity and is an independent predictor of mortality. | Baseline to end of Month 9. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mental (Cognitive) Function | Executive functioning, as measured by the California Stroop test | Baseline and Month 9 | 
| Lung (Pulmonary) Function | FEV1 (Forced Expiratory Volume during the first second), and Peak Expiratory Flow | Baseline and Month 9 | 
| Kidney (Renal) Function | Twenty-four hour urine collections will be performed by patients at Baseline and at Month 9. Creatinine Clearance, a measure of Renal function will be determined by calculating the glomerular filtration rate (GFR), which is the sum of filtration rates in all functioning nephrons. | Baseline and Month 9 | 
| Muscle Strength | Unilateral Maximal Voluntary Isometric and Concentric Strength | Baseline and Month 9 | 
| Telomere Length | A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Telomere shortening is associated with aging, mortality and aging-related diseases. Average telomere length will be measured in white blood cells by real time PCR technique. | Baseline and Month 9 | 
| Testosterone | Serum free and total Testosterone levels | Baseline and Month 9 | 
| Estrogen | Serum Estrogen levels | Baseline and Month 9 | 
| DHEAS | Dehydroepiandrosterone is an endogenous steroid hormone that has a role in the synthesis of sex steroids (androgens and estrogens), as well as neurotrophic and other effects | Baseline and Month 9 | 
| IGF-1 | Insulin Like Growth Factor -1(IGF-1) declines continuously with aging in adults, and has been shown to mediate a number of pathways that are associated with longevity. | Baseline and Month 9 | 
| High Sensitivity C-Reactive Protein | C-Reactive Protein is a blood protein that is a marker of inflammation. Studies have suggested that a persistent level of inflammation plays a major role in cardiovascular and other degenerative and aging related diseases. | Baseline and Month 9 | 
| P16INK4a (A marker of cellular aging) | The cyclin- dependent kinase inhibitor CDKN2A, commonly referred to as p16INK4a or p16, has been established as a general marker of cellular senescence or aging. The expression of p16INK4a has been shown to increase exponentially with chronologic age. P16-INK4a is performed on a small specimen of blood drawn from the subjects, as well as from skin biopsy samples. | Baseline and Month 9 |