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I'm Getting Older! Is there a pill for that? By Dr. Dean Kellogg

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Dr. Dean Kellogg's presentation from TPR's Think Science event on Friday, August 16, 2019.

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I'm Getting Older! Is there a pill for that? By Dr. Dean Kellogg

  1. 1. “Come on, Doc! I’m getting older! Is there a pill for that? Dean L. Kellogg, Jr., MD. Ph.D. Departments of Medicine and Physiology University of Texas Health Science Center and Geriatric Research, Education, and Clinical Center Audie L. Murphy VA Hospital
  2. 2. The Aging and the Geriatric Population A Wide Spectrum
  3. 3. The Aging and the Geriatric Population
  4. 4. www.livingto100.comGoal of Anti-aging Therapy….. Make more ‘Successful Agers’….with a long and healthy life!
  5. 5. PROVEN ‘Anti-aging’ Therapy: Calorie Restriction extends healthspan and lifespan
  6. 6. Calorie restriction retards aging in animals… but is it practical in humans?
  7. 7. The Quest for ANTI-Aging Pills…… NIA’s Intervention Testing Program PURPOSE: To identify nutritional and pharmaceutical interventions (already FDA approved) that could be safely employed to extend the lifespan and healthspan of mice
  8. 8. •Curcumin •Green tea extract •Nitrofluorbiprofen •4-hydroxy-phenylbutyl Nitrone •Medium-chain triglyceride oil •Oxaloacetic acid •Resveratrol •Methylene blue •Simvastatin Agents that did not extend lifespan in laboratory animals
  9. 9. •Aspirin •17αEstradiol •NGDA (nordihydroguaiaretic acid) •Protandim Agents that extend lifespan in male but not female laboratory animals
  10. 10. •Acarbose-greater effect in males with small effect in females-but had to be started in youth •Rapamycin-greater effect in females-could be started on ‘old’ mice’ 2 Agents that extend lifespan in both MALE and FEMALE laboratory animals
  11. 11. RAPAMYCIN…a weird drug from a weird place….Easter Island=Rapa Nui
  12. 12. Moai
  13. 13. Moai Dig into the soil of Rapa Nui and find that there is more than meets the eye! RAPAMYCIN (Sirolimus)
  14. 14. ITP: Mice on Rapamycin are “Younger” in activity levels and coat appearance Control Female RAPA Female Control Male RAPA Male ALL Dead 9-14% Lifespan increase Activity level maintained in males RAPA effects observed if started late in life
  15. 15. FDA Approved Uses Of Rapamycin in Humans • Rapamycin is FDA approved for use as an immunosuppressive drug in preventing transplant rejection, with drug eluting stents to limit coronary artery re-stenosis, and for lymphangioleiomyomatosis. • Rapalogs (drugs like rapamycin) are FDA approved for use as cancer treatments. • Most human studies of RAPA involved transplant patients who take a combination of immunosuppressive drugs thus interpretation of RAPA safety and effects are difficult.
  16. 16. Anti-aging Use of Rapamycin in Healthy Humans (Science, News & Analysis, 2013) • Some researchers say NO. • “Rapamycin leads to insulin resistance—a precursor of diabetes—in mice and humans, and transplant recipients have developed diabetes.” • “I’d be very hesitant to be a participant” in a clinical trial, Miller says. • Some researchers say YES. • “We don’t have a huge body of evidence of its effects in a healthy older adult.” IS RAPAMYCIN SAFE TO GIVE TO HEALTHY OLDER PERSONS?
  17. 17. Inclusion Criteria -Subjects all in good health with all chronic diseases (hypertension, coronary artery disease, etc.) clinically stable. -AGE 80-95 (Phase 1) -AGE 70-95 (Phase 2) •Participants on therapy (either Rapamycin 1mg qD or placebo) for the 4 months (Phase 1) or 2 months (Phase 2). •Added RAPA or placebo to other medications subjects were already taking Study Design
  18. 18. Assessment of Rapamycin SAFETY • Physical examinations • Clinical blood work • Urinalysis • Oral Glucose Tolerance Tests • EKG • Self-reported side-effects • Pts called on weekly basis
  19. 19. IMMUNOLOGICAL TESTS Rapa improved antibody responses in older mice! – PHASE 1 -Tests on Immunity • Hepatitis B naïve participants are immunized with the hepatitis B vaccine. Humoral (antibody titer) and cellular (T cell proliferation) responses are assessed. – PHASE 2 -Tests on Immunity • Participants are immunized with the Flu vaccine. Humoral (antibody titer) and cellular (T cell proliferation) responses are assessed. – Tests on Inflammation • Immune parameters characteristically altered by aging are assessed. These include: i) serum cytokine levels; ii) variety of white blood cell (B cell and T cells) studies.
  20. 20. PHYSICAL PERFORMANCE TESTS • Hand Grip (3 trials hand dynamometer-Lt and Rt) • Timed Walk (3 trials-40 feet)
  21. 21. COGNITIVE TESTS • EXIT (Executive Interview 25-which includes letter fluency) • SLUMS (St. Louis University Mental Status exam) includes memory test, digit span, and animal fluency • TAPS (Texas Assessment of Processing Speed) a digit/symbol coding test available in alternate forms to eliminate learning effects
  22. 22. 28 Subjects-Ages, Sex, and Final Rapamycin Levels
  23. 23. A B C D E F G H I J K L Pre Post Pre Post PLACEBO RAPA 4.8 4.4 4.0 3.6 Albumin Serumconcentration(g/dL) Pre Post Pre Post PLACEBO RAPA 4.8 4.4 4.0 3.6 Albumin Serumconcentration(g/dL) Weight Weight(kg) Pre Post Pre Post PLACEBO RAPA 70 80 90 100 110 Weight Weight(kg) Pre Post Pre Post PLACEBO RAPA 70 80 90 100 110 White blood cell count WBCx103/μl Pre Post Pre Post PLACEBO RAPA 4 5 6 7 White blood cell count WBCx103/μl Pre Post Pre Post PLACEBO RAPA 4 5 6 7 300 200 100 Triglycerides Triglyceridesinserum(mg/dL) Pre Post Pre Post PLACEBO RAPA 300 200 100 Triglycerides Triglyceridesinserum(mg/dL) Pre Post Pre Post PLACEBO RAPA Low density lipoprotein LDLconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 75 100 125 150 Low density lipoprotein LDLconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 75 100 125 150 High density lipoprotein HDLserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 30 50 70 High density lipoprotein HDLserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 30 50 70 Serum protein Serumprotein(g/dL) Pre Post Pre Post PLACEBO RAPA 6.5 7.0 7.5 Serum protein Serumprotein(g/dL) Pre Post Pre Post PLACEBO RAPA 6.5 7.0 7.5 Hemoglobin A1c HgbA1c(percent) Pre Post Pre Post PLACEBO RAPA 5.0 5.5 6.0 6.5 Hemoglobin A1c HgbA1c(percent) Pre Post Pre Post PLACEBO RAPA 5.0 5.5 6.0 6.5 Platelets Pre Post Pre Post PLACEBO RAPA 150 200 250 Plateletsx103/μl Platelets Pre Post Pre Post PLACEBO RAPA 150 200 250 Plateletsx103/μl Calcium Calciumserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 9.0 9.5 10.0 Calcium Calciumserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 9.0 9.5 10.0 Hematocrit Hematocrit(%) Pre Post Pre Post PLACEBO RAPA 35 40 45 Hematocrit Hematocrit(%) Pre Post Pre Post PLACEBO RAPA 35 40 45 120 110 100 90 80 Fasting blood glucose Glucoseserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 120 110 100 90 80 Fasting blood glucose Glucoseserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA A B C D E F G H I J K L Pre Post Pre Post PLACEBO RAPA 4.8 4.4 4.0 3.6 Albumin Serumconcentration(g/dL) Pre Post Pre Post PLACEBO RAPA 4.8 4.4 4.0 3.6 Albumin Serumconcentration(g/dL) Weight Weight(kg) Pre Post Pre Post PLACEBO RAPA 70 80 90 100 110 Weight Weight(kg) Pre Post Pre Post PLACEBO RAPA 70 80 90 100 110 White blood cell count WBCx103/μl Pre Post Pre Post PLACEBO RAPA 4 5 6 7 White blood cell count WBCx103/μl Pre Post Pre Post PLACEBO RAPA 4 5 6 7 300 200 100 Triglycerides Triglyceridesinserum(mg/dL) Pre Post Pre Post PLACEBO RAPA 300 200 100 Triglycerides Triglyceridesinserum(mg/dL) Pre Post Pre Post PLACEBO RAPA Low density lipoprotein LDLconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 75 100 125 150 Low density lipoprotein LDLconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 75 100 125 150 High density lipoprotein HDLserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 30 50 70 High density lipoprotein HDLserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 30 50 70 Serum protein Serumprotein(g/dL) Pre Post Pre Post PLACEBO RAPA 6.5 7.0 7.5 Serum protein Serumprotein(g/dL) Pre Post Pre Post PLACEBO RAPA 6.5 7.0 7.5 Hemoglobin A1c HgbA1c(percent) Pre Post Pre Post PLACEBO RAPA 5.0 5.5 6.0 6.5 Hemoglobin A1c HgbA1c(percent) Pre Post Pre Post PLACEBO RAPA 5.0 5.5 6.0 6.5 Platelets Pre Post Pre Post PLACEBO RAPA 150 200 250 Plateletsx103/μl Platelets Pre Post Pre Post PLACEBO RAPA 150 200 250 Plateletsx103/μl Calcium Calciumserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 9.0 9.5 10.0 Calcium Calciumserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 9.0 9.5 10.0 Hematocrit Hematocrit(%) Pre Post Pre Post PLACEBO RAPA 35 40 45 Hematocrit Hematocrit(%) Pre Post Pre Post PLACEBO RAPA 35 40 45 120 110 100 90 80 Fasting blood glucose Glucoseserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA 120 110 100 90 80 Fasting blood glucose Glucoseserumconcentration(mg/dL) Pre Post Pre Post PLACEBO RAPA CLINICAL LAB TEST RESULTS: Blood chemistry and Red Blood Cells •Reduced H/H and indices within RAPA and between Groups
  24. 24. METABOLIC TEST (OGTT) RESULTS •No differences in insulin sensitivity
  25. 25. White Blood Cells 30 CD4+ T cells PLACEBO RAPA %ofCD3+Tcells Ratio CD4+/CD8+ PLACEBO RAPA %ofnaïveCD4+cells PLACEBO RAPA PLACEBO RAPA %ofCD4+cells %ofmemoryCD4+cells TREG cells (CD4+foxp3+) PLACEBO RAPA %ofCD4+parentpopulation 0 6 0 6 0 5 10 15 20 0 6 0 6 0 20 40 60 80 100 Naïve CD4+ (RA+RO-) PLACEBO RAPA %ofCD4+cells 0 6 0 6 0 20 40 60 80 Memory CD4+ (RA-RO+) Memory CD4+ PD1+ 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 5 10 15 20 0 6 0 6 0 20 40 60 G H I J K L 30 CD4+ T cells PLACEBO RAPA %ofCD3+Tcells Ratio CD4+/CD8+ PLACEBO RAPA %ofnaïveCD4+cells PLACEBO RAPA PLACEBO RAPA %ofCD4+cells %ofmemoryCD4+cells TREG cells (CD4+foxp3+) PLACEBO RAPA %ofCD4+parentpopulation 0 6 0 6 0 5 10 15 20 PLACEBO RAPA %ofCD4+parentpopulation 0 6 0 6 0 5 10 15 20 0 6 0 6 0 20 40 60 80 100 Naïve CD4+ (RA+RO-) PLACEBO RAPA %ofCD4+cells 0 6 0 6 0 20 40 60 80 Memory CD4+ (RA-RO+) Memory CD4+ PD1+ 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 5 10 15 20 0 6 0 6 0 20 40 60 G H I J K L CD8+ T cells PLACEBO RAPA %ofCD3+Tcells Memory CD8+ (RA-RO+) Naïve CD8+ PD1+ PLACEBO RAPA PLACEBO RAPA PLACEBO RAPAPLACEBO RAPA Naïve CD8+ (RA+RO-) PLACEBO RAPA %ofCD8+cells Memory CD8+ CD28+ Memory CD8+ PD1+ %ofnaïveCD8+cells %ofmemoryCD8+ %ofmemoryCD8+ %ofCD8+cells 0 6 0 6 0 10 20 30 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 10 20 30 40 50 0 6 0 6 0 10 20 30 40 50 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 20 40 60 80 100 M N O P Q R CD8+ T cells PLACEBO RAPA %ofCD3+Tcells Memory CD8+ (RA-RO+) Naïve CD8+ PD1+ PLACEBO RAPA PLACEBO RAPA PLACEBO RAPAPLACEBO RAPA Naïve CD8+ (RA+RO-) PLACEBO RAPA %ofCD8+cells Memory CD8+ CD28+ Memory CD8+ PD1+ %ofnaïveCD8+cells %ofmemoryCD8+ %ofmemoryCD8+ %ofCD8+cells 0 6 0 6 0 10 20 30 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 10 20 30 40 50 0 6 0 6 0 10 20 30 40 50 0 6 0 6 0 20 40 60 80 100 0 6 0 6 0 20 40 60 80 100 M N O P Q R 0 6 0 6 0 10 20 30 B cells (CD20+) PLACEBO RAPA %ofsinglets T cells (CD3+) PLACEBO RAPA Myeloid lineage (CD11b+) PLACEBO RAPA Myeloid P1 subset Myeloid P2 subset Myeloid P3 subset PLACEBO RAPA %ofCD11b+ 0 6 0 6 0 10 20 30 %ofCD20-parentpopulation 0 6 0 6 0 10 20 30 %ofCD20-parentpopulation 0 6 0 6 50 60 70 80 90 100 PLACEBO RAPA PLACEBO RAPA %ofCD11b+ %ofCD11b+ 0 6 0 6 0 10 20 30 40 0 6 0 6 0 5 10 15 20 A B C D E F 0 6 0 6 0 10 20 30 B cells (CD20+) PLACEBO RAPA %ofsinglets T cells (CD3+) PLACEBO RAPA Myeloid lineage (CD11b+) PLACEBO RAPA Myeloid P1 subset Myeloid P2 subset Myeloid P3 subset PLACEBO RAPA %ofCD11b+ 0 6 0 6 0 10 20 30 %ofCD20-parentpopulation 0 6 0 6 0 10 20 30 %ofCD20-parentpopulation 0 6 0 6 50 60 70 80 90 100 PLACEBO RAPA PLACEBO RAPA %ofCD11b+ %ofCD11b+ 0 6 0 6 0 10 20 30 40 0 6 0 6 0 5 10 15 20 A B C D E F •No differences
  26. 26. Cytokines (Inflammatory Mediators) IL-13 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.87 0 200 400 600 IL-15 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 5 10 15 20 IL-17A 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.31 0 10 20 30 IL-6 (ELISA) 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.09 0 5 10 15 20 VEGF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.36 0 200 400 600 800 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.63 0 200 400 600 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.95 0 10 20 30 40 50 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.85 0 50 100 150 IL-8 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.11 0 20 40 60 IL-10 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 10 20 30 IL-12p40 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 10 20 30 IL-12p70 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.25 0 10 20 30 40 50 IL-4 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.61 0 20 40 60 80 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.04 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 10 20 30 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 50 100 150 200 250 IL-1 p = >0.99 IL-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.02 0 5 10 15 20 MCP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.73 0 500 1000 1500 IFN2 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.65 0 50 100 150 IFN 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 50 100 150 IP-10 p = 0.77 0 500 1000 1500 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.90 0 100 200 300 400 EGF Eotaxin 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.50 0 200 400 600 800 G-CSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.14 0 50 100 150 GMCSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.44 0 20 40 60 80 100 A B C D E F G H I J K L M N O P Q R S T U V W XIL-13 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.87 0 200 400 600 IL-13 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.87 0 200 400 600 IL-15 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 5 10 15 20 IL-15 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 5 10 15 20 IL-17A 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.31 0 10 20 30 IL-17A 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.31 0 10 20 30 IL-6 (ELISA) 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.09 0 5 10 15 20 IL-6 (ELISA) 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.09 0 5 10 15 20 VEGF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.36 0 200 400 600 800 VEGF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.36 0 200 400 600 800 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.63 0 200 400 600 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.63 0 200 400 600 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.95 0 10 20 30 40 50 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.95 0 10 20 30 40 50 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.85 0 50 100 150 MIP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.85 0 50 100 150 IL-8 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.11 0 20 40 60 IL-8 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.11 0 20 40 60 IL-10 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 10 20 30 IL-10 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.19 0 10 20 30 IL-12p40 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 10 20 30 IL-12p40 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 10 20 30 IL-12p70 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.25 0 10 20 30 40 50 IL-12p70 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.25 0 10 20 30 40 50 IL-4 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.61 0 20 40 60 80 IL-4 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.61 0 20 40 60 80 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.04 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 10 20 30 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.04 TNF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 10 20 30 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 50 100 150 200 250 IL-1 p = >0.99 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 50 100 150 200 250 IL-1 p = >0.99 IL-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.02 0 5 10 15 20 IL-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.02 0 5 10 15 20 MCP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.73 0 500 1000 1500 MCP-1 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.73 0 500 1000 1500 IFN2 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.65 0 50 100 150 IFN2 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.65 0 50 100 150 IFN 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 50 100 150 IFN 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.26 0 50 100 150 IP-10 p = 0.77 0 500 1000 1500 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml IP-10 p = 0.77 0 500 1000 1500 0 500 1000 1500 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.90 0 100 200 300 400 EGF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.90 0 100 200 300 400 EGF Eotaxin 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.50 0 200 400 600 800 Eotaxin 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.50 0 200 400 600 800 G-CSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.14 0 50 100 150 G-CSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.14 0 50 100 150 GMCSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.44 0 20 40 60 80 100 GMCSF 0 wks 6 wks 0 wks 6 wks PLACEBO RAPA pg/ml p = 0.44 0 20 40 60 80 100 A B C D E F G H I J K L M N O P Q R S T U V W X •No differences
  27. 27. Other Results? •No statistically significant differences in immunization, physical performance, cognitive testing
  28. 28. ANY Beneficial Results? •Reduced weight (1.1#) in RAPA group while placebo group gained (0.5#)
  29. 29. Subject and Family Comments - “I couldn’t tell I was taking anything different.” -“We saw a slight increase in his cognitive and memory abilities on the med. Not marked but a very slight increase.” - “His overall disposition seemed better.” -“He was more frisky on the rapamycin…..can you give him some more?”
  30. 30. POSSIBLE ADVERSE REACTIONS • Stomatitis (2 pts-1 Rapa and 1 placebo-resolved so continued participation) • Diarrhea (2 pts-ended participation) • Acneform Facial Rash (1 pt-ended participation) ALL POTENTIAL ADVERSE REACTIONS PREVIOUSLY REPORTED IN TRANSPLANT PATIENTS
  31. 31. A Randomized Control Trial to Establish the Feasibility and Safety of Rapamycin Treatment in an Older Human Cohort: Immunological, Physical Performance, and Cognitive Effects Ellen Kraiga,b,*, Leslie A. Linehanb, Hanyu Lianga, Terry Q. Romoa,g, Qianqian Liuc, Yubo Wue, Adriana D. Benavidesd, Tyler J. Curiela,e, Martin A. Javorsa,f, Nicolas Musia,e,g, Laura Chiodog, Wouter Koekb,f, Jonathan A.L. Gelfonda,c, and Dean L. Kellogg, Jr.a,e,g CONCLUSION: Rapamycin is just as safe to use in healthy older persons as transplant patients….but what about benefits?
  32. 32. Possible Rapamycin Benefits?
  33. 33. The Search for Rapamycin Benefits: Cardiovascular Effects in 70+yo Persons Initial Results: IMPROVED CARDIAC FUNCTION? Measured by cardiac MRI in 6 older persons pre post 0 50 100 150 Flow: Transmitral Total Volume ml p = 0.0211 paired, parametric 41 42-no data 43 44 45 46
  34. 34. Successful Aging to All!
  35. 35. THANKS • CTSA • SA Pepper Center • Dr. Ellen Kraig • Terry Romo • Leslie Linehan • Beth Wu • Darcy Bair-Kelps • Che Kelly

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