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Why Can’t I Think Clearly Walk Straight Be Happy? Luigi Ferrucci, MD, PhD

Why Can’t I Think Clearly Walk Straight Be Happy? Luigi Ferrucci, MD, PhD Longitudinal Studies Section Clinical Research Branch National Institute of Aging. Physical Function. Cognition. ?. Mood. Walking. Homeostatic Equilibrium (Biological Housekeeping Mechanisms). Physical

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Why Can’t I Think Clearly Walk Straight Be Happy? Luigi Ferrucci, MD, PhD

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  1. Why Can’t I Think Clearly Walk Straight Be Happy? Luigi Ferrucci, MD, PhD Longitudinal Studies Section Clinical Research Branch National Institute of Aging

  2. Physical Function Cognition ? Mood Walking

  3. Homeostatic Equilibrium (Biological Housekeeping Mechanisms) Physical Function Mood Cognition • Specific Interactive Mechanisms • Including • Underlying Physiological Mechanisms • “Use or Lose” Mechanisms” • Changes in Behavioral and Social Constraints Walking

  4. A Bioenergetic HYPOTHESIS 1. The dysregulation of one or more elements of the network of mechanisms that maintain a stable homeostasis have negative effects on physical function, cognition and mood; 2. Such dysregulation may trigger a contro-regulatory response aimed at slowing down the human machine (principle of Maximum Efficiency). As a side effect, these events trigger a vicious cycle that leads to accelerated functional decline. Walking

  5. Inflammation Inflammation The Homeostatic Network in the BLSA Homeostatic Network Outcome Mobility Domains Insul., Ghrelin, Leptin, Adiponectin, Resistin, IGF-1, Testosterone, Estradiol, DHEAs, Cortisol, Thyroid, PTH Hormones CNS PCR, IL-6, sIL-6R, gp130, TNF-α, TNFr1, TNFr2, IL-18, IL-15, Homocysteine PNS Heart Rate Variability Muscles Autonomic Mobility Carbonylated Proteins Bone, Joints Ox Stress Food Intake, VitD, VitB12, Folate, VitE, Albumine. Energy Nutrition Self-Report Accelerometer Feedback Phys Activity Walking

  6. The Mild Pro-Inflammatory State of Aging 1.5 1.5 IL-6 IL-6 1 1 IL-6r IL-6r IL-1ra IL-1ra 0.5 0.5 IL-18 IL-18 n of SD from the sex-specific mean 0 0 -0.5 -0.5 Men Women -1 -1 1 1 CRP CRP Fibrinogen Fibrinogen 0.5 0.5 0 0 n of SD from the sex-specific mean -0.5 -0.5 -1 -1 Women Men -1.5 -1.5 20-39 40-49 50-64 65-74 75-84 85+ 20-39 40-49 50-64 65-74 75-84 85+ Age Groups Age Groups Ferrucci L et al. Blood. 2005;105:2294-9. Walking

  7. Interleukin-6 Serum Levels Predict Incident Disability A Case Cohort Study Nested in the EPESE 95% CI 1.0 0.8 Adjusted probability 2.5 pg/ml 0.6 Probability of Mobility Disability 0.4 95% CI 0.2 0 -0.5 0 0.5 1 1.5 2 2.5 3 Ln (IL-6) Ferrucci et al. JAGS 1999;47: 639-44 Walking

  8. Inflammation, Muscle Strength, and Physical Performance The Women’s Health and Aging Study Walking Speed Adjusting for Hip Flexor Strength Walking Speed 0.7 0.7 Walking Speed on a 4-m Course (m/sec) Walking Speed on a 4-m Course (m/sec) 0.6 0.6 0.5 0.5 0.4 0.4 0 1 2 3 0 1 2 3 Follow-up (yrs) Follow-up (yrs) Walking Ferrucci L et al. J Am Geriatr Soc 2002; 50: 1947-54

  9. Walking

  10. IkB Proteasome-Degradation IkB NF-κB1 (p50) RelA (p65) Inflammatory Cytokines Bacterial Products Growth Factors Mitogens Virus Stress Signals LPS IKKγ Ubiquitination IKKα IKKβ P P u IkB u NF-κB1 (p50) RelA (p65) Synthesis Cell Proliferation Cyclin D1, c-myc Inflammation (Chemokines, Cytokines, Immune Receptors, Adhesion Molecules) Angiogenesis Regulation of VEGF, TNF, IL-1 Nucleus Immortality Telomerase expression Cell Survival and Cell Death Antiapoptotic (i.e. Bcl-xl, hs-20) and pro-apoptotic gene expression (i.e. Fas) Walking

  11. Age and NF-κB Activation P65/Rel A (Western Blot) P65/Rel A (Western Blot) Age < 60 years 12 6 Age ≥ 60 years * 10 5 * 8 4 GAPDH relative units intensity 6 Intensity 3 P=0.06 4 2 2 1 0 C 2h 4h 0 C 2h 4h P-value Variable b ± S.E. Age 0.032 ± 0.008 <.0001 Nuclear p65/RelA Time 2h 4.072 ± 1.250 0.0011 Time 4h 8.726 ± 1.325 <.0001 Age*Time 2h -0.035 ± 0.019 0.0697 Age*Time 4h -0.092 ± 0.021 <.0001 Walking * p<0.01 compared non-stimulated

  12. Senile PlaqueFocus of Inflammatory Reaction Thinking C.J.Pike

  13. Thinking

  14. Thinking

  15. Thinking

  16. Thinking

  17. Buntix, 1996 Devanand, 1996 Henderson, 1997 Chen, 1999 Palsson, 1999 Geerlings, 2000 Summary estimate .01 .5 1.0 5.0 Risk (Odds) Ratio and 95% Confidence Interval .05 Thinking

  18. Happy

  19. Happy

  20. Happy

  21. ACC

  22. Happy

  23. Happy

  24. Well, How is This Going to Help? Happy

  25. Physical Function Cognition NF-κB? Mood Very Happy

  26. "It would be so nice if something made sense for a change." (Alice’s Adventures in Wonderland; July 4, 1865 - Charles L. Dodgson)

  27. Thank You for Your Attention

  28. Happy

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