1. The Biological Background of Health and Aging Luigi Ferrucci, MD, PhD National Institute of Aging Baltimore, MD PROMOTING HEALTH IN AGING A joint symposium of The New York Academy of Medicine and the Royal Society of Medicine

2. Aging and Trajectory of Function

5. Predicted Median Life Expectancy by Age and Gait Speed in Men 65 70 75 80 85 90 95 0 5 10 15 20 25 30 35 40 45 Median Survival (years) Age years) Gait Speed, m/sec 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6

6. Aging Phenotypes Changes in Body Composition Changes in Body Composition Energy Imbalance Production/Utilization Energy Imbalance Production/Utilization Homeostatic Dysregulation Homeostatic Dysregulation Neurodegeneration Physical and Cognitive FRAILTY Disease Susceptibility Reduced Functional Reserve Reduced Healing Capacity and Stress Resistance Unstable Health Failure to Thrive Geriatric Syndromes AGING Gait Disorders Falls Cognitive Impairment Sleep Disorders Disability Urinary Incontinence Delirium Decubitus Ulcers Comorbidity Aging Phenotypes and the Genesis of Geriatric Syndromes Ferrucci L, Studenski S. Clinical Problems of Aging. In: Harrison’s Principles of Internal Medicine, 18 th Ed. Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. McGraw Hill 2011 (In Press)

7. Aging Phenotypes Changes in Body Composition Changes in Body Composition Energy Imbalance Production/Utilization Energy Imbalance Production/Utilization Homeostatic Dysregulation Homeostatic Dysregulation Neurodegeneration Physical and Cognitive FRAILTY Disease Susceptibility Reduced Functional Reserve Reduced Healing Capacity and Stress Resistance Unstable Health Failure to Thrive Geriatric Syndromes AGING Gait Disorders Falls Cognitive Impairment Sleep Disorders Disability Urinary Incontinence Delirium Decubitus Ulcers Comorbidity Aging Phenotypes and the Genesis of Geriatric Syndromes Ferrucci L, Studenski S. Clinical Problems of Aging. In: Harrison’s Principles of Internal Medicine, 18 th Ed. Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. McGraw Hill 2011 (In Press)

8. Weight (Kg) Lean Mass (Kg) Fat Mass (Kg) Weight (Kg) Lean Mass (Kg) Fat Mass (Kg) Men Women Weight, Muscle and Fat Longitudinal Changes in Body Composition with Age 2030405060708090 100 80 60 40 20 0 30405060708090 100 80 60 40 20 0 Waist Circumference (cm) Ferrucci, L., Studenski, S.: Clinical Problems of Aging. In: Harrison’s Principles of Internal Medicine, 18 th Ed. Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. McGraw Hill 2011 (In Press)

9. Muscle Low Grip Strength (Men <25 Kg; Women<15 Kg) according to Age and COPD 0 20 40 60 80 100 20-3940-4950-5960-6970-7980-8990+ COPD Healthy Controls Age (years) Percent with Low Grip Strength OR=1.0 OR=1.2 OR= 1.6 OR=2.1 OR=2.7 OR=2.8

10. Muscle Longitudinal Changes in Knee Extensor Max Torque (Nm) According to Diabetes Knee Extension Max Torque (Newton.metres) 100 120 140 160 80 Without Diabetes (n=1056) With Diabetes (n=154) 20304050607080 Age (years) The Baltimore Longitudinal Study of Aging

11. 25-34 versus <25 35-44 versus 25-34 45-54 versus 35-44 55-64 versus 45-54 65-74 versus 55-64 75-84 versus 65-74 85+ versus 75-84 Muscle Strength/ Mass Ratio in BLSA Participants 60-70 yrs Old Muscle CSA (Mid-Thigh) Knee Extension Torque

12. Muscle Strength/Mass Ratio in BLSA Participants 60-70 yrs Old BLSA (unpublished)

13. Muscle Mid-Thigh CT Images for Women with BMI 30-32 (BLSA) Age=80 Years Age=55 Years Age=33 Years

14. Fat Cross-Sectional Relationship of Age with Visceral and Subcutaneous Abdominal Fat BLSA 2011 (unpublished data) Age (years) 20406080100 Age (years) 20406080100 0 20K 40K 60K 80K Fat Area (mm2) Subcutaneous Fat Visceral Fat Thanks to Sokratis Makrogiannis and Ramona Ramachandran

15. Aging Phenotypes Changes in Body Composition Changes in Body Composition Energy Imbalance Production/Utilization Energy Imbalance Production/Utilization Homeostatic Dysregulation Homeostatic Dysregulation Neurodegeneration Physical and Cognitive FRAILTY Disease Susceptibility Reduced Functional Reserve Reduced Healing Capacity and Stress Resistance Unstable Health Failure to Thrive Geriatric Syndromes AGING Gait Disorders Falls Cognitive Impairment Sleep Disorders Disability Urinary Incontinence Delirium Decubitus Ulcers Comorbidity Aging Phenotypes and the Genesis of Geriatric Syndromes Ferrucci L, Studenski S. Clinical Problems of Aging. In: Harrison’s Principles of Internal Medicine, 18 th Ed. Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. McGraw Hill 2011 (In Press)

16. 10 5 0 -5 -10 -15 -20 -25 20-29 30-39 40-49 50-59 60-69 70-79 Percent Change in Peak VO 2 in mL/min Men Women Percent Longitudinal Changes Peak VO 2 per Decade Age (decade) 4000 3500 3000 2500 2000 1500 1000 500 Peak VO 2 (mL/min) 2030 4050 607080 Age(years) Longitudinal Changes in Peak VO 2 Men Women

17. The Domains of Energy Fitness, Resting Metabolic Rate and Efficiency Minimum energy to sustain life in “good health” Repair, recovery & regulation Energy for casual walking Instability, infirmity & inefficiency 3-6 ml O 2 /kg/min 0-5 ml O 2 /kg/min <0-11 ml O 2 /kg/min Reserve energy for sustained or intense activity <0-33 ml O 2 /kg/min Homeostatic Effort due to Diseases and/or Aging Excess cost of Movement due to Energetic Inefficiency Sources of Energy Waste

18. Age (yrs) 20406080100 500 1000 1500 2000 2500 3000 RMR (Kcal/day) RMR crude RMR adjusted* * RMR Adjusted for sex, FFM and FM Association Between Age and RMR Crude and After Adjusting for Sex, Lean Mass and Fat Mass VariableΒ±S.E.p Age (yrs)-4.4±1.2<.0001 Sex (F)1.6±54.40.97 Lean Mass (Kg)25.3±2.7<.0001 Fat Mass (Kg)3.3±1.5<.05

19. 202530354045 Basal Metabolic Rate (kcal/hr/m 2 ) 0 1 2 Excessive Mortality High Basal Metabolic Rate Is a Risk Factor for Mortality: The Baltimore Longitudinal Study of Aging Ruggiero C. et al. Journals of Gerontology: Medical Sciences 2008; 63A:698

20. 40 35 30 25 Resting Metabolic Rate (kcal/m 2 /hr) 30 50 70 90 10 Age (years) Deceased Survived <35 yrs35-49 yrs50+ yrs Age at the Baseline Assessment High Basal Metabolic Rate Is a Risk Factor for Mortality: The Baltimore Longitudinal Study of Aging Ruggiero C. et al. Journals of Gerontology: Medical Sciences 2008; 63A:698

21. Age (yrs) 406080100 500 1000 1500 2000 2500 RMR (Kcal/day) RMRadj=2246-12.33*Age RMRadj=1914-6.07*Age Association Between Age and RMR In “Healthy” and “Not-Healthy” BLSA Participants Not Healthy Healthy

22. Energy Expenditure per Meter (ml O 2 /kg/m) Usual Gait Speed (m/s) ) Walking Energy Expenditure (ml/kg/min) Treadmill 1.6 Miles/hour Peak Walking Energy Walking Energetic Efficiency in the BLSA

23. Factors that May Affect Energetic Efficiency Global Motor Efficiency = (biomechanical work)/(O 2 consumption) O 2 Consumption O 2 Consumption Work Performed Work Performed Spirometer Exercise Testing

25. Energetic Cost of Walking and Max Knee Extension Range of Motion in BLSA Participants Ko S. and coll. Submitted to Gait and Postures d d 4 3 2 1 0 30 40 5060 70 Oxygen Consumption for Walking (mL/Kg/10 m) Maximal Knee Range of Motion During Gait (degrees) Y=3.0-0.046*X (r 2 =0.46. p<0.01)

26. Aging Phenotypes Changes in Body Composition Energy Imbalance Production/Utilization Homeostatic Dysregulation Neurodegeneration Physical and Cognitive FRAILTY Disease Susceptibility Reduced Functional Reserve Reduced Healing Capacity and Stress Resistance Unstable Health Failure to Thrive Geriatric Syndromes AGING Gait Disorders Falls Cognitive Impairment Sleep Disorders Disability Urinary Incontinence Delirium Decubitus Ulcers Comorbidity Aging Phenotypes and the Genesis of Geriatric Syndromes Ferrucci L, Studenski S. Clinical Problems of Aging. In: Harrison’s Principles of Internal Medicine, 18 th Ed. Longo, Fauci, Kasper, Hauser, Jameson and Loscalzo. McGraw Hill 2011 (In Press)

27. Source: Driscoll I et al. Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology. 2009 Jun 2;72(22):1906-13. Longitudinal Changes of Regional Brain Volumes In Normal Aging and MCI.

28. Kobilo T et al. Learn. Mem. 2011;18:605-609 ©2011 by Cold Spring Harbor Laboratory Press Dentate Gyrus Cell Proliferation and Neurogenesis, and Open-Field Locomotion 1 day after last BrdU injection 4 weeks after last BrdU injection Enriched Environment only Controls Physical Activity only Enriched Environment and Physical Activity

29. Open Field Locomotion and Hippocampal BDNF levels. Kobilo T et al. Learn. Mem. 2011;18:605-609 ©2011 by Cold Spring Harbor Laboratory Press Enriched Environment only Controls Physical Activity only Enriched Environment and Physical Activity Controls Physical Activity onlyEnvironment + Physical ActivityEnriched Environment only

30. Aging Phenotypes Changes in Body Composition Energy Imbalance Production/Utilization Homeostatic Dysregulation Neurodegeneration Physical and Cognitive FRAILTY Disease Susceptibility Reduced Functional Reserve Reduced Healing Capacity and Stress Resistance Unstable Health Failure to Thrive AGING Chronic Diseases Affect Aging Phenotypes Diseases CVD Diabetes CKD COPD Cancer HIV Dementia Parkinson Others? Geriatric Syndromes