Extraordinary people who died too young

• Aristotle (384 BC–322 BC) = 62 yrs old

• Dante Alighieri (1265–1321) = 56 yrs old

• Christopher Columbus (1451–1506) = 55 yrs old

• Leonardo da Vinci (1452–1519) = 67 yrs old

• William Shakespeare (1564–1616) = 52 yrs old

• René Descartes (1596–1650) = 54 yrs old

• Johann Sebastian Bach (1685–1750) = 65 yrs old

• George Washington (1732–1799) = 67 yrs old

• Albert Einstein (1879–1955) = 76 yrs old

Life expectancy almost doubled between

1840 and 2007

Source: Christensen et al. Lancet 2009.

U.S. demographics: Percent age 65 and over

Source: U.S. Census Bureau.

4.15.4

9.9

13

16.3

20.4

Prevalence of chronic disease

• About 80% of adults over 65 years of age have at least one

chronic disease, and 50% have two or more chronic diseases

• Cardiovascular disease, cancer, stroke and diabetes account for

nearly 70% of the deaths in the United States and Europe

Risk factors for CVD

• 43.1% of men and 35.8% of women in the U.S. have an

LDL-cholesterol > than 130 mg/dl

• 65% and 88% of people 60 or older have hypertension (>140/90

mmHg) or pre-hypertension (BP> 120/80 mmHg), respectively

• Median CRP for Americans is ~ 2mg/L; 16.4% have a CRP higher

than 5 mg/L

• Age-adjusted prevalence of high-risk waist circumference is

~37% in men (≥ 102 cm) and 55.1% in women (≥ 88 cm)

Biomarkers for many chronic diseases are still

missing

• In 2011 we have good risk factors predictive of

coronary heart disease, stroke, type 2 diabetes

• In 2011 risk factors for cancer, Alzheimer’s and

autoimmune diseases are still missing

• In 2011 markers of biological aging are still missing

Cancer: the silent killer

• Among women age 40 to 79 and among men 60 to 79, cancer is

the leading cause of death in the U.S.

• The lifetime probability of developing cancer is ~46% for men

and ~38% for women

Cancer rates among Japanese migrants to

Hawaii (1973-1977)

Source: Peto J. Nature 2001.

Mortality rate of prostate cancer increased

over time in Asia

Source: Sim HG. Et al. Eur J of Cancer 2005.

Age-specific prevalence of latent and

clinical prostate cancer

Histological prostate cancer Clinical prostate cancer

Source: Dhom G. J Cancer Res Clin Oncol 1983.

Calorie restriction without malnutrition

increases healthspan and lifespan

up to 50% in rodents

Sources: Masoro EJ. Mech Ageing Dev. 2005, Weindruch R. N Engl J Med 1999.

Mammalian animal models of longevity

Source: Fontana L et al. Science 2010.

Conserved Nutrient Signaling Pathways

Regulating Longevity

~30% of the CR rodents die

without any gross pathological lesion

Source: Shimokawa I et al. J Gerontol 1993.

~20% of centenarians are escapers

In a longitudinal study of the 424 centenarians:

• 19% were ESCAPERS (without common age-associated disease

before 100 years of age)

• 43% were delayers (age-associated disease after 80)

• 38% were survivors (age-associated disease before 80)

Source: Evert et al., J. Gerontol. A Biol. Sci. Med. Sci 2003.

Long-term cardiometabolic effects

of CR in humans

• Prevention of obesity and type 2 diabetes

• Improved lipid profile

• Powerful anti-hypertensive and anti-inflammatory effects

• Prevention of atherosclerosis

• Improvement of left ventricular diastolic function (younger hearts)

Source: Fontana et al. JAMA 2007.

CR practitioner before starting CR and

after 7 years of CR

Source: Fontana L et al. Science 2010.

Body weight

T-chol and LDL-c

Fasting glucose

Blood pressure

180 lb or 81.6 kg (BMI 26.0 kg/m2)

244 mg/dl and 176 mg/dl

87 mg/dl

144/87 mmHg

134 lb, or 60.8 kg (BMI 19.4 kg/m2)

165 mg/dl and 97 mg/dl

74 mg/dl

94/61 mmHg

Common carotid artery

82 yrs old CR

Common carotid artery

77 yrs old Runner

Long-term CR reduces metabolic factors

associated with cancer in humans

• Reduces adiposity

• Reduces insulin

• Reduces sex hormones

• Reduces inflammation

• Reduces oxidative stress

Source: Longo and Fontana. Trends Pharmacol Sci 2010.

Long-term CR reduces plasma IGF-1

concentration by 30-40% in rats

Source: Breese CR et al. J Gerontol Biol sci 1991.

Long-term CR does NOT reduce

serum IGF-1 concentration

Source: Fontana et al., Aging Cell 2008.

Moderate protein restriction reduces

serum IGF-1 concentration

Source: Fontana et al., Aging Cell 2008.

Diet composition: protein restricted vegan diet

versus CR diet

Source: Fontana et al., Aging Cell 2008.

Serum IGF-1 is associated with

increased risk of breast and prostate cancer

Source: Hankinson SE, Lancet 1998 & Chan JM, Science 1998.

31 genetically-diverse inbred mouse strains

(median lifespan: 251-964 days)

Plasma IGF-1 levels are

negatively correlated with

median lifespan in mice

For the longer-lived strains (>600 days), the negative

correlation between lifespan and IGF-1 is stronger:

6 mos R=-0.53, P<0.01; 12 mos R=-0.39, P<0.01; 18

mos R=-0.3, P<0.05. Source: Yuan et al., Aging Cell 2009.

Protein requirements for healthy adults

EAR (50th percentile) = 0.65 g/kg/d

RDA (97.5th percentile) = 0.83 g/kg/d

n = 224 individual subjects

from 32 studies

Source: Rand WM et al. AJCN 2003.

My goal is to study and implement strategies

for the promotion of SUCCESSFUL AGING

SUCCESSFUL AGING defined as

the ability of human beings to AVOID DISEASE AND

DISABILITY and remain:

• physically and cognitively healthy

• happy and creative

• empowered

• contributing to social and productive activities

• active & independent

..... for as long as possible.

Ideally, healthy lifespan = lifespan

↓ Calorie intake

↓ Protein intake

↑ Phytochemicals

intakeExercise

The “longevity” puzzle

Mechanisms in humans?

Vitamin D

OPTIMAL CALORIE INTAKE FOR

SUCCESSFUL/HEALTHY AGING

Source: Fontana L. et al. JAMA 2007.

Antioxidant Vitamins: Cause-Specific Mortality

Functional Whole Foods

• Tea

• Milk

• Blueberries-Anthocyanins

• Broccoli-Isothiocyanates

• Fish Oil

• Nuts

• Wine

• Chocolate

Source: Nemetz, P. N. et al. Arch Intern Med 2008;168:264-270.

Heart disease mortality rates for the U.S. population: 1900-2004

Coronary Heart Disease Mortality Among Adults

in the U.S. 1980-2002

Concealed Leveling of Mortality Rates

Source: J Am Col Card 2007;50: 2128-2132.

Source: J Am Col Card 2007;50: 2128-2132.

Concealed Leveling

of Mortality Rates

Trends in Age-specific Mortality Rates

From Coronary Heart Disease

Coronary Heart Disease Mortality Among Young

Adults in the U.S. From 1980 Through 2002

Concealed Leveling of Mortality Rates

Source: J Am Col Card 2007;50: 2128-2132.

Survival Mechanisms

• Ability to Store Fat

• Ability to Lower Metabolic Needs During Famine

• Desire for Sweet, Fatty, Salty Food

• Inflammatory Response When Energy Reserve Present

Source: Jo Robinson 2004.

Sweet, Fatty, Salty

Peach vs. Coke

Survival Mechanisms

• Ability to Store Fat

• Ability to Lower Metabolic Needs During Famine

• Desire for Sweet, Fatty, Salty Food

• Inflammatory Response When Energy Reserve Present

Source: Wellen, K. E. et al. J. Clin. Invest. 2005;115:1111-1119.

Metabolism and Immunity are Closely Linked

Rosenzweig, A. N Engl J Med 2003;348:581-582

Three Stages in the Movement of Endothelial Progenitor Cells from Bone Marrow to Vascular Endothelium

Source: Rosenzweig, A. N Engl J Med 2003;348:581-582.

Adult Stem Cells

Smoking, Aging and Rust

Smoking, Aging and Rust

Source: Chiu, C.-J. et al. Am J Clin Nutr 2007;86:180-188.

Multivariate-adjusted mean dietary glycemic index (dGI) by age-related macular degeneration (AMD) groups

Macular Degeneration and Diet

1 year AAV9-RegVEGF

1 year PBS

Stem Cells and Rabbit Femoral Artery

25.0

30.0

35.0

40.0

45.0

50.0

5.00 5.50 6.00 6.50 7.00 7.50 8.00

Weig

ht

(g)

Age (mo)

Body Weight

SB

SBe

HF

HFe

Source: Webster K PLoS ONE February 2011 | Volume 6 | Issue 2 | e17263.

Regression of Plaque with Diet and Exercise

in Mice

High Fat

High Fat + Exercise

Med Diet

Med Diet + Exercise

Regression of Plaque with Diet and Exercise

in Mice

Source: Webster K PLoS ONE February 2011 | Volume 6 | Issue 2 | e17263.

Kids

Malnutrition USA 2010

HOPS Results: Quintiles

(Controlling for “High PE” school)

Source: 47th American Heart Association (AHA) Annual Conference on Cardiovascular Disease Epidemiology and Prevention.

Fat and Fit vs.

Normal Weight

Obesity

Source: The Journal of Nutrition Vol. 127 No. 5 May 1997, pp. 943S-947S.

The response to long-term overfeeding in

identical twins

The

Cosmo

Effect

GS-56-F..Obese

• TC 210

• LDL 108

• HDL 85

• TG 83

• LDL-A 269-277

• HDL2B 27%

Normal

Weight

Obesity

RP 42 yo FH early CAD

TC 190, BMI 23, Runs 5 K races

Source: Ebbeling, C. B. et al. JAMA 2007;297:2092-2102.

Change in Body Weight vs. Insulin Levels

Source: Jeppe T Friborg Lancet Oncol 2008; 9: 892–900.

Cancer patterns in Inuit

populations

Communities

Communities

Source: Frank LD Preventive Medicine 2008;47:172-78.

Probability of obesity and distance walked

Source: Am J Preventive Med 2004;27(2) :87-96.

Probability of obesity in relation to time spent

driving or as a passenger

Source: Am J Preventive Med 2004;27(2) :87-96.

Probability of obesity in relation to land-use mix

Source: Am J Preventive Med 2004;27(2) :87-96.

Eskimos

Source: Jeppe T Friborg Lancet Oncol 2008; 9: 892–900.

Cancer patterns in Inuit populations

Coronary CT-Normal Coronaries

Coronary Calcium Movie

Noninvasive Coronary CT-Bypass

87.3% 9.3% 3.4%

Events Stratified by ATP III & CAC Categories

All Subjects

Data = Event Rates (95%CI)

62.9% 23.1% 14.1% 49.8% 27.4% 22.9%51.5% 28.8% 19.7%

Low risk

0

8

12

20

Even

t R

ate

in

5 Y

ears

[%

]

16

4

<100 100-399 ≥400 <100 100-399 ≥400

Intermediate risk High risk

ATP III

CAC <100 100-399 ≥400

Source: Erbal, R JACC;2010:vol 56, #17

Source: Detrano NEJM Volume 358:1336-1345.

Coronary Calcium as a Predictor of Coronary

Events in Four Racial or Ethnic Groups

(MESA)

Copyright restrictions may apply.Source: Lakoski, S. G. et al. Arch Intern Med 2007;167:2437-2442.

Survival in women at low risk by Framingham score by amount of coronary calcified plaque

Low Score

Medium

Scores

High Score

Diabetes and All Cause Mortality

Source: New England Journal of Med icin 364;9 nejm.org march 3, 2011.

Quantification of Coronary Atherosclerosis

and All-Cause Mortality

Source: J Am Coll Cardiol 2011;57:1455–64.

Carotid Disease

MT 45 yo WF, BMI=22, +FH Carotid Ultrasound,

HDL=96, FRS<1%

JR-65 yo wf, BMI 19.3, - FH, +BP, HDL 120

LDL Size

PS 66 yo TC=314,LDL=229 Calcium Score=0,

Large LDL

50 yo TC=185

Bypass age 46, Very small LDL

LDL Size Distribution Spectrum

HDL Metabolism

NL Function HDL GGE

(80 yo WF with Calcium Score=0)

Functional TestingEndothelial Function

ITS To Stop Bleeding Fast"60% of preventable combat deaths are from extremitybleeding,and 50-70% of all combat injuries are extremity wounds."