extraordinary people who died too young · extraordinary people who died too young • aristotle...
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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
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
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.
~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
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.
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
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
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.
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
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.
HOPS Results: Quintiles
(Controlling for “High PE” school)
Source: 47th American Heart Association (AHA) Annual Conference on Cardiovascular Disease Epidemiology and Prevention.
Source: The Journal of Nutrition Vol. 127 No. 5 May 1997, pp. 943S-947S.
The response to long-term overfeeding in
identical twins
Probability of obesity in relation to time spent
driving or as a passenger
Source: Am J Preventive Med 2004;27(2) :87-96.
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.
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