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Physiology of Aging

Prof. Dr. Hardi


Darmawan, MPH&TM,
FRSTM,
Sriwijaya AIF School
Medical
Palembang, South Sumatera -
Indonesia
1. Outline

General Concepts
Theories of Aging
Aging at the Cellular and Molecular
Level
Interventions in the Aging Process
What is aging?
2. Definition

A process of senescence
is not a disease
occurs at different rates
among individuals
within individuals
does not generally cause symptoms
2. Definition

Aging

Disease Non-disease

Usual Successful

Rowe & Kahn, Science 237:143, 1987


2. Definition

Aging is NOT a disease.

Aging is a

DEVELOPMENTAL PROCESS.
2. Definition

Greta Garbo
2. Definition

Optimal Best example or idealized


Usual - most common
Universal seen in all humans
All are influenced by:
Genetics - Lifestyle
Physiology - Socioeconomics
3. Etiology

Interplay of
Hormonal pauses
Free radical activity
Glycation Theory
Wear & tear theory
Telomere shortening
Immune dysfunction
genetics
4. Demography
Significance of Human Aging
People live longer now than ever before
By 2030, 20% of the US population will be 65 and older
Significant challenge to medicine-ethical, financial, etc.
4. Demography
Significance of Human Aging

What is normal in
the aging process
primary aging
More susceptibility to
disease secondary
aging
More heterogeneity in
the elderly population
Onset indeterminable
and progression varied
Genetic and
environmental factors
4. Demography
Indonesian Life Expectancy

2000 2005 : 67.8 years


2020 2025 : 73.6 years

Saparman,Sragen (143 yrs) Mak Encuh, Bandung (131 yrs)


4. Demography
Life Expectancy List by the United
Nations (2005-2010)
Rank Country Life Expectance at Life Expectance at birth Life Expectance at
birth (years) Overall (years) Male birth (years) Female
1 Japan 82.6 78.0 86.1
2 Hong Kong 82.2 79.4 85.1
3 Iceland 81.8 80.2 83.3
4 Switzerland 81.7 79.0 84.2
5 Australia 81.2 78.9 83.6
6 Spain 80.9 77.7 84.2
7 Sweden 80.9 78.7 83.0
8 Israel 80.7 78.5 82.8
9 Macau 80.7 78.5 82.8
10 France (Metro) 80.7 77.1 84.1
11 Canada 80.7 78.3 82.9
12 Italy 80.5 77.5 83.5
36 United States 78.3 75.6 80.8
4. Demography
Life Expectancy at birth
4. Demography
Longest-lived Humans
4. Demography
The places where people live the
longest

Okinawa, Japan
Ovodda, Sardinia, (Italy)
Loma Linda, CA (USA)
4. Demography
Keys to longevity-Okinawa

hara haci bu
Rainbow diet
Diet: soy > fish, meat,
eggs, dairy
BMI 20.4
~1200 cal diet
DHEA levels decline more
slowly
4. Demography
Keys to longevity-Ovodda, Sardinia
As many men live to
100 as women
Sardinians who
emigrated at 20, 30
or 40 years of age
still manage to
reach100
Descended from only
a few original settlers
isolated,
4. Demography
Keys to longevity-Loma Linda, CA
Seventh Day Adventists
Members live 5-10 years
longer than fellow
citizens
No drinking or smoking
Many adhere to a
vegetarian diet the
church advises
Spiritual life
Regular churchgoers of
whatever faith - live
4. Demography
Keys to longevity

How long would you live if you were


a
Sardinian, 7th Day Adventist who
moved to
Okinawa at 20 years of age?
4. Demography
Broken Limits to Life Expectancy

Female life-
expectancy
in Japan has risen for
160 years at a steady
pace of almost 3
m/yr!

Oeppen & Vaupel Science 296: 1029-31 (2002)


4. Demography
Compression of Morbidity

Fries, JF Ann Int Med 139:455-9 (2003)


5. Physiology of Aging

What is normal
(clinically expected)
aging physiology?
Aging Physiology

Source Undetermined
Overview of Aging Physiology

Skin Musculoskeletal
Body System
Composition Renal
Vision GI
Special Senses Cardiovascular
Nervous System
Aging Skin
Physiologic Changes in the
Dermis with
Skin Aging
more easily damaged
Delayed wound healing
Decreased inflammatory response
Decreased protection from
ultraviolet light
Decreased urticarial reaction
Wrinkling, sagging skin
Skin easily stretched under low
loads
Loss of resiliency
Diminished absorption
Altered thermal regulation
Source Undetermined

Decreased sensitivity to pain and


pressure
Source Undetermined
Aging and Central Adiposity

Source Undetermined
Source Undetermined
Source Undetermined
Age-Associated Factors -
Vision

visual acuity (cataracts,


macular degeneration)
dark adaptation
peripheral vision
(glaucoma)
contrast sensitivity Source Undetermined

accommodation
Age-Associated Factors-
Special Senses

Auditory and Vestibular


Presbycusis: high frequency hearing loss
Vestibular dysfunction
Smell
Oral/Dental
Teeth: 40% of elderly are edentulous
Taste
Salivary function
Pearson Scott Foresman, wikimedia
commons
Age-Associated Factors-
Nervous System

CNS: decrease in nerve cell


number
basal ganglia atrophy
dopamine and muscular
rigidity
step height
reaction time
PNS: decreased vibratory Grays Anatomy, wikimedia commons

sensation
Age-associated Factors:
Musculoskeletal system
30% loss in muscle mass 3rd to 8th decade -
sarcopenia.

Osteoarthritis
weight bearing (spine/knees/1st metatarsophalangeals)
repeated strain (distal interphalanges/1st carpometacarpals)

Osteopenia/-porosis (80% women >65 y/o


osteopenia)
decreased activity, dietary calcium, estrogen withdrawal
OSTEOPOROSIS AND FRACTURES
Low dietary intake of
calcium
Loss of endocrine
protection
Reduced endogenous
production of vitamin D
Disuse
Disease Chronic Renal
Disease, Rheumatoid
Arthritis, Thyroid Disease
Medications Steroids,
Thyroxin.
OSTEOPOROSIS

Age related disorder,


aging disease major morbidity/mortality
atherosclerosis CV diseases
metabolic syndrome
tumors
neurodegenerative diseases
OSTEOPOROSIS
till
Asymptomatic bone fracture &
complication risk
bone mineral density Fragility fracture
Loss of architectural integrity
Should understand
physiology pathophysiology
Immuno senescence & inflammatory of aging
Immuno senescence lifelong antigenic load
chronic
hyper immune system activation
production proinflammatory
Proinflammatory cytokines - IL-1, IL-6, TNF
inverse CRP
Immuno senescence shape the same
immunological cell & cytokine
TNF, IL-1, Rank-L, M-CSF expression
osteoclast precursor

Why not build the osteoblast


aging & estrogen deficiency :
most important risk - osteoporosis
IMMUNE MECHANISM OF
OSTEOPOROSIS
The skeleton is physiologically in a state of
dynamic equilibrin between

formation vs reabsorption
osteoblasts vs osteoclasts

tuning by cytokins
growth factors
ACCUMULATION
Age immune profile
memory/effector cells expressing
Rank L resident in bone
secreting
osteoclastogenic
proinflammatory cytokins
NATURAL BONE
BUILDING PLAN

1. Hormones
2. Minerals
3. Vitamins
4. Diet
5. Digestion
6. Exercise
Hormones
Vit D is a steroid
hormones
Determinat for bone
health & all ages
determinant
SUMMARY OF HORMONES TO TREAT BONE LOSS (1)
1. Estrogen to prevent bone loss : estradiol
transdermal titrated area 1 mg/ml
2. Progesterone
To build bone & balance estrogen
50-300mg oral / transdermally
SUMMARY OF HORMONES TO TREAT BONE LOSS (2)

3. DHEA/testosterone
Start DHEA (5-25 mg/day)
Testosterone 1-5 mg/night
4. Melatonin (0.5 3 mg/night)
5. GH if IgF -1 low or below mid range
SUMMARY OF VITAMINS TO TREAT BONE LOSS

1. Vitamin D3 2000-5000 u/d


2. Vitamin K2 50-150 mcg/d
3. Vitamin C 1000mg 4000mg/d
4. Vitamin B 100mg/d, if
homocysteine not
improving use
Methyl B12/ folic
acid
5. Vitamin E 200-800 U
Summary of Mineral to treat Bone Loss

1. Magnesium
DIET & BONE HEALTH
Enzyme function optimally at PH neutral
Acidic by products accelerate bone loss
High protein & diary (western diet) chronic metabolic
acidosis
Bones ability to neutralize acid load -- depend on KT stores
K+ intertitial fluid
K+ Ca++ from bone to buffer in a place of K T
chronic high steroids KT
diuretics

Eating alkaline diet


Rich fresh fruit vegetables
Limited protein & diary
Artificial sweetness
Preservatives
HORMONE DEFICIENCIES MANY IF NOT MOST OF THE SIGNS,
COMPLAINTS, CAUSES OF SENESCENCE
Age-related signs : Age-related
- wrinkles physiology :
- skin & hair - Intestinal transit
thinning - cardiac output
- hair loss - kidney function
- muscle atrophy - liver function
- abdominal
Age-related
obesity
Age-related symptoms :
diseases :
- fatique
-
- cognition
cardiovascula - depression
r
- cancer
- obesity
- diabetes
- osteoporosis
ACIDIFYING FOODS Alkalinizing Foods
Sugar Honey, maple syrup,
Yeast, wheat breads stevia
Soft drinks, alcohol, tea, Goats milk
coffee Soy milk
Cranberries Umeboshi plums
Sweet potato Sea salt
Salt Most herbal teas
HOPS Lemon, limes, grapefruit,
Corn oil onion
White balsamic vinegar Olive oil
Saccharine, aspartame Miso
benzoate Most fruits & vegetables
Aging Renal Physiology

GFR 30-46%
Tubular function
Renal plasma flow ~50%
CrCl = [(140 - age) x (BW)]/[72 x SrCr ]
Multiply x 0.85 for females
BW in kg (LBW or IBW with edema or obesity)
Grays Anatomy,
wikimedia commons
Absorption: GI Physiology

GI absorptive cells
GI motility or normal
Sphincter activity
GI blood flow
Gastric acid secretion
Active transport

Source Undetermined
Wikimedia commons
Afterload: Vascular Changes
Vascular Smooth Muscle
Increased thickness of intima and media
Matrix
Collagen deposition, increased fibronectin,
crosslinking (AGEs)
Fragmentation of elastin, calcium deposition

Net result is increased vascular stiffness.


Summary: Age-associated changes in
cardiovascular physiology

Maintenance of resting left


ventricular function.
Decreased ability to compensate
for stress or impaired LV function.
Blunted heart rate response to exercise
requires a compensatory increase in
stroke volume to increase cardiac output.
Effect of Aging & CAD on Exercise LV
Ejection Fraction

Fleg et al., J App


Physiol, 1993
Aging
and
Aerobic
Capacity

Source Undetermined
6. Theories of Aging
THEORIES OF AGING
Mechanism of Aging

Albert Einstein

HillaryldClinton 61
Theories of Aging
1. Wear & Tear Theory 10. Mitochondrial Theory
2. The Neuroendocrine Theory 11. Error & Repair Theory
3. The Genetic Theory 12. Redundant DNA Theory
4. The Free Radical Theory 13. Cross Linkage Theory
5. The Waste Accumulation 14. Autoimmune Theory
Theory 15. Calorie Restriction Theory
6. Limited Number of Cell 16. Gene Mutation & DNA
Division Theory Damage Theories
7. Hayflick Limit Theory 17. Order to Disorder Theory
8. Death Hormone Theory 18. Telomerase Theory of Aging
9. Thymic Stimulating Theory 19. Technodemography Theory

ld 62
WEAR AND TEAR
THEORY

Dr. August Weismann


(German Biologist, 1882)
Cell damage (over use & abuse)
Liver, stomach, kidneys, skin and so on

Worn down by : toxin in diet and
environment
Excess of fat, sugar, caffeine, alcohol, nicotine
UV rays of sun
Physical Strain
Emotional Stresses
Wear & tear :
Organ
Sometimes cellular

Young body compensation ?


night heavy drinking
Binge of pizza, hamburger,
sweets

Age body loses repair ability,


caused by :
Diet, environmental toxins,
bacteria, viruses
ld 66
Balanced Diet
Energy intake 50/25/25
50% Carbohydrate - fruits & vegetables
25% Protein - 2/3 plant, 1/3 meat
preferably fish
25% Fat (mono & poly) unsaturated

67
Balanced Anti Aging Diet
Caloric restriction Keep low end of
ideal body weight
Okinawan diet

68
Okinawan Diet
7 servings of
vegetables
7 servings of grains
4 servings of fruits
Abundance of soy
3 times per week fish
Alcohol in moderation
Low caloric diet

John Hopkin study Okinawa 300


men + woman

69
Diet Timur Tengah
(Mediterania)
Buah segar
Sayuran
Melibatkan Sereal dari
beberapa
komponen
gandum utuh
makanan Kacang
Ikan
Daging Unggas
Minyak Zaitun

70
Positive Food Intake
Fruits - Minerals & Vitamin
Vegetables - Fibres & Phytonutrients
Spices Hormone modulator, Cancer
Preventive
Mushrooms/Ginsengs Adaptogen
SOD
Glisodin

71
Hydration
Drink liquids (ml)= 33 x body weight(kg) /day
Hydrate before during & after exercise
Test hydration status
Specific gravity 1020

72
Killer Intake - Delicious

Avoid high fat, salt, sugar.


Avoid trans fatty acid cooked fat
Avoid acralamide heated carbohydrate
Avoid preservatives & additives

Eat as a commoner, live as a lord & Cheat Occasionally!


Selvaraj Y S

73
Elderly people die of diseases :
could have resisted when they
are younger

The concept of wear and tear differ


from person to person depend
upon :
Lifestyle
Methods to reverse the wear and tear

ld 74
The
Neuroendrocrine
Theory
Vladimir Dilman PhD,
Network of biochemicals
govern release of
hormones or vital elements

ld 75
Young :
Hormones work together to
regulate (bodily functions)
Eq : response to heat & cold
level of sexual activity

Hormones release, different


organ under the governance of
hypothalamus (Walnut size)

ld 76
Hormone :
Vital for
repairing &
regulating
your bodily
functions

Aging
hormones
ld 77
Young :
: Menstruation
: High libido
Growth hormone (HGH) :
(muscle man)

HGH, testosterone, thyroid H


as you age
gained weight

ratio fat to muscle

ld 78
The
Genetic Theory

Genetic code :
programming encode in DNA
types
Physical & Mental
ld
Functions 79
Anti aging medicine :
Augmenting basic building of DNA
Preventing damage
Increasing repair of DNA
ld 80
Genetics

20 % der altersbedingten
Erkrankungen haben eine
genetische Basis: Diabetes,
Arthritis, HLA-assoziierte
ld Erkrankungen, Dyslipidmie, 81
genetische Formen der mentalen
82

The Free Radical Theory


R. Gerschman 1954
Dr Denham Harman (Nebraska)

ld 82
Free Radical
Molecule that differs from
conventional molecules that
possesses a free electron, a
property that makes it react with
other
Molecule : highly volatile
Is not only
destructive ways negative
Positive things

ld 83
Free Radical Theory
Oxidative Stress = Free Radicals >
Antioxidants
Accelerated Aging
Diabetes
Sun exposure
Poor nutrition
Stress

Effect
Free radical overactivity
Imbalance between Antioxidant-Free
radical
Oxidative stress 84
RADIKAL BEBAS
Yaitu atom atau molekul yang mengandung elektron
yang tidak berpasangan pada orbit terluarnya.
Bersifat reaktif dan tidak stabil
Disebut juga prooksidan
Simbol R
Dalam jumlah sedikit bermanfaat

85
Encyclopedia Life Sciences 2001
Jenis Radikal Bebas
ROS : Reactive Oxygen Species:
Paling banyak terpapar pada manusia
Paling banyak diteliti

RNS : Reactive Nitrogen Species


dll

862001
Encyclopedia Life Sciences
ROS
(Reactive Oxygen Species)
Superoxide Oksigen merupakan zat yang
O2
vital namun di lain pihak
OH Hidroxyl merupakan bahan yang
RO2 Peroxyl merusak
Oksigen merupakan sumber
RO Alkoxyl
utama ROS
HO2 Hydroperoxyl Penghasil utama superoxide

87
Encyclopedia Life Sciences 2001; J Clin Ivest. 2005
Sumber Radikal Bebas
RADIKAL BEBAS

INTERNAL EKSTERNAL

Proses metabolisme Polusi


Proses respirasi Radiasi ultraviolet
Zat kimia
Rokok
Alkohol
dll
88
www.wellnessjournal.net
Oxygen distribution
Tight flux + Energi
O2 ADP
respiratio work
n cell

H2O ATP
free radicals
89
90
91
Encyclopedia Life Sciences 2001
Cumulative Oxidative Damage during Aging
O2

Aerobic metabolism
Cytochrome oxidase Mitochondrial ubisemiquinone peroxisomal enzymes, cytosolic oxidases,
cyctochrome P-450, macrophages, activated neutrophils

Catalase, GSH peroxidase SOD


H2 O
H2 O2 O2 NO

X
Secondary ROMs Redox-sensitive
Hydroxyl, alkoxyl, peroxyl, Cellular functions
phenoxyl, semiquinone, carbon- X Cellular differentiation
centered, thiyl, peroxynitrite Signal transduction,
transcriptional control
X Oxidative
stress
Macromolecules
Redox-sensitive
DNA, RNA, proteins, lipids
Cellular functions
X Cellular differentiation
Signal transduction,
Repair or
degradation of Oxidized, macromolecules transcriptional control
oxidized DNA, RNA, proteins, lipids
molecules
Irreversible molecular damage Physiologic attrition

Weindruch, R & Sohal, RS NEJM 337:986-94 Aging, disease, and death


www.oxidativestressresource.org

93
ANTIOKSIDAN
Yaitu senyawa yang dapat memperlambat,
mencegah atau menangkal reaksi radikal bebas

Clinical Nutrition Insights 1998

94
(Asian J. Androl 2004 Mar 95
6:
59- 65)
ANTIOKSIDAN
Yaitu senyawa yang dapat memperlambat atau mencegah
atau menangkal interaksi oksidan dengan target molekulnya

Antioksidan Endogen / Antioksidan Eksogen /


Primer (antioksidan yang Sekunder (antioksidan
dihasilkan oleh tubuh) yang di dapat dari luar
- SOD (Superoxide tubuh/makanan)
dismutase) - Vit. C, E, A, beta-carotene
- GPx (Glutathione
peroxidase) - Selenium, zinc, dll
- Catalase - Lycopene, polyphenol,
dll
96
Clinical Nutrition Insights 1998
Perbandingan Efek Protektif Antioksidan

1) The main essential enzymes


Superoxide dismutase (SOD), catalase, glutathione
perioxidase (GPx)
2) The electron trapping molecules
Vitamins A, E, C, beta-carotene, flavonoids, trace
elements.
SUPEROXIDE DISMUTASE (SOD)
Salah satu antioksidan enzimatik
Sebagai enzim, SOD merupakan katalisator untuk
memfasilitasi reaksi konversi superoxide menjadi
hidrogen peroxyde SOD menjadi pertahanan
intrasel pertama (tahap paling awal) terhadap radikal
bebas (ROS)

2O2 (superoxide) + 2H+ H2O2 + O2


SOD
98
Phytothrapie 2005;3: 1-4
Superoxyde Dismutase (SOD)
Hydrogen peroxide selanjutnya dinetralkan menjadi H2O
& O2 oleh GPx dan Catalase

99
Phytothrapie 2005;3: 1-4
100
Superoxyde Dismutase (SOD)
Ada 3 bentuk SOD:
Isoform 1: Cu/ZnSOD (SOD1) pada sitosol & inti sel

Isoform 2: MnSOD (SOD2) dalam mitokondria

Isoform 3: EC-SOD (SOD3) dalam ekstraseluler &

cairan plasma

Adv Clin Exp Med 2007;16(4):5618

101
Produksi SOD Di Dalam Tubuh

Semakin tua usia produksi SOD semakin menurun


Niwa Y. Circulation102
1981
? Systemic Inflammatory = Silent,
Minimally Persistent Inflammation
AA, Arachidonic Acid (Omega 6) high in contemporary diet
higher AA in cell membranes
AA is readily released than EPA (Omega 3)
AA reacts avidly than EPA with cyclo-oxygenase enzyme

AA-eicosanoids > EPA-eicosanoids = Systemic Inflammation


Silent Inflammation = Inflammation without the 5 cardinal
signs
pain, red, swell, heat and loss of function
103
Glycation Theory
Occurs in everyone, but at a faster rate in
diabetics
Reaction with glucose with macromolecules
devastating effects on macromolecules
Rigidifying cross linkages between
macromolecules
Condition related to AGE
Senile dementia
Vascular Stiffening
Cataract 104
Oxidative Stress Bodily
Damage
Heart disease
Hypertension
Cancer
Inflammatory bowel disease (IBD)
Arthritis
Diabetes
Alzheimer's disease
Parkinson's disease
Stroke

105
Genetic Basis of Aging Theories
High conservation of maximum life span
between species
Similarity of attained age between
monozygotic twins compared to dizygotic
twins or nontwin siblings
Examples of exceptional longevity within
families
Subsets of aging features in human genetic
syndromes of premature aging

106
5 Strategies of Healthy Aging
Balanced Diet
Precision Exercise & Hydration
Practical Stress Management
Optimal Nutritional Supplement
Physiological Hormone Replacement
Therapy

107
3 Phases of Aging
Sub-Clinical Phase
25 35 year
of chronological age

Transitional Phase
35 45 year
of chronological age

Clinical Phase
45 onwards
of chronological age 108
Sub-Clinical Phase
Growth hormone drops to about 14%
Free radical formation and cellular
damage
Not obvious with the naked eye
Bone aging & skin aging minimal
Feel Good & Normal
Generally in denial

109
Transitional Phase
Growth Hormone production dropped by
25%
Biomarkers show early changes
Clinically graying hair
Visual acuity reduction
Pigmentation
Energy & Strength reduction
110
Clinical Phase
Growth hormone, melatonin, DHEA, Sex
hormone decline
Skin cellular dehydration, collagen
breakdown & elastin loss leading to
thinning & wrinkles
Sarcopenia & Arthritis
Degenerative diseases
111
Evolutionary Theory
Risk of mortality increases with time after
reproduction
Genes that confer early benefits On
reproductive fitness are selected, even if
they cause deleterious effects later in life
No selective pressure against genes that
confer negative effects later in life
Strong pressure to retain genes that
diminish vulnerability in young and old alike

112
113
114
115
116
Telomerase Theory of Aging
Geron Corporation (Menlo Park, California)
Telomeres : sequences of nucleic acids
extending from the ends of chromosoms
Telomeres : maintain integrity of chromosoms
Telomeres shortened cellular damage

Cellular death

aging
117
ld 117
revisi ke-2 118
Short Telomeres are associated
with unhealthy aging and a
shorter life span
Telomeres from the ends
of human chromosome
Telomeres shortened
limit proliferation of
human cells, by inducing :
Replicative senescence
Differentiation
Apoptosis
Increasing cancer risk

Telomere Shortening & Aging (2007).


H.Jiang, Z.Ju, K.L Rudolph: Z Gerontol. Geriat 40:314-324
revisi ke-2 119
120
121
Short Telomeres have been
associated with maladies in
these tissue
Immune cells- : Osteoblasts, MSCs
memory and nave Retinal pigmented
Heart tissue of eye
cardiomyocytes
Chondrocytes
Hematopoietic stem
cells Skeletal muscle
Lung alveolar cells Kidney cortex
Skin dermis, Neurons
epidermis,
vasculature
Vascular intima
(endothelium)

122
Replication Potential of
Normal Human Cells
Replication Potential of
Normal Human Cells

Telomeras Telomeras Telomeras Telomeras


e- e- e+ e+
Replication Potential of
Normal Human Cells

Telomeras Telomeras Telomeras Telomeras


e- e- e+ e+
Aging, Cancer, and p53

Ferbeyre, G & Lowe, SW Nature 415: 26-7 (2002).


Interactions between p53/p21 and p16/Rb

2012 Cell Proliferation Group | http://cellpro.csc.mrc.ac.uk


Immune Senescence
(Perturbation of adaptive immune system with age)
Altered/diminished immune responsiveness
Decreased response to new antigens
Decreased vaccine efficiency (e.g., influenza)
Compromised immune surveillance
Altered immune system physiology
Thymic involution
Decreased production of lymphocytes
Inversion in proportional representation of memory vs nave cells
(T memory cells increase and T nave cells decrease with age)
Altered immunoregulation
Increase in autoimmune syndromes (SLE, RA, SS, others)
Oligoclonal expansion of T- and B-cells (decrease in diversity
with age)
Monoclonal gammopathies
Interventions in the Aging
Process
Cell-based therapies
Hormonal therapies
Genetic manipulations
Dietary therapies
Other: hypothermia, exercise
Dietary Therapies
Caloric Restriction
Extends average and maximum life spans by 30-40% if initiated
in early adulthood, and by 20% if started in early middle age
Usually 30-60% reduction in calories with adequate content of
essential nutrients
Effect preserved in a variety of species, including rodents, fish,
flies, and worms
Effect of Dietary Restriction on
Life Span
100 Ad libitum
85 kcal/wk
50 kcal/wk
40 kcal/wk

75

50

25
25

0
0 10 20 30 40 50 60
Age (mo.)

Weindruch, R & Sohal, RS NEJM 337: 986-94 (1997).


Caloric Restriction in Non-human Primates
Caloric Restriction in Non-human Primates
Caloric Restriction in Humans

Okinawans
Biosphere 2 Project
Short-term studies in humans
Caloric Restriction in Humans

Common to both Lower levels of plasma insulin


CR nonhuman Lower body temperature 25% CR in humans
primates & long- x 6 months
Maintenance of higher plasma
lived males DHEA levels

Roth, GS er al. Science 305:1423-6 (2004)


Sirtuins (protein deacetylases):
mediators of caloric restriction ?
Resveratrol, a sirtuin activator, improves health and survival of
mice on a high-calorie
i l f diet
i hi h
Baur, JA et al. Nature 444:337-42 (2006)
Effects of Resveratrol
Dietary
Therapies
Antioxidant supplementation
Does not significantly change median or maximum life
span
Except for vitamin E (and possibly vitamin C) being able
to lower lipid oxidative damage, no evidence to support
reduction in oxidative damage in humans
A compound with catalase and SOD activities (EUK-134)
extends longevity in nematodes
Foods with a high oxygen radical absorbance capacity
(ORAC) may be more protective than other antioxidant
preparations
Antioxidants may help reduce the incidence of ARMD
Butler, RN et al. J. Gerontol. 57A: B333-8 (2002).
Pharmaceuticals that have potential to
extend life span
National Institute of Aging has organized a multi-site study of
in genetically heterogenous mice
Of the agents being tested, aspirin nordihydroguaiaretic acid
have been found to lead to significant increases in life span in
males
Rapamycin leads to an increase in maximum longevity in
both males and females
Other compounds currently being tested as part of this
initiative can be found at
http://www.nia.nih.gov/ResearchInformation/ScientificResou
rces/CompoundsInTesting.htm.
Rapamycin Extends Lifespan

Rapamycin:
-- extended median and maximal lifespan of both male and female mice
-- led to an increase in lifespan of 14% for females and 9% for males
-- reproducible extended life span at three independent test sites in genetically
heterogeneous mice
-- did not affect disease patterns compared to control mice
Harrison DE et al., Nature 2009
Other dietary manipulations that extend
maximum life span

Low-methionine diets
Brief, but early nutritional deprivation

Strong, R et all, Aging Cell (2009) Sun, L et al., J. Gerontol. (2009)


The Seven Step Program :
1. Nutritional Modification
2. Nutrient Supplementation
3. Herbs
4. Pharmaceuticals
5. Hormone Replacement
Therapy
6. Mental Training
7. Mind / Body Exercise
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Maria Olivia da Silva
132 tahun
Brasil
Lahir : 28
Feb 1880
2 x menikah
Anak 14

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Physical signs that suggest
hormone deficiencies in famous
people

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Thierry Hertoghe,MD, Atlas of Endrocrinology for Hormone Therapy, HIS,pg 320)
Physical signs that suggest hormone
deficiencies
in famous people

147
Thierry Hertoghe,MD, Atlas of Endrocrinology for Hormone Therapy, HIS,pg 324)
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revisi ke-2 149
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151
Mrs. B.Gozali,MD 84 years old
She was doing her flying fox (30 meters height from ground).
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TITIEK PUSPA

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Prof. Hardi Darmawan & Robert Goldman

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Prof Dr. Hardi Darmawan, MPH&TM, FRSTM bersama Sir Richard J. Roberts, Ph.D. F. R. S
1993 Nobel Laureate in Physiology or Medicine
2017