19 theory of aging process

8/11/2019 19 Theory of Aging Process

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Theory of Aging ProcessProf.dr.Hardi Darmawan, MPH TM, FRSTM

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DEFINITION OF AGING

Old and aging depends on the age andexperience of the speaker.

Chronological age - number of years

lived

Physiologic age - age by body function

Functional age - ability to contribute to

society


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CHRONOLOGICAL CATEGORIES

Young-Old - (ages 65 - 74)

Middle-Old - (ages 75 - 84)

Old-Old - (age 85 and older)


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Doh!

Chronologic age is not an accurate predictor ofphysical condition or behavior

Sue Saxon & Mary Jean Etten, PhysicalChange & Aging


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Rather,

Physical condition seems to be driven by:

Lifestyle choices

exercise

nutrition stress management

Genetics

Environment


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Demographics of Aging

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Americans over the age of 65 will rise fromapproximately 12% in 2000 to20% in 2030

Over 85 year-olds are the most rapidlyincreasing demographic group.

Baby-boomers are rapidly approachingretirement age


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AAAAAAHHHHHHH!!!!

US Census Bureau Data for US population ofadults age 65 and older

1990 30 million

2030 70 million

2050 96 million


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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.

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Significance of Human Aging

What is normal in theaging process primaryaging

More susceptibility todisease secondary

aging More heterogeneity in

the elderly population

Onset indeterminable

and progression varied Genetic and

environmental factors

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Significance of Human Aging

Gender is a significant factor

Lifestyle a primary factor Various theories of aging attempt to explain the process

bottom line, there is disruption of homeostasis.

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Stages of Life

Chronological age typically used to note lifes transitions


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Indonesian Life Expectancy

2000

2005 : 67.8 years

2020 2025 : 73.6 years

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


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Aging is not an inevitableprocess leading to disease and

deterioration13


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Normal aging

Characteristic of aging

Theories of aging

Genetic molecular, cellular / tissue change

Functional changes

Common disease

Physiology of aging

Effects of aging on the different organ

Metabolics disorder in aging15


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NORMAL AGING

Despite stereotype most of the elderly age well !

Most of our images are based on the frail sub-set who frequently use medical services

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Normal Aging

Generally normalaging in

associated with areduction infunctional reserve

capacity intissues andorgans.

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Normal Aging

At advanced age more

common to seeevidence of impairedhomeostasis andresponse to external

insults e.g. illness.

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Temperature Regulation and Aging

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Risk Factors for Hypothermia inElderly

Decreased thermogenesis

Decreased vasoconstriction in response to cold Decrease in intensity of shivering

Medications e.g. Chlorpromazine

Socio-economic (nutrition, heating, etc)

Co-morbidities including falls / immobility

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Decreased ability tosweat

Decreased ability toredirect heat :

Reduced capacity forvasodilation peripherally

Modest ability toincrease cardiac output

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Risk Factorsfor Hypothermia in Elderly


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Summary of Normal Aging Changes

Despite stereotype most of the elderly age well!

Most of our images are based on the frail sub-set

who frequently use medical services Generally normal aging in associated with a

reduction in functional reserve capacity in tissuesand organs

At advanced age more common to see evidence ofimpaired homeotasis and reponse to externalinsults eg. Illness.

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Characteristic of Aging

Mortality increases exponentially

Biochemical composition of tissue changes

Physiologic capacity decreasedAbility to maintain homeostasis diminishes

Susceptibility and vulnerability to disease increases

nvironmental and Genetic factors influence

the rate of age

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Characteristic of Aging

Loss of physiologic reserve and decreasedhomeotatic control may result from :

Allostatic load (persistent activation of normalneuroendrocrine, immune and autonomicresponses to stress)

Development of homeostasis (altered

response to physiologic stresses)

Changes are generally irreversible

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Physiological Theories of Aging

Genetic Theories

Gene

Error

Somatic mutation

Programmed

Nongenetic Theories

Immunologic /Autoimmune

Free Radical

Wear & Tear

Cross link or Collagenhttp://prolongyouth.com/theories.h

tml
http://prolongyouth.com/theories.htmlhttp://prolongyouth.com/theories.htmlhttp://prolongyouth.com/theories.htmlhttp://prolongyouth.com/theories.html


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Psycho-Social Theories of Aging

DisengagementTheory

Activity Theory

Continuity Theory
http://images.google.com/imgres?imgurl=www.cdc.gov/aging/images/afr_amer_couple.jpg&imgrefurl=http://www.cdc.gov/aging/orglinks.htm&h=278&w=199&sz=14&tbnid=NrfUL3YTHfcJ:&tbnh=108&tbnw=78&start=57&prev=/images%3Fq%3Daging%26start%3D40%26hl%3Den%26lr%3D%26ie%3DUTF-8%26sa%3DNhttp://images.google.com/imgres?imgurl=gbgm-umc.org/gifsumw/AGING.JPG&imgrefurl=http://gbgm-umc.org/gifsumw/&h=357&w=498&sz=213&tbnid=UmQe15IRtRIJ:&tbnh=91&tbnw=126&start=45&prev=/images%3Fq%3Daging%26start%3D40%26hl%3Den%26lr%3D%26ie%3DUTF-8%26sa%3DN


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Theories of Aging :Genetic

Synopsis : senescence results from activationor suppression of specific aging genes

In support :

1. Longevity appears to be hereditable2. Some genetic disorders lead to accelerated

aging

In opposition :

1. Evolutionary pressures appear to select forreproductive fitness rather than senescence

2. Little direct evidence of genetic

programming of senescence in humans. 27


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Theories of Aging :Chromosomal Alterations

Synopsis:Age-acquired chromosomal instabilitiescontribute to gene silencing or expression of diseaserelated genes (eg. Cancer genes)

In support : Damage by free radicals causes mitochondrial DNA

(mtDNA) mutations in muscle and brain

Defective mitochondrial respiration and further oxidant

injury creates a cycle of damage Mitochondrial mutations and defective respiration have

been linked to neurodegeneration

In opposition : The practical impact on non-diseased aging

appears to be minimal 28


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Theories of Aging : Immunologic

Synopsis: time-acquired deficits, primarilyin T-cell function, increase susceptibility toinfections and cancer

In support : no direct support as causativeof healthy aging, supplementation does notalter aging in humans

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Theories of Aging : Oxidative Stress

Synopsis : Oxygen converted duringmetabolism causes protein, lipid and DNAdamage over time

In support :Mutations in oxidative stress pathway can

extend life span

Mutations in other pathways that increaselongevity resist oxidative damage

In opposition : antioxidants do not delay humansenescence or disease

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CELLULAR CHANGES

Loss of proliferative potential, e.g.:

Slower onset of lymphocyte proliferation

Diminished cloning efficiency of individual Tcells

Fewer population doublings of fibroblasts

Proliferative potential does not invariably

diminish with age

Changes in gene expression, signal transductionand telomere length contribute to cellular aging.

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Cell Death

Age-dependent problems with apoptosis couldresult in leukemias, lymphomas and abnormaltissue repair.

Apoptosis may play a role in age-relatedneurodegeneration, e.g.:

Neuronal loss in Alzheimers disease may be due tocytotoxicity of -amyloid, which can induce apoptosisin cultured cells

Putative toxins such as free radicals have beenimplicated in neuronal loss in Parkinsons disease

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Physiology of Aging

Why do we need to know thephysiology of aging?

to tell the difference betweenphysiological and pathologicalphenomena in the geriatric population

To appreciate the impact of normalage-related degeneration on diseasesand their management.

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Successful Aging

Chronologic age and physiologic age not the same Due to complex interactions of genetics and

environment

Individuals age at different rates and there issignificant variability


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Successful Aging

Prevalence of disease increases with age

Proposed pathways of aging:

Aging with disease and disability

Usual aging; absence of pathology but presence ofdecline in function

Healthy aging; no pathology or functional loss

Pathway goals:

De-emphasize aging characterized by decline Emphasize heterogeneity among elderly

Underscore positive pathway of aging

Highlights possible avoidance of disease associated withaging


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Successful Aging - homeostasis less efficient, butstill present


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Goals ofSuccessful Aging

Compression ofdebilitating disease intofinal portion of life

Maintain high-level offunction until end of life

Death with dignity andcomfort

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Aging and Disease

Aging is associated with

increase in incidenceand severity of disease

Factors predisposeindividuals to

functional losses laterin life


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IntegrativePhysiology of

Aging

Why do we age?

Who do we need toknow the physiology

of aging?


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Why do we age

2 categories of theories :Aging events occur randomly and accumulatein time : Stochastic Theory

Accumulated errors in making bodily andcell proteins Error Catastrophe TheoryCross-linking of big molecules such asproteins accumulates over time Cross-linking theory

Repeated damage to DNA and incompleterepair wear and Tear Theory

Aging is inevitable : Nonstochastic Theory

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Why do we age

2 categories of theories :

Aging is inevitable : Nonstochastic Theory

Certain organ-systems such ashypothalamus, immune andneuroendocrine systems have in-builtpacemakers that involute with agepacemaker theory

There is familiar predisposition for longevityand thus there may be a genetic basis foraging genetic theory

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C ll S d h


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Cell Senescence and Death

Cell senescence much like apoptosis

Occurs throughout life

Arresting growth of damaged/dysfunctional cells

Beneficial early in life; may contribute to aging later


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Cell Senescence and Death

Inducers can cause cancer Senescence allows cells to respond to inducers,

but cells withdraw from growth cycle -incapable of tumorigenesis

Contribution of cell senescence to aging:

Altered secretions of cells Proteases, inflammatory cytokines, growth factors

Erosion of structure and integrity of tissues

EFFECTS OF AGING ON THE DIFFERENT ORGANS


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SKIN AND AGING

44Hillary Clinton

Albert Einstein




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Skin and Aging

In general, the skin is drier, thinner and wrinkled

Other age-related changes include :

Loss of the inter-digitations between the epidermis anddermis

Decline in the vascular supply

Decline in the immune cells of the integument Decline in the activation of vitamin D

Clinical consequences include :

Vulnerable to tearing, bruising and breakdown

Pressure ulcers (decubiti) more likely

Delayed response to topically-administered toxic agents

Sunlight exposure results in premature age-related changesin the skin.

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Age Related Changes in Immune System

Age related changes include :

The thymus involutes with age

T-cell immunity tends to decline

Cytokine level and function may change with age

Humoral (B-cell) immunity declines with age

Changes in neutrophil function with increasedmargination, reduced migration to site ofinflammation/infection and altered phagocytosis

Autoantibodies increase with age

Clinical Consequences :

Decline in cell mediated immunity may result inTB reactivation and shingles

Vaccine response may be impaired

Altered presentation of infection46




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Sight and Aging

Reduction of pupil size slowsadjustment to light changes

Corneal surface flattens

admitting less light into theeye

Reduced lens transparencyinterferes with reception of

colour wavelengths Reduced blood supply and

radiation damage to retinalarea.

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Smell and Aging

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eardrum and

ossicles thicken

and becomew

less flexibleLoss of hair

cells in the organ

of the corti

Loss of cochlearneurons




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Taste with Aging

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Examples of ClinicalRelevance

Older adults may need longer to adjust to changesin lighting and may need increased contrast tofacilitate depth perception

Loss of high frequency sounds, which includeconsonants, make what is heard unintelligible,leading to the frequent complaint, I can hear youbut I cant understand what you are saying

It is important to recognize, that a response thatdoes not correspond to a question may relate tosensory, rather than cognitive, impairment

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Cortical Changes and Aging There is some selective loss in the

number and size of neurons

Dendritic connections may decrease

A number of neurotransmitters changes,which may result in neurotransmitter

imbalances

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CT Scan Changes and Aging

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Memory and Aging

May have more difficultywith certain components ofmemory

Typically, older adults needmore time to process

information May have difficulty coming

up with namesspontaneously (retrieval)

For healthy older adults,these changes representmore inconvenience thansignificant functionalimpairment

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BANANA


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TURMERIC

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BANANA


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Sleep and Aging

Sleep patterns tend tochange, resulting in :

A decrease in Stage IV(deep) sleep

An increase in Stage I(light) sleep

An increase in thenumber of nighttime

awakenings

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Sensation and Peripheral Nervous

Function Increased threshold observed for peripheral

sensory modalities

Nerve conduction time slows with agesecondary to loss of the myelin sheath

The net effect of these changes is a decrease in

both amount and speed of afferent informationconduction to the spinal cord and highercenters.

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EFFECTS OF AGING ON THE


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Spinal Cord

Modest decrease innumber of cells in thespinal cord

Other changes representdisease processes, such asdegenerative disease of thespine and intervertebraldisks with compression ofthe spinal cord andentrapment of the nerveroots.

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EFFECTS OF AGING ON THE

DIFFERENT ORGANS



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Reduction in the absolutenumbers of motorneurons

Distance between thejunctional axon and themotor end-plate is

increased Folds of the motor end-

plate are flattened

The concentration of Ach

receptors at the motorend-plate is decreased

The amount and releasedof Ach in the junctional

vesicles is decreased59


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Cardiac Output and Age

No change at rest in :

Cardiac output

End-diastolic

End-systolic

Volumesejection

fraction

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Summary of Cardiac Morphological Changes

Consequences :

Higher systolic BP more common

Trend towards diastolicdysfunction

Reduced ability to increase heartrate

Increased postural hypotension 61

1

4

3

2

l d h


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Age-related Respiratory ChangesDecreased chest expansion :

Kyphoscoliosis

Calcification of intercostalcartilage

Arthritis of the costovertebral

joints

Decreased elastic recoil of thelungs

Reduced diaphragm function

Increased airways obstruction

Reduced vital capacity

Increased residual capacity

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Consequences of Age related Changes


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Consequences of Age-related Changes

Increased energy ofbreathing

Increased airwaysresistance

Increased in dead-space

Reduced V/Q ratioresulting in a decreasein the partial pressure ofoxygen in blood whenbreathing room air.

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Oropharyngeal

Modest change in taste Modest reductions in sub-

mandibular and sublingualgland secretions

Swallowing intact in normalelderly

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Gastric Function and Aging

Modestreduction influid emptyingfrom stomach

Decline in gastricsecretions

Atrophic gastritismore common

Prone toincreased pH

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Small Intestineand Aging

Modest changes inmotility

Normal transit

time andabsorption inabsence of disease

Pancreas showsdecrease in overall

weight, ducthyper-plasia, andlobular fibrosis

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Liver Function and Aging

Standard LFTsunchanged

Microsomal

oxidation, has beenfound to be slowedwith aging

Metabolism through

Cytochrome P450system delayed

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Large Intestine Function and Aging

Changes in motility

Increase inretropropulsion

Increased transit time Tendency to

constipation

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Glomerular Function and Aging

Decline in renal blood flow from 1200mL/minute at age30 to 40 years to 600mL/minute at age 80

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b l i d A iEFFECTS OF AGING ON THE DIFFERENT ORGANS


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Tubular Function and Aging

Decline in ability to excrete concentrated urine

Delayed or slowed response to sodium deprivation or asodium load

Delayed or sluggish response to an acid load 70

Urogenital Changes In Men and


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Urogenital Changes In Men andWomen

The urethra is more likely tobe colonized by gramnegative organisms

Alterations in mucosa leadto increased bacterialadherence

Decreased blood flow maylead to longer time toorgasm

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M l S ifi Ch


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Male Specific Changes

Decreased bloodflow may lead to adecrease in erectilefunction

Sperm count tends

to decline andchromosomalabnormalities tendto increase

The prostateincreases in sizeand prostatic fluidreduced.

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Female Specific Changes


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Female Specific Changes

Reproductivecapacity is lost at thetime of menopause

Ovary, uterus, andvagina tend toatrophy followingmenopause

Tendency to urgencyand stressincontinence

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S i


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Sarcopenia

Between ages 30 and 75:

Lean body mass decreasesdue to loss of skeletal musclemass

Number and size of muscle

fibers progressively decrease.

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Successful Aging


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Successful Aging

Recent research:

Elderly individuals with weak muscles are at greaterrisk for mortality than age-matched individuals

Increase in amount and rate of loss of muscleincreases risk of premature death

Physical inactivity is 3rd leading cause of death in

US and plays role in chronic illnesses of aging



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Muscle Fibres and Aging - Impact

Type I (slow twitch, aerobic) muscle fibers are resistant to age-associatedatrophy, at least until the ages of 60 to 70 years

Type II (fast-twitch, anaerobic) muscle fibers appear to decline withincreased

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CHARACTERISTIC FAST FIBRES SLOW FIBRES

TYPE IIb TYPE IIa TYPE I

Number of mitochondria Low High/Moderate High

Resistance of Fatique Low High/Moderate High

Predominant EnergySystem

Anaerobic Combination Aerobic

ATPase Activity Highest High Low

Velocity:Speed ofShortening

Highest Intermediate Low

Efficiency Low Moderate High

Specific tension High High Moderate



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Muscle Strength and Aging

Decrease in the ability to maintain forceproduction is not so much a function of ageas it is related to muscle group location

The muscles of the lower extremity arebetter able to maintain force output whencompared to the muscles of the upperextremity

Research indicates that elderly muslce canadapt positively, just like young muscle, toresistance exercise

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Vulnerability to Falls

Reduced sensory input includingpropioceptive information

Delayed nerve conduction

Reduced numbers of motorneurons

Reduced fast twitch fibres

Reduced muscle mass

Environment always important!

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Endocrine Changes with Aging


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Endocrine Changes with Aging

Change in GTT Insulinresistance increase

Increased incidenceDM

Decrease in

ADH/vasopressin responseto osmotic stimuli

Risk of dehydration or

hyperosmolar state

Tendency to thyroiddysfunction

Abnormal TFTs

Growth hormone,melatonin and DHEA,

decline with aging?

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Hormone Deficiencies many if not most of the


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signs, complaints, causes of Senescence

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Age-related

physiology :- Intestinal transit

- cardiac output

- kidney function

- liver function

Age-related signs :-wrinkles- skin & hairthinning- hair loss- muscle atrophy

- abdominal obesityAge-related symptoms :

- fatique- cognition

- depression

Age-relateddiseases :- cardiovascular- cancer

- obesity- diabetes- osteoporosis- dementia


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Melatonin Deficiency : onset


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Melatonin Deficiency : onset

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Changes with thyroid treatment


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Changes with thyroid treatment

87Thierry Hertoghe,MD, Atlas of End rocrin olog y for Horm one Therapy, HIS,pg 109

Osteoporosis and Fractures


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Osteoporosis and Fractures

Low dietary intake of

calcium Loss of endocrine

protection

Reduced endogenous

production of vitamin D

Disuse

Disease Chronic Renal

Disease, RheumatoidArthritis, Thyroid Disease

Medications Steroids,Thyroxin.

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Osteoporosis


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Osteoporosis

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Age related disorder,

aging disease major morbidity/mortality

atherosclerosis CV diseases

metabolic syndrome

tumors

neurodegenerative diseases


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Osteoporosis

90

Asymptomatic bone fracture & complication

bone mineral density

Loss of architectural integrity

Should understand physiologypathophysiology

Immuno senescence & inflammatory of aging

Immuno senescence lifelong antigenic loadchronic immune system activation

proinflammatory

till

Fragility fracturerisk

hyper

production


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Proinflammatory cytokines - IL-1, IL-6,

TNF inverse CRPImmuno senescence shape the same

immunological cell & cytokine

TNF, IL-1, Rank-L, M-CSF expression osteoclast precursor

Why not build the osteoblastaging & estrogen deficiency : most

important risk - osteoporosis

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Immune Mechanism of Osteoporosis

The skeleton is physiologically in a state of dynamicequilibrin between

formation vs reabsorption

osteoblasts vs osteoclasts

tuning by cytokins

growth factors

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accumulation Age immune profile

memory/effector cells expressing

Rank L resident in bone

secreting

osteoclastogenic

proinflammatory cytokins

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Natural Bone


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Building Plan

1. Hormones

2. Minerals

3. Vitamins

4. Diet

5. Digestion6. Exercise

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HormonesVit D is a steroid hormones

Determinat for bone

health & all agesdeterminant


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Summary of Hormones to treat bone loss (1)

1. Estrogen to prevent bone loss : estradiol

transdermal titrated area 1 mg/ml2. Progesterone

To build bone & balance estrogen

50-300mg oral / transdermally97


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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

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Summary of Vitamins to treat Bone Loss


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Summary of Vitamins to treat Bone Loss

1. Vitamin D3 2000-5000 u/d2. Vitamin K2 50-150 mcg/d

3. Vitamin C 1000mg 4000mg/d

4. Vitamin B 100mg/d, ifhomocysteine not

improving use

Methyl B12/ folicacid

5. Vitamin E 200-800 U

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Summary of Mineral to treat Bone Loss


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1. Magnesium

100

y

Oxide, glycinate, aspartate 200-600 mg/dMagnesium

Orotate, citrate, aspartate 800-1500 mg/dCalcium

20mg/d or 6mg/d formaintenanceSilicon Citrate in trialkali powder or

alone in capsulePotassium

Boron 2-3 mg/d, manganese 15-20 mg/d,copper 1-2 mg/d, zinc 20-50 mg/dTrace Mineral

170-680 mg/dStrontium

Diet & Bone Health


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Enzyme function optimally at PH neutral

Acidic by products accelerate bone loss

High protein & diary (western diet) chronic metabolicacidosis

Bones ability to neutralize acid load -- depend on KT stores

K+ intertitial fluid

K+ Ca++ from bone to buffer in a place of KTchronic high steroids

diuretics

Eating alkaline diet

Rich fresh fruit vegetables

Limited protein & diary

Artificial sweetness

Preservatives

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KT

A idif i F d Alk li i i F d


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Acidifying Foods

Sugar

Yeast, wheat breads

Soft drinks, alcohol, tea, coffee

Cranberries

Sweet potato

Salt

HOPS

Corn oil

White balsamic vinegar

Saccharine, aspartame

benzoate 102

Alkalinizing Foods

Honey, maple syrup, stevia

Goats milk

Soy milk

Umeboshi plums

Sea saltMost herbal teas

Lemon, limes, grapefruit,onion

Olive oilMiso

Most fruits & vegetables


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NAD+ dependentdeacetylase

Diverse physiologicalprocess

Longevity

103

Implicated in

SIRT1

Audrey Hepburn

is

a

SIRT


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SIRT 1

A key mediator of beneficial effects of :

Caloric restriction

Regulates lipid

Regulates glucoseRegulates metabolism

By deacetylating metabolic regulators

SIRT1 levels are regulated by microRNAs(miRs)

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Nuclear receptor FxR / SHP cascade

pathway expression of MiR-34A

SIRT 1

This cascade is useful for age relateddisease including metabolic disorders

105

controltargets


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107

SIRT 1

SIRT 1

SIRT 1

SIRT 1

Effects of a urinar factor from omen in earl

HAF [hCG associated factors :Maternin & Maxima peptides]


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Effects of a urinary factor from women in early

pregnancy on HIV-1, SIV and associated disease

Yanto Lunardi-Iskandar1

, Joseph L. Bryant1

, William A. Blattner1

, ChiaLing Hung2, Louis Flamand1, 3, Parkash Gill4, Phillipe Hermans5, Steven

Birken6 & Robert C. Gallo1

1Institute of Human Virology, University of Maryland, 725 West Lombard Street,

Baltimore, Maryland 21201-1192 USA2

Advanced BioScience Laboratories Inc., 5510 Nicholson Lane, Kensington, Maryland20895 USA3Presently at Laboratory of Virology, Rheumatology and Immunology Research Center,

Pavillen CHUL and Laval University, Quebec, Canada4University of Southern California, School of Medicine, 1441 Eastlake Avenue, Los

Angeles, California 90033 USA

5University Libre de Bruxelles, CHU St-Pierre Hospital, Dept. des Maladies Infectious,322 rue Haute, 1000 Bruxelles, Belgium6, College of Physicians and Surgeons of Columbia University,

630 W. 168th Street, New York, New York 10032 USA

Nature Medicine 4, 428 - 434 (1998)

doi:10.1038/nm0498-428108

YU1563

MATERNIN/MAX GLP AS ANTI-HIV, DIABETES ANTI AGINGHomozygotes transgenic HIV-1 mice
http://nobel-biosciences.com/index.htmlhttp://nobel-biosciences.com/index.html


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UnRx

Maxima

MATERNIN

UnRX

Rx synthetic GLP Maternin peptide109

Some age gracefully
http://nobel-biosciences.com/index.htmlhttp://nobel-biosciences.com/index.html


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some not

19 theory of aging process

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