Aging

and

TRACT GASTROINTESTINAL

?What IS Aging

.Practically
Aging = reduced tissue/physiological function

Aging = increased susceptibility to disease

(age-related diseases)

Aging = decreased resistance to stress

( physical and psychological)

Why do we age --- GENES

Genes determine species-specific
life span )LAGs(
(e.g., mice, monkeys, humans, tortoises )

Genes determine differences among

individuals within a species
(e.g., big/small noses)
(genetic polymorphisms)

Species-specific longevity genes

Flies )Drosophila

melanogaster(
Nematodes )Caenorhabditis elegans(
Mice )Mus musculus(
Humans )Homo sapiens(
Galapagos turtles )Geochelone elephantopus(
Life spans ranging from 2-3 weeks to
!years 100-200

.(Cancer, osteoporosis, diabetes, etc)

Fitness

Disease

AGING in MICE AND MEN

MICE
Months 18

Years 50

AGE )log(
!Mice and Humans are 97% genetically similar

HUMANS

Species-specific longevity genes

What are the genes that determine why
mice live <4 years, whereas humans
?live >100 years

,Potentially big pay-off

but complicated by development/evolution

Individual longevity genes

(polymorphisms)
,Smaller pay-off
but possibly amenable to intervention
??(environment, life style, drugs)

Aging

Can we do
.? Intervention

DIET
!Eat well, but not too much
Food ----> simple molecules
oxygen )mitochondria( ----> energy+
FOOD ---> ENERGY
Oxygen metabolism ----> damaging byproducts

(ROS, oxidative stress)

Anti-oxidant defenses good, but not perfect

(different among species)

OPTIMAL food
less ROS, less damage, more defenses=
! longer lifespans

DIET

DIET

CALORIC RESTRICTION
! GOOD NEWS
calorie restriction 30-40%
without malnutrition
extends HEALTHY lifespan 40-50%
( worms, flies, mice, rats -- maybe monkeys)

!BAD NEWS
!!Life SEEMS longer
(let's develop that CR pill)

EXERCISE

Yes, yes, yes .. )but not too much(

,Exercise ---> healthier muscles
May be prevent telomere shortening .greater fitness

!Greater protection from oxidative stress

(not such a paradox, anti-oxidant defenses)

!Think good thoughts

Avoid undue stress
:Physiological stress
Stress hormones, a double edged sword

:Physical stress
Overwhelm cellular defense mechanisms

--- Why do we age

PAST ENVIRONMENT
Genes evolve in response to environment

! This is REALLY why we age

..Aging before cell phones

"Protected"
Environment
,climate control
)
biomedical intervention
.(etc

SURVIVORS

100%

"Natural"
Environment
,hazards, predators)
.(infection, etc

:HUMANS yrs 40
:MICE
mos 4

AGE

yrs 80
yrs 3-4

!GOOD NEWS
,If we keep our "protected" environment
!we WILL evolve longer life spans

!BAD NEWS
!It's going to take a LONG time

?Sooo. What's to be done about aging now

Optimize present environment

!New therapies on the horizon

Cell based therapies
Drug based therapies

! Support basic research in aging

Individual longevity genes

Most identified so far are
disease-susceptibility genes
its role in several biological processes not directly
related to lipoprotein transport, including
Alzheimer's disease )AD(, immunoregulation, and
cognition.)e.g., ApoE4(
Solution = preventive drugs
Healthy centenarian studies are
!underway
= ??????Solution

Cell based therapies

!Stem cells
embryonic
adult
nuclear transplant )cloning(
!Telomerase
increase cell divisions
anti-cancer therapy

Drug-based therapies

,Anti-oxidants, mitochondrial protectors

. etc

!Hormones
growth hormone
insulin/IGF )lessons from worms and flies(
estrogen

!CR mimetics

Elizabet Blackburn Physiology

nobel prize Winner 2009

We can determine How long We

!!?Live

Future Re search

Aging
Definition
Aging is the progressive, universal decline first in functional
reserve and then in function that occurs in organisms over
. Aging is heterogeneous
It varies widely in different individuals and in different organs
. within a particular individual
Aging is not a disease; however, the risk of developing disease is
. increased, often dramatically, as a function of age
The biochemical composition of tissues changes with age;
physiologic capacity decreases, the ability to maintain
homeostasis in adapting to stressors declines, and vulnerability to
. disease processes increases with age

Biology of Aging
As we age, we become increasingly unlike one
another. For any variable one can measure, the
variation in the distribution of values in a
population increases with age. While the mean
value may trend up or down, the age-related
increase in the range of values is striking
testimony to the diverse manifestations of the
aging process. In addition, homeostatic
mechanisms are slower to respond to stressors
and take longer to restore normal function as we
age. The ability to maintain stable function in the
face of a change in the environment is called
.allostasis and it declines with age

Demography of Aging
Improvements in environmental )e.g., clean water and
improved sanitation( and behavioral )nutrition, reduced
risk exposures( factors and the treatment and prevention
of infectious diseases are largely responsible for the 30. year increase in life expectancy since 1900
In the United States, by 2030, 1 person in 5 will be >65
.years

Global Aging
At present 59% of older adults live in
the developing countries of Africa,
Asia, Latin America, the Caribbean,
.and Oceania
The developed world has the largest
absolute number of older adults and is
experiencing the largest percentage
. increase

Gastrointestinal Disorders

Gastrointestinal )GI( disorders

represent the third cause of
consultations by general practitioners
among subjects older than 65 years in
.Western countries

Gastrointestinal Disorders
Age-related anatomical and physiologic changes occur in the
major organ systems, affecting functions as diverse as swallowing
and hepatic and renal clearance of therapeutic drugs. Because of
these factors, and because older patients are more likely to be
receiving multiple drugs for concomitant illness, they are more
prone to drug-drug interactions and to medication-induced injury
of the esophagus and stomach. In addition, several
gastrointestinal disorders, notably gastroesophageal reflux and
.peptic ulcer disease, are commonly seen in the elderly

J Clin Gastroenterol. 1991;13 Suppl 2:S65-75Bozymski EM, Isaacs KL

Department of Medicine, University of North Carolina, Chapel Hill 27599-7080

Objectives
Define age-related changes in the gastrointestinal tract
Discuss common G.I. problems associated with aging
Describe the risk factors for gastro-esophageal reflux
disease
Describe the risk factors for peptic ulcer development
List the causes of diarrhea and fecal incontinence in
the elderly

Epidemiology
Over 35 million people aged > 65 years in the United
States
of the 2003 US population were older than 65 12%
million aged 65-74 18.3
million aged 75-84 12.9
million aged 85 4.7

to 40% of geriatric patients will have at least

GI symptom in any year

1 35%

Common problems in this age group include constipation, fecal

incontinence, diarrhea, irritable bowel syndrome )IBS(, reflux
disease, and swallowing disorders

. Hall KE, et al. Gastroenterology. 2005;129:1305-1338

He W, et al. 65+ in the US: 2005. US Census Bureau Web site. Available at:
.http://www.census.gov/prod/2006pubs/p23-209.pdf. Accessed 11/30/06

 The Age Wave

Increase in the Number of Persons
Aged 65+ Years in the United States

72
)20%(

Number )millions(

55

Population

Percent of population

)16%(

40
31
26
20
12
3

)4%(

)4%(

5
)5%(

7
)5%(

17

35

)13%(

)12%(

)13%(

)11%(

)10%(

)9%(

)8%(

)7%(

Year
He W, et al. 65+ in the US: 2005. US Census Bureau Web site. Available at:
.http://www.census.gov/prod/2006pubs/p23-209.pdf. Accessed 11/30/06

Motility an GI tract
Normal aging is associated with significant changes in the function
of most organs and tissues. In this regard, the gastrointestinal
More important is the impact of various age-related diseases on
gastrointestinal motility in the elderly: for example, long-standing
diabetes mellitus may reduce gastric emptying in up to 50% of
patients; depression significantly prolongs whole-gut transit time;
hypothyroidism may prolong oro-caecal transit time; and chronic
renal failure is associated with impaired gastric emptying. In
addition, various, frequently used drugs in the elderly cause
disordered gastrointestinal motility. These drugs include
anticholinergics, especially antidepressants with an anticholinergic
effect, opioid analgesics and calcium antagoniststract is no
.exception

Gastrointestinal Disorders

Available data allow the conclusion to be drawn

that impaired intestinal motility, as evidenced by
attenuated migrating motor complex activity,
. results in bacterial overgrowth

GI Motility
pristalsism and
Migratory
Myo electric
complex

Gastrointestinal Disorders
Heart disease, cancer, and stroke have become the
leading "killers" among older adults, while deaths due to
infection have decreased. Adults surviving into late life
suffer from high rates of chronic illness; 80 percent have
at least one and 50 percent have at least two chronic
condition. There is a strong association between the
presence of geriatric syndromes )cognitive impairment,
falls, incontinence, vision or hearing impairment, low
body mass index, dizziness( and dependency in
activities of daily living

Geriatric diseases of the

upper digestive tract
During aging, secretion and motility of the upper GI tract slow
down. The reduction of these functions, however, does not create
complaints. In the higher age groups, a number of symptoms from
age-dependent diseases occur more frequently, e.g., dysphagia in
response to cerebral ischemia, or disturbed gastric emptying
caused by diabetic visceral neuropathy. Moreover, certain GI
diseases occur more often in the elderly, e.g., chronic atrophic
gastritis, NSAR-induced gastric ulcers, malignancies, and others.
In contrast, almost nothing is known about diseases or symptoms
of the GI tract that might be specific for the elderly. With only a few
exceptions, there are no age-dependent clinical differences.
Nevertheless, intestinal diseases often develop more rapidly and
.the mortality is higher in the elderly than in younger people
.Z Gerontol. 1992 Sep-Oct;25)5(:286-8

Age-Related Changes in the

Gastrointestinal Tract
Hormone
Hormone
responsiveness
responsiveness

Motility
Motility

Visceral
Visceral
sensitivity
sensitivity

Drug
Drug
metabolism
metabolism

Areas identified as
:important to aging are
Pathophysiology of
swallowing disorders
Esophageal reflux
Dysmotility symptoms

:Pancreas
:Pancreas
Structure
Structure
and
andfunction
function

Liver
Liversensitivity
sensitivity
totostress
stress

Lithogenic
Lithogenic
bile
bile

Immunity
Immunity
Colonic
Colonic
function
function

GI immunobiology
Cellular mechanisms
of neoplasia in the GI
tract
Decreased visceral
sensitivity

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

Esophageal Aging
Dysphagia, regurgitation, chest pain, heartburn- associated nausea
are common in the elderly
Presbyesophagus: )age-related changes in esophageal function(
Decreased contractile amplitude
Polyphasic waves
Incomplete relaxation of the lower esophageal sphincter )LES(
Esophageal dilation

GERD

Common in the elderly

Impaired clearance of acid
Longer duration of reflux episodes
Atypical symptom presentation

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

Aging and the Stomach

Decreased
Clearance of liquids from
stomach
Perception of gastric distention
Cytoprotective factors
Mucosal blood flow and
impaired sensory neuron
function in animal models

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

. Cullen DJE, et al. Gut. 1997;41:459-462

Increased
Contact time with NSAIDs or
other noxious agents in delayed
emptying
Tendency for gastric mucosal
injury in delayed emptying
Prevalence of H. pylori
associated with increased risk
of bleeding peptic ulcer,
pernicious anemia, and
lymphoma

Nutrition
Geriatric patients, especially aged > 85 years, are at risk
: for decreased food intake due to several factors
Mobility impairment
Ability to obtain food
Loss of taste, may be due to decreased olfaction
Poor dentition
Decreased appetite
Anorexia of Aging, may be related to neuroendocrine changes
Depression

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

Gastrointestinal Bleeding Is
Common in the Elderly
GI bleeding in the 75%
upper tract

Esophagus
Stomach
Small bowel

GI bleeding in 25%-20%
the lower tract
Terminal ileum
Colon
Rectum

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

Gastrointestinal Bleeding in the

Elderly
Of the 75% bleeding in the upper
tract
bleeding is due to NSAID use 50%
bleeding is due to ulceration or 50%
erosions )peptic or esophageal(

Females are at higher risk than males

Continued bleeding and rebleeding
are the highest predictors of mortality
and morbidity in older patients

.Hall KE, et al. Gastroenterology. 2005;129:1305-1338

.Image courtesy of David C. Metz, MD

Colorectal Cancer in the Elderly

An estimated 106,680
cases of colon and 41,930
cases of rectal cancer were
expected to occur in 2006
of all cases occur in 90%
individuals aged > 50 years

.American Cancer Society. Cancer Facts and Figures 2006. Atlanta: American Cancer Society; 2006
.Burt RW. Gastroenterology. 2000;119:837-853
. Image courtesy of Subhas Banerjee, MD