TRACT GASTROINTESTINAL

Agingand

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-specificlife span )LAGs(

(e.g., mice, monkeys, humans, tortoises)

Genes determine differences amongindividuals 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 to100-200 years!

AGE )log(

Fi

tnes

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Dis

ease

(C

ance

r, os

teop

oros

is, d

iabe

tes,

etc

).

AGING in MICE AND MEN

18 Months 50 Years

MICE HUMANS

Mice and Humans are 97% genetically similar!

Species-specific longevity genes

Potentially big pay-off,but complicated by development/evolution

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

live >100 years?

Individual longevity genes(polymorphisms)

Smaller pay-off,but possibly amenable to intervention

(environment, life style, drugs)??

Aging

Can we do Intervention ?.

DIETEat well, but not too much!

FOOD ---> ENERGY

Oxygen metabolism ----> damaging byproducts

(ROS, oxidative stress)

OPTIMAL food =less ROS, less damage, more defenses

longer lifespans !

Anti-oxidant defenses good, but not perfect

(different among species)

Food ----> simple molecules +oxygen )mitochondria( ----> energy

DIET

CALORIC RESTRICTION

GOOD NEWS !30-40% calorie restriction

without malnutritionextends HEALTHY lifespan 40-50%

(worms, flies, mice, rats -- maybe monkeys )

BAD NEWS!Life SEEMS longer!!

(let's develop that CR pill)

DIET

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..……

100%S

UR

VIV

OR

S

AGE

"Natural" Environment

(hazards, predators, infection, etc).

80 yrs3-4 yrs

"Protected" Environment

( climate control, biomedical intervention

etc).

40 yrsHUMANS:4 mos MICE:

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

Healthy centenarian studies areunderway!

Solution = preventive drugs

Solution?????? =

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(

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

AgingDefinition

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 DisordersAge-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 KLDepartment 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–12% of the 2003 US population were older than 65

•18.3 million aged 65-74•12.9 million aged 75-84

•4.7 million aged ≥ 85

•35% to 40% of geriatric patients will have at least 1 GI symptom in any year

–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 ”

0

10

20

30

40

50

60

70

80

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Pop

ulat

ion

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

Number )millions(Percent of population

3 (4%)

5 (5%)

9 (7%)

17(9%)

26(11%)

31(13%)

35(12%)

40(13%)

55(16%)

72(20%)

4 (4%)

7 (5%)

12(8%)

20 (10%)

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 tractNormal 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 Motilitypristalsism 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

Motility

Immunity

Drug metabolism

Visceralsensitivity

•Areas identified as important to aging are:

–Pathophysiology of swallowing disorders

–Esophageal reflux

–Dysmotility symptoms

–GI immunobiology

–Cellular mechanisms of neoplasia in the GI

tract

–Decreased visceral sensitivity

Hormoneresponsiveness

Lithogenicbile

Pancreas:Structure

and function

Liver sensitivityto stress

Colonicfunction

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

Hall KE, et al. Gastroenterology. 2005;129:1305-1338.Cullen DJE, et al. Gut. 1997;41:459-462 .

DecreasedDecreasedIncreasedIncreased• Clearance of liquids from

stomach• Perception of gastric distention• Cytoprotective factors• Mucosal blood flow and

impaired sensory neuron function in animal models

• 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

•20%-25% GI bleeding in the lower tract

–Terminal ileum–Colon–Rectum

•75% GI bleeding in the upper tract

–Esophagus–Stomach–Small bowel

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

Gastrointestinal Bleeding in the Elderly

•Of the 75% bleeding in the upper tract

–50% bleeding is due to NSAID use–50% bleeding is due to ulceration or

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

•90% of all cases occur in 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 .