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Warren Rosenberg, Ph.D.
Life Expectancy vs. Lifespan
 There has not been much, if any, gain in
increasing human lifespan
While we have made gains in health and quality of life we
have not substantially increased the maximum years of life
Sophocles (496 - 406 B.C.E)
Hippocrates (460 - 377 B.C.E.)
Andrea della Robia (1435 - 1525)
Titian (1488 - 1576 )
90 years of age
83 years of age
90 years of age
88 years of age
What is aging?
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Chronologically, it is the passage of time which, in
humans, is measured in years
F
Biologically, it is a set of structural and functional
changes that occur with the passage of time,
characterized as developmental stages. In the postmaturational period, it is characterized by and
increasing vulnerability to environmental
challenges.
Contemporary Theories of Aging
F
Programmed/Genetic Theories (Active Aging)
F
Error/Environment Theories (Wear-and-Tear Aging)
Aging follows a biological timetable and is controlled in the
same was as is the passage from infancy to childhood,
childhood to adolescence, adolescence to adulthood and
adulthood to senescence
Aging results from environmental assaults to our systems that
gradually diminish the capacity to sustain normal structures
and functions such as ultraviolet radiation’s effect on the skin
and saturated fat’s effect on the cardiovascular system
The Genetics of Aging
Over 200 genes influence the aging process
Progeria: Premature Genetic Aging
Hutchinson-Gilford progeria syndrome
• 30 – 40 cases worldwide : 1 in 8 million are affected
• 5 – 10 X increase in the rate of aging
• Death occurs at average age of 13 from heart attack or stroke
• Single letter substitution in the 25,000 letter LMNA (laminin A) gene
on Chromosome 1
• Creates a 50 amino acid long deletion at the end of the laminin protein
• Results in defective nucleus membrane in about 50% of body’s cells
• Now looking at the LMNA gene in centenarians
Other Age-Related Genes
INDY gene – doubles the life of fruit flies (150 yrs humans)
daf genes (nematode worms) increase lifespan by 5X
-increases enzymes that detoxify ROS
SIR genes (SIR2-yeast, worms ; SIRT1-humans)
- activated by caloric restriction
also activated by polyphenols (apples & tea), and
resveratrol (grapes & red wine)
-possible action on blunting the p53 tumor suppressor gene
and blocking programmed cell death (apoptosis)
Klotho gene – produces klotho protein which supresses
insulin pathway (20-30% life extension in mice)
Telomere Theory
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Studying human fibroblast cells in culture,
Leonard Hayflick (1961) uncovered a limit
to cellular mitotic divisions which he termed
replicative senescence
Telomeres, protective lengths of DNA on the
end arms of chromosomes, are synthesized by
the enzyme telomerase
Telomeres in mature cells, lacking telomerase, grow shorter with
each cell division (end replication problem)
When telomeres fall below a critical length, cells will no longer
divide
Telomeres are believed to be the mechanism for keeping track of
cell divisions; telomere length correlates with the number of
remaining cell divisions (telomeres as replicometer)
Oxygen Free Radicals and other ROS
“You can drop cigarettes. Avoid alcohol. But there’s
one toxin you just can’t dodge: oxygen. With every
gulp of air, oxygen gives you life. Some of it, however
gets converted inside your cells into a radical molecule
that can wreak havock, degrading those same cells and
others. A growing number of scientists say this damage
is what causes aging.”
Scientific American 2000
Free Radical Theory of Aging
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Oxygen free radicals are generated by environmental
factors such as UV and cosmic radiation and as a
byproduct of normal aerobic metabolism
The unstable free radical (with an unpaired electron) will
interact with other molecules in a chain-reaction damaging
proteins, cell membranes and DNA Antioxidant
compounds within the cell (SOD, catalase, peroxidase,
glutathione) neutralize the free radicals and terminate their
reactions - but some minor damage is done
Little-by-little, over time, this damage accumulates
AGE’s –oxidized glucose molecules cross-link proteins
When accumulated damage exceeds some threshold,
impairment of cellular function occurs
Free Radical Theory of Aging
Age-Reversing Benefits of Exercise
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Endurance exercise increases VO2max by 30% in healthy patients, aged
60-70, over a 6 month period
(J. Appl. Physiol. 1984. 57:4)
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9-12 month program of walking 45min/day, 4 days/week increased
aerobic capacity by 24% (J.Appl Physiol. 1992.72:5)
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Master athletes (mean age 63) had 30% higher muscle mitochondrial
content compared with 27 yr old runners
(J. Appl. Physiol. 1990. 68:5)
F
Muscle mass in 68 yr old men engaged in 12-17 yrs of strength training
was identical to 28 yr old men engaged in aerobic sports (Acta Physiol
Scand. 1990. 140:1)
continued
Age-Reversing Benefits of Exercise
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12 week resistance training program doubled quadriceps and tripled hamstring
strength in older men; increase was 5% per session - identical to gains in
younger men
(J Appl Physiol. 1988. 64:3)
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8 weeks of high intensity exercise in frail nursing home residents (aged 86-96)
increased strength by 74% and muscle mass by 9%. Walking speed increased
50% in half of the participants (JAMA. 1990. 263(22)
F
43% reduction in risk of death among vigorous exercisers; 29% reduction
among occasional exercisers in paired twin studies (JAMA. 1998. 279:6)
Exercise & Aging: Good or Bad ?
Exercise and oxidative damage
Endurance exercise can increase oxygen utilization from 10 to 20 times over the resting state. This
greatly increases the generation of free radicals, prompting concern about enhanced damage to muscles
and other tissues. The question that arises is, how effectively can athletes defend against the increased
free radicals resulting from exercise? Do athletes need to take extra antioxidants?
Because it is not possible to directly measure free radicals in the body, scientists have approached this
question by measuring the by-products that result from free radical reactions. If the generation of free
radicals exceeds the antioxidant defenses then one would expect to see more of these by-products.
These measurements have been performed in athletes under a variety of conditions.
Several interesting concepts have emerged from these types of experimental studies. Regular physical
exercise enhances the antioxidant defense system and protects against exercise induced free radical
damage. This is an important finding because it shows how smart the body is about adapting to the
demands of exercise. These changes occur slowly over time and appear to parallel other adaptations to
exercise.
On the other hand, intense exercise in untrained individuals overwhelms defenses resulting in
increased free radical damage. Thus, the "weekend warrior" who is predominantly sedentary during the
week but engages in vigorous bouts of exercise during the weekend may be doing more harm than
good. To this end there are many factors which may determine whether exercise induced free radical
damage occurs, including degree of conditioning of the athlete, intensity of exercise, and