Warren Rosenberg, Ph.D.

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) 90 years of age Hippocrates (460 - 377 B.C.E.) 83 years of age Andrea della Robia (1435 - 1525) 90 years of age Titian (1488 - 1576 ) 88 years of age

Life Expectancy vs. Lifespan

What is aging?

Chronologically, it is the passage of time which, in humans, is measured in years

Biologically, it is a set of structural and functional changes that occur with the passage of time, characterized as developmental stages. In the post-maturational period, it is characterized by and increasing vulnerability to environmental challenges.

Programmed/Genetic Theories (Active 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

Error/Environment Theories (Wear-and-Tear Aging)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

Contemporary Theories of Aging

Over 200 genes influence the aging process

The Genetics of Aging

• 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

Hutchinson-Gilford progeria syndrome

Progeria: Premature Genetic Aging

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)

Other Age-Related Genes

Telomere Theory

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)

“You can drop cigarettes. Avoid alcohol. But there’sone toxin you just can’t dodge: oxygen. With everygulp of air, oxygen gives you life. Some of it, howevergets converted inside your cells into a radical moleculethat can wreak havock, degrading those same cells andothers. A growing number of scientists say this damageis what causes aging.”Scientific American 2000

Oxygen Free Radicals and other ROS

Free Radical Theory of Aging 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

Endurance exercise increases VO2max by 30% in healthy patients, aged 60-70, over a 6 month period(J. Appl. Physiol. 1984. 57:4)

9-12 month program of walking 45min/day, 4 days/week increased aerobic capacity by 24% (J.Appl Physiol. 1992.72:5)

Master athletes (mean age 63) had 30% higher muscle mitochondrial content compared with 27 yr old runners(J. Appl. Physiol. 1990. 68:5)

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

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)

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)

43% reduction in risk of death among vigorous exercisers; 29% reduction among occasional exercisers in paired twin studies (JAMA. 1998. 279:6)

Age-Reversing Benefits of ExerciseAge-Reversing Benefits of Exercise

Exercise and oxidative damageEndurance 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

Exercise & Aging: Good or Bad ?