Cellular & Organismal Aspects of Senescence & Longevity

1. Cellular & Organismal Aspects of Senescence & Longevity Summary/Comments based on David J. Waters in Wilmoth & Ferraro, eds., Chap. 4 P.M. Schwirian, Mar., 2009

2. Chapter Purpose: To Provide-- • “…a contemporary perspective on the biology of aging focusing on fundamental questions that reflect on some of the most critical gaps in our understanding of organismal senescence & human longevity.” (p. 59)

3. Some Terminology: Organismal Senescence • “…The deteriorative changes that result in decreased viability and ultimately in an increase in an organism’s risk for mortality.”

4. In Contrast to:Aging • “…any time-dependent changes that occur during the life course of an organism.” (p. 59) • “…aging encompasses changes that are good (wisdom), bad, (atherosclerosis), and indifferent (baldness) in terms of their effect on viability & survival.”

5. What ARE the Goals of Biogerontology Research? • To determine “…how morbidity can be compressed, culminating in extension of a healthy life span” • pms Comment: We all want to die healthy.

6. What Are NOT the Goals of Biogerontology Research? • Reversal of Aging • Achieving Immortality • pms Comment: Not everyone agrees with this.

7. The Goal of this Chapter: • To discuss some of the diverse, complementary approaches that are used in biogerontology research

8. The Approaches • 1) Lessons from Evolutionary Biology • 2) Cellular Senescence • 3) The Determinants of Life: Genes, Environment & Chance • 4) Hormones & Aging • 5) Caloric Restriction • 6) Rusting Out: The Oxidative Stress Hypothesis

9. pms Comment: • These represent the major directions that biogerontology research has taken in the past couple of decades. While they are considerably different in focus, they don’t necessarily conflict. But none are “proven” at this point.

10. 1) Lessons From Evolutionary Biology • The Big Idea: Reproduction is what it’s all about. • Kirkwood (1977,1990)-Disposable soma hypothesis—In short, after reproduction, the body (soma) can be thrown away.

11. E.B. cont’d: • A related theory---Antagonistic Pleiotrophy Theory In short: Genes that confer an early advantage in life may exert detrimental effects in the post-reproductive period. BECAUSE—An organism is built to successfully and advantageously complete it’s maturation and reproduction---PERIOD!

12. 2) Cellular Senescence: Aging in the Cell Culture Lab • Hayflick’s work: Replicative Senescence • The nub: normal diploid cells has a limited # of population doublings • That # is known as the Hayflick Limit—and is specific to each type of organism

13. C.S. cont’d. • The # of doublings a cell can undergo is determined by the length of its telomeres—which function as a protective “cap” @ the end of the chromosome. • Telomeres get shorter w/ each cell division; when too short, the ability to replicate is lost and cell division stops.

14. C.S., Cont’d. • OF Particular Note: • “…stem cells and most tumor cells possess the enzyme telomerase, which effectively maintains telomere length and allows these cells to escape the rules of replicative senescence • Which Explains: • Why CA’s grow so fast • Why scientists are itching to get their paws on stem cells

15. 3) The Determinants of Life Span:GENES • Several models suggest that life span is under genetic control. • How many? Maybe 7,000 (polygenic control) • OR—Oligenic control—”…a few critical genes may account for the lion’s share of the 25-30% portion of human life span that is heritable.” (p.65)

16. Determinants of Life Span, cont’d:Environment • Lifestyle is important • “Both the external environment, (e.g., diet exposure to chemicals) and the internal environment (e.g., hormones, oxidative stress) significantly influence an individual’s life span.” (p.64)

17. Determinants of Life Span, cont’d:CHANCE • There is room for a third element—CHANCE • “That chance has an important impact on life span is supported by observations that genetically identical organisms raised under identical conditions have differences in life span—all of the individuals do not drop dead on the same day.” (p. 64)

18. 4) Hormones & Aging: Nothing is Raging • “The endocrine system…is profoundly & predictably affected by aging.” (p.66) • Lower circulating levels of: • Growth hormone • Estrogen • Testosterone • DHEA

19. Hormones, cont’d: • “It follows (from many clinical observations) that hormone supplementation might prove a useful intervention to decrease significantly the rate of age-associated physiological decline.” (p.67) • Issues: Dosages; Timing; Tissue-specific actions—some good, some bad.

20. 5) Caloric Restriction: Impractical Intervention, Invaluable Research Tool • *NOTE: The experimental paradigm of CR is distinct from starvation: CR animals receive fewer calories but nutritionally adequate levels of all essential nutrients. • As early as 1935, it was reported that restricting food intake delayed onset of age-related diseases & extended the lifespan of rodents.

21. CR, cont’d: • Mechanism by which CR extends life span has not been determined—under intense investigation • “One thing is certain: CR…significantly alters numerous biochemical, immunologic, & hormonal networks.” (p. 69)

22. CR, Cont’d: • Some really cool findings in fruit-fly expts.: • “…full-fed and CR flies accumulated irreversible damage at the same rate. However, for each given level of damage, CR flies had a significant survival advantage over full-fed flies. Apparently CR allows an organism to cope with the cellular damage that accumulates with aging, which translates into a reduced risk for mortality.” (p.69)

23. CR, cont’d: • The tricky part is figuring out WHY CR works. • Also, the CR regimen is largely impractical as a dietary regimen for humans—even intermittent CR. It may well have deleterious health consequences we know nothing about.

24. 6) Rusting Out: The Oxidative Stress Hypothesis • Origins: Harman’s (1956) free radical theory—i.e., that organisms would inevitably suffer age-related accumulation of macro-molecular damage induced by Reactive Oxygen Species (ROS), leading to physiological decline and increased risk of mortality

25. OSH cont’d: • More recently, animal studies provide “substantial correlative data” to support the hypothesis. • BUT—”…definitive evidence that oxidative stress causes organismal senescence is lacking.” (p. 70).

26. OSH, cont’d: • Targets of oxidative stress: • LIPIDS—There is a change in membrane fluidity—the RESULT: disruptions in cells’ ability to process information from its environment and interaction w/ other cells. • PROTEINS—Essential enzymes are inactivated. RESULT: alteration in cell’s ability to recognize & dispose of worn out protein—OUTCOME—slowing and inefficiency of all cell functions.

27. TARGETS, cont’d: • NUCLEIC ACIDS—Causes deleterious mutations. RESULT: diminution of cellular Fx and/or contribution to CA development. • “In summary, a vast library of experimental observations lends support to the notion that oxidative stress significantly contributes to organismal senescence.” (p. 73)