2. Aging theories R-Sharifan, MD Mashhad-1393

3. Childhood Adolescence Young Middle age Adulthood Aged

4. What is Aging? The gradual and spontaneous changes that occur in maturation from infant to young adult due to decreased of accommodation response to stress. These changes create a normal physiologic decline seen in middle and late adulthood. Decline in basal function Reduction in reserve capacity

5. What is Aging? Otto Bismarck Older than 60 (65) years (Chronological age) According to WHO : 45-59 Middle 60-74 Young old 75-90 Old over 90 Oldest old

6. Senescence The process by which a cell looses its ability to divide, grow, and function. This loss of function ultimately ends in death. A degenerative process, only. Has no positive features.

7. Why do we get old?

8. Intrinsic cellular mechanism (35% ?) Environmental influence (65% ?) “The link between genes and lifespan is unquestioned. The simple observation that some species live longer than others -- humans longer than dogs, tortoises longer than mice -- is one convincing piece of evidence.” 50 genes for cellular longevity Why do we get old?

9. Gerontology : study of the social, psychological and biological aspects of aging. Aging theories : Biological theories Psychosocial theories

10. Biological theories Two main biological theories : Programmed theories Error theories Programmed Theories Aging has a biological timetable or internal biological clock. Error Theories Aging is a result of internal or external assaults that damage cells or organs so they can no longer function properly. Many theories are a combination of programmed and error theories.

11. Programmed vs. Error Theories Programmed Theories Programmed Senescence Theory Endocrine Theory Immunology Theory Error Theories Wear and Tear Theory Rate-of-Living Theory Cross-linking Theory Free Radical Theory Error CatastropheTheory Somatic Mutation Theory

12. Programmed Senescence Theory The result of sequential switching “off” or “on” of specific genes. Aging when occurred that age-related disorders were happened. Example – “Hayflick’s Limits” (1965) Fibroblasts removed from umbilical cord & cultured Fibroblasts divide and repeated until ~ 50 divisions Will not divide past this point

13. Programmed Senescence Theory Telomeric Theory This is an extension of the “Hayflick Limit.” Telomeres are specialized DNA sequences at the end of chromosomes. They shorten with each cell division. When the telomeres become too short, the cell enters the senescence stage. In the normal process of DNA replication, the end of the chromosome is not copied exactly, which leaves an unreplicated gap.

14. Programmed Senescence Theory Telomeric Theory The enzyme, telomerase, fills the gap by attaching bases to the end of the chromosomes. As long as the cells have enough telomerase to do the job, they keep the telomeres long enough to prevent any important information from being lost as they go through each replication. With time, telomerase levels decrease. With decreasing telomerase levels, the telomeres become shorter and shorter so cell enter to senescence phase.

15. Programmed Senescence Theory Telomeric Theory Shortened telomeres are found in: Atherosclerosis Heart disease Hepatitis Cirrhosis

16. Programmed Senescence Theory Telomeric Theory 90% of cancer cells have been found to possess telomerase. Telomerase prevents the telomere from shortening. This allows the cancer cells to reproduce, resulting in tumor growth. Research areas Measuring telomerase may help detect cancer. Stopping telomerase may fight cancer by causing death of cancer cells. Telomerase may be used to help with wound healing or the immune response.

17. Endocrine theory Biological clocks act through hormones to control the speed of aging. Hormones effects growth, metabolism, temperature, inflammation and stress. Insulin/IGF-1 has important role in hormonal control of aging. Examples- Menopause Decreased level of estrogen & progesterone Hot flashes, insomnia

18. Immunologic Theory A programmed decline in the immune system leads to an increased vulnerability to disease, aging and death. In puberty immune system has the most potency With advanced age dysregulated immune response was occured and play role in CVS disorder, alzhiemer and cancer. Example- Decreased T cells (helper cells) in adults Increased diseases in older adults Increased autoimmune diseases in adults Example- decreased Ab efficacy and volume

19. Error theory Aging is a result of internal or external assaults that damage cells or organs so they can no longer function properly. Wear and Tear Theory Free Radical Theory Rate-of-Living Theory CatastropheTheory Cross-linking Theory Somatic Mutation Theory

20. Wear and tear theory Years of damage to cells, tissues and organs eventually wears them out, killing both them and the body. Weismann in 1882 Example- Wearing out of the skeletal system such as in osteoarthritis Wear and tear can be viewed as a result of aging and not the cause of it.

21. Rate-of-Living Theory The greater an organism’s basal metabolic rate, the shorter the life span. Free radicals or other metabolic by-products play a role. Example Animals with the most rapid metabolisms tend to have the shortest lifespans, i.e, birds have a shorter lifespan than humans. Studies examining the relationship between metabolic rates and longevity have produced inconsistent results, limiting the usefulness of this theory.

22. Cross-linking theory The accumulation of cross-linked proteins damages cells and tissue, slowing down bodily processes. Lohn Bjorksten in 1942 Example Non-enzymatic glycosylation reaction occur when glucose molecules attach to proteins causing a chain of chemical reactions resulting in a structural change to the proteins. Loss of flexibility of connective tissue Microvascular changes in arteries

23. Free Radical Theory During aging, damage produced by free radicals cause cells and organs to stop functioning. Gerschmann in 1954 and then Harmans A free radical is a molecule with an unpaired, highly reactive electron. One type of very reactive free radical is the oxygen free radical or reactive oxygen species (ROS), which may be produced during mithocondrial breathing metabolism or as a result of environmental pollution.

24. Free Radical Theory

26. The free radical “grabs” a electron from any molecule it its vicinity. It does this because electrons like to exist in pairs. When it “grabs” an electron from another molecule, it damages the other molecule.

27. Free Radical Theory Some of the molecules that may be damaged by free radicals are fats, proteins, and DNA (both in the nucleus and in mitochondria). If membrane fats are attacked, then you get the breakdown of the cell membrane. If it is a red blood cell membrane, you get hemolysis. If proteins are attacked, you get the breakdown of proteins, which may result in the loss of biological function and the accumulation of “catastrophic” compounds. If DNA is attacked, you will get a mutation that may cause aging or cancer.

28. Free Radical Theory

29. Free radicals do not go unchecked. The body has a multi-layed defense system that reacts and detoxifies the damaging radicals. Defenses include: Natural antioxidants in the body, such as bilirubin. Enzymes such as superoxide dismutase (SOD), catalase, & glutathione peroxidase. Dietary antioxidants such as beta carotene, and the vitamins C and E.

30. Free Radical Theory

31. Under normal conditions, body natural defense mechanisms prevent most of the oxidative damage from occurring. The free radical theory of aging proposes that, little-by- little, small amounts of damage accumulate and contribute to deterioration of tissues and organs.

32. anti-oxidant molecule repaired membrane damaged DNA The anti-oxidant molecule destroys the damaging free radical. The membrane repairs itself, but the DNA remains damaged, impairing the cells function. In addition, the anti-oxidant molecule now has an unpaired electron and thus becomes a new radical.

33. Free Radical Theory For example, when Vitamin E “scavenges” free radicals, it becomes a free radical and may be more carcinogenic than the original free radical. This is the reason why taking high doses of vitamin E SUPPLEMENTS appears to INCREASE cancer risk in a person, not decrease cancer risk. Not all free radicals cause damage. You use free radicals as part of your immunological response system. Macrophages engulf bacteria Free radical reactions produced inside the macrophage oxidize and kill bacteria. Question: Does it make any biological sense to try to eliminate all free radicals in your body by taking supplements?

34. Catastophic theory Any damage to the enzyme systems that synthesize proteins in the body results in faulty protein synthesis. The faulty proteins continue to accumulate in the cell until they reach a level that damages the cells, tissues, and organ When enough damage accumulates, this may result in cell malfunctioning ( aging) leading to death.

35. Somatic mutation theory Genetic mutations occur and accumulate with age in the somatic cell causing the cell to: Deteriorate Malfunction Accumulation of mutations result in : Damage to the DNA The theory states that aging is an imbalance between DNA’s ability to repair itself and accumulating DNA damage. When the damage exceeds the repair, the cell malfunctions and this can lead to senesence.

37. Psychological Theories of Aging

38. 1.Full-Life Development Theories (Erik Erikson) 2.Mature-Life Theories 1.Robert Peck’s Theory 2.The Activity Theory (Neugarten’s Theory) 3.The General Theory of Disengagemen 4.Continuty theory

39. Full-Life Development Theory Eric Erickson was one of the first psychological theorists to develop a personality theory that extends to old age.

40. Full-Life Development Theory

42. Disengagement Theory Developed by Cummings and Henry in late 1950’s. “aging is an inevitable, mutual withdrawal or disengagement, resulting in decreased interaction between the aging person and others in the social system he/she belongs to.” Withdrawall and introspection mechanism.

43. Activity Theory Developed by Robert Havighurst in the 1960’s. Supports the maintenance of regular activities, roles, and social pursuits. Persons who achieve optimal age are those who stay active. As roles change, the individual finds substitute activities for these roles.

44. Continuity Theory By Neugarten and co-workers in reaction to the disengagement theory “basic personality, attitudes, and behaviors remain constant throughout the life span”