CELLULAR AGING (1).pptx

Anatpath

1. CELLULAR AGING Dr Ogbata Stanley Emeka Dip SLT, MBBS, FMCPath CONSULTANT ANATOMIC PATHOLOGIST.

2. OUTLINE Definition/introduction Causes/ mechanisms of cellular aging Functional and Structural Changes that Accompany Aging Organ changes (morphology) in ageing Life expectancy Factors affecting life expectancy Diseases of Premature Aging

3. Definition/introduction Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences. Cellular aging begins from conception and continues till death. Cellular aging may lead to death of the cell or decreased capacity of cells to respond to injury and increasing difficulties in maintaining physiological homeostasis.

4. Definition/introduction ct’d Perhaps one of the most striking discoveries about cellular aging is that it is not simply a consequence of cells “running out of steam,” but in fact is regulated by genes that are evolutionarily conserved from yeast to worms to mammals. Several mechanisms, some cell intrinsic and others environmentally induced, are believed to play a role in aging.

5. Definition/introduction ct’d Shakespeare probably characterized aging best in his elegant description of the seven ages of man. It begins at the moment of conception, involves the differentiation and maturation of the organism and its cells, at some variable point in time leads to the progressive loss of functional capacity characteristic of senescence, and ends in death.

6. Definition/introduction ct’d With aging physiological and structural changes develop in almost all systems. There is progressive loss of functional capacity.

7. Causes/ mechanisms of cellular aging DNA Damage: A variety of exogenous (physical, chemical , and biologic) agents and endogenous factors such as ROS threaten the integrity of nuclear and mitochondrial DNA. Although most DNA damage is repaired by DNA repair enzymes, some persists and accumulates as cells age. Several lines of evidence point to the importance of DNA repair in the aging process.

8. Causes/ mechanisms of cellular aging ct’d Next-generation DNA sequencing studies have shown that the average hematopoietic stem cell suffers 14 new mutations per year, and it is likely that this accumulating damage explains why, like most cancers, the most common hematologic malignancies are diseases of the aged. Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase , a protein involved in DNA replication and repair and other functions requiring DNA unwinding.

9. Causes/ mechanisms of cellular aging ct’d A defect in this enzyme causes rapid accumulation of chromosomal damage that may mimic some aspects of the injury that normally accumulates during cellular aging. Genetic instability in somatic cells is also characteristic of other disorders in which patients display some of the manifestations of aging at an increased rate, such as Bloom syndrome and ataxia- telangiectasia , in which the mutated genes encode proteins involved in repairing double-strand breaks in DNA

10. Causes/ mechanisms of cellular aging ct’d Cellular Senescence: All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally nondividing state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells. Cells from children have the capacity to undergo more rounds of replication than do cells from older people. Two mechanisms are believed to underlie cellular senescence:

11. Causes/ mechanisms of cellular aging ct’d Mechanisms of Cellular Senescence Telomere attrition: One mechanism of replicative senescence involves progressive shortening of telomeres, which ultimately results in cell cycle arrest. Telomeres are short repeated sequences of DNA present at the ends of linear chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation.

12. Causes/ mechanisms of cellular aging ct’d When somatic cells replicate, a small section of the telomere is not duplicated and telomeres become progressively shortened. As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest. Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase .

13. Causes/ mechanisms of cellular aging ct’d Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. Telomerase is expressed in germ cells and is present at low levels in stem cells, but it is absent in most somatic tissues. Therefore, as most somatic cells age, their telomeres become shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely.

14. Causes/ mechanisms of cellular aging ct’d The causal links between telomere length and cellular senescence have been established in mouse models. Genetically engineered mice with shortened telomeres exhibit reduced life spans that can be restored to normal by telomerase activation. Telomere shortening is also associated with premature development of diseases, such as pulmonary fibrosis and aplastic anemia.

15. The role of telomeres and telomerase in replicative senescence of cells

16. Role of telomerase in maintaining chromosomal length

17. Causes/ mechanisms of cellular aging ct’d Activation of tumor suppressor genes: In addition to telomere attrition, activation of certain tumor suppressor genes, particularly those encoded by the CDKN2A locus, also seems to be involved in controlling replicative senescence. The CDKN2A locus encodes two tumor suppressor proteins, expression of one of which, known as p16 or INK4a, is correlated with chronologic age in virtually all human and mouse tissues examined. By controlling G1- to S-phase progression during the cell cycle, p16 protects cells from uncontrolled mitogenic signals and pushes cells along the senescence pathway.

18. Causes/ mechanisms of cellular aging ct’d Defective Protein Homeostasis: Protein homeostasis involves two mechanisms: maintenance of proteins in their correctly folded conformations (mediated by chaperones) and degradation of misfolded , damaged, or unneeded proteins by the autophagy-lysosome system and ubiquitin proteasome system.

19. Causes/ mechanisms of cellular aging ct’d There is evidence that both normal folding and degradation of misfolded proteins are impaired with aging. Mutant mice deficient in chaperones of the heat shock protein family age rapidly, and conversely, those that overexpress such chaperones are long-lived. Similar data exist for the role of autophagy and proteasomal degradation of proteins.

20. Causes/ mechanisms of cellular aging ct’d Of interest, administration of rapamycin , which inhibits the mTOR (molecular target of rapamycin ) pathway, increases the life span of middle-aged mice. Rapamycin has multiple effects, including promotion of autophagy . Abnormal protein homeostasis can have many effects on cell survival, replication, and functions. In addition, it may lead to accumulation of misfolded proteins, which can trigger apoptosis.

21. Causes/ mechanisms of cellular aging ct’d Dysregulated Nutrient Sensing: Paradoxical though it may seem, eating less increases longevity. Caloric restriction increases life span in all eukaryotic species in which it has been tested, with encouraging results even in nonhuman primates and in a few unusually disciplined people who are the envy of others! Because of these observations, there has been much interest in deciphering the role of nutrient sensing in aging. Although incompletely understood, there are two major neurohormonal circuits that regulate metabolism.

22. Causes/ mechanisms of cellular aging ct’d Insulin and insulin-like growth factor 1 (IGF-1) signaling pathway: IGF-1 is produced in many cell types in response to growth hormone secretion by the pituitary gland. IGF-1, as indicated by its name, mimics intracellular signaling by insulin and thereby informs cells of the availability of glucose, promoting an anabolic state as well as cell growth and replication. IGF-1 signaling has multiple downstream targets; relevant to this discussion are two kinases : AKT and its downstream target, mTOR , which, as the name implies, is inhibited by rapamycin .

23. Causes/ mechanisms of cellular aging ct’d Sirtuins : Sirtuins are a family of NAD-dependent protein deacetylases . There are at least seven types of sirtuins in mammals that are distributed in different cellular compartments and have nonredundant functions designed to adapt bodily functions to various environmental stresses, including food deprivation and DNA damage.

24. Causes/ mechanisms of cellular aging ct’d Sirtuins are thought to promote the expression of several genes whose products increase longevity. These include proteins that inhibit metabolic activity, reduce apoptosis, stimulate protein folding, and counteract the harmful effects of oxygen free radicals. Sirtuins also increase insulin sensitivity and glucose metabolism, and may be targets for the treatment of diabetes.

25. Causes/ mechanisms of cellular aging ct’d It is thought that caloric restriction increases longevity both by reducing the signaling intensity of the IGF-1 pathway and by increasing sirtuins . Attenuation of IGF-1 signaling leads to lower rates of cell growth and metabolism and possibly reduced cellular damage. This effect can be mimicked by rapamycin . An increase in sirtuins , particularly sirtuin-6, serves dual functions:

26. Causes/ mechanisms of cellular aging ct’d (1) contribute to metabolic adaptations of caloric restriction and (2) promote genomic integrity by activating DNA repair enzymes through deacylation . Although the anti-aging effects of sirtuins have been widely publicized, much remains to be known before sirtuin -activating pills will be available to increase longevity. Nevertheless, optimistic wine lovers have been delighted to hear that a constituent of red wine may activate sirtuins and thus increase life span!

27. Mechanisms that cause and counteract cellular aging.

28. Functional and Structural Changes that Accompany Aging The insidious effects of aging can be detected in otherwise healthy persons. The great leaps of imagination in theoretical physics and mathematics are almost exclusively made by the young. In many sports, an athlete in his or her 30s may be referred to as aged. 

29. Functional and Structural Changes that Accompany Aging ct’d Even in the absence of specific diseases or vascular abnormalities, beginning in the fourth decade of life there is a progressive decline in many physiologic functions, including such easily measurable parameters as: muscular strength, cardiac reserve, nerve conduction time, pulmonary vital capacity, glomerular filtration, and vascular elasticity.

30. Functional and Structural Changes that Accompany Aging ct’d These functional deteriorations are accompanied by structural changes. Lean body mass decreases and the proportion of fat rises. Constituents of the connective tissue matrix are progressively cross-linked. Lipofuscin (wear and tear) pigment accumulates in organs such as the brain, heart, and liver.

31. Functional and Structural Changes that Accompany Aging ct’d The salient characteristic of aging is not so much a decrease in basal functional capacity as it is a reduced ability to adapt to environmental stresses. Although resting pulse is unchanged, the maximal increase with exercise is reduced with age and the time required to return to normal heart rate is prolonged. Similarly, the aged show impaired adaptation to ingested carbohydrates: fasting blood glucose levels are often normal compared with younger people, but they rise higher after a carbohydrate meal and decline more slowly.

32. Decrease in human physiologic capacities as a function of age.

33. ORGAN CHANGES (MORPHOLOGY) IN AGEING Although all organs start showing deterioration with ageing, the following organs show evident morphologic and functional decline: 1. Cardiovascular system: Atherosclerosis, arteriosclerosis with calcification, Mönckeberg’s medial calcification, brown atrophy of the heart, loss of elastic tissue from aorta and major arterial trunks causing their dilatation.

34. ORGAN CHANGES (MORPHOLOGY) IN AGEING ct’d 2. Nervous system: Atrophy of gyri and sulci , Alzheimer’s disease, Parkinson’s disease.

35. ORGAN CHANGES (MORPHOLOGY) IN AGEING ct’d 3. Musculoskeletal system: Degenerative bone diseases, frequent fractures due to loss of bone density, age-related muscular degeneration.

36. ORGAN CHANGES (MORPHOLOGY) IN AGEING ct’d 4. Eyes: Deterioration of vision due to cataract and vascular changes in retina. 5. Hearing: Disability in hearing due to senility is related to otosclerosis . 6. Immune system: Reduced IgG response to antigens, Frequent and more severe infections.

37. ORGAN CHANGES (MORPHOLOGY) IN AGEING ct’d 7. Skin: Laxity of skin due to loss of elastic tissue. 8. Cancers: 80% of cancers occur in the age range of 50-80 years.

38. LIFE EXPECTANCY Mankind has pursued immortality from time immemorial. Individuals age because their cells age. Although public attention on the aging process has traditionally focused on its cosmetic manifestations, aging has important health consequences, because age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease.

39. LIFE EXPECTANCY CT’D In general, survival is longer in women than men (3: 2). About a century ago, the main causes of death were accidents and infections. But now with greater safety and sanitation, the mortality in the middle years has sufficiently declined.

40. LIFE EXPECTANCY CT’D The average age of death of primitive man was barely 20-25 years. However, currently average life-expectancy in the west is about 80 years. In India, due to improved health care, it has gone up from an average of 26 years at the time of independence in 1947 to 64 years at present.

41. LIFE EXPECTANCY CT’D However, the maximum human lifespan has remained stable at about 110 years. Higher life expectancy in women is not due to difference in the response of somatic cells of the two sexes but higher mortality rate in men is attributed to violent causes and greater susceptibility to cardiovascular disease, cancer, cirrhosis and respiratory diseases, for which cigarette smoking and alcohol consumption are two most important contributory factors.

42. Factors affecting life expectancy 1. Intrinsic genetic process i.e. the genes controlling response to endogenous and exogenous factors initiating apoptosis in senility. It has been seen that long life runs in families and high concordance in lifespan of identical twins has been observed. Studies in centenarians have shown that they lack carrier of apolipoprotein E4 allele which is associated with risk for both heart disease and Alzheimer’ s disease.

43. Factors affecting life expectancy ct’d 2. Environmental factors e.g. consumption and inhalation of harmful substances, type of diet, role of antioxidants etc. 3. Lifestyle of the individual such as diseases due to alcoholism (e.g. cirrhosis, hepatocellular carcinoma), smoking (e.g. bronchogenic carcinoma and other respiratory diseases), drug addiction. 4. Age-related diseases e.g. atherosclerosis and ischaemic heart disease, diabetes mellitus, hypertension, osteoporosis, Alzheimer’s disease, Parkinson’s disease etc. They cause progressive accumulation of sublethal injury over the years at cellular and molecular level.

44. Diseases of Premature Aging In humans, the modest correlation in longevity between related persons and the excellent concordance of life span among identical twins lend credence to the concept that aging is influenced by genetic factors. The existence of heritable diseases associated with accelerated aging buttresses this notion. The entire process of aging, including features such as male-pattern baldness, cataracts, and coronary artery disease, is compressed into a span of less than 10 years in a genetic syndrome termed Hutchinson-Guilford progeria .

45. Diseases of Premature Aging ct’d The cause of progeria is apparently a mutation in the LMNA gene, whose product is a protein termed lamin A. The mutant gene codes for a defective precursor of the lamin A protein, which has been termed progerin . This abnormal protein accumulates in the nucleus from one cell generation to the next, thereby interfering with the structural integrity of the nucleus and resulting in a lobulated shape.

46. Diseases of Premature Aging ct’d The buildup of progerin also interferes with the organization of nuclear heterochromatin, a component that is thought to regulate the expression of numerous genes. Interestingly, the nuclear changes in cells from patients with progeria were corrected by treating the cells with inhibitors of farnesyltransferase , which prevents progerin from becoming farnesylated .

47. Diseases of Premature Aging ct’d Experimental suppression of the production of progerin has also corrected the nuclear changes in cultured cells from patients with progeria . Hutchinson-Guilford progeria is now recognized to be one of about 10 disorders associated with mutations in the LMNA gene, comprising a group termed laminopathies . It is not known whether changes in lamin A contribute to normal aging, but cell nuclei from aged persons have been shown to acquire defects similar to those seen in cells from patients with progeria .

48. Progeria . A 10-year old girl shows the typical features of premature aging associated with progeria

49. Diseases of Premature Aging ct’d Werner syndrome (WS) is a rare autosomal recessive disease characterized by early cataracts, hair loss, atrophy of the skin, osteoporosis, and atherosclerosis. Affected persons are also at increased risk for the development of a variety of cancers. Patients typically die in the fifth decade from either cancer or cardiovascular disease. This phenotype of patients with WS gives the impression of premature aging. .

50. Diseases of Premature Aging ct’d WS is caused by loss of function of the Werner (WRN) gene, which codes for a protein with multiple DNA-dependent enzymatic activities, including ATPase , helicase , exonuclease , and strand annealing. There is experimental evidence that WRN plays a role in the resolution of replication blockage and in telomere maintenance. Its loss leads to defective processing of DNA damage and replication. Experimentally, epigenetic inactivation of WRN by transcriptional silencing associated with promoter hypermethylation results in chromosomal instability and increased apoptosis. It is thought that the increased incidence of cancer in WS may reflect chromosomal changes, whereas accelerated aging probably reflects telomere dysfunction.

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