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Theories of Aging Chapter 2 Outline 1. 2. Mechanisms of Aging General theories of aging a. Aging by Program b. Gene Theory c. Gene Mutation Theory d. Cross-Linkage Theory e. Free Radical Theory f. Cellular Garbage Theory g. Accumulation-of-Errors Theory h. Wear-and-Tear Theory i. Auto-Immune Theory • • New Antigens Increase in Auto-Immune Reactions Aging is characterized by a general reduction in functional capabilities and by structural changes in the body. Q: What causes the changes associates with aging? If the underlying cause of aging can be determined, it might be possible to interfere with the process, thus, extending human longevity Goal of increasing human life span can be attained either by 1. suppressing the cause of death in younger people 2. delaying the aging process that make us more susceptible to disease and death as we grow older Mechanisms of Aging Biological components of humans 1. They contain cell that continue to divide and produce as long as the person is alive (the rate of cell division decreases w/ age) 2. Post-mitotic cells: type of body cells that actively dividing during embryonic development, but incapable of dividing after birth (no longer capable of undergoing mitosis; e.g, nerve and muscle cells) 3. Intercellular substance: large components of non-cellular material located b/w cells, such as collagen that provides support in the skin, bone, cartilage, tendons & other tissues All 3 subject to physiological controls that function w/in the body Early hypotheses: • Vigor declines as a result of change in cells that are capable of dividing • Vigor declines due to loss/injury of cells no longer dividing (nerve & muscle) • Vigor declines w/ age due to changes in intercellular materials General Theories of Aging Criteria to validate a proposed theory of aging: 1. Changes must occur commonly in all members of a given species 2. The proposed process must be progressive with time (changes must be obvious as the person grows older) 3. The process must produce changes that cause organ dysfunctions and ultimately cause a particular body organ or system failure Characteristics of the Theories • Link aging with death of increasing numbers of cells as they “wear out” for extended usage & prolonged exposure to various deleterious factors • Mechanical or chemical explanations for cellular changes & dysfunctions that are characteristics of aging • Self-poisoning that occurs at the cellular level increases steadily w/ age, ultimately reaching levels that cause organism to malfunction or cease to function • Genetic mechanisms; changes due to somatic mutations or loss of biological info. General Categories of Aging Theories: • Aging results from some form of damage. An organ or a system becomes worn or damaged, adding more stress on other organs. Damage or excessive wear in one particular organ/system causes a down-ward spiral in body functioning. • There are non-reversible physical or chemical changes within cells that gradually alter the cellular function • Aging is genetically programmed by some sort of neurological center that functions as a biological clock ; intrinsic aging chronometer (brain) A. Aging by Program • Begins at birth, each species has its own average longevity aging is programmed in each species • The site of localized aging chronometer (time keeper) is Hypothalamus (in the base of the brain) • Hypothalamus contains centers that control the production of growth hormones by pituitary gland, as well as the development and activities of the gonads (thyroid, adrenal) • Hormones and neurons carry out the information originated from this center; ability of the organism to transmit the message declines w/ age – Decrease nerve conduction rates – Change in structure & amounts of hormone – Receptors for nerve impulses or hormones may become less capable of reacting appropriately to incoming impulse or molecular message • Thymus, lymphoid gland, may be involved in some manner in the programmed regulation of aging. • It atrophies at the onset of adolescence, implying that aging occurs more readily in the absence of thymus Some research exclude the role of central nervous system in programmed aging • Each normal cell type has a finite number of divisions and then die. (fibroblasts taken from embryo divide 50 times, if take from adult only divide 20X) Cells isolated from patients suffering from Werner’s syndrome only divide 10-20 times Werner’ syndrome: rare condition in which affected individuals show advanced signs of aging while still in their twenties These suggest that cell death is an inherent property of the cells, rather than being controlled by hypothalamus or some other aging chronometer Explanation for programmed longevity: Perhaps only in early life do the genes produce mRNA, tRNA, rRNA, and enzymes. As cells grow old these substances will be used up & if not replenished, cells will cease functioning • The amount of these substances in each cell can specifically limit the number of divisions of that particular cell type Q: how can there be life long division of many cell types in the body if each cell type is capable of only a limited number of cell divisions? • There are several generations of dormant “renewal cells” in each tissue that begin dividing at different These are, in effect, reserve embryonic cells. Only when these are used will the tissue begin to show signs of aging. General consensus about aging by program: Its unlikely that aging results from the loss of capacity to divide, rather the finite division capacity of cells shown in culture is rarely, if ever, reached in the body. Thus, the reactions of at least some cells in the body is different than when they are cultured. Cells that are under constant stress (such as cells lining the intestine, those in active layer of epidermis, RBCs) undergo more than 50 division during a person’s life. Other functional losses that occur in cells produce physiological dysfunctions in the cells. This causes the cells to show aging changes before they reach their finite limits to divide. B. Gene Theory • The gene theory suggests that: “Aging is programmed but due to one or more harmful genes within each organism” • These harmful genes become active only late in life and alter the physiology of the organism in ways that result in its death • Alternatively, there are genes that direct cellular functions in early years and become altered in later years, thus, altering their function • In their altered state, these genes may be responsible for the functional decline and structural changes associated with aging • Gene theory suggests: Human life span is an inherited trait (support: studies of twins) • There is considerable similarity in age at death of pairs of monozygous (single egg) twins, whereas this is not apparent in dizygous (2 eggs) twins C. Gene Mutation Theory • Mutations occur in the genes of cells composing the various tissues during life which alter the functioning of the cells, generally to the detriment of the cells • Gene mutation theory: Accumulation of cells w/ altered structure and function that results from these mutations may lead, w/ the passage of time, to malfunctions and eventually death • Natural Radiation accelerates aging process (mouse liver cells) • Gene composition: Nucleotide; NT (sugar, base, phosphate molecule), NTs joined together to form double stranded DNA (deoxyribonucleic acid) • Damaged DNA can be repaired accomplished by enzymes w/in the cell cutting out the damaged region of the gene & adding back a new set of NTs, utilizing the undamaged strand as template • With the passage of time, gene repair mechanisms become less efficient, some mutations remain uncorrected, thus, causing structural and functional aging changes (damaged DNA, mRNA, ribosomes) D. Cross-linkage Theory • • • Proteins (building blocks of cells) are composed of peptides. Protein denaturation is irreversible (e.g., cooked egg is denatured and its physical state is changed permanently. Protein denaturation is caused by the formation of cross-links between peptide strands, which causes structural and functional changes in protein. Cross-linkers are chemicals that develop between hydrogen atoms in the peptide • Cross-linkage theory: With age & formation of new cross-links, the structure of some proteins in the cells is irreversibly altered. protein function alters organ/ system dysfunction (e.g., enzymes and collagen) • Enzymes: organic catalysts; accelerate the rate of chemical reactions (digestions, metabolism, etc.) • Collagen: metabolically inert supportive tissue located between cells, composed of protein fibers embedded in intercellular matrix. Collagen structural changes is responsible for loss of blood vessel elasticity that occurs with age • • Increase in collagen deposition w/ aging excess fibers: Fibrosis • Collagen is important component of connective tissue (CT). When specific cells/ tissues die, replaced by CT which lacks functional capabilities of original cells Also interfere with oxygen and nutrient supply Example: Elastic fibers in skin degenerate with age replaced by collagen fibers that are less flexible elasticity of skin decreases with age • • • Molecular changes in the matrix surrounding collagen fibers also occur w/ age less permeable capillaries less permeable reduced transport of gas, nutrients, waste across their walls significantly affects metabolism (e.g., kidney: decreased filtration, renal failure • The theory also suggests: some essential molecules, other than pr., may become crosslinked w/age (example: DNA disruption of immunological response, OR clogged arteries, reduced kidney function, stiff joints in diabetics) • • Cross-linked pr-glucose complexes: advanced glycation end products (AGEs) Functional abnormalities: decreased enzymatic activity and reduced degradation of abnormal proteins With age AGEs accumulate in collagen, hemoglobin, the lens of eyes, Connective tissue: less elastic and stiffer (blood vessels), AGEs also interact with DNA interfere w/ the ability of cell to repair DNA • • • E. Free Radical Theory • Free radicals: cellular chemicals containing an unpaired electrons; formed as byproducts of normal processes involving interaction w/ O2 • Free radicals, through unpaired electron, react chemically w/ other substances (protein & unsaturated fats) alteration of membrane structure changes in membrane permeability • Free radicals also react w/DNA chromosomal mutations damaging normal genetic machinery • Free radical theory: there may be gradual accumulation of free radicals in cells w/ time; as they exceed threshold concentrations, they may contribute to changes commonly associated w/ aging • Upon reaction w/ a molecule, free radicals self-propagate & can increase dramatically in number • Anti-oxidants inhibit free radical production by preventing oxidation (e.g., Vit A, C, E, enzymes. In aging cells anti-oxidants are either ineffective or saturated by high numbers of free radicals or older cells produce fewer anti-oxidant substrates • F. Cellular Garbage Theory • As cells age, accumulate large amounts of various by-products of normal cellular metabolism. These include free radicals, aldehydes, histones, lipofuscins. • Lipofuscins: yellow brown pigment common in many types of aging cells (also referred to as “age pigment”) lipofuscins are Cellular Garbage • Cellular garbage theory: Gradual accumulation of inert substances such as lipofuscins in cells interferes w/ normal functioning of the cell. • However, such interference w/ lipofuscins have not been reported. • These substances interfere w/ normal cellular functioning by causing deleterious changes in cellular components including proteins and nucleic acids • Older cells are less efficient in repairing these damages changes may be irreversible more damage aging G. Accumulation-of-Errors Theory • Cellular dysfunction, and ultimately cell death, could result from the accumulation of random errors in the mechanisms by which new protein is being synthesized. • Protein synthesis: DNAmRNA (nuclear–cytoplasmic transport) ribosomes • Any error in the formation of proteins (enzymes) has significant effect on cellular activities they participate in. • Accumulation-of-Errors theory suggests: Aging is caused by a buildup of errors in protein synthesis with time. Errors would cause the production of faulty enzymes faulty proteins • Experimental data: Enzyme activity, but not structure, decrease in older persons. • Data: proteins are synthesized properly in older cells, and any alteration occurs after they are made “This theory is highly questionable” H. Wear-and-Tear Theory • This theory supports the concept that Aging is a Programmed Process • Each animal, & each cell, has a specific amount of metabolic energy available to it and that the rate at which this energy is used determines animal’s length of life. • Data: rats kept in cold & restricted food uptake longer life • In fact, reduction of calorie intake is the most effective method for modifying the rate of aging in rats. Old rats on this diet behave and look like young ones. “Though, no similar data in humans” • Besides depletion of available energy, theory includes other contributing factors to aging changes such as effects of accumulation of harmful byproducts of metabolism and of faulty enzymes due to random errors I. Autoimmune Theory • Antigen (Ag): Foreign substances that invade the body • Antibody (Ab): Immune systems’ specific response to Ag to attempt to destroy it • To selectively destroy foreign proteins, the immune system must recognize the structures of all of the many proteins present in the body and suppress its tendency to form Abs against these body proteins • Due to gradual atrophy of thymus and slow response to stimuli by T & B cells, with age, the functionality of immune system decreases (IL-2) • Autoimmune Theory suggest: with advancing age the immune system is no longer able to faultlessly distinguish foreign proteins from the body’s own proteins. Thus, auto-Abs are generated that attack & destroy normal cells. • Categories of Autoimmune theories: a. new Ags appear and b. increase in autoimmune reactions a. New Antigens • Sources of new Ags: 1. Result of mutations that cause the formation of altered RNA or DNA, and consequently of altered protein • These proteins can not be recognized by the immune system and would act as new (and foreign) Ags. 2. Some cells may be hidden in the body during embryonic development & the immune system does not contact them during development. • IS would not be suppressed to make Ab against them as it won’t recognize them as being normally present. Due to disease or damage, the cells will be released into circulation considered foreign Abs produced against them b. Increase in Autoimmune Reactions • Autoimmune reactions increase progressively as a person ages because of changes in Ab molecule • Abs can be modified by interaction with their specific Ag, aggregating into a mass, being split into smaller components (poly-peptides) • After these modifications, Abs acquire antigenic potential against body and stimulate body’s immune system • Continuous circulation of Ag-Ab complex affects various organs & tissues • Also, microorganisms that exist in body for long periods may have Ags that cross-react, thus, causing pathological changes in normal tissues • Also, drugs taken as medication may form complexes with body proteins; the immunes system recognizes these as foreign substances IR Summary No one theory adequately explains the process of growing old. Aging processes are better explained if a number of these theories are integrated.