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1. Theories of ageing 1.1. History 1.2. Categories of ageing theories 1.2.1. Wear and tear theories 1.2.2. Genetic theories 1.2.3. Article - Poor, poor Dolly, old before her time 1.2.4. General imbalance theories 1.2.5. Accumulation theories 1.2.6. DHAC 1.2.7. Miscellaneous
Theories of Ageing
According to Kenney "The physiologic hypothesis of aging and its termination by eugeric death is that the decline of function proceeds to the point where an internal environment compatible with the life of the cell can no longer be maintained". NOTE: Function can include adaptability, impairment, loss in reserve of physiological capacities and eventually death.
Rates of Decline of Functions With Ageing Per Decade After Apex Nerve conduction velocity 15% BMR 20%
Cardiac index 30% Vital capacity 50% Renal blood flow 50% Max O2 60-70% Stature (height) 1 cm Lean body mass 10%
We observe a loss of function with ageing:
- Functions totally lost o Female reproduction o Menstruation o High frequency hearing
- Structural changes - functional loss o Units of function lost but remaining units maintain normal function o Kidney nephrons o FT fibre number o Skeletal muscle diameter
- Reduced efficiency of a unit o Decreased conduction velocity in nerve fibres
- Control systems o With feedback, control loss of female sex hormones e.g. estrogen and increased gonadotropins o The system, when exposed to stress has reduced reserve as well
Biological ageing refers to the slow, progressive, structural and functional changes that take place at the cellular, tissue, and organ levels, ultimately affecting the performance of all body systems.
Strehler (1959) characterized ageing by four (4) main features: i) It is destructive - compromising functionality ii) It is progressive, and irreversible iii) It is intrinsic, i.e. determined by internal rather than external factors iv) It is universal, i.e. all individuals of the same species display a largely uniform ageing pattern, with all
mutation theory which attributes ageing to accumulation of genetic errors in postmitotic cells over the life span of the cells.
- Notes o Most theories developed before 1960 are considered obsolete and would have fallen under the general headings listed above but most would be considered "wear and tear" theories. For example, experimental results cast the somatic mutation theory into doubt as it was shown that the effect of any irradiation dose is considerably diminished if its application is spread out over time. As well, it is now known that there exists a chromosome repair mechanism. In order to shorten the life span of animals, irradiation doses of 12-20 times that found in a normal life span were required. This suggests that mutation effects may contribute to ageing, but do not explain the results alone. o The Somatic Mutation Theory led to the Genetic Mutation Theory that attributed a causative role in ageing to the same types of mutations, but in premitotic stem cells rather than in postmitotic mature cells. o The Somatic Mutation Theory made no mention of the source of mutation, merely that genetic errors came into being and resulted in defective protein synthesis. Proteins of erroneous structure then began to accumulate within cells. This model was popularized by Orgel (1963) who used the term "error catastrophe" to describe the process. However, extensive research on the fidelity of transcription and translation demonstrated a higher efficiency of DNA damage repair than this could.
Categories of Ageing Theories
WEAR AND TEAR THEORIES (Damage Theories)
Body parts (cells, organs etc.) wear out with continued use and stop functioning e.g. neurons and other cells lose ability to regenerate which results in mechanical or chemical exhaustion. Perhaps too simplistic (organ based
theory).
NOTE : These theories are based upon the fact that the damage may be extremely as well as internally casual.
- Chemical micro insults - air, food, smoke, metabolism
- Viruses, trauma, free radicals, environmental radiation, high body temperature
- Damage probably results from an accumulation of incompletely repaired insults
- Free radical o Naturally produced chemical elements from metabolic processes o Highly reactive and disruptive at cell level o Highest concentration in cell mitochondria o Damaging to DNA membrane and ability to synthesize proteins o Also produced by external exposure to radiation and chemical toxins such as ozone, hydrogen peroxide, aluminum o Antioxidants include vitamins A & C, beta- carotene o Chemical reactions (natural) produce irreversible objects in molecules o Unpaired electron in outer orbit o Could lead to damage because of accumulation of incompletely repaired insults o The power of this theory lies in that it does not belong or depend on any one biomacromolecule, cell, tissue, or system as the initiating step in a failure cascade
- Cross-Linking (Collagen 33% of body protein) o Tough fibrous protein holding cells together becomes stiffer with age, perhaps through a molecular process producing "cross-links" with DNA strands o Cross links = tangles of protein: stiffening of tissues, rigidity of blood vessels, tight ligaments and tendons, cataracts, and atherosclerosis o A cross-linking agent may "oxidize" cellular
which accelerate ageing (DNA mutations of the mitochondria) o Genetic structure of cell chromosome is damaged which results in synthesis of the wrong proteins and mutated cells o Mutagenic agents damage the orderly process of cell formation which results in an ability of cells to manufacture essential enzymes for maintenance of the cell life. o Best (or worst) example is found in cancer research - radiation therapy to prevent or subside the increased mutation rate.
- Cellular Error (Error - Catastrophe) o Cell death from errors in the sequence of information transfer which result in non- identical protein formation and an inability to carry out normal cell function o Faulty proteins accumulate in the cells - error catastrophe - which results in changes with age and ultimately cell death o Repair failure leads to premature cell death
Poor, poor Dolly, old before her time
by Robin McKie
SO FAR, SO GOOD. "Dolly’s doing fine. The world’s most famous sheep is shaping up." So ran the headlines marking the first birthday of the Earth’s most distinguished clone.
In a few weeks time, Dolly will be three. But this time round, the greeting may be a little more muted - for Dolly has a problem. Her telomeres have come up short.
Sounds nasty and you might be right. Telomeres are the bits of DNA that cap the ends of the chromosomes found inside the cells of all living creatures. Every time a cell divides, it sheds a little bit of telomere. You can judge an animal’s age by the lack of length of its telomeres.
And Dolly’s have been found wanting. They are 20 per cent too short for a three-year-old sheep, and are more like those of a nine-year-old - a striking finding given that Dolly was cloned
from a six-year-old sheep’s udder cell. In other words, she appears to have inherited all the wear and tear that would normally be found in her mother’s cells.
And that is a crucially important finding for two reasons. First, it suggests that Dolly is destined to play a critical role in understanding that most baffling and dispiriting of phenomena: ageing. Scientists have wondered whether it is a cellular business. In other words, do the building blocks of living beings contain the seeds of their own destruction, and after their allotted span, just die out, triggered by telomere depletion? Or is ageing more to do with larger processes; the failure of repair mechanisms to correct the accretion of physiological flaws, for example?
Sheep when not merged with mint sauce, live for about 14 years
Dolly offers us a chance to find out. Sheep, when not merged with mint sauce, live for about 14 years. Dolly has 11 to go, and if she fails to make it, her stunted telomeres may be blamed. Equally, if she lasts through to her sheepish dotage, then scientists will also have learned an important lesson.
There is, however, a second point to be noted from the discovery of Dolly’s truncated telomeres. When her creation was announced in February 1997, the world and its pundits went into a lather of pipe-sucking hysteria about the creation of human clones. It was assumed a monstrous regiment of Identikit humans would soon be marching in step towards global domination. In vain, scientists tried to point out that it took 277 attempts before they succeeded in making Dolly. Researchers have still not mastered the ability to clone mice, never mind an ape or a monkey.
And now comes news of Dolly’s telomeres. Clone a 50-year-old man and by the time his son is in his teens, his cells would have the age of an OAP's. Not much cop really, or as Dolly’s creators put it last week, "It’s another good reason to stop talking about human cloning." And not before time...
GENERAL IMBALANCE THEORIES
- Found in brain, endocrine glands, or immune system
- Systems gradually fail to function
ACCUMULATION THEORIES
- Lipofuscin , age pigment o An insoluble cross-linked lipoprotein accumulates in lysosomes and takes up useful cytoplasmic volume and thus impairs cellular function o Accumulates due to insufficient lysosomal function o Lipofuscin accumulates first in nerve cells and myocardial cells o Many consider this accumulation as the most characteristic biomarker of ageing o However leupeptin, a lysosomal thiol proteinase inhibitor causes accumulation of lipofuscin o Like granules in nerve and pancreatic cells of young animals, which demonstrates that lipofuscinogenesis is not exclusively an ageing phenomenon ß The difference is that younger cells can eliminate it effectively, where in older cells its lysosomal decomposition slows, like any other cellular function with age
- Free Radical o Some consider the Free Radical Theory an accumulation theory.
- Membrane permeability to potassium (K+) o This is a variant of the Free Radical Theory o Proposed by Zsolt Nagy (1978, 1991) o Theory is based on the observation that membrane permeability to K+ decreases over the lifetime of an organism o Since the membrane is the most vulnerable structure to attack by free radicals o And since lipid-lipid, protein-lipid and protein-protein cross-links are continuously being formed, and since they form more efficiently in dense structures than in dilute ones, (for kinetic reasons contact between
molecules is more frequent) this affects the probability of cross-link formation (Remember: membrane proteins display the shortest half-life among all cellular proteins)
NOTE: Membrane Hypothesis of Ageing (MHA) models limit ageing affects to the cellular level only and do not attempt to explain how ageing might be occurring throughout the different systems of an organism.
DYSDIFFERENTIATIVE HYPOTHESIS OF AGEING & CANCER (DHAC)
- Cutter (1985) postulated that underlying most of the vast complexities of ageing is a primary ageing process: the drifting away of cells from their proper state of differentiation
- This is thought to be due to Aregulatory changes (not gene mutation) of highly differentiated cells (Specialized genes)
- Dysdifferentiated cells in important regulatory systems initiated a cascade of changes throughout the organism. The summation of these changes is the ageing process.
DHAC differs from other genetic-based models in three key ways: i) The model is not dependent upon gross changes in genes themselves, lacking the gross impairment of vital functions ii) The majority of DNA in a cell is involved with gene regulation; a higher probability of getting
hit= by a mutagen. Regulatory changes, not gene mutation, lead to dysdifferentiation. iii) Very small changes occur in the genetic apparatus, insufficient to alter genes responsible for >housekeeping= functions, but sufficient to alter specialized >luxury= genes in highly differentiated cells
- DHAC postulates special stabilizing mechanisms for maintenance of differentiated state of cells. Such mechanisms are considered more effective in longer-
- Dolly o Her telomeres have come up short o Dolly was cloned from a 6 years old ewe and today she is three but her telomeres are comparable to a 9 year old o Dolly appears to have inherited all the wear and tear found in her mother's cells
- London Free Press Article (Dec. 27/99 Section C page 1) o The slow downhill slippery slope of ageing 45 o Disorders to consider: sleep, brain, skin, eyes, smell, libido, feet, urination, bones o Add to this muscle, heart, hearing, taste, fat, nerves, endocrines, organ function o That is the inevitable - ageing with or without taxes!
