Increased free radical injury The cells of lower organism i.e. bacterial cells are immoal at least in principle. If a bacterial cell is placed in .ourable condition it will grow and divide indefinitely. What about cells of higher organisms like birds or mammals ?? - Until mid twentieth century it was thougth that cells from higher species were also immoal i.e., capable to grow indefinitely under proper conditions. Hayflick theory of aeging suggests that human cells is limited in the number of times it can divide. -Hayflick theorized that human cells ability to divide is approximately 50 times, after which, they simply stop dividing. - It was believed that the hayflick limit is a genetic program that prevents cell division after a ceain no. of cell cycles. Why would our cells need to have such program?? - The current view is that a built in limit on the number of possible cell divisions reduce the risk of uncontrolled growth resulting in cancer. Indeed, studies indicate that in cancer cells this genetic clock is broken allowing them to grow indefinitely. Could it be that ageing is the result of cells inability to divide once they have reached the Hayflick limit??. - There is no straight answer to that at present. It appears that in some tissues such as the skin and the lining of blood vessels the hayflick limit may be an impoant pa of the aeging process. - On the other hand, cells in the brain, retina, nerves and muscles normally do not divide and never even approach the Hayflick limit. Molecular mechanism responsible for Hayflick limit (Telomerase theorey of Aging) In the cells of higher organisms chromosomes are capped with special DNA structures called Telomers. The main role of Telomers is to protect the ends of chromosomes from degradation. - During cell division the chromosomes are duplicated through the process of DNA replication. - However due to the nature of this process, the very ends of Telomers cannot be copied. - Imagine a road machine that moves along the road and makes a new layer of asphalt behind it. The machines design is such that it can move only when it is on the road. When it has reached the end of the road there is an new layer of asphalt over the entire road except for the spot under the machine. To be able to cover the remaining spot, the machine must move past it but it cannot because it is already at the end of the road. - Similar scenario occurs during the replication of chromosome. - Thus the very end of the each telomere never gets copied. - Which leads to progressive shoening of Telomers after each cell division. It appears that after its Telomers have shoened beyond a ceain point the cell loses the ability to divide (This does not occurs in bacteria because their chromosomes are circular and do not have telomers) Free radicals theory of ageing It is now widely believed that degeneration occurs primarily in response to oxidative stress. During oxidative stress, a highly reactive oxygen molecules (ROS) are released. These molecules characteristically have unpaired electron in their outer orbit. - Small quantities of ROS are formed spontaneously under normal conditions, as the byproduct, of redox processes such as oxidative phosphorylation in the mitochondria and y3 oxidation of fatty acids. - However, generation of free radicals is significantly enhanced in condition of oxidative stress, irradiation, chemical exposure. Free radicals are extremely reactive speciese since by reacting with other molecules they try to stabilize their configuration and obtain the lacking electrons. - The inacromolecules that are extremely susceptible to ROS mediated damage are nucleic acids, phospholipids and proteins. - Oxidation of both nuclear and mitochondrial DNA may result in mutation and aberrant protein synthesis. - Oxidative damage to cell membrane phospholipids may impair transmembrctne transpo mechanisms and signal transduction. Under normal conditions, ultrastructural alterations caused by ROS are recognized and eliminated by cellular repair mechanisms:- - It is however, impoant to emphasize that the cumulative damage exeed by ROS with time, exceeds repairing potential of the cellular machinery which ultimately leads to decline in physiological capacity of the whole organism. Molecular evidence of increased oxidative stress is -> "accumulation of lipofuscin". Under normal conditions a network of cellular defence system including "catalase", "peroxidase, "superoxide dismutase" effectively scavenges small amounts of ROS generated. - However, the capacity of antioxidant system is limited and the rate at which antitoxidant agent are resynthesized declines with age. Cross linkage theory of Aging An impoant theory implicated in age related cell degeneration is accumulation of advanced glycosylation end (AGE) products. - Advanced glycosylation end products are .formed by non enzymatic reaction between sugar and protein. - It has been demonstrated that physiological control of blood glucose becomes less tight with age which leads to impaired glucose tolerance and prolonged periods of elevated glucose that our AGE formation. Generation of AGE induces pathology a number of mechanisms. - Glycosylation of several proteins have been documented such as hemoglobin, fibrinogen lipoprotein ferritin. Of paicular impoance is glycosylation of extracellular matrix proteins such as collagen. - Cross linking of collagen type I molecule in large vessels decrease their elasticity which may predispose these vessels to shear stress and endothelial injury. Proteins cross linked are resistant to proteolvtic digeston. "Thus crosslinking decreases protein removal while enhancing deposition". Consequences of AGE induced abnormalities includes. - Narrowing of blood vessels. - Capturing of other plasma proteins such as LDL - Thickening of basement membrane - Decreased elasticity of blood vessels, skins, ligament... In addition AGE bind to specific receptors on immune cells which trigger the release of inflammatory mediators and generation of ROS which fuher increase AGE induced damage. Membrane theory of aeging As the body grow older the cell membrane becomes less lipid. This impedes its efficiency to conduct normal function and in paicular there is a toxic accumulation. - This cellular toxin is referred to as "lipofuscin" and as we grow older, lipofuscin deposits become more evident in the brain, hea and lungs and also in the skin. Somatic mutation theory of aging Somatic mutations tend to accumulate steadily during life and somatic cells become increasingly susceptible to the cumulative effect of DNA damage which leads to aging. Accumulation of senescent cells Renewing tissues become dysfunctional through loss of ability to renew