BIOLOGY-PATHOGENESIS OF AGING AND DISEASE

Free radicals and mortality

Life is a network of chemical reactions and these occur in a gradient of reactivity. The sequence of reactions occur because of oxidation reactions with loss of electrons . With loss of electrons an element or compound is ready to accept electrons from a donor atom thus causing the reaction..life thus continuously endeavours to create active compounds or free radicals. Some of these free radicals are hydrogen peroxide, hydroxyl radical,free oxygen radical,nitric acid and are responsible for driving most of life’s reactions.Free radical are however maximally produced in mitochondria in cells which act as sources and powerhouse. Mitochondria were originally free living bacteria which was captured by the eukaryotic cell and now acts in a symbiotic relationship. They have their own DNA which is responsible for their fission during cell mitosis.

     The free radicals produced  during the lifetime of cells however reacts with cell structural elements like DNA and protein also and wears them out .Over a period of time the cell will die. Prokaryotes however have solved the problem of longevity by three means. Firstly they divide to form daughter cells before damage is irreversible. They are thus immortal. However some damage occurs before cell division and this is overcome by exchange of genes in conjugation. After conjugation ,new genes are received which can overcome deficient mutated genes. In spite of all this bacteria having defective genes die out in large numbers and are compensated by high rate of reproduction.

Mortality in metazoans

 Multicellular organisms cannot divide like bacteria and become immortals as they are built up by a plan of sequential gene activation. They thus use the body as a disposable soma destined to die due to oxidative damage accumulated during a lifetime. The immortal part are the sex cells which divide while the organism is young and pass on un damaged DNA to progeny. Here also certain dominant disease causing genes may cause mortality in childhood. These are rapidly eliminated from the gene pool as the child is unable to grow up ,reproduce and pass on these genes to the next generation. However certain genes in gametes which manifest in old age and cause mortality will be accumulated in the gene pool. These are the chronic diseases of humankind. 

    Whereas the nuclear DNA divides by mitosis during reproductive cell formation the same is not true for mitochondrial DNA. The mitochondria are passed  to male or female gametes without duplication.A possible result over generations maybe mitochondrial DNA damage accumulation and their eventual loss from cells. Metazoans produce  male gametes with abundant mitochondria for motility. However these damaged mitochondria are not passed on to fertized eggs and only the haploid male DNA is transferred. Female gametes however have undamaged DNA which is protected in layers of tissues and follicles in ovary. They thus escape damage due to their inactive state. The gamete thus receives un damaged mitochondria from the female side

   Metazoans have varied longevity and this depends on the species. The longevity is firstly fixed by total production of free radicals over the period of life. Species having high metabolic rate produce more free radicals and die early. It is moreover dependent on fecundity. Organisms producing more litters per year invest less resources on maintenance of soma and die early.The maintenance involves production of antioxidants enzymes such as glutathione and DNA repair proteins for damaged DNA. Humans have achieved extremely low fecundity during evolution  a strategy meant to make offspring’s knowledge ready for survival rather than mass production ,and have a corresponding longer longevity…

Pathogenesis of disease

  Longevity in humans is determined by the metabolic rate and normally should extend till 110 years when gradual deneration of organs should lead to death. However it is modified by two factors and most humans die before this age of diseases. 

   The dominant disease accelerating damage is insulin resistance. Human have evolved in a low nutrition environment due to scarcity of food over millions of years. This led to low levels of insulin secretion which is the principal hormone required to adjust carbohydrate ,lipid and protien metabolism after intake of food. Low insulin levels and genetic insulin resistance is protective from free radicals as less sugar enters cells for oxidation.As sugar is unable to enter cells due to insulin resistance it is converted to glycogen and fats and serves as reserve energy. Civilizational change today has led to over nutrition and high insulin secretion to intake of glucose and lipids. Insulin resistance is now a handicap as excess sugar and fat gets deposited in adipose tissue. .

      Insulin resistance causes rebound high insulin secretion . This leads to lipo lysis in adipose tissue and fatty acids travel to liver causing high amounts of VLDL.These are converted rapidly into HDL which are then removed from circulation more quickly.Morever a large number of LDL small molecules form as a result and these are easily oxidised. High levels of FFA and LDL are deposited in endothelial cells as they circulate and cause oxidative damage.High  cholesterol in VLDL and LDL and triglycerides in chylomicrons also result in endothelial damage.LDL is further engulfed by macrophages which become foam cells and then undergo Apoptosis with further oxidative stress. Smooth muscles proliferate in vessel walls narrowing them. Ultimately atherosclerotic  plaques form in vessel walls.These can undergo rupture with activation of thrombotic pathway and acute ischaemia. Cerebral strokes and. Myocardial infarction occur. 

  Another mechanism by which insulin resistance affects organs is by glycation of protiencs ,carbohydrates due to high sugar levels in blood. These damage vessels in kidneys leading to nephropathy,eye retinopathy and neuropathy in nerves. They are mediated partly by free radical injury and affected by gene polymorphism in antioxidants

Genetic polymorphism and disease

 The second cause of disease in old age is genetic polymorphism in protective enzymes of oxidative free radical injury. With age the enzymes protecting the body from free radical injury reduce in quantity and get depleted. However this should not occur till age of 110 years .the normal longevity of humans. However it occurs because of varying genes activity in individuals. Thus the protective enzymeu Apo 4 is less active in patients of Alzheimer’s disease . This results in damage to micro tubules within neurons by free radicals and fibril formation. Outside neurons same mechanism forms plaques. Ultimately large number of neurons are lost leading to dementia.Similar lack of antioxidant enzymes result in primary hypertension where again vessel intima,smooth muscles undergo oxidative injury. Oxidative injury also affects renal tubules leading to salt absorption,afferent arteriolar constriction and glomerular injury and protein loss.

    Malignancy is a major disease and increases with age. It is affected by free radical which cause inflammation and cell proliferation. When genetic polymorphism in antioxidants is present the cell proliferation becomes chronic and mutations leading to various cancers occur

Ack:Oxygen;Genetic predisposition to disease