Causes of Ageing

The impairment of physiological function (senescence) result in decrease of response against stress while increased susceptibility to diseases.

Senescent phenotype is the characteristic of each species.

There is no consensus on the causes but some cause effect relationship can be ascertained. There are two groups of theories :

• Programmed (endogenous) theories
• Damage or error (e theories :xogenous) theories
• Compromise theory

Programmed

It holds that ageing occurs as per the internal biological clock in continuation of the growth and development from childhood, hence a genetically controlled process ; of 3 types :

• Endocrine theory
• Immunity theory
• Programmed senescence theory

Endocrine (or Neuro - Hormonal) theory : Proposed by Finch; brain acts as biological clock and controls ageing through release of certain neurohormones. Defects in their secretion alter the hormonal balance and causes malfunctioning. GH level decreases to half in adult. Estrogen and progesterone level goes down after menopause ; decreases in melatonin level; level of DHEA (dehydroepiandrosterone) from adrenal goes down which has potential to prevent disease like cancer, multiple sclerosis.

Immunity theory : Due to programmed death (apoptosis) of thymus at an age there is decline in the body immunity and body becomes more vulnerable to infections causing ageing and death. Neurohormonal theory along with immunity theory is called Pacemaker theory of ageing.

Programmed Senescence theory: This includes switching on and off of certain genes to cause age – associated deficits/ defects. e.g. – B and T lymphocytes having receptors for self antigens undergo apoptosis. This eliminates 90% of all B-cells formed in bone marrow. A similar process occurs with T-cells in thymus. Some people believe that on chromosome 1 and 4 have senescence specific genes whose activation causes ageing.

Damage or error theories :

(Exogenous theory) Errors in various process occurring in body cause the damage at cell or tissue level which may be the possible reasons for ageing.

These are like: living theory, free radical theory, wear and tear theory, cross-linking theory, error catastroph theory and somatic mutation theory. Hayflick (1962) experimentally demonstrated the ageing in cells in vitro caused by exogenous means.

(a) Rate Living Theory (Metabolic Rate Theory) :Higher BMR enhances the ageing process, resulting in shorter life-span, whereas low BMR slows down/delays the ageing. Accumulation of

metabolic wastes is responsible for ageing – this is also known as Clinker’s theory.

(b) Free-radical theory: Free-radicals carry an extra unpaired electron on their surface. They are produced during ATP synthesis inside mitochondria. Some of the drugs also elicits the formation of free-radicals within our body. Free-radicals act as electrophiles and can readily take e– from another molecule which in turn becomes a free-radical. Thus, a chain reaction is started. Free-radicals can damage cell-membranes and may influence their permeability. Free-radicals can also alter the structure of proteins, lipids and nucleic acids. According to this theory, free-radicals bring harmful changes in mitochondrial DNA resulting in insufficient functioning and hence, the age- related effects. Degenerative effects like cancer, atherosclerosis, cataracts and neurodegeneration also result from free-radicals.

Vitamin C, E and β-carotene protect against free-radical damages. In addition, body has some inbuilt protective mechanism in the form of presence of various anti-oxidant enzymes-glutathione transferase, superoxide dismutase etc.

(c) Wear and Tear Theory: Vital cell parts wear with time/age. DNA is damaged due to UV rays, oxygen radicals and various toxic chemicals resulting structural changes (Thymine dimer formation) in DNA thus resulting in mutations. Although body possess its own DNA repair systems. The rapidity with which the damaged DNA is repaired, determines the life span of a person/animal. Human DNA repair system is more efficient than that present in mice, dog, monkey or tiger. So, humans have longer life span. In the absence of efficient DNA repair system, any damage to DNA results in defective genes as a result of which defective proteins would be produced and hence inefficient metabolism, as a result the process of ageing sets in.

(d) Cross-linking theory (Theory of advanced glycosylation end products): Non-enzymatic association of glucose with proteins results in cross-linking leading to the formation of advanced glycosylation end products

(AGEs). The formation of AGEs, alters the structural and biological role of proteins. Formation of cross-links brings about stiffening of various tissues (collagen) which is hallmark of ageing. It also results in hardening of arterial wall, clouded eyes, defunctioning of nerves and less efficiency of kidneys. Diabetic patients have higher chances of formation of AGEs and premature ageing and shorter life expectancy.

(e) Error Catastrophe Theory: Any error in the synthesis of RNA and proteins accumulates with time results in catastrophic damage to cells, tissues and organs.

(f) Somatic Mutation Theory: Somatic mutations may occur occasionally. They accumulate with age resulting in deterioration and malfunctioning of cells/organs.

Compromise Theory

This suggests that ageing is the outcome of interaction between genes and the environment, e.g., domestication increases the span of animals.

Alzheimer Disease - permature ageing of brain.

In Werner syndrome - cellular ageing occur early. (Person become an aged one in his/her 20s). In cancer, cellular ageing is prolonged. According to one hypothesis ageing occur due to telomere shortening which leads to loss of DNA from the end of chromosomes causing depletion of essential genes which probably inhibit the cellular ageing process.

What is Lipofuschin

A pigment (yellow brown) found in senescent or aged cells, more commonly in neurons . A polymer of lipids and phospholipids complexed with protein formed by lipid peroxidation of poly-unsaturated lipids in cellular membrane. It is obstinately related with organ shrinkage known as Brown’s atrophy in liver and heart.