GOOD MORNING

AGEING AND ITS IMPLICATIONS

BY DR.SHAZIA HUSSAIN

Gerontology" refers to the study of the biological aspects of aging.

What Is Aging?
Ageing is one of the most complex biological processes, whose definition is intrinsically related to its phenotype. Ageing is defined as the organic process of growing older and showing the effects of increasing age

 Ageing begins at the moment of conception, involves the differentiation and maturation of the organisms and its cells, at some variable point in time leads to the progressive loss of functional capacity characteristics of senescence and ends in death. Ageing is a universal, intrinsic, progressive and deleterious process.

THEORIES OF AGEING
Mevdeve in an excellent review stated that there were more than 300 theories of ageing and the number kept increasing till date. Evolutionary theories Systemic theories Molecular and cellular theories

Evolutionary Theories of Aging Because of the species-specific nature of mammal aging, scientists turned to evolutionary mechanics in attempts to explain aging observations. The various evolutionary theories are: Mutation accumulation theory Disposable soma theory Antagonistic pleiotropy theory

Medawars Hypothesis
Peter Medawar (1952) proposed that age measured relative to age of first reproductive capability was a factor in the evolution process. Adverse effects (e.g. aging) that occurred well beyond puberty would have relatively little impact on the organisms ability to reproduce and propagate its design relative to the same effects occurring at a younger age. Subsequent theorists Williams, Kirkwood, and others suggested that aging might be a side effect of some design feature that created individual benefit in younger animals.

Mutation accumulation theory

The mutation accumulation theory is based on Medawar's Hypothesis, which suggests that the evolutionary effect of adverse events declines following the age at which an organism is initially capable of reproduction. Although there is substantial agreement that evolutionary impact of adverse events declines with age, Medawar proposed that it declined to the point of being negligible. Medawar's hypothesis provided an explanation for the enormous differences in life span between different mammal species by tracing those differences to corresponding differences in age of sexual maturity. Indeed, age of sexual maturity correlates moderately well with life span in mammals.

Disposable soma theory

In 1977, a statistician named Thomas Kirkwood published his disposable soma theory of aging. Kirkwoods idea was that organisms only have a limited amount of energy that has to be divided between reproductive activities and the maintenance of the non-reproductive aspects of the organism (soma). Aging is the result of natural degrading processes that result in accumulation of damage but the damage can be repaired by the organism at the expense of reproduction.

Antagonistic pleiotropic theory

According to the antagonistic pleiotropy theory of ageing, natural selection has favoured genes conferring short-term benefits to the organism at the cost of deterioration in later life. The 'disposable soma' theory expresses this as a life-history strategy in which somatic maintenance is below the level required to prevent ageing, thus enabling higher immediate fertility.

Systemic theories

Neuroendocrine theory Immunologic theory

Neuroendocrine theory
First proposed by Professor Vladimir Dilman and Ward Dean MD, this theory elaborates on wear and tear by focusing on the neuroendocrine system. This system is a complicated network of biochemicals that govern the release of hormones which are altered by the walnut sized gland called the hypothalamus located in the brain. The hypothalamus controls various chain-reactions to instruct other organs and glands to release their hormones etc. The hypothalamus also responds to the body hormone levels as a guide to the overall hormonal activity.

 But as we grow older the hypothalamus loses it precision regulatory ability and the receptors which uptake individual hormones become less sensitive to them. Accordingly, as we age, the secretion of many hormones declines and their effectiveness (compared unit to unit) is also reduced due to the receptors down-grading.

Immunological theory
According to this theory , programmed decline in the functioning of the immune system leads to incresed vulnerability to infectious diseases thus causing aging and death

Molecular and cellular theories

Error catastrophic theory Free radical theory Waste product theory

Error catastrophic theory

According to this theory, damage to mechanisms that synthesise proteins, results in faulty proteins, which accumulate to a level that causes catastrophic damage to cells, tissues and organs.

The Free Radical Theory

According to this theory, accumulated damage caused by oxygen radicals causes cells to stop functioning and eventually organs also stop functioning. An oxygen free radical is a byproduct of normal metabolism produced when cells turn food and oxygen into energy. This free radical, in need of a mate, takes an electron from another molecule, which in turn becomes unstable. This chain reaction produces a series of compounds, some of which are harmful. They damage proteins, membranes and nucleic acids, particularly DNA, organelles, etc. All these damages within the body caused by oxygen free radicals causes ageing

Waste product theory

When cells divide, the quantity of waste material per cell decreases because the wastes are "diluted" by apportionment between the daughters which result from the division. The quantity of waste present in a symmetrically or asymmetrically dividing population of cells is governed by a first-order non-linear differential equation. In the derivation of the equation, it is assumed (a) that waste is created at a rate which is either constant or proportional to the amount of waste already formed, (b) that waste is neither destroyed nor transported across cell walls, and (c) that the rate of cell division at large values of time is inversely proportional to the amount of waste per cell raised to a power. Relations among the parameters of the differential equation specify conditions under which its solutions rise to a critical value. If the amount of waste per cell given by a solution of the differential equation exceeds this value, it is assumed that deleterious effects become evident and that cell death follows

Biomarkers of ageing
Lipofuscin: It is a small granular yellw brown pigment. It is a mixture of lipid-composed of lysosomal digested that has been leftover. This particular pigment is associated with aging through wear and tear that can appear in nerve cells, heart, muscle, kidney, liver, ganglion cells and adrenals. Lipofuscin, does commonly surround the nucleus and it is also a category of lipochrome.

 Lipofuscin accumulation as an aging theory focuses on maintaining a positive balance of the substance. The yellow-brown product does accumulate in various cells through aging. The increasing accumulation of lipofuscin in cells, like heart, muscle, nerve, ganglia and nerve cells demarcates aging. Lipofuscin accumulation can lead to various age-related illnesses. This includes severe health predicaments such as vision loss, macular degeneration, Batten, Alzheimers and Parkinsons disease, chronic obstructive pulmonary disease, melanosis coli and denervative atrophy and many others.

DNA damage in ageing

The DNA damage theory of aging proposes that aging is a consequence of unrepaired DNA damage accumulation. Damage in this context includes chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction) . In humans, DNA damage occurs frequently and DNA repair processes have evolved to compensate. On average, approximately 800 DNA lesions occur per hour in each cell,

 In any cell some DNA damage may remain despite the action of repair processes. The accumulation of unrepaired DNA damage is more prevalent in certain types of cells, particularly in non-replicating or slowly replicating cells, which cannot rely on DNA repair mechanisms associated with DNA replication such as those in the brain, skeletal and cardiac muscle.

Premature aging syndromes

Progeroid syndrome. Werners`s syndrome. Hutchinson gilford`s syndrome. Cockayne syndrome. These syndromes originate in genes that are related to DNA repair/metabolism

 Progeroid syndrome,(neonatal): A rare congenital condition characterized by poor growth, aged facial appearance, and mental retardation. Death occurs usually by 6 years of age

Werner`s syndrome
Werner Syndrome ("Adult progeria") is a very rare, autosomal recessive disorder characterized by the appearance of premature aging Werner's syndrome more closely resembles accelerated aging than any other segmental progeria. For this reason, Werner syndrome is often referred to as a progeroid syndrome, as it partly mimics the symptoms of Progeria.

Weber-Cockayne syndrome, or Neill-Dingwall Syndrome Is a rare autosomal recessive congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight(photosensitivity), and premature aging. Hearing loss and eye abnormalities (pigmentary retinopathy) are other common features, but problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies. The underlying disorder is a defect in a DNA repair mechanism.

Hutchinsons gilford syndrome

Symptoms appear in infancy. Premature ageing Cells from Hutchinson-Gilford patients appear to have diminished replicative capacity, but not nearly as short a life span as cells from Werner patients. Nevertheless, the genetic and biochemical causes of progeria remain unknown.

Telomere theory
Telomeres are bits of junk DNA at the end of chromosomes that protect real DNA every time a cell divides. What happens is that, the very last bit of a chromosome cant be copied 100% - a little bit gets cut off. It was thought that, as cell divide, the telomeres get shorter each time, until, they are gone. At that point, the real DNA cannot be copied anymore and the cell simply ages and no longer replicates. In population level studies, researchers have shown that older people have shorter telomeres. Eventually, the cells with shorter telomeres can no longer replicate and, taken over time and lots of cells, tissue damage and the dreaded signs of aging can show up.

 Most cells can replicate about 50 times before the telomeres are too short. Some believe that telomeres are the secret to longevity and there are circumstances in which the telomeres will not shorten

Pathologic and Physiological Age-Related Changes

In humans, some functions like hearing and flexibility begin to deteriorate early in life ,most of our body's functional decline tends to begin after the sexual peak, roughly at age 19. Aging is characterized by changes in appearance, such as a Gradual reduction in height and weight loss due to loss of muscle and bone mass, A lower metabolic rate, Longer reaction times, Declines in certain memory functions, Declines in sexual activity

In women, Menopause, A functional decline in audition, olfaction, and vision, Declines in kidney, pulmonary, and immune functions, Declines in exercise performance, and multiple endocrine changes.

 The incidence of a number of pathologies increases with age . These include diabetes, heart disease, cancer, arthritis, and kidney disease. The incidence of some pathologies, like sinusitis, remains relatively constant with age, while that of others, like asthma, even decline. Therefore, it is important to stress that aging is not merely a collection of diseases. With age we become more susceptible to certain diseases.

 Heart diseases are the number one cause of death in people aged 85 and older, followed by cancer, cerebrovascular diseases, Parkinson's and Alzheimer's diseases, pneumonia, and chronic lower respiratory diseases. While diseases like cancer and heart diseases are major causes of death at all ages.

Conclusion
Aging theory has been treated as an academic issue. However it is increasingly clear that our approach to age-related diseases could be dramatically affected by our understanding of the aging process and that therefore aging theory has become a public health issue. Efforts should therefore be expended to definitively resolve the theory issues and develop research funding policy based on the results.

Thank you

References
997 - 2001, 2004, 2005, 2008, 2010 by Pedro de Magalhaes, Integrative Genomics of Ageing Group. Free radical research dec 2006 Williams, G.C. (1957). "Pleiotropy, natural selection and the evolution of senescence" (PDF). Evolution 11 (4): 398 411. doi:10.2307/2406060. JSTOR 2406060.

 Journal of Bioscience Hypotheses 2 (2): 59 64. doi:10.1016/j.bihy.2008.12.02 Robbins pathologic basis of diseases 7th, edition .