Biology Of Ageing Cellular And Subcellular Level Notes

Biology Of Ageing

Old age is a concept of longevity in human beings. At the evolutionary level, living beings can continue their existence by either immortality or by reproduction; most evolutionary theories have supported a link between longevity and reproduction.

However, ageing is distinct from mortality and disease although older individuals are more vulnerable to disease. With ageing, the mechanism of homeostasis is slow; hence the response to various stresses takes longer to revert back to normal structure and function.

Read And Learn More: General Pathology Notes

The average age of death of primitive man was barely 20–25 years. However, worldwide average life-expectancy is about 70 years. In India, due to improved health care, it has gone up from an average of 26 years at the time of independence in 1947 to 68 years in 2017.

In general, survival is longer in women than men (3 : 2). About a century ago, the main causes of death were accidents and infections. But now with greater safety and sanitation, the mortality in the middle years has sufficiently declined. However, the maximum human lifespan has remained stable at about 110 years.

Higher life expectancy in women is not due to difference in the response of somatic cells of the two sexes but higher mortality rate in men is attributed to violent causes and greater susceptibility to cardiovascular disease, cancer, cirrhosis and respiratory diseases, for which cigarette smoking and alcohol consumption are two most important contributory factors.

In general, the life expectancy of an individual depends upon the following factors:

• Intrinsic genetic process:  the genes controlling response to endogenous and exogenous factors initiating apoptosis in senility. It has been seen that long life runs in families and high concordance in lifespan of identical twins has been observed. Studies in centenarians have shown that they lack carrier of apolipoprotein E4 allele which is associated with risk for both heart disease and Alzheimer’s disease.
• Environmental factors:  For example, Consumption and inhalation of harmful substances, type of diet, role of antioxidants etc.
• Lifestyle of the individual: Such as diseases due to alcoholism (for example Cirrhosis, hepatocellular carcinoma), smoking (For example, Bronchogenic carcinoma and other respiratory diseases), drug addiction.
• Age-related diseases: For example, Atherosclerosis and ischaemic heart disease, diabetes mellitus, hypertension, osteoporosis, Alzheimer’s disease, Parkinson’s disease etc.

Cellular Basis Of Ageing:

Individuals age because their cells slowly decline to function. This is reflected in structural and functional changes in different organs and systems of the human body with ageing.

Changes at cellular and subcellular levels linked with ageing are supported by the following theories:

• Telomere shortening and cellular senescence:
  • It has been observed that cultured human fibroblasts replicate for certain number of times (about 50 population doublings) and then the culture dies out (called Hayflick limit).
  • It means that in vitro there is reduced functional capacity to proliferate with age. It has been observed that with every cell division there is progressive shortening of telomere present at the ends of linear chromosomes (loss of about 50–200 base pairs during each mitosis).
  • This process is called cellular clock. In normal somatic cells, there is no telomerase activity which exists in germ cells forrepairing the loss of telomere. Thus, progressive loss of telomere in somatic cells in ageing results in exit of senescent cells from the cell cycle and inability to renew lost cells.
  • On the contrary, in cancer there is reactivation of telomerase and thus immortalisation of cancer cells by continued proliferation
• Free radical theory of ageing:
  • Ageing is partly caused by progressive and reversible molecular oxidative damage due to persistent oxidative stress on human cells.
  • In normal cells, very small amount (3%) of total oxygen consumption by the cell is converted into reactive oxygen species.
  • The rate of generation of reactive oxygen species is directly correlated with metabolic rate of the organisms.
  • With ageing, there is low metabolic rate with the generation of toxic oxygen radicals, which fail to get eliminated causing their accumulation and hence cell damage due to mitochondrial injury.
  • The role of antioxidants in retarding oxidant damage has been reported in some studies.
• Mitochondrial dysfunction:
  • With ageing, mitochondrial production of ATP declines and oxygen free radicals rise, especially hydrogen peroxide and superoxide oxygen.
  • This results in the accumulation of oxidative injury to mitochondrial proteins and DNA.
  • Reduced number of mitochondria, megamitochondria, vacuolisation and disrupted cristae are seen in senescent cells.
• DNA damage:
  • Long duration of exposure to several exogenous agents (physical, chemical and biological), and endogenous agents (reactive oxygen species) targets the nuclear and mitochondrial DNA of the cell.
  • Although normally, damaged DNA is repaired by DNA repair enzymes but in ageing the repair mechanisms start to weaken or fail.’
  • Examples of conditions having defect in DNA repair enzymes and associated with premature ageing are Werner’s syndrome (defective DNA helicase), Bloom syndrome and ataxia telangiectasia.
• Altered gene expression:
  • With age, there is reduced expression of many genes and proteins associated with mitochondrial function. ‘
  • Other changes occurring with ageing are in epigenetic state of chromosomes (reduced methylation and histone acetylation) and in microRNAs (reduced expression).
  • Higher expression of gene products by sirtuins, a family of protein deacetylases, promotes longevity by inhibiting metabolic activity, reduce apoptosis, reduce harmful effects of reactive oxygen species and stimulate protein folding.
• Reduced autophagy:
  • With age, there is impaired chaperon-mediated autophagy which is normally required for intracellular degradation of worn out organelles by lysosomes and ubiquitin-mediated proteasomal system.
  • This results in the accumulation of waste products in the cells in cellular ageing e.g. lipofuscin, tau proteins, β-amyloid.
• Activation of tumour suppressor genes:
  • Tumour suppressor genes regulate cell division and are implicated in both cancer and in senescence.
  • In ageing, two of the common tumour suppressor genes, Rb gene and p53, lead to arrest of cell division followed by either apoptosis
• Caloric regulation theory:
  • It has been observed that caloric restriction delays ageing. Caloric restriction reduces the release of growth factors such as GH, insulin and insulin-like growth factor 1 (IGF-1); these hormones are activated by nutrients but restricted nutrition delays ageing.
  • Besides, caloric restriction also increases lifespan and better health span by reducing the risk for diabetes, hypertension and cardiovascular disease and cancer.

On the other hand, extreme obesity (with a body mass index >35) has a higher risk of dying early.

Organ Changes In Ageing: Although all organs start showing deterioration with ageing.

The following organs show evident morphologic and functional decline:

Cardiovascular system Atherosclerosis, arteriosclerosis with calcification, Mönckeberg’s medial calcification, brown atrophy of the heart, loss of elastic tissue from aorta and major arterial trunks causing their dilatation.

• Nervous system Atrophy of gyri and sulci, Alzheimer’s disease, Parkinson’s disease.
• Musculoskeletal system Degenerative bone diseases, frequent fractures due to loss of bone density, age-related muscular degeneration.
• Eyes Deterioration of vision due to cataracts and vascular changes in the retina.
• Hearing Disability in hearing due to senility is related to otosclerosis.
• Immune system Reduced IgG response to antigens, frequent and more severe infections.
• Skin Laxity of the skin due to loss of elastic tissue.
• Cancers As discussed later in Chapter 7, 80% of cancers occur in the age range of 50–80 years.

Biology of Ageing:

The life expectancy of an individual depends upon certain factors:

• Genetic
• Environmental
• Lifestyle and
• Some age-related diseases

Individuals age because their cellular function slowly declines.

Changes at cellular and subcellular level are explained on the basis of several theories:

Shortening of telomere without replacement of damaged ends persistent oxidative stress (accumulation of free radicals), mitochondrial dysfunction, DNA damage, altered gene expression, reduced autophagy, activation of tumour-suppressor genes and extreme obesity.

Ageing can be counteracted by antioxidants and caloric restriction. Ageing causes decline in morphology and function of multiple organs: The cardiovascular system, nervous system, muscles, bones, eyes, ears, immune system and skin.

About 80% of cancers are seen in the age range of 50–80 years persistent oxidative stress (accumulation of free radicals), mitochondrial dysfunction, DNA damage, altered gene expression, reduced autophagy, activation of tumour suppressor genes and extreme obesity.

Ageing can be counteracted by antioxidants and caloric restriction. Ageing causes a decline in morphology and function of multiple organs: The cardiovascular system, nervous system, muscles, bones, eyes, ears, immune system and skin. About 80%, of cancers are seen in the age range of 50–80 years.