Various theories on ageing

Numerous theories abound as to what causes the ageing process. Anne-Marie Marynycz, President of the Association of Professional of Australia, explains sone of the most widely accepted theories today.

Ageing is universal and is evident across most species of living creatures. However, it becomes difficult to define the term ‘ageing’ because an accurate definition must include some understanding of the biological mechanisms that underpin ageing. Old age in humans is generally associated with impaired adaptive and homeostatic mechanisms. Consequently this may lead the individual to have altered and negative responses to environmental and internal stresses and, subsequently, this altered response in the long term may contribute to increasing disability and mortality.

Various theories of ageing have been postulated. These can be grouped into either a Genetic Programmed Theory of Ageing or Molecular Damage Theories which reflect the theory of Unprogrammed Ageing. These two groups of opposing ageing theories reflect the fact that the process of biological ageing is multidimensional. Both groups of theories attempt to explain a particular aspect of ageing from their own rationale, but the theoretical distinction between the two groups seems to be a grey area because both groups accept some of the attributes of the opposing theory in their own rationales.

Hayflick (1961) proposed a theory of biological ageing (Hayflick limits) which he felt should explain the following age related changes which were seen as:

• An impairment of the individual
• Changes that occurred in a progressive manner
• Intrinsic changes from within and not those influenced by the environment
• Universal changes which affected everyone within a certain species (Hayflick 1988).

Blumenthal (1999) noted in his paper that there has been a universal acceptance of two additional attributes by gerontologists to support Hayflick’s proposal and they are:

• Age related changes are irreversible; and
• Age related changes are genetically programmed.

Recent understanding of the theory of programmed ageing is that ageing is a result of a sequence of events which are encoded in a genome. Genes exist whose function when expressed is to bring death to the organism. Individual species have characteristic lifespans, and within a species genetically determined differences occur in a lifespan. The assumption of this theory is that some genetic programme determines the maximum lifespan for each species, but moreover the theory of programmed ageing recognises that some forms of damage contribute to ageing and that environmental factors influence the outcome of programmed ageing to some degree (De Magalhaes, 2005).

Unprogrammed theory of ageing

Also referred to as damage-based theories, this implies that ageing results from a continuous process of damage accumulation originating in by-products of metabolism. This damage is a by-product of normal cellular processes or a consequence of inefficient repair systems (De Magalhaes, 2005). However, studies by Kirkwood and Austad (2000) recognise that certain genetic factors, such as defensive or protective genes, do play a role in ageing.

Telomere theory of ageing

This provides a plausible mechanism in the Hayflick limits for the theory of programmed ageing. It stems from the finding that the tips of the chromosomes (telomeres) in the body cells shorten with each round of chromosomal replication of cell division. This implies that, eventually, essential genetic information at the chromosomal extremities is lost, thus disrupting vital cellular functions and causing death (Griffith et al, 1999). Various studies on telomeres and telomerase have supported Hayflick’s theory of programmed ageing.

Research by Blackburn (1992) found that the enzyme telomerase elongates telomeres by working together with telomere-binding proteins. Other studies by Kim et al, (1994) found that telomerase was found to be active in ‘gametogenesis’, or allowing germ lines to achieve immortality. Most immortal somatic cell lines from tumours lack Hayflick limits and express telomerase (Kim et al, 1994). Somatic tissue from patients with Werners Syndrome experience rapid erosion of initial normal telomeres (Faragher et al, 1993) and this erosion can be prevented with telomerase (Wyllie et al, 2000).

Gene theory

This theory falls under the category of programmed ageing as it implies that ‘programming is due to one or more harmful genes within each organism'(Spence, 1999). There are two ideas inherent in this theory:

• Genes which are responsible for directing cellular activities early in life become altered in later life and therefore their function becomes altered. This results in functional and structural alteration, causing ageing.
• Genes which become active in later years alter the physiology of the organism and cause its death (Spence, 1999).

Genetic theories of ageing are supported by studies that indicate life expectancy is genetically pre-programmed within a species. Studies of life expectancies of twins and siblings have confirmed that there is indeed a genetic component to ageing and longevity.

Both the telomere theory of ageing and the gene theory support the general theory of programmed ageing in that both relate to some aspect of cell activity which is intrinsic, progressive and universal within a species. On the other hand, the gene mutation theory falls under the category of unprogrammed ageing as it implies that the accumulation of cells with altered structures and functions resulting from mutations causes ageing and death (Spence, 1999). Mutations can occur naturally as a result of occasional errors in DNA replication during cell division since replication may not be 100 percent accurate in copying all the base units (millions) in a DNA molecule.

Mutations can also be caused by exposure to radiation, alcohol, lithium, organic mercury and chemicals. DNA mutations and chromosomal abnormalities tend to increase with age in mice as well as in humans (De Magalhaes, 2005). However, it is still unclear whether these changes are effects or causes of ageing. An assumption of the gene mutation theory is that the cell has an effective repair mechanism which could repair damaged DNA. However, over time these mechanisms for repair do become inefficient, allowing some mutations to remain in the altered state causing loss of viable functionality and thus leading to ageing (Spence, 1999).

Cross-linkage theory

This theory (unprogrammed ageing) proposes that with advancing age our protein DNA and other structural molecules develop ‘cross-links’ to one another. These links decrease the mobility or the elasticity of protein and other molecules.

Damaged proteins are broken down by enzymes called proteases and the apparent cross-linkages inhibit the activity of proteases. The end result is a build up of cross-linking compounds which can cause mutations in the cell and irreversibly damages the cell so that it is unable to eliminate wastes and transport ions. Eventually, this form of cell damage leads to organ and tissue failure. The most commonly affected body proteins are:

• enzymes, which are unable break down damaged proteins
• collagen, a supportive tissue in the dermis which forms the structural framework of many organs. Increasing age leads to fibrosis (excess of collagen fibres)
• Elastin – increasing age means decreasing elasticity of the skin
• The matrix (ground substance), causing it to become less permeable and effectively slowing the process of metabolism
• DNA, which loses its ability to effectively direct protein synthesis, eventually leading to serious implications of immunological responses by the body (Spence, 1999).

The gene mutation theory and the cross-linkage theory are both advocates for unprogrammed ageing as the rationale for both theories lies in the fact that ageing is caused by irreversible damage to the cell via mutations. Both theories suggest that mutations of the cell which impair either the structure or the function of the cell becomes increasingly evident as we get older and it implies that these processes ultimately cause ageing.

Free radical theory

Following on from the gene mutation and cross-linkage theories, another damage-based theory is the free radical theory (unprogrammed ageing). It proposes that protective mechanisms decrease or free radical formation increases with advancing age. Free radicals are highly reactive molecules which can be produced by normal cell metabolism, irradiation reactions, chain reactions with other free radicals or oxidation of various pollutants such as ozone. Free radicals interact with and damage cellular components such as lipids, proteins and nucleic acids.

Thankfully the human body has defence repair mechanisms that can thwart oxidative activities and remove and repair damaged cells. Antioxidants such as B-carotene, and vitamins C and E are key defence antioxidants that protect the cells from free radical damage. Interventions which may prevent the accumulation of age-related free radicals include supplementation with natural or synthetic antioxidants such as melatonin, L-carnitine and vitamins C and E. A study by Grune and Davis (2001) on
Vitamin E has shown to have beneficial antioxidant effects in humans.

Stress protein theory

Another unprogrammed ageing theory, it proposes that just as in the case of DNA damage response, activation of the ER/UPR (Endoplasmic Reticulum/Unfolded Protein Response) stress response by damaged proteins can lead to both loss of cellular function and, if overwhelmed, apoptosis (Feder, 1994). Stress proteins form the crucial function of protein repair and recycling in the cell and they are characterised as having the following attributes:

• They behave as ‘molecular chaperones’ by regulating the folding of new proteins, they assist in the correct formation of the new proteins and they assist in supplying these proteins throughout the cell
• They actively decide which damaged proteins will be catabolised, thereby preventing an accumulation of damaged proteins in the cell
• They make decisions to protect and repair proteins which are threatened by environmental stress (Feder, 1994).

When comparing the theory of free radicals to the stress protein theory, it is difficult to understand how random damage by free radicals can lead to the significant and reproducible loss in tissue function observed during tissue ageing. The stress protein theory advocates that it is not damage per se that leads to the phenotype of ageing but it is the cellular response to that damage which is the crucial factor. The stress protein theory believes that ageing occurs only when damage is extensive enough and it is of a type capable of producing a cellular response leading either to cell senescence or apoptosis. It is these cellular responses which are crucial in tissue deterioration during ageing (Sierra, 2006).

Cellular garbage or accumulated waste theory

Another unprogrammed ageing theory, there is some similarity between the cross-linkage theory and the cellular garbage or accumulated waste theory, which proposes that the ‘gradual accumulation of inert cell garbage, along with reactive substances, interferes with normal functioning of the cell and thereby contributes to ageing.’

These substances of normal metabolism include such things as free radicals, histones, aldehydes and lipofuschins. Lipofuschins are inert, yellow-brown pigments that are strongly cross-linked molecules which manifest as the ‘ageing pigment’. Lipofuschins are stored within membrane-bound vesicles for the duration of the cell life and unfortunately the cells are unable to eliminate them. The non-inert substances such as the free radicals cause considerable harmful and irreversible damage to the cells.

The cellular garbage theory however is weak in its concept. Although there is some evidence of garbage accumulation in some cells, it is not prevalent in all cells. Both the cross-linkage theory and the cellular garbage theory posit that it is the accumulated wastes within the cell that through cross-linkages leads to cell impairment and loss of structure and function which causes ageing.

Wear and tear theory

Again, this is an unprogrammed ageing theory. It proposes that each individual’s lifespan is controlled by the specific quantity of metabolic energy allocated within itself. Once this is spent, the individual is dead. It holds true that the rate at which this energy is used determines how long the individual will live. Wear and tear theories validate random damage by free radicals, the stress protein theory of repair and defence, and the DNA damage response theories.

The wear and tear theory espouses that once the individual has used up all his or her metabolic reserves to live (whether it be in the defence against external damage by pollutants or the cellular response to the damage), the individual will die. However, according to Spence (1999) this theory links itself to the programmed ageing process by virtue of a ‘finite’ limit to cell metabolic energy. Unfortunately, this theory falls considerably short in its explanation of ‘universality’ of ageing that is common within a species. And universality of ageing is a basic tenet of programmed ageing.

Autoimmune theory

This is based on the knowledge that the immune system components (thymus and bone marrow cells) are affected by ageing. Age-related defence response of the immune system leads to the elderly becoming more susceptible to cancer, infections and autoimmune diseases such as rheumatoid arthritis. The autoimmune theory also attempts to explain a relationship between diminished immune functioning and an increase in the body’s autoimmune response.

When autoimmunity occurs, the body reacts against itself and produces antibodies in response to its own constituents. I believe this theory falls under the category of
unprogrammed ageing because of the following supportive salient points:

• New antigens appear later in life and these may be a result of mutations causing altered RNA and DNA, thus forming new proteins
• Autoimmune reactions increase as one gets older due to the modifications of the antibodies, either by combining with specific antigens or being split into smaller components
• Cross-reactions of drugs taking place with proteins that the body does not recognise – that is, they become foreign to the self.
• Cross-reactions of antigens produced by the long-living micro-organisms in the body causing pathological changes (Spence, 1999).

The autoimmune theory of ageing encompasses attributes which belong to the gene mutation theory, such as the alteration of RNA and DNA and the formation of new proteins, and the formation of new proteins which are formed due to the cross-reactions of drugs with proteins which the body does not recognise. The cross-linkage theory also lends support to the autoimmune theory, where cross-reactions of antigens which are produced by micro-organisms in the body cause pathological changes in the body. These changes lead to the failure of the body to respond effectively as a defence mechanism.

The process of ageing is multidimensional and it reflects extrinsic influences on intrinsic factors and therefore I believe not one single theory above can satisfactorily explain the process of biological ageing. Without a doubt, I believe there is strong interactivity between the two major theories of ageing. The predominant mechanism or combination of mechanism depends on the particular tissue or cell type in question and it is really the cells themselves which reflect how it is able to deal with the situation at any given time.