Module 2: Biology and Physiology of Aging

2.2: Theories of Aging

2.2.9: Theories of Biological Aging

As noted earlier, there are many ways to organize current theories of aging, but they are not mutually exclusive. The theories covered in this module include several of the most current that have clinical implications; these are starred (*) below. Data on the others are available for a brief review at the bottom of this page.

I. Stochastic Theories

1. Free radical theories (*)
2. Somatic mutation and DNA repair
3. Error theory
4. Protein modification
1. Cross linking
2. Codon Restriction
3. Nonenzymatic glycation/Maillard reaction (*)
5. Waste product accumulation (amyloid, lipofuscin)

II. Programmed/Genetic Theories

1. Neuroendocrine
1. Pineal Gland/Melatonin (*)
2. Immunologic
3. Telomeres (*)
4. Longevity genes (*)

Additional Theories of Biological Aging:

In reviewing this brief summary of the additional early theories of aging, it becomes even more evident that many theories overlap and/or are not mutually exclusive. In addition, the changes underpinning many of these theories can also be explained by the theories discussed in the main text of the module, especially the free radical theory and the glycosylation theory.

Neuroendocrine Theory Of Aging
This theory is based on the fact that not much happens without some interaction with the neuroendocrine system. For example, neurons are lost; the brain tends to get smaller (atrophy); and loss of female and male hormones influences osteoporosis, cardiovascular disease risk, and fertility. Because of its central location, the hypothalamus has been considered a possible aging “pacemaker”. However, critics of this theory note that it lacks universality. Many unicellular organisms don’t have the types of complex interactive neurological systems of primates; yet they age. In addition, this theory suffers from the “cause and effect” or “chicken and the egg” problem—which came first? Do changes in the neuroendocrine system cause aging or are they the result of aging?

Immunological Theory Of Aging
We can’t live without a functioning immune system. However, the immune system becomes less effective with age. Our ability to produce antibodies decreases with age; certain types of autoimmune manifestations increase with age; and our ability to distinguish self from non-self (a primary function of the immune system) decreases with age. Proponents of this theory suggest that the genetic control of the immune system, i.e., the major histocompatibility complex, may be one of the gene systems that controls aging. In addition, the immune system peaks at puberty and then declines, especially the T-cell (cell mediated) component. Further, thymic involution occurs after puberty. In addition, deficits in immune system function are linked with many age-related pathologies and predisposition to certain health problems.

Critics of this theory point out that, like the neuroendocrine theory, it lacks universality: organisms without complex immune systems also age. Further, the immune system and the neurohumoral system interact, making it difficult to identify a primary site for aging. Cells that are not within the immune system also undergo age-related changes. So this theory also suffers from the cause and effect problem: Do age-associated diseases cause rather than result from the immunological deficit?

Cross-Linkage Theory Of Aging
The cross-linkage theory of aging focuses on extra-cellular activities although cross-linking can occur within the cell. According to this theory, age changes occur secondary to linkages that form between two or more macromolecules. As these linkages increase and accumulate over time, molecular aggregation and immobilization occur, and these aggregations become more inert and resistant to catabolic processes. Intracellular transport may be affected. Arguments to support this theory include: 1) evidence exists that cross-linkages occur and some do accumulate over time; 2) it has a physiological basis; and 3) it is potentially universal since it occurs in molecules containing nucleic acids. Critics argue that cross-linkages may still turn over and it still hasn’t been shown how the rate of cross-linking could be governed to account for the variable life-spans of different species.

Waste-Product Accumulation Or Age-Pigment Theory
This theory is based on the finding that pigmented inclusion bodies (termed lipofuscin) accumulate within non-dividing cells (neurons, skeletal, and cardiac muscle). It has been suggested that this occurs as the result of auto-oxidative processes, which links this theory to the free radical theory discussed in the main text of the module. Critics point out that the distribution of the pigment is rather random as is its rate of accumulation. It is also not universal—it doesn’t occur in all cells – and it may be a side effect of the aging process rather than the cause.

Codon Restriction Theory
Information from DNA is transferred to mRNA (transcription) and this information is then translated into protein. The translation depends on the cell’s ability to decode or decipher the codon in the mRNA molecules. The codon is a specific sequence of three consecutive nucleotides, part of the genetic code that specifies a particular amino acid in a protein or starts or stops protein synthesis. This reading is done by transfer RNA (tRNA) and aminoacyl-tRNA synthetase. The codon restriction theory proposes that the fidelity or accuracy of this translation of information from our DNA specifying what proteins to make or not make is impaired with aging. In its favor, there is some evidence from studies that tRNA and aminoacyl t-RNA decrease or change with age which would alter the cells’ ability to decode the information. However, critics point out that it is difficult to explain the basic cause(s) for the alterations with aging in these message-reading molecules and the implications of such changes in the aging phenomena are not clear.

Somatic Mutation and Error Theories of Aging
The Somatic Mutation Theory focuses on the fact that mutations in the cell can accumulate and alter the function of the cell enough to cause age-related changes. The theory appears to have evolved initially from an understanding of what radiation did to cells. The Error theory is similar but focuses on intrinsic errors occurring in the DNA which result in inaccurate protein synthesis, which in turn is thought to cause age-related changes.