Aging can be defined as a gradual time-dependent deterioration in normal function.
Theories attempt to explain why we age and to identify the processes that affect cells, organs and biological systems. Aging is fundamentally the result of changes in cellular structure, function, biochemistry and metabolism.
While lifestyle and genetic predisposition are important determinants of an individual’s aging, these factors do not explain the biological basis of aging universal to all human beings. It is widely believed that there are multiple mechanisms that account for the aging process. There are a number of theories that have been put forward in attempt to explain the aging phenomenon.
Cross-linking theory
This theory has been derived from the observation that as we age, the proteins, DNA and other molecules in our body such as enzymes, form inappropriate bonds with each other. These bonds or ‘cross-linkages’ impair the affected protein’s ability to carry out its normal functions. Such dysfunctional proteins are resistant to the mechanisms that normally destroy damaged or useless proteins. A group of enzymes called proteases are responsible for this breaking down of damaged or useless proteins. But the cross-linkages present within the impaired proteins prevent protease activity from having an effect on them. Consequently, these impaired proteins are free to float around, becoming a source of potential harm in the body.
Oxidative Damage/Free Radical theory
It has been postulated that the accumulation of cellular damage due to oxidative stress is a factor that may be responsible for cellular ageing. Free radicals, such as reactive oxygen species (ROS), are generated by normal metabolism using oxygen in cells of the body. Major sources of free radicals include intermediates of the electron transport chain and intracellular enzymes such as oxidases. The enzyme Cytochrome P450, which is induced by alcohol and drugs, as well as ionising radiation also unleash free radicals in cells.
Antioxidants are a group of molecules within cells that have the job of neutralising free radicals. However, not all free radicals are swept up and eliminated. Free radicals that are relentless can go on to cause cellular damage, targeting DNA, RNA, proteins, cell membranes, and mitochondria. Such damage is referred to as oxidative stress or oxidative damage. Free radicals are also capable of causing cross-linkages of proteins and age pigments.
The overall effect, as can be imagined, is that oxidative damage builds up over time. Hence, it is believed to be a contributing factor in the aging process. The free radical theory has been linked to the idea of ‘wear and tear’.
Another point worth mentioning is that free radicals and oxidative damage play a part in age-related conditions, such as cancer, heart disease, diabetes and Alzheimer’s disease.
Accumulation of Damage to DNA theory
Damage to DNA occurs throughout our lives. Such damage may arise during normal DNA replication. Mistakes in DNA replication can occur, and although they are mostly corrected by DNA repair enzymes, some persist. DNA damage can also arise because of free radicals, and environmental factors like radiation and toxins. Genetic mutations accumulate, ultimately leading to cell malfunction and death. It is believed that this series of events is an important part of the aging process.
This theory also considers damage to mitochondrial DNA as a significant factor in aging. Mitochondria, the powerhouses of cells, are organelles within cells that provide the cell’s energy needs. Each mitochondrion in a cell possesses its own DNA. Mitochondria and their DNA are quite vulnerable to oxidative damage, considering the fact that mitochondria are the major site of ROS production in the cell. Mutations to mitochondrial DNA impair the ability of mitochondria to generate ATP, and reduced generation of ATP leads to deterioration of cell function and hence, aging.
Calorie restriction increases lifespan?
The DNA damage theory of aging has given rise to the belief that ‘calorie restriction’ may in fact slow down the aging process. A number of ideas have been put forth illustrating the putative effects of calorie restriction:
- Studies in animals have revealed that calorie restriction is linked to an increased lifespan
- It is believed that calorie restriction requires lower levels of metabolism, therefore leading to lower levels of reactive oxygen species being generated. Hence, there is decreased damage to mitochondria and mitochondrial DNA.
- Calorie restriction leads to decreased DNA replication and consequently lower chances of mutations that can develop into cancer.
- Decreased cellular proliferation, because of calorie restriction, leads to increased rates of apoptosis, or programmed cell death, especially of pre-neoplastic cells. This again entails a reduced cancer risk.
- The level of stress imposed by calorie restriction activates certain proteins which are capable of activating DNA repair enzymes. This has the effect of stabilizing the DNA, and without these proteins DNA is prone to damage.
The Replicative Senescence theory
Most human cells have a limited ability to replicate. The “Hayflick limit” refers to the finite number of divisions (or population doublings), which is around 50, that a body cell can undergo before it dies. It has been suggested that the Hayflick Limit is determined by the length of telomeres in cells. Indeed, the process of telomeres shortening is closely linked to the idea of replicative senescence.
Telomeres are the regions, like caps, at the ends of chromosomes which feature repeat sequences of TTAGGG in humans. They have an important function in protecting the sequences at the end of chromosomes. Each time a cell divides, and chromosomal replication occurs, the telomeres at the end of each chromosome shortens.
Telomerase is an enzyme containing RNA and protein that acts to ensure the ends of chromosomes do not shorten. Telomerase is only expressed in germ cells and in some stem cells. It is also present in cancer cells. However, it is not present in adult somatic cells. As a result, as cells age, their telomeres shorten to a point when chromosomal replication can no longer occur and the cells exit the cell cycle. This usually happens after about 40 to 60 population doublings (divisions) in young human cells. When they exit the cell cycle, they become ‘senescent’ which refers to the cells being arrested in a terminally non-dividing state.
This cellular phenomenon of is believed to play a part in aging. ‘Telomeres shortening’ is no longer believed to be the ‘cellular clock’ that governed the aging process it was once thought to be. However, scientists do acknowledge that they do contribute to aging.
Theories are theories
While there are an array of theories and various studies have been conducted, on how we age, there is yet to be a definitive answer, and there is yet more to be unravelled and understood. But what perhaps can be said with some degree of certainty is that, as the scientist Hayflick proposed, that the overall effect of the factors that affect and influence human life, is that we exceed our reserve capacity. Hence, the saying "Always keep your reserve".
References:
1. Baynes, J.W., & H.D. Marek. (2009). Medical Biochemistry (3rd ed.). Philadelphia: Saunders Elsevier.
2. Boron, W.F., & Boulpaep, E.L. (2008). Medical Physiology (2nd ed.). Philadephia: Saunders Elsevier.
2. Theories of Aging. (2006). US: American Federation for Aging Research.
Michelle Parker - Michelle is a freelance writer who has an Arts degree majoring in English, and is currently studying a Medicine degree.
Join the Conversation