Senescence 101: The major theories of aging

Senescence 101: The major theories of aging

What causes aging? Why do most species such as most animals and fungi age? Over the years, scientists have come up with different theories to explain the reasons behind aging or senescence and the specifics of the aging process.

The Major Theories of Aging: Explanations of the Aging Process

1. The Evolutionary Theories of Aging

There are several theories that collectively explain the aging process from an evolutionary perspective and based on the Darwinian concept of natural selection. German evolutionary biologist August Weismann introduced the programmed theory of aging in 1889 that argues aging stems from the need to replace the old to make room for the new generation.

Other theories have emerged during the 1900s. The three mainstream evolutionary theories of aging are the mutation accumulation theory proposed by British zoologist Peter Medawar in 1952, the antagonistic pleiotropy hypothesis first introduced by American evolutionary biologist George C. Williams in 1957, and the disposable soma theory proposed by English biologist Thomas Kirkwood in 1977.

The mainstream theories mentioned above generally suggest a link between reproductive capabilities and longevity. They provide an explanation from an evolutionary perspective why reproductive success declines alongside bodily functions with age. For example, the disposable soma theory asserts that the body of an organism favors reproduction over repair and maintenance in terms of allocation of limited energy. The antagonistic pleiotropy hypothesis asserts that natural selection favors the youth over old age whenever a conflict of interest arises.

2. Free-Radical Theory of Aging

Renowned biochemist and gerontology professor Denham Harman pioneered the development and subsequent introduction of the free-radical theory of aging during the 1950s and its further redevelopment during the 1970s. The theory argues that organisms age and eventually die due to the accumulation of cellular damage due to free radicals over time.

Note that a free radical is an atom or a molecule that has a single unpaired atom in its outer shell. Some free radicals are not chemically reactive, but most of them are highly reactive and cause damage due to oxidation. All organisms live in environments containing free radicals with reactive oxygen species or ROS. Energy production from mitochondrial respiration in eukaryotes generates ROS.

Damage specifically occurs when a free radical reacts to another molecule within the body of an organism. Reaction transpires as the free radical snatches an electron from another molecule to pair with its unpaired electron. The reaction turns the molecule into another free radical, which in turn, would seek another molecule to snatch its electron. A chemical chain reaction of radical production transpires.

The reactivity of free radicals causes damage at the molecular and cellular levels. For example, reaction transpiring in a strand of DNA results in DNA cross-linking that in turn, produces various age-related signs, including cancer. Cross-linking between fat and protein molecules leads to wrinkles. The oxidization of low-density lipoprotein by a free radical is a critical factor in the formation of plaque in arteries, thereby leading to cardiovascular diseases.

3. The Hayflick Limit

The Hayflick limit or the Hayflick phenomenon explains that most cells found in the human body and other animals have limited division numbers. To be more specific, the limit illustrates the number of times a normal cell population will divide before cell division stops. When applied to the theory of aging, the Hayflick limit explains that the reason behind aging stems from the inability of cells to divide.

American anatomist Leonard Hayflick advanced the concept of limited cell division in 1961 although other scientists such as Weismann had earlier proposed similar theories. Nonetheless, the Hayflick limit explains that each time a cell divides or undergoes mitosis, the telomeres found on the ends of each chromosome shortens slightly. Note that telomeres are specialized DNA sequences that prevent chromosomes from unraveling and deterioration, as well as from fusing with neighboring chromosomes.

Cell division ceases once telomeres reach a critically short length. Once most of the cells in tissues and organs stop dividing, signs of aging become visible. It has also been noted that the age of cell populations tend to correlate with the physical signs of aging of an organism. The Hayflick limit fundamentally provides a theory of aging at the cellular level.

Several studies support the link between the Hayflick limit and aging. For example, studies showed that supplying cells with an exogenous source of telomerase resulted in the maintenance of youthful cellular state and indefinite cellular division. Other studies found out that telomere dysfunctions are involved in the premature aging characteristic of progeria.

4. Tumor Suppression through Cellular Senescence

Related to the concept of Hayflick limit and similar to the notion that certain types of cells have limited numbers of division are other mechanisms related to cellular senescence. To be more specific, most organisms, including humans, have developed tumor-suppressor mechanisms that prevent uncontrolled cell division and promote the overall integrity of tissues and organ systems. These mechanisms found within cells are thought to be an evolutionary tradeoff.

In humans, specific genes and proteins are responsible for initiating the tumor-suppression mechanisms in cells. The Forkhead box O3 or FOXO3 is a protein encoded by the FOXO3 gene that is responsible for triggering cellular apoptosis or programmed cellular death. The p53 protein initiates either a DNA repair or apoptosis when DNA damage is irreversible or as a response to shortened telomeres. The p16 is another tumor suppressor protein encoded by the CDKN2A gene that plays an important role in regulating cell cycle through deceleration of the cycle progression.

There are other tumor-suppressor genes and proteins found in the human body and in other organisms that collectively form the natural anticancer mechanisms found within cells. These mechanisms are both beneficial and detrimental because they prevent the development of tumor through the proliferation of cancerous cells while also making aging inevitable as the entire body of an organism losses its regenerative capabilities.

5. Systems-Based Theory of Aging

The systemic or systems-based theories of aging collectively assert that the aging process results from the decline in the function of specific organ systems of organisms critical for controlling and maintaining other organ systems, as well for maintaining adaptive capabilities against environmental factors. The decline progresses along with age and it overlaps with other theories of the causes of aging. Nevertheless, these theories also provide an understanding of the physiological changes occurring with aging.

One theory under the systems-based model is the neuroendocrine theory that the cause of aging stems from changes in the neural and endocrine functions fundamental for coordinating communication and responsiveness of all organ systems, for programming physiological responses to environmental stimuli, and for maintaining a peak condition for reproduction and survival.

There are many reasons why the neuroendocrine system fails to function properly. One notable reason is that chronic exposure to high levels of stress due to physical, biological, or emotional factors may weaken the adaptive capabilities. Other reasons center on the decreasing secretion of hormones and neuron functions that coincide with age progression.

The immunological theory of aging is another component of the systems-based model. Australian virologist F. M. Burnet first postulated this theory during the 1950s and the 1960s and developed by biologist Roy Walford and other researchers. It claims that the immune system is programmed toward a functional decline over time. Such has been demonstrated in elderly people who tend to exhibit decreased resistance to infections and protection against cancer.

Related to the immunological theory of aging is the inflation theory that has been extensively investigated by Italian professor and research Claudio Franceschi who specialized in geriatrics, pathology, and genetic epidemiology. Chronic inflammation leads to oxidative damage, thus supplementing the free radical theory, as well as weakens response to stress, thus complementing the neuroendocrine theory.

The neuroendocrine-immuno theory of aging is a combination of the neuroendocrine theory and immunological theory stemming from the discoveries about the complex interactions between the neuroendocrine and immune systems. Studies have revealed that some age-associated changes in each system are mutually interdependent even in old age.

FURTHER READINGS AND REFERENCES

  • Harman, D. (1956). Aging: A Theory Based on Free Radical and Radiation Chemistry.” Journal of Gerontology. 11(3): 298-300. DOI: 10.1093/geronj/11.3.298
  • Kirkwood, T. B. (1977). “Evolution of Aging.” Nature. 270: 301-304. DOI: 10.1038/270301a0
  • Tosato, M., Zamboni, V., Ferrini, A., & Cesari, M. 2007. “The Aging Process and Potential Interventions to Extend Life Expectancy.” Clinical Interventions in Aging. 2(3): 401-412. PMCID: PMC2685272
  • Weinert, B. T. & Timiras, P. S. 2003. “Invited Review: Theories of Aging.” Journal of Applied Physiology. 95(4): 1706-1716. DOI: 10.1152/japplphysiol.00288.2003
  • Weismann, A. 1889. Essays Upon Heredity and Kindred Biological Problems. Oxford: Clarendon Press
  • Weismann, A. 1892. Über Leben und Tod. Jena, Germany: Gustav Fischer Verlag
  • Williams, G. C. 1957. Pleiotropy, Natural Selection, and the Evolution of Senescence. Evolution. 11: 398-411. DOI: 10.2307/2406060