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Abhijit De*, Chandan Ghosh
Department of Pharmaceutical Science,
Bengal School of Technology, Sugandha,
Hooghly, West Bengal, India

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. In this review, several theories and mechanisms have been put to explain the molecular basis of aging. For example, random damage of the DNA of somatic cell is believed to accumulate with increasing age. Free radicals produced during oxidation of metabolites for energy production also damage DNA and proteins.


PharmaTutor (ISSN: 2347 - 7881)

Volume 5, Issue 2

Received On: 12/09/2016; Accepted On: 14/12/2016; Published On: 01/02/2017

How to cite this article: De A, Ghosh C; Basics of aging theories and disease related aging-an overview; PharmaTutor; 2017; 5(2); 16-23

Aging is an extremely complex and multifactorial process that proceeds to the gradual deterioration in functions. It usually manifests after maturity and leads to disability and death. The signs of aging start to appear after maturity, when optimal health, strength and appearance are at the peak. After puberty, all physiological functions gradually start to decline (e.g. the maximum lung, heart and kidney capacities are decreased, the secretion of sexual hormones is lowered, arthritic changes, skin wrinkling, etc). The precise biological and cellular mechanisms responsible for the aging are not known, but according to Fontana and Klein “they are likely to involve a constellation of complex and interrelated factors, including oxidative stress–induced protein and DNA damage in conjunction with insufficient DNA damage repair as well as genetic instability of mitochondrial and nuclear  genomes; [1] noninfectious chronic inflammation caused by increased adipokine and cytokine production; [2] alterations in fatty acid metabolism, including excessive free fatty acid release into plasma with subsequent tissue insulin resistanc; [3] accumulation of end products of metabolism, such as advanced glycation end products, amyloid, and proteins that interfere with normal cell function; sympathetic nerve system and angiotensin system activation as well as alterations in neuroendocrine systems; and loss of post-mitotic cells, resulting in a decreased number of neurons and muscle cells as well as deterioration in structure and function of cells in all tissues and organs[4]. In Biological terms, aging represents the molecular biochemical, physiological and structural change that take place in an organism. At all levels of biological organization, there is a progressive decline in adaptation to maintain the homeostatic balance in the functioning of various organs that is characteristic of the adult organism. In general, life span of a multicellular organism is characterized by a smooth transition from the developmental phase to the reproductive phase.

There are many theories trying to explain the aging process, each from its own perspective, and none of the theories can explain all details of aging. Some important theories of aging are:

a. Wear and tear theory
This is based on the idea that changes associated with aging result from damage by chance that accumulates over time. The wear-and-tear theories describe aging as an accumulation of damage and garbage that eventually overwhelms our ability to function. The process of aging derives from imperfect clearance of oxidatively damaged, relatively indigestible material and their accumulation hinders cellular catabolic and anabolic functions (e.g. accumulation of lipofuscin in lysosomes)[5].

b. Oxidative stress and free radical theory
Organisms age because of accumulation of free radical induced damage in the cells such as superoxides (O2-), hydrogen peroxide (H2O2), Hydraxyl radicals (OH-), etc. It was subsequently discovered that reactive oxygen species (ROS) generally contribute to the accumulation of oxidative damage to cellular constituents, even though some of them are not free radicals, as they do not have an unpaired electron in their outer shells. Consistently, aged mammals contain high quantities of oxidized lipids and proteins as well as damaged/mutated DNA, particularly in the mitochondrial genome. The oxygen consumption, production of ATP by mitochondria and free-radical production are linked processes [6]. Increases in mitochondrial energy production at the cellular level might have beneficial and/or deleterious effects. Increased regeneration of reducing agents (NADH, NADPH and FADH2) and ATP can improve the recycling of antioxidants and assist the antioxidant defense system. On the other hand, enhanced mitochondrial activity may increase the production of superoxide, thereby aggravating the oxidative stress and further burdening the antioxidant defense system. The mitochondria are the major source of toxic oxidants, which have the potential of reacting with and destroying cell constituents and which accumulate with age. The result of this destructive activity is lowered energy production and a body that more readily displays signs of age (e.g., wrinkled skin, production of lower energy levels). Damaged mitochondria can cause the energy crisis in the cell, leading to senescence and aging of tissue. Accumulation of damage decreases the cell's ability to generate ATP, so that cells, tissues, and individuals function less well. The gradual loss of energy experienced with age is paralleled by a decrease in a number of mitochondria per cell, as well as energy producing efficiency of remaining mitochondria. A major effect of mitochondrial dysfunction is an inappropriately high generation of ROS and proton leakage, resulting in lowering of ATP production in relation to electron input from metabolism. Leaked ROS and protons cause damage to a wide range of macromolecules, including enzymes, nucleic acids and membrane lipids within and beyond mitochondria and thus are consistent with the inflammation theory of aging as being proximal events triggering the production of pro-inflammatory cytokines. Free radicals can damage the mitochondrial inner membrane, creating a positive feedback-loop for increased free-radical creation. Induction of ROS generates mtDNA mutations, in turn leading to a defective respiratory chain. Defective respiratory chain generates even more ROS and generates a vicious cycle.

c. Telomere shortening theory
Telomeres are the strands of DNA that make up the ends of chromosomes. Because of    the way in which DNA is replicated, the length of the telomeres shortens each time the cell divides. Consequently, the length of telomeres in the cells of older people tends to be shorter than in younger people. It is thought that, once the telomeres reach a certain minimum size, they can cause the cell to become senescent. In humans, cells can divide approximately fifty times before cell division ceases, presumably as a result of the exhaustion of the telomeres. This is referred to as the ‘Hayflick limit’ after the scientist who first observed it. Telomere shortening has therefore been identified as a factor that could contribute to aging.

Figure 1: Telomeres are DNA caps that sit on the ends of chromosomes. Telomeres shortening and cell replication ceases.

d. The cross linking/Glycation hypothesis of Aging
The cross linking hypothesis is based on the observation that with age, our proteins, DNA, and other structural molecules de­velop inappropriate attachments or cross-links to one another. These unnecessary links or bonds decrease the mobility or elasticity of proteins and other molecules.  Proteins that are damaged or are no longer needed are nor­mally broken down by enzymes called proteases. However, the presence of cross-linkages inhibits the activity of proteases. These damaged and unneeded proteins, therefore, stick around and can cause problems.  One of the main ways cross-linking occurs is through a process called glycosylation or glycation. Glucose molecules can stick to proteins, then transform into brownish molecules called advanced glycosylation endproducts, or AGEs. When both of the sticky ends of AGEs adhere to neighboring proteins, they form permanent cross-links that disable the proteins’ functions. Cross-linking of the skin protein collagen, for example, has proven at least partly responsible for wrinkling and other age-related dermal changes Cross-linking of proteins in the lens of the eye is also believed to play a role in age-related cataract formation. Recently, scientists have found evidence that glycation contributes to the formation of beta-amyloid the protein that clumps together in the brains of Alzheimer’s patients. Carnosine occurs in very low concentrations in the brain and other tissues. In the laboratory carnosine has been shown to delay the senescence or aging of human cells called fibroblasts. Carnosine works by preventing cross-linking of pro­teins.

e. The genome maintenance hypothesis/Somatic mutation
Damage to our DNA happens thousands of times every day in every cell in our body throughout our lives. This damage can be caused by oxidative free radicals, mistakes in replication, or outside environmental factors such as radiation or toxins. Mutations or spontaneous changes in the structure of our genes that occur in our egg or sperm cells will be passed on to future generations, if those mutations are not so poten­tially disruptive as to be fatal to our offspring. Mutations that occur in the rest of the cells of the body will only affect that individual and cannot be passed on to future generations. Most of those body cell, or somatic, mutations will be corrected and eliminated, but some will not. Those will accu­mulate, eventually causing the cells to malfunction and die. This process, it has been suggested, is a crucial component in the aging process. This theory also encom­passes a role for mitochondria, the cellular powerhouses, as impor­tant factors in aging. Mitochondria create damaging free radicals as a by-product of normal energy production. Somatic mutations in the DNA of the mitochondria accumulate with age, increasing free radical production, and are associated with an age-related decline in the functioning of mitochondria.

f. Neuroendocrine hypothesis of aging
The Neuroendocrine system refers to the complex connections between the brain and nervous system and our endocrine glands, which produce hormones. The hypothalamus, a structure at the base of the brain, stimulates and inhibits the pituitary gland, often called the “master gland,” which in turn regulates the glands of the body (ovaries, testes, adrenal glands, thyroid) and how and when they release their hormones into our circulation. As we age, this system becomes less functional, and this can lead to high blood pressure, impaired sugar metabo­lism, and sleep abnormalities. The effects that the various hormones our different glands produce have on different facets of aging have been studied extensively.

g. The evolutionary senescence theory of aging-
The most widely accepted overall theory of aging is the evolutionary senescence theory of aging. Unlike the earlier programmed theory of evolution and aging, which tried to find reasons why evolution might favor aging, evolutionary senes­cence theory focuses on the failure of natural selection to affect late-life traits. Natural selection, because it oper­ates via reproduction, can have little effect on later life. Genes and mutations that have harmful effects but appear only after reproduction is over do not affect reproductive success and therefore can be passed on to future generations. In 1952, Peter Medawar proposed that the inability of natural selection to influence late-life traits could mean that genes with detrimental late-life effects could continue to be passed from generation to gen­eration. This theory is called the mutation accumulation theory. A few years later, George Williams extrapolated on this idea by formulating the theory of “antagonistic pleiotropy.” Antago­nistic pleiotropy means that some genes that increase the odds of successful reproduction early in life may have deleterious effects later in life. Because the gene’s harmful effects do not appear until after reproduction is over, they cannot be eliminated through natural selection. An example of antagonistic pleiotropy in humans is p53, a gene that directs dam­aged cells to stop reproducing or die. The gene helps prevent cancer in younger people, but may be partly responsible for aging by impairing the body’s ability to renew deteriorating tissues. Be­cause of antagonistic pleiotropy, it is likely that tinkering with genes to improve late-life fitness could have a detrimental effect on health at younger ages.

h. Mitohormesis theory of aging
This theory is based on the “hormesis effects”. It describes beneficial actions resulting from the response of an organism to a low-intensity stressor. It has been known since the 1930s that restricting calories while maintaining adequate amounts of other nutrients can extend the lifespan in laboratory animals. Michael Ristow's group has provided evidence for the theory that this effect is due to increased formation of free radicals within the mitochondria causing a secondary induction of increased antioxidant defense capacity. The best strategy to enhance endogenous antioxidant levels may actually be oxidative stress itself, based on the classical physiological concept of hormesis[7].

i. Mitochondrial theory of aging
Mitochondria are the cell’s chief energy producing organelles. A cell can contain hundreds of mitochondria, the DNA of which encodes a subset of mitochondrial RNA and proteins. The mitochondrial theory of ageing proposes that mutations progressively accumulate within the mitochondrial DNA, leading to a cellular ‘power failure’[8]. The consequences are predicted to be particularly dire for non-proliferative cells in organs that have a minimal capacity to regenerate (quiescent tissues), such as the heart and brain. The activity of master regulators of mitochondrial function and number diminishes with ageing, further contributing to mitochondrial deficiency. With age, telomere damage in the nucleus triggers the activation of p53, which can have different effects. In proliferative cells, p53 halts both cell growth and DNA replication, potentially causing apoptotic cell death. p53 also represses the expression of PGC-1 in mitochondria, reducing the function and number of these organelles, and so leading to age-related dysfunction of mitochondrion-rich, quiescent tissues. The mitochondrial derangements driven by loss of PGC-1 activity may independently lower the threshold for the generation of toxic intermediates such as reactive oxygen species (ROS), which damage mitochondrial DNA, thus setting up a vicious cycle of further mitochondrial dysfunction[9].

Figure 2: Common causes of aging



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