THEORY OF AGING PROCESS

1. Genetic Clock

Many theories suggest that ageing results from the accumulation of damage to DNA in the cell, or organ. Since DNA is the formative basis of cell structure and function, damage to the DNA molecule, or genes, can lead to its loss of integrity and early cell death.

Examples include:

Accumulative-Waste Theory: The biological theory of ageing that points to a buildup of cells of waste products that presumably interferes with metabolism.

Wear-and-Tear Theory: The very general idea that changes associated with ageing are the result of chance damage that accumulates over time.

Somatic Mutation Theory: The biological theory that ageing results from damage to the genetic integrity of the body’s cells.

Error Accumulation Theory: The idea that ageing results from chance events that escape proof reading mechanisms, which gradually damages the genetic code.

Some have argued that ageing is programmed: that an internal clock detects a time to end investing in the organism, leading to death. This ageing-Clock Theory suggests, as in a clock, an ageing sequence is built into the operation of the nervous or endocrine system of the body. In rapidly dividing cells the shortening of the telomeres would provide such a clock. This idea is in contradiction with the evolutionary based theory of ageing.

Cross-Linkage Theory: The idea that ageing results from accumulation of cross-linked compounds that interfere with normal cell function. Free-Radical Theory: The idea that free radicals (unstable and highly reactive organic molecules), or more generally reactive oxygen species or oxidative stress create damage that gives rise to symptoms we recognize as ageing.[63][65]

Reliability theory of ageing and longevity : A general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-ageing elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Ageing, therefore, is a direct consequence of systems redundancy. Reliability theory also predicts the late-life mortality deceleration with subsequent levelling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the Weibull distribution: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.

Mitohormesis : It has been known since the 1930s that restricting calories while maintaining adequate amounts of other nutrients can extend lifespan in laboratory animals. Recently, 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 antioxidantdefence capacity.

Misrepair-Accumulation Theory: Wang et al. suggest that ageing is the result of the accumulation of "Misrepair". Important in this theory is to distinguish among "damage" which means a newly emerging defect BEFORE any reparation has taken place, and "Misrepair" which describes the remaining defective structure AFTER (incorrect) repair. The key points in this theory are:

1. There is no original damage left unrepaired in a living being. If damage was left unrepaired a life threatening condition (such as bleeding, infection, or organ failure) would develop.

2. Misrepair, the repair with less accuracy, does not happen accidentally. It is a necessary measure of the reparation system to achieve sufficiently quick reparation in situations of serious or repeated damage, to maintain the integrity and basic function of a structure, which is important for the survival of the living being.

3. Hence the appearance of Misrepair increases the chance for the survival of individual, by which the individual can live at least up to the reproduction age, which is critically important for the survival of species. Therefore the Misrepair mechanism was selected by nature due to its evolutionary advantage.

4. However, since Misrepair as a defective structure is invisible for the reparation system, it accumulates with time and causes gradually the disorganisation of a structure (tissue, cell, or molecule); this is the actual source of ageing.

5. Ageing hence is the side-effect for survival, but important for species survival. Thus Misrepair might represent the mechanism by which organisms are not programmed to die but to survive (as long as possible), and ageing is just the price to be paid.

2. Somatic mutation

somatic mutation theory states that random changes to the DNA of your cells can cause your cells, and eventually your body, to stop functioning correctly. A deeper understanding of this theory requires a greater biological understanding of your body.

Throughout your life time, your body is constantly creating new cells. Every time one of your cells divides to create two new cells, there is a possibility that the DNA from the first cell will be copied incorrectly. This results in a mutation, a change in the copy of your DNA contained by the new cells. This mutation may be caught and corrected, but some mutations will be missed and some of these mutations will affect the way the new cell functions.

All of the cells in your body are considered somatic cells, with the exception of your reproductive cells (sperm and eggs). The mutations occurring in cells other than your reproductive cells are therefore referred to as somatic mutations. These mutations will not be passed on to your children since they are not found in your reproductive cells. They do, however, accumulate in your cells as you get older. Uncorrected mutations in one cell get passed on when that cell divides and new mutations may also occur. Eventually, many of your cells have multiple mutations and these mutations begin to impact the way your body functions, causing many of the problems associated with aging.

Although this theory explains one of the ways in which our bodies age, there are currently many other equally plausible theories. Many of these, including the somatic mutation theory of aging, fall into the general category of "wear-and-tear" theories. These theories state that damage accumulated over time causes the body to age. Different theories suggest different causes of this damage, including: mutations, environmental factors such as UV light, and chemical factors which affect DNA structure.

Other theories suggest that aging is a pre-programmed bodily function, a function already set to occur in a specific way from the moment we're born. One such "aging-clock" theory is the telomere theory which claims that we age because our telomeres (protective caps on the end of each chromosome) wear away during cell replication. Most other theories of aging are based on the idea that certain substances build up in our bodies as we age, substances that include everything from cell waste to auto-antibodies (antibodies that attack the body's own tissues).

Evidence supporting many of these theories about the biological causes of aging is plentiful and it is likely that more than one of the theories described above are correct. Many of these theories are compatible with the somatic mutation theory of aging, a theory which is well supported, but unlikely to provide a full explanation of the reasons we age.

3. Senescence of the immune system.

The immune system undergoes constant physiological changes over the human lifespan. The infant has no immunity of its own at birth; immune function develops quickly over the first few years and then builds to a complete maturation by puberty. In fertile women, immunity fluctuates cyclically in sync with the menstrual cycle; dramatic changes occur during pregnancy as well as the postpartum period.

Throughout life, homeostasis is preserved in all systems through tightly regulated interactions between numerous interdependent body tissues (Figure 1). Driven by inalterable genetic factors, environmental insults, such as UV light, and lifestyle factors like nutrition and nicotine use, body tissues, with age, experience a progressive deterioration of cellular and tissue functions, largely due to genetic decay and the byproducts of metabolism. The study of aging in the immune system has revealed that immunosenescence represents a substantial remodeling of major immune functions.

Immunosenescence in both genders impacts cellular, humoral and innate immunity. Significant consequences of aging include atrophy of the thymus, changes in both the total numbers and subsets of lymphocytes, changes in the function of both B and T cells, changes in the patterns of secretion of cytokines and growth factors, disruption of intracellular signaling, changes in the patterns of antibody production, loss of antibody repertoire, loss of response to antigens and mitogens and disruption of immunological tolerance

Although aging affects many immune cell types, the cumulative effects of aging on T-cell function are the most consistently observed and most extensive. The human thymus decreases in both size and cellularity in a process called thymic involution; thymus tissue is replaced with fat. By 60 years, thymus-derived hormones are absent from the circulation.

Involution of the thymus in humans occurs in concert with a depletion of naive T cells and a shift in the T-cell population toward memory CD4+ cells.[13] In young adulthood, the CD4+ subset is characterized by roughly equivalent numbers of memory and naive CD4+ cells but in older adults becomes predominantly memory CD4+,]a shift that reduces the potential antigenic repertoire. The shift toward memory T cells with age is largely a consequence of the imbalance in T-cell maturation produced by thymus involution paired with an age-related impairment of T-cell proliferation in concert with clonal expansion of T cells activated by specific antigens. The shift toward memory cells in the T-cell compartment affects cytokine production as well, with less IL-2 produced (primarily a product of naive T cells) but more IL-4 (primarily a product of memory T cells).

The cumulative loss of T helper (Th) cells with age plays a profound role in immunosenescence, ultimately affecting both cellular and humoral immunity. Disruption of Th cells and alterations of cytokine levels that control B-cell functions compromise humoral immunity substantially, with decreased production of long-term immunoglobulin (Ig)-producing B cells as well as a reduction of Ig diversity. Although B-cell numbers do not change significantly, there is a significant impairment of B-cell response to primary antigenic stimulation; specific immunoglobulins produced become more random, and those produced have decreased affinity for their specific antigen. With age, therefore, the B-cell repertoire poised to respond to new antigenic challenge is limited, and the predominance of memory T cells seen with thymic involution is mirrored in the B-cell compartment. IL-15, particularly, stimulates proliferation of memory T cells; IL-15 levels are nearly double in healthy adults 95 years or older (3.05 pg/ml compared with both older adults [60–89 years] 1.94 pg/ml and midlife adults [30–59 years] 1.73 pg/ml).

Immunosenescence is compounded by the presence in the aged of a chronic low-grade inflammation characterized by increased proinflammatory cytokines, such as IL-6 and TNF-a, compounds that create oxidative stress and decrease cellular antioxidant capacity. These proinflammatory cytokines are positively associated with stress as well as salivary cortisol levels and may play a significant role in creating the degenerative changes associated with aging. Other body processes, most notably innate immunity and interactions of immunity with the neuroendocrine system, also contribute to immune system aging.

Antigen-presenting cells such as dendritic cells (DCs) and macrophages serve as a bridge between the innate and the adaptive immune systems. Antigen-presenting cells interact with foreign molecules and release pathogen-specific cytokines that drive the activation of naive CD4 helper cells into either Th1 or Th2 effector cells.

Production of IL-12 and IFN-g drive commitment of naive T cells to the Th1 lineage. Th1 cells produce cytokines that favor a cell-mediated response (IL-2, lymphotoxin, IFN- and TNF- ), warding off γ βintracellular pathogens, mounting delayed-type hypersensitivity responses to viral and bacterial antigens and eliminating tumor cells.

Production of IL-4 and IL-10 drive commitment to the Th2 subtypes. Th2 cells release cytokines which produce an environment favoring humoral immunity (IL-4, -5, -6, -10, and -13) by stimulating Th2 cell proliferation, differentiation, and participation in humoral immunity.

In the aged, however, naive cells are less likely to become effectors. In those that do, there is a documented shift towards a Th2 cytokine response.

The molecular and cellular changes associated with aging have substantial clinical ramifications. The elderly have impaired ability to achieve immunization but much higher levels of circulating autoantibodies, (due to the lack of naive effectors) impaired response to viral infections, increased risk of bacterial infections, and increased risk of both neoplastic and autoimmune disease.

4. Free radicals

According to the free radical theory, radicals damage cells in an organism, causing aging. Mitochondria, regions of the cell that manufacture chemical energy, produce free radicals and are the primary sites for free radical damage. By eliminating free radicals from cells through genetic means and dietary restriction, laboratories have extended the maximum age of laboratory animals. The administration of antioxidants, which eliminate radicals, to laboratory animals fails to increase maximum lifespan.

The nucleus of an atom is surrounded by a cloud of electrons. These electrons surround the nucleus in pairs, but, occasionally, an atom loses an electron, leaving the atom with an unpaired electron. The atom is then called a "free radical," or sometimes just a "radical," and is very reactive. When cells in the body encounter a radical, the reactive radical may cause destruction in the cell. According to the free radical theory of aging, cells continuously produce free radicals, and constant radical damage eventually kills the cell. When radicals kill or damage enough cells in an organism, the organism ages.1

The production of radical oxygen, the most common radical in biological systems, occurs mostly within the mitochondria of a cell. Mitochondria are small membrane-enclosed regions of a cell that produce the chemicals a cell uses for energy. Mitochondria accomplish this task through a mechanism called the "electron transport chain." In this mechanism, electrons are passed between different molecules, with each pass producing useful chemical energy. Oxygen occupies the final position in the electron transport chain. Occasionally, the passed electron incorrectly interacts with oxygen, producing oxygen in radical form.2

The primary site of radical oxygen damage is mitochondrial DNA (mtDNA). Every cell contains an enormous set of molecules called DNA which provide chemical instructions for a cell to function. This DNA is found in the nucleus of the cell, which serves as the "command center" of the cell, as well as in the mitochondria. The cell fixes much of the damage done to nuclear DNA. However, mitochondrial DNA (mtDNA) cannot be readily fixed. Therefore, extensive mtDNA damage accumulates over time and shuts down mitochondria, causing cells to die and the organism to age.4

Protection of mtDNA from radicals slows aging in laboratory animals. Some laboratories have produced fruit flies that live one-third longer than normal fruit flies. These labs genetically altered the fruit flies to produce more natural antioxidants. Antioxidants are molecules that eliminate radicals, so elevated levels of antioxidants prevent much of the mtDNA damage done by radicals.3 Other labs severely restricted the food intake of laboratory rats, causing a 50% increase in maximum lifespan compared to rats allowed to eat freely.2 The mitochondria of starved rats are not provided with enough material to function at full capacity. Therefore, the electron transport chains in mitochondria of the starved rats pass fewer electrons. With fewer electrons passed, fewer oxygen radicals are produced, so aging slows.

One main problem with the free radical theory is the failure of antioxidants administered as dietary supplements, like vitamins E and C, to significantly increase maximum lifespan. Proponents of the radical theory believe that dietary antioxidants, unlike natural antioxidants produced by cells, do not reach mitochondrial DNA, leaving this site susceptible to radical attack. Interestingly, even though supplemental antioxidants fail to increase maximum lifespan, they do increase the chances of living to the maximum lifespan. This may be due to antioxidant protection of other parts of the cell, like cellular proteins and membranes, from radical damage.2

The goal of all research on the free radical theory is to slow aging and increase maximum lifespan. The achievements so far are astounding; increasing the lifespan of fruit flies and rats is an impressive feat. Despite such success, no practical applications of the theory have been perfected. Genetic alteration is both controversial and difficult for humans. Starvation, while lengthening lifespan, is an unappealing alternative. Dietary antioxidants fail to increase maximum lifespan. However, the production of radicals and their role in aging is well understood. Further research may apply this knowledge in the development of a practical method to prevent or repair mtDNA radical damage.