The Aging Process: Apoptosis and the Elderly: Part XI
Apoptosis is a term coined in 1972 to describe programmed cell death characterized by an organized and controlled sequence of molecular and cellular events culminating in the removal of a cell from its potential or current physiological or pathological function. It is an active, genetically controlled process by which multicellular organisms regulate cell numbers thus removing unwanted or damaged cells. Apoptosis is a highly orchestrated cell death process that allows cells to die in a controlled fashion. All cells have the intracellular machinery necessary for programmed cell death. Whether or not they use that machinery depends on the cell type, its tissue context, the presence or absence of physiological death-promoting signals, and the extent to which a cell is damaged or dysfunctional.
There are two ways in which cells die: they are killed by injurious agents or they are induced to commit suicide. The two ways are called necrosis and apoptosis. Apoptosis is an active process of cellular self-destruction, a regulated energy-dependent process involving the activation of a cascade of proteases and endonucleases (i.e. caspases). Necrosis occurs as a result of injury causing severe molecular and/or structural damage leading to progressive, irreversible and catastrophic metabolic failure. This results in membrane disruption, cell swelling and eventual cell lysis and fragmentation, with an associated acute inflammatory response. The cell death pathway switches on in certain cells and a cascade of proteases is activated, leading to lysis that results in rupture of a cellís plasma membrane, leading to the release of cytoplasm and the death of these cells.
Unlike necrosis, the apoptotic process is active, energy requiring and precisely regulated. The lack of inflammation is the hallmark of apoptosis as compared with necrosis. It differs from classical necrosis in its histological appearance, in not being degenerative in nature, in affecting only scattered cells and in not being accompanied by inflammation. It occurs in normal adult tissues, where it is probably implicated in cellular turnover and is involved both in physiological involution and pathological atrophy of tissue. It occurs spontaneously in tumor growth, often substantially retarding their growth and it is enhanced in tumors responding to at least some types of therapy. Apoptosis takes care of unwanted, injured or virus-infected cells. Failure of apoptosis can cause autoimmune disease. It can lead to cancer (It could play an important role in future drug therapy for treatment of cancers.)
Apoptosis occurs in the presence of the P53 protein, which functions as a regulator of both cellular proliferation and apoptosis. The induction of p53 results in (1) arrest of cell cycle, to allow for DNA repair or (2) apoptosis, when repair is impossible. The p53 tumor suppressor gene encodes a 53?Da nuclear phosphoprotein that plays a major role in the synthesis, repair and apoptotic function of the cell cycle. These mechanisms have likely evolved to maintain the stability of the genome during cellular stress from DNA damage, hypoxia and activated oncogenesis. When cellular DNA is damaged, the p53 protein arrests growth until the damage is repaired. Alternatively, p53 will induce apoptosis if damage is severe.
Bcl-2 is an onco-protein, which protects cells against programmed cell death. It was found to be responsible for certain types of cancer and also was found to be widely expressed in fetal tissue. It is part of a growing multi-gene family, whose members can act either as up-regulators or down-regulators of apoptosis. The Bcl-2 family member's heterodimerize with one another and through this interaction regulate apoptosis. Therefore, the fate of a cell will be decided by the ratio of the pro-apoptotic and anti-apoptotic protein.
From the above description, one can see that our overall health relies to a great extent on the proper balance between the normal removal of damaged or unneeded cells via apoptosis and proliferation of the cells that comprise our body. Increasing evidence suggests that apoptosis is involved in many physiological processes and pathological conditions. It plays an important role during development in maintaining tissue homeostasis, in responding to cellular damage, and in preventing neoplastic disease.
There are various types of apoptosis, induced by different kinds of stimuli and in cells and tissues of different natures. On the basis of the nature of apoptosis-inducing stimuli, two main apoptotic pathways can be identified: an activation-induced apoptosis, initiated by a variety of signals, such as the binding of ligands to their death-promoting receptors on the cell surface and a damage-induced apoptosis, triggered by damage to the nucleus or other cellular parts.
Apoptosis is strongly involved in many changes characteristic of immunosenescence such as thymic involution, alteration of T cell repertoire, accumulation of memory/effector cells and autoimmunity. (T cell function is decreased in elderly compared to young individuals. This perceived deterioration of immune responses is designated "immunosenescence" and is found in both long and short-lived species as a function of their age relative to life-expectancy rather than chronological time)
The first report of a Swedish longitudinal study of the very old has provided supportive data. Initially, data were collected on 102 donors aged 86 - 92. Two years later, 75 of these were still alive. A comparison of the two groups showed that non-survival was associated with the clustered parameters of poor T cell proliferative responses, high CD8 (cytotoxic/suppressor cell) cell fraction, and low CD4 (helper/delayed-type hypersensitivity [DTH] cell) and CD19 (B) cells. It was found that no single parameter was predictive for survival, but that a cluster of the above parameters was predictive.
Other data illustrating the importance of the immune system in healthy aging come from other studies on centenarians. By and large, unlike the "average" elderly, the healthy very elderly (centenarians) are found to have well-preserved immune functions, similar but not identical to, the "young" immune system. They are among the 76,000* Americans who hold the distinction of being centenarians, a group now believed to be the fastest growing group of Americans.
The most effective way available to scientists to determine the reasons people live long is to examine independently functioning centenarians, people who live to 100 years of age or more. One such study (Hitt et al 1990) found that 905 of the centenarians were independently functioning at the age of 90 years. The implications of this study include the idea that morbidity is relatively compressed in the centenarian and may be a model for disease-delay aging.
In order to develop a therapy along these lines, researchers have looked at factors such as body fat, metabolism, family and pedigree studies, cardiovascular and other risk factors, thyroid function, immune function, blood clotting etc. To date, no particular environmental trait, such as diet, economic status or level of education has been found to superficially correlate with the ability to survive to extreme old age
During senescence, the activation-induced and damage-induced apoptotic pathways could be differently modulated, with variable impacts in the aging process. Changes in either of these two main apoptotic networks that may occur during aging could lead to disease. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degeneration and inflammatory pathologies and neoplastic diseases whose incidence increases with age.
Apoptosis eliminates cells without lysis or necrosis, which frequently results in inflammation reaction, allowing organism to remove damaged or dysfunctional cells without collateral damage of the tissue. In post mitotic tissue, where cell proliferation cannot replace lost cells, apoptosis minimizes cell loss, whereas in renewable tissues it is an important mechanism for maintaining size, integrity and health of the tissue.
Apoptosis may increase with age owing to the increased level of oxidative stress and ischemic injury (Schindowski, K., Leutner S, Muller,WE., Eckert A. Age related changes of apoptotic cell death in human lymphocytes. Neurobiol Aging 2000; 21:661-670)
A critical role of telomere shortening and p53 activation leads to apoptotic induction of premature cellular aging and heart failure in mammals. However, there are evidences that apoptotic mechanisms may become less efficient with age, at least in some tissues, and under defined stimuli, leading to accumulation of errors and loss of phenotypic fidelity. (Gershon D. The mitochondrial theory of aging: is the culprit a faulty disposal system rather than indigenous mitochondrial alteration? Exp Gerontol 1999; 34:613-619). This phenomenon would lead, on the one hand, to the survival of the cells, and this to longevity of the organism, and, on the other hand, to the accumulation of damaged cells, and thus to the appearance of the aged phenotype. Moreover, a decrease of apoptotic activity may compromise endogenous defense mechanisms against cancer, contributing to unsuccessful aging.
It is more sensible to think in terms of organ-specific and stimulus-specific modulation (according to the inducing agent or condition, in relation to the different apoptotic pathways). In the elderly, an increased apoptosis in certain tissues and organs can lead to rapid senescence, while decreased apoptosis in other organs (colon) can lead to increased risk of tumors. As a consequence, the influence of apoptosis on lifespan may result from a delicate balance between its antitumor and pro-aging effects.
Decreased apoptosis lowers the risk of death because of ischemic disease, but increases this risk because of cancer. To achieve successful aging, any detrimental impact of abnormal apoptosis must therefore be kept under control. A panel of experts created by the International Longevity Center-USA reported that "there is as yet no convincing evidence that administration of any specific compound, natural or artificial can globally slow aging in people, or even in mice or rats." (Download report at http://www.ilcusa.org)
The aging process does not represent a well-defined and stable condition but varies from subject to subject and in reality may be considered the result of dynamic interaction among various components searching for optimal biological balance. Apoptosis has a central role in this complex scenario. In particular, immunosenescence represents a significant example of the subtle modulation of apoptosis in the elderly. Age-related apoptosis of T-lymphocytes is an important determinant of immune deterioration in humans. However, failure of lymphocytes to exert the apoptotic program can lead to disorders that characterize the immune system during aging (e.g. the progressive accumulation of memory/effector T cells and the progressive filling of the immunological space.
F. G. Ferguson, A. Wikby, P. Maxson, J. Olsson & B. Johansson: Immune parameters in a longitudinal study of a very old population of Swedish people: A comparison between survivors and nonsurvivors. J Gerontol Ser A-Biol Sci Med 1995; 50: B378-82
C. Franceschi, D. Monti, P. Sansoni & A. Cossarizza: The immunology of exceptional individuals: the lesson of centenarians. Immunol Today1995 16, 12-6
Gunawardena K, Murray DK et al. Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis. Prostate 2000; 44:287-293
Hitt, R, Young-Xu Y., Perls T. Centenarians: the older you get, the healthier youíve been. Lancet 1990; 354:652.
Go Back to Article I of Articles on Aging-Mortality risk factors
The Aging Process-Part II-Gender Difference
The Aging Process-Part III-Cellular Senescence
The Aging Process-Part IV-Biological Aging
Go to Article V of Articles on Aging-Arteriosclerosis
The Aging Process-Part VI-Aging in Males
The Aging Process-Part VII-Aging in Women
The Aging Process-Part VIII-Infectious Disease
Process of Aging-Part IX-DHEA
The Aging Process-Part X-Skin, Skeleton and Brain
The Aging Process-Part XII-Biomarkers for Aging
The Aging Process- Part XIII- Body Odors
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Harold Rubin, MS, ABD, CRC, Guest Lecturer
posted August 17, 2004
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