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Mech Ageing Dev 1997 Oct;98(1):1-35
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3206, USA.
It has become a staple assumption of biology that there is an intrinsic fixed limit to the number of divisions that normal vertebrate cells can undergo before they senesce, and this limit is in some way related to aging of the organism. The notion of such a limited replicative lifespan arose from the often repeated observation that diploid fibroblasts cannot proliferate indefinitely in monolayer culture, and that the number of divisions before senescence is directly related to the in vivo lifespan of different species. The in vitro evidence is countered by estimates that the number of cell divisions in some organs of rodents and man are one or more orders of magnitude higher than the in vitro limit, with no indication of the degenerative changes seen in culture. Serial transplantation experiments in animals also exhibit many more cell divisions than the in vitro studies, with some indicating an indefinite replicative lifespan. I present evidence that vertebrate cells are severely stressed by enzymatic dispersion and sustain cumulative damage during serial subcultivations. The evidence includes large increases in cell size and its heterogeneity, reductions in replicative efficiency at low seeding densities, appearance of abnormal structures in the cytoplasm, changes in metabolism to a common cell culture type, continuous loss of methyl groups and reiterated sequences from DNA, and a constant rate of decline of growth rate with passage. This evidence is complemented by the reduction induced in the replicative life span of diploid cells by a large array of treatments which have different primary targets in the cells. The most consistent and general observation of cell behavior in aging animals, with only a few exceptions, is a reduction in the rate of cell proliferation. This reduction is perpetuated when the cells are grown in culture, indicating it is an enduring and intrinsic property of the cells rather than a systemic effect of the aging organism. A similar heritable reduction in growth rate can be induced in established cell lines by prolonged incubation at quiescence. The reduction can be exaggerated by subculturing the quiescent cells under suboptimal conditions, just as the effects of age are exaggerated under stress. The constant decline of growth rate that occurs during serial passage of diploid cells may represent a similar decay of cell function. I propose that the limit on replicative lifespan is an artifact that reflects the failure of diploid cells to adapt to the trauma of dissociation and the radically foreign environment of cell culture. It is, however, a useful artifact that has given us much information about cell behavior under stressful conditions. The overall evidence indicates cell in vivo accumulate damage over a lifetime that results in gradual loss of differentiated function and growth rate accompanied by an increased probability for the development of cancer. Such changes are normally held to a minimum by the organized state of the tissues and homeostatic regulation of the organism. The rejection of an intrinsic limit on the number of cell divisions eliminates the need for a cellular clock, such as telomere length, that counts mitoses. I offer a heuristic explanation for the gradual reduction of cell function and growth capacity with age based on a cumulative discoordination of interacting pathways within and between cells and tissues. I also make a case for the use of established cell lines as model systems for studying heritable damage to cell populations that simulates the effects of aging in vivo, and represents a relatively unexplored area of cell biology.
Recent Prog Horm Res 1997;52:307-357
Klein DC, Coon SL, Roseboom PH, Weller JL, Bernard M, Gastel JA, Zatz M, Iuvone PM, Rodriguez IR, Begay V, Falcon J, Cahill GM, Cassone VM, Baler R
Section on Neuroendocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
A remarkably constant feature of vertebrate physiology is a daily rhythm of melatonin in the circulation, which serves as the hormonal signal of the daily light/dark cycle: melatonin levels are always elevated at night. The biochemical basis of this hormonal rhythm is one of the enzymes involved in melatonin synthesis in the pineal gland-the melatonin rhythm-generating enzyme-serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT, E.C. 220.127.116.11). In all vertebrates, enzyme activity is high at night. This reflects the influences of internal circadian clocks and of light. The dynamics of this enzyme are remarkable. The magnitude of the nocturnal increase in enzyme activity ranges from 7- to 150-fold on a species-to-species basis among vertebrates. In all cases the nocturnal levels of AA-NAT activity decrease very rapidly following exposure to light. A major advance in the study of the molecular basis of these changes was the cloning of cDNA encoding the enzyme. This has resulted in rapid progress in our understanding of the biology and structure of AA-NAT and how it is regulated. Several constant features of this enzyme have become apparent, including structural features, tissue distribution, and a close association of enzyme activity and protein. However, some remarkable differences among species in the molecular mechanisms involved in regulating the enzyme have been discovered. In sheep, AA-NAT mRNA levels show relatively little change over a 24-hour period and changes in AA-NAT activity are primarily regulated at the protein level. In the rat, AA-NAT is also regulated at a protein level; however, in addition, AA-NAT mRNA levels exhibit a 150-fold rhythm, which reflects cyclic AMP-dependent regulation of expression of the AA-NAT gene. In the chicken, cyclic AMP acts primarily at the protein level and a rhythm in AA-NAT mRNA is driven by a noncyclic AMP-dependent mechanism linked to the clock within the pineal gland. Finally, in the trout, AA-NAT mRNA levels show little change and activity is regulated by light acting directly on the pineal gland. The variety of mechanisms that have evolved among vertebrates to achieve the same goal-a rhythm in melatonin-underlines the important role melatonin plays as the hormonal signal of environmental lighting in vertebrates.
Pierpaoli W, Lesnikov V
Biancalana-Masera Foundation for the Aged, Neuroimmunomodulation Laboratory, Ancona, Italy.
The models developed in our laboratory demonstrate that ageing initiates and progresses in the pineal gland. However, the ageing postponing effects of pineal grafting into older recipients cannot be explained by a simple maintenance and/or normalization of the night melatonin synthesis and release. We propose here that the pineal gland monitors and regulates, via its control of neuroendocrine function, the maintenance of 'self-identity' and the capacity of the immune system to recognize and react against any noxious, endogenous or exogenous agent. Senescence is characterized by the extinction of this central pineal function. The progressive decline of the self-recognition capacity distinguishes the typical diseases of ageing expressed as emergence of peripheral desynchronization and autoimmune, anaplastic, neoplastic and degenerative processes. Our approaches aim at a prevention and/or restoration of central pineal functions.
Biomed Pharmacother 1997;51(2):49-57
Institut de Cancerologie et d'Immunologie & Hopital Suisse de Paris, France.
The author has focused the subject on the perduration of puberty thymus involution as a cause of immunity aging, a term in which he does not include senescence. The decrease between immune reactions against HIV1 at 25 years of age and those at 35 is considerable; the decrease is also indirectly revealed by spontaneous tumor exponentially growing incidence after 40 years in man and its equivalent, 16 months in mice: the immunity parameters indicate a regression correlated with this incidence growth. He regrets the neglect of suppressor cell and anti-idiotype problems by the basic immunologic research. Given the role of cofactors non specifically related to the antigen, such as that CD28 and its ligands, he suggests the interest to approach immunology via the science of chaos and fractals, which would be more appropriate than classical methodology to study highly complex phenomena on which apparently minimal interventions may induce considerable effects.
Neuroendocrinology 1997 May;65(5):369-376
Shimokawa I, Higami Y, Okimoto T, Tomita M, Ikeda T
Department of Pathology, Nagasaki University School of Medicine, Nagasaki City, Japan.
The present study was designed to investigate the modulating effect of aging and lifelong dietary restriction (DR), a powerful anti-aging intervention in laboratory rodents, on growth hormone (GH) secretion from pituitary cells in response to GH-releasing hormone (GHRH) in the presence of somatostatin (SS)-28. Dispersed pituitary cells from 6- and 24-month-old rats fed ad libitum (AL-Y, AL-O, respectively) and 24-month-old rats dietary restricted from 6 weeks of age (DR-O) were subjected to a reverse hemolytic plaque assay under variable conditions including GHRH (0, 1, 10 nM) and SS-28 (0, 10 nM). The proportion of GH plaque-forming cells in dispersed pituitary cells increased by GHRH and decreased by SS-28. The proportion of these cells was lowest in AL-O rats; it was lower in DR-O than in AL-Y rats, particularly in the presence of SS-28. The reduction in these cells by SS-28 was greatest in Group AL-O. The mean area of these plaques, reflecting the amount of GH released from individual cells, was not different among the three rat groups in the absence of SS-28. In contrast, SS-28 produced a significantly higher reduction in the plaque area in Group AL-O compared with AL-Y and DR-O rats. Our results indicated that: (1) aging did not alter the responsiveness of GH-secreting cells to GHRH for GH secretion, while increased sensitivity of GH-secreting cells to SS-28 was noted in aged rats; (2) lifelong dietary restriction did not modulate the responsiveness to GHRH but partially inhibited the age-related increase in the sensitivity to SS-28 of GH-secreting cells, and (3) the major impact of the dietary regimen may include modulation of the number of pituitary cells, which leads to a high proportion of GH-secreting cells compared with that in AL rats at the same chronological age.
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