G. Hofecker

Models of the biological age of the rat. I. A factor model of age parameters.

The hypothesis of biological age postulates a fixed pattern in the aging of the multicellular organism. As a test of this hypothesis 23 age parameters of the rat were submitted to factor analysis. The data used in this study were a result of a long-term cohort study on 240 male Sprague-Dawley rats, which covered an age range of 10-30 months. The age parameters were obtained from various systems and levels of organization. The analysis revealed that there is a fixed pattern in the variations of the parameters. In this factor pattern the parameters are grouped into six factors, five of which can be attributed to the aging process. The first factor is interpreted as representing primary aging, factors 2-5 are interpreted as an expression of system-specific secondary processes of multicellular aging. Approximately 40% of the total variation of all parameters turned out to be random or due to processes other than aging.

Investigations on the kinetics of collagen-metabolism in young and old rats

Abstract Collagen is one of the most important body-proteins (about 30%) whose structure, function and turnover depends on certain diseases and on the aging process. After designing a general model of collagen-metabolism the course of the specific activity of hydroxyproline in three different collagen-modifications of skin and tail-tendon was investigated for 32 days in Sprague-Dawley rats with an age of 3 resp. 20–24 months. These modifications are typical for the structure of collagen. From this course and from the specific activity in blood and urine the turnover rates of one single modification into one another were calculated. From the size of these determined constants conclusions could be drawn upon the different ways of collagen-biosynthesis in young and old animals. Moreover this model should give information about the nature of this way of collagen-synthesis in different diseases of connective tissue.

Changes of DNA repair mechanisms during the aging of the rat

Recent studies have shown a significant reduction in DNA repair capacity in aging rats. Therefore we were interested in investigating which repair mechanism is concerned in this reduction. We investigated: excision repair (ER); single-strand break repair (SSBR); double-strand break repair (DSBR); and gamma-endonuclease susceptibility (ES) by means of the following methods: [3H]thymidine ([3H]dThd) incorporation into DNA after damage by N-methyl-N-nitrosourea (MNU); nucleoid sedimentation after damage by methyl methanesulfonate (MMS); neutral elution techniques after damage by 4-nitroquinoline-1-oxide (NQO); and determination of ES sites by velocity sedimentation in an alkaline sucrose gradient after damage by gamma-irradiation. Studies were done with male Sprague-Dawley rats aged 9, 18 and 28 months using nine different organs. We were able to determine a distinct age dependency of excision repair, a slight reduction of single-strand break repair, an elevation of gamma-endonuclease susceptible sites and no significant change in double-strand break repair in the course of aging. Therefore we see a shift in the pattern of DNA repair: in old age strand break repair mechanisms become more important, while repair replication is reduced. From this we can conclude that genetic expression is altered during the aging process, with all the consequences for the disposition toward certain diseases.

The influence of persistent crowding on the age changes of behavioral parameters and survival characteristics of rats

One hundred fifty-six male Sprague-Dawley rats were submitted to crowding (12 rats/Makrolon-IV cage) from an age of 5 months onwards. An equal number from the same age cohort served as a control (6 rats/Makrolon-IV cage). As part of an age-test program, behavioral parameters (spontaneous motor activity, reactive motor activity and maze-learning ability) were measured at various ages between 8 and 30 months. The rats were sacrificed for additional measurements after the behavioral tests. Survival curves and age-specific mortality rates were calculated for those rats which died spontaneously in the course of the study. Control rats showed a significant decrease in spontaneous motor activity after an age of 18 months. Reactive motor activity of the controls revealed a fall in the number of large movements between 9 and 15 months, whereas the number of small movements increased up to an age of 30 months. Crowding conditions increased significantly both spontaneous and reactive activity. Maze-learning ability declined significantly with age in the controls whereas crowded rats revealed a tendency to better performance which seemed to be submitted to a seasonal rhythm. Crowded rats showed an improved survival characteristic, beginning at an age of 700 days. Mortality curves turned out to be distinct and parallel by straight line regression. It has been concluded that the positive effects of crowding on behavioral parameters and survival could be attributed to a decrease in vulnerability rather than to a lowered rate of aging.

Age dependence of signal transduction and cell signaling as a major factor of intervention into the aging process

Nowadays, it has become necessary to investigate the mechanisms underlying aging changes and their modulation. Of particular interest are the cellular and molecular level cell-cell and cell-matrix interactions. Thus, we partly determined in rats aged 9 and 31 months (a) the concentrations and the activities of signal molecules, such as G-proteins, cyclic adenosine monophosphate (cAMP) and kinases (cellular) and collagens, proteoglycans (PG) and fibronectin (extracellular) in vivo in the skin of the back, as well as in isolated fibroblasts and keratinocytes; (b) the cell proliferation and (c) we tried to retard the aging process in the skin by topical application (or by addition to cell cultures) of fetal mesenchymal cells, PGs, and soya matrix and we compared the above mentioned parameters with those obtained by stimulation of skin cells with growth factors. There are indications that there is (a) no change in the quantity of Gs-proteins but a reduction of the binding capacity. We found lower concentrations of cAMP, a reduced activity of protein kinase C in vivo, a higher collagen crosslinking, a lower PG concentration and no change of the amount of fibronectin in the old rats skin and (b) there is a more or less extensive restoration of these parameters by all the above mentioned stimuli. So, we conclude that all the above mentioned influences modulate the aging process of the skin and its cells by intervention into the signaling pathways, by mediating new signals to the cells and hence by readjusting damaged feedforward systems in the cells.

Assessment of modifications of the rate of aging in the rat.

Multivariate models of BA are, at present, the only way of measuring the main subject of gerontological research, namely, aging of the organism as a whole. Aging is obviously not a completely random process without any regularity, but shows a pattern which is determined by the organisms principles of order and its answer to the stochastic events of primary aging. Based on this theoretical concept, which is supported by results of factor analysis, multicellular aging may be described by a single complex variable, BA. However, the non-linearity of age changes and the different extent to which primary and secondary aging are involved, as well as factors other than aging, restrict the sensitivity of multiple regression models. Sensitivity may be increased by selecting parameters according to their discriminating power revealed by discriminant analysis. Wherever influences on aging are to be tested, a combination of the three types of multivariate methods will allow for an objectivation of effects and provide clues to a possible mode of action.

Lebensdauer: Genetische Determinierung und lebensverlängernde Strategien

Altern ist ein grundlegender physiologischer Prozess, der ausnahmslos in allen arbeitsteiligen multizellularen Organismen auftritt. In dieser Arbeit werden wir uns beim Begriff „Spezies“ besonders auf Mammalia beziehen—auf Abweichungen wird hingewiesen. Aus medizinisch-biologischer Sicht umfasst der Begriff „Altern“ die regressive Phase des stetigen Wandels von Struktur und Funktion, den Burger (1947) als Biomorphose bezeichnete (Abb. 1.2.1).