George A. Sacher

The stochastic theory of mortality.

Theories devised to account for the form of human life tables-except those that are of a purely actuarial nature (for example, Pearson, 1897; Benjamin, 1959)-fall into two classes that can be labeled the predestination theories and the process theories. It is interesting that, with a few notable exceptions, predestination theories are written in terms of one life-table function, the curve of deaths, and process theories in terms of another, the rate or force of mortality. The curve of deaths is defined as the first derivative of t,he survivorship curve, ( d N / d t ) , where t stands for time or age, and N represents the number of individuals surviving to age t. On the other hand, the force of mortality, p, is given by the equation

Evolution of Longevity and Survival Characteristics in Mammals

The comparative analysis of aging patterns in mammals is at present in a highly fragmented state, because the data now available were gathered by investigators from various disciplines for various purposes, and are not all equally suitable for the purposes of this survey. Nevertheless, it is possible to discern evidence of a consistent pattern of longevity and aging in the class Mammalia. This brief review will examine this pattern, although the paucity of data in some areas limits the discussion to a semiquantitative examination of the possibilities.

Effects of age on cell proliferation in mouse duodenal crypts.

Abstract Using tritiated thymidine as a DNA label the generation times (GT) and durations of G 1 , S, G 2 and M have been established for BCF 1 mice at 55, 100, 300, 400, 675, 825 and 1050 days of age. GT was shown to be almost 50 per cent longer in the 1050-day-old BCF 1 than in the 55-day-old animals. The increase in GT is, however, not gradually progressive, but takes place at the end of the growing period between 55–100 days and at the beginning of “senility” at around 825 days of age. The first change involves an increase in G 1 from 1·9 to 4·7 hr, while the change in the old animals is due to an increase in both S and G 1 . The increase in GT in the old mice is accompanied by a pronounced decrease in the number of cells in the proliferative compartment.

The Role of Brain Maturation in the Evolution of the Primates

In 1959 I showed a close allometric relationship between the maximum lifespans for captive extant mammalian species and their adult brain weights and body weights (Sacher, 1959). The same quantitative relationship was later found to hold within individual taxa as diverse as the Rodentia (Sacher, unpublished), the Odontoceti (Sacher, 1981), and, in particular, the Haplorhini (Sacher, 1975).

Age Changes in Rhythms of Energy Metabolism, Activity, and Body Temperature in Mus and Peromyscus

The decrease in resting metabolic rate with age for experimental animals and man is, as someone has remarked, the most over-confirmed fact in gerontology (Pettegrew and Ewing, 1971; Grad, 1953; Kleiber et al., 1956; Schock and Yiengst, 1955; Keys et al., 1963). However, if one looks at the information available on age changes in the metabolism of activity, in respect to either its amount or its temporal organization within the diel cycle, the scene is much more sparsely populated. The qualitative registration of motor activity, sufficient to distinguish between the active and inactive phases of the circadian cycle, has, of course, been extensively used for the measurement of the circadian periods of experimental animals, and one investigation has appeared on the change in length of the circadian period with age in Peromyscus (Pittendrigh and Daan, 1974). However, those studies are not closely related to the objective of the present paper, which is to examine the modulation of energy metabolism, motor activity, and body temperature over the diel cycle as a function of age. For this purpose we need quantitative, closely spaced measurements of at least three variables: (a) the kinetic energy of motor activity; (b) rate of energy expenditure, measured indirectly by rate of oxygen consumption or carbon dioxide production; and (c) deep body temperature, measured by radiotelemetry. Two additional variables would be valuable but cannot yet be conveniently measured on the unconstrained animal: skin temperature and rate of heat loss. Monitoring of diel cycles of body temperature and/or oxygen consumption is widely employed for ecological energy budgeting, analysis of thermoregulation and hibernation studies (Heusner et al., 1971; Kayser and Hildwein, 1969; Heusner, 1957), and for research on circadian rhythm (Ehret et al., this volume), but we have no information about the diel cycles for any of the aforementioned variables in relation to aging.

Tail collagen aging in mice of thirteen different genotypes and two species: relationship to biological age.

Abstract Collagen aging rates were tested in mice of thirteen different genotypes and two species by measuring the breaking times of tail tendon fibers in a concentrated urea solution. Repeated on the same individuals, the results of this test indicated increased collagen age after only 1 month in 27 of 29 cases in two different experiments. Irradiated CBA mice and autoimmune susceptable NZB mice had normal collagen aging rates, as did a mutant with small body size ( lit/lit ) and two mutants with genetic anemias ( W/W V and an/an ). Tail collagen from CBA mice aged more rapidly than that from B6 mice or their F 1 hybrid during the latter halves of their lives. At advanced ages, collagen in female mice aged faster than collagen in males of most strains. These differences were not correlated with the mean lifespans of these animals, casting doubt on the hypothesis that collagen aging is a measurement of biological age. On the other hand, this test showed that tail collagen in wild-type Mus musculus aged about twice as rapidly as that in wild-type Peromyscus leucopus over the ages where both species were alive for comparison. This fits the hypothesis, because mice of the Peromyscus leucopus species live twice as long, however the difference is significant only in females because of the variability of Peromyscus males. Tail tendon collagen of mutant obese mice aged more rapidly than that of normal mice of the same strain. No differences in tail temperatures were detected, so accelerated collagen aging in obese mice may result from their very high insulin levels or other metabolic defects.

RADIATION EFFECTS ON CELL POPULATIONS IN THE INTESTINAL EPITHELIUM OF MICE AND ITS THEORY

Mice were exposed to 1000 R of X‐rays to their trunks and sacrificed every day up to the tenth day after exposure. Cell counts were made on histological sections of the duodenum. The cell counts in the crypts were reduced to about 50% of the control value on the first day after exposure. The cell counts began to recover on the third day and an overshoot of 170% was observed on the fourth day; thereafter the crypt cell counts tended to return to the control level. The cell counts on the villi reached their minimum value on the third day after exposure. Following an overshoot on the sixth day, the villus cell counts returned to the control level by the tenth day. The above experimental results were analysed using a two‐compartment model with a feedback term. A logistic proliferation was assumed for the proliferative crypt cells, while for the postmitotic villus cells the compartment was assumed to be a first in‐first out type. The calculated results with this model are in general consistent with the experimental ones. The model seems to possess some essential features of the dynamics of cell renewal in the intestinal mucosa.

Dose, Dose Rate, Radiation Quality, and Host Factors for Radiation-Induced Life Shortening

This paper reviews the effects of ionizing radiations on disease incidence and life shortening in experimental animals, with the aim of establishing a phenomenological model of the dose and time kinetics for the production of late radiation damage. Aspects of this problem have been discussed previously (Sacher, 1956a). At that time, mammalian cellular radiology had barely begun its dramatic development, and there were no experimental data against which to test the hypothesis adopted then, that the phenomena of radiation life shortening are due to chromosome breakage and rejoining. This hypothesis was stated most explicitly by Muller (1950), but it was also implicit in the discussion of lethal effects in cells by Lea (1947), and in a real sense it was a development that epitomized the classical period of radiation genetics.

Comparative heat stability of blood catalase

Abstract The thermal stability of the catalase in whole blood lysates of a variety of mammalian species has been measured. A total of 26 varieties of mammal has been examined, and the T 50 (temperature at which 50% of the activity is lost under the conditions employed) varies from as low as 48.1 ° to as high as 67.1 °. The T 50 is in no way correlated with the absolute level of catalase activity. Thermal stability curves, and hence T 50 values, are sharply reproducible for individuals of a given species regardless of sex or age. Various species within a given genus tend to have similar T 50 values. Various genera, even within a single family, however, might vary widely in T 50 . In the laboratory mouse, a mutation in a structural gene, which has been shown elsewhere to produce a new molecular modification of the catalase, shows a T 50 which is significantly different from that of the catalase of the original, nonmutant strain.

Comparative effectiveness of several x-ray qualities for acute lethality in mice and rabbits.

Early studies of the relative effectiveness of different qualities of ionizing radiation, reviewed by Packard (1), were chiefly concerned with the effect of X-rays of therapeutic quality on small biological test objects. A more recent review by Zirkle (2) has summarized biological studies that have used a broad range of radiation qualities in an effort to correlate response to the energy transfer involved. Acute radiation death in mammals has not been widely employed as a criterion of relative effectiveness of X-rays in the therapeutic range. Potter (3) demonstrated a relationship between exit dose and lethality in rats with 100and 400-kvp X-rays wherein equal effect was noted when the exit doses were similar for compared qualities. A like relationship was observed by Ellinger et al. (4) for the exit dose and LDso in mice exposed to 140and 200-kvp X-rays. The implication that nonuniformity of depth dose can account for variation in effectiveness of X-rays has not been well established. Thus, the present study examines the relationship of acute lethality and depth-dose distribution in mice and rabbits exposed to X-rays ranging from 80 to 250 kvp.