Aging is the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age. These time-related changes are attributed to the aging process. The nature of the aging process has been the subject of considerable speculation. Accumulating evidence now indicates that the sum of the deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it. In mammalian systems the free radical reactions are largely those involving oxygen. Dietary manipulations expected to lower the rate of production of free radical reaction damage have been shown (i) to increase the life span of mice, rats, fruit flies, nematodes, and rotifers, as well as the "life span" of neurospora; (ii) to inhibit development of some forms of cancer; (iii) to enhance humoral and cell-mediated immune responses; and (iv) to slow development of amyloidosis and the autoimmune disorders of NZB and NZB/NZW mice. In addition, studies strongly suggest that free radical reactions play a significant role in the deterioration of the cardiovascular and central nervous systems with age. The free radical theory of aging provides reasonable explanations for age-associated phenomena, including (i) the relationship of the average life spans of mammalian species to their basal metabolic rates, (ii) the clustering of degenerative diseases in the terminal part of the life span, (iii) the beneficial effect of food restriction on life span, (iv) the greater longevity of females, and (v) the increase in autoimmune manifestations with age. It is not unreasonable to expect on the basis of present data that the healthy life span can be increased by 5-10 or more years by keeping body weight down, at a level compatible with a sense of well-being, while ingesting diets adequate in essential nutrients but designed to minimize random free radical reactions in the body.

https://www.pnas.org/content/pnas/78/11/7124.full.pdf

The aging process

Evidence from many sources shows that the control of gene expression in higher organisms is related to the methylation of cytosine in DNA, and that the pattern of methylation is inherited. Loss of methylation, which can result from DNA damage, will lead to heritable abnormalities in gene expression, and these may be important in oncogenesis and aging. Transformed permanent lines often lose gene activity through de novo methylation. It is proposed that epigenetic defects in germline cells due to loss of methylation can be repaired by recombination at meiosis but that some are transmitted to offspring.

https://science.sciencemag.org/content/sci/238/4824/163.full.pdf

The inheritance of epigenetic defects.

Free radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. This phenomenon is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Past improvements in general living conditions have decreased the chances for death so that they are now near limiting values in the developed countries. In these countries the intrinsic aging process is the major cause of disease and death after about age 28. The free radical theory of aging postulates that aging changes are caused by free radical reactions. The data supporting this theory indicate that average life expectancy at birth may be increased by 5 or more years, by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.

Free radical theory of aging.

The aging process.

Scrapie is a slowly developing disease of the nervous system. Experiments on the effects of ultra-violet irradiation of suspensions of infected mouse brain extracts confirm that the agent responsible for it does not depend on a nucleic acid for its ability to replicate. No evidence is obtained, however, to indicate whether the agent is associated with a protein.

Does the Agent of Scrapie Replicate without Nucleic Acid

THE relation between the long-term effects of radiation and ageing has been the subject of much investigation in recent years, but little quantitative work has been done on the variation with age of the effects produced by a given dose of radiation. Using a single dose, Abrams1 found a maximum mortality-rate in mice 4 weeks old. Hursh and Casarett2 measured the LD50 in rats of different ages, and found a decrease with age in the latter period of life ; somewhat similar results were obtained by Sacher3 for mice. We are carrying out a systematic study4 of the long-term effects of radiation in mice, with particular reference to the dependence of these effects on age. As part of this work, we have investigated the variation of sensitivity with age, using as a criterion of radiation damage the LD50 at 30 days.

Variation of sensitivity to ionizing radiation with age.

The causes of death in mice exposed at the age of 30 days to a single whole-body dose of 15 MeV X-rays have been analyzed from the point of view of both percentage incidence and distribution in time. Ten groups of death causes were used, based on post-mortem findings. In the lower dose groups (50 to 457 r), the percentage incidence was found, in most cases, to vary very little with dose, but some diseases, e. g. leukaemia, did show a definite increase, and others, e. g. pulmonary tumours, a definite decrease with increasing dose. The changes in incidence were linearly related to the dose. The analysis of survival curves for each cause of death separately has revealed that while all causes were advanced by radiation, some were advanced more than others. A definite correlation was found between the acceleration of a given cause of death and the rate of change of the percentage incidence with dose. This suggests that the change of incidence is merely the result of the changed times of onset of disease; an actuarial correction has confirmed this suggestion. It is concluded that the probability of any one disease occurring remains the same in irradiated as in the control animals, the main effect of the radiation being an advancement, at different rates, of all causes of death. The age of the animal at irradiation may be an important factor in deter­mining the relative acceleration of the different diseases. In the high dose groups (549 to 780 r) a definite decrease in incidence of neoplastic diseases has been established. This may be due to a 4 9radiotherapeutic’ effect in cells which later in life might have become manifest as neoplasms.

Long-term effects of a single whole-body exposure of mice to ionizing radiations - II. Causes of death

A systematic study has been made of the reduction of life span in mice exposed to a single whole-body dose of 15 MeV X-rays. 4604 mice of an inbred A substrain were used, all of the same age, 30 days, when irradiated. Nine dose groups, from 50 to 780 r, were used, with a large number of control mice, which were kept to the end of their lives under the same conditions as the irradiated animals. An analysis of the survival curves has revealed two effects of radiation: a reduction in the median age and an increase in standard deviation of the distribution of ages at death. The latter was found to be a quadratic function of dose and it is suggested that the increase is the result of the larger spread in the ages of onset of diseases in irradiated animals. The reduction of life span was found to be proportional to dose, with no threshold. It amounts to 5∙66 ± 0∙18 weeks per 100 r, or to 38 % of the median life span for a dose equal to the LD 50 (698 r). The difference between the life-shortening in males and females was not statistically significant. The data have also been analyzed in terms of Gompertz plots and it was found that they cannot be represented by straight lines, although the displacement of the curves caused by radiation is roughly proportional to dose. The fact that after correcting for the change in standard deviation, all survival curves are parallel to each other, suggests that the effect of exposure is to ‘age9 the animal, by the removal of a few weeks of its early life.

Long-Term Effects of a Single Whole-Body Exposure of Mice to Ionizing Radiations. I. Life-Shortening

Mammalian Cytogenetics and Related Problems in Radiobiology

Results are reported from a systematic investigation on the reduction of life-span and causes of death in mice exposed at the age of 30 days to a single whole-body dose of 15-Mev x radiation. Dose levels ranged from 100 to 800 r. A quantithtive relation was demonstrated between shortening of life and dose. A full post-mortem examination was carried out on each animal that died to try to estublish the cause of death. It was concluded that the shortening of life produced by radiation is due to the hastening of all causes of death rather than the induction of a specific disease. (C.H.)

Patricia J. Lindop

Papers

Variation of sensitivity to ionizing radiation with age.

Long-term effects of a single whole-body exposure of mice to ionizing radiations - II. Causes of death

Long-Term Effects of a Single Whole-Body Exposure of Mice to Ionizing Radiations. I. Life-Shortening

Mammalian Cytogenetics and Related Problems in Radiobiology

Shortening of life and causes of death in mice exposed to a single whole-body dose of radiation.