Douglas Grahn

Biological evidence for limits to the duration of life

Projections of duration of life for humansbased on mathematical models have led someresearchers to claim that there is no lowerlimit to death rates or upper limit to lifeexpectancy, and that a life expectancy of 100will be achieved in the 21st century. Toassess the biological plausibility of theseclaims, we examined temporal aspects ofbiological phenomena in three mammalianspecies. Our examination revealed that: (1)physiological declines associated withreproduction consistently occur at ages thatare less than one-third of the median age atdeath, (2) physiological parameters associatedwith aging in humans lose eighty percent oftheir functional capacity by age 80, and (3)young versus old individuals can bedistinguished by the pathologies detected atdeath. The biological evidence suggests thatorganisms operate under warranty periods thatlimit the duration of life of individuals andthe life expectancy of populations. We usethese findings to discuss the issue of limitsto the duration of life and the validity ofmathematical models used to forecast humanlongevity.

Continuing the search for a law of mortality.

Scientists have long attempted to explain why closely similar age patterns of death are characteristic of highly diverse human and non human populations....Early efforts [to develop a general law of mortality] were conducted using mortality curves based on all causes of death. The authors predict that if comparisons of mortality are based instead on `intrinsic causes of death (i.e. deaths that reflect the basic biology of the organism) then age patterns of mortality consistent with the historical concept of a law might be revealed. Using data on laboratory animals and humans they demonstrate that age patterns of intrinsic mortality overlap when graphed on a biologically comparable time scale. These results are consistent with the existence of a law of mortality following sexual maturity as originally asserted by Benjamin Gompertz and Raymond Pearl. The societal medical and research implications of such a law are discussed. (SUMMARY IN SPA AND FRE) (EXCERPT)

Life shortening in mice exposed to fission neutrons and gamma rays I. Single and short-term fractionated exposures.

Quantitative dose-response relationships are presented for life shortening in mice from all causes of death after irradiation with 0.85-MeV fission neutrons or60 Co γ rays, delivered either in a si...

The Comparative Tumorigenic Effects of Fission Neutrons and Cobalt-60 γ Rays in the B6CF1 Mouse

In the period from 1971 to 1986, both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse were exposed at 110 +/- 7 days of age to single, 24 once-weekly or 60 once-weekly doses of fission neutrons or 60Co gamma rays. A small group of males was also exposed to gamma rays for 22 h/day, 5 days/week, for either 23 or 59 weeks, the elapsed times for the 24 and 60 once-weekly series. All mice were followed for their natural lifetimes. A gross pathology report is available on 32,000 animals, and a histopathology record is available on about 19,000. About 85% died with or from one or more neoplastic diseases. The principal tumors observed at death were of lymphoreticular (45-60%), vascular (20%), or pulmonary (35-50%) origin. From 4 to 10% died with fibrosarcomas, hepatocellular tumors, ovarian tumors, and tumors of the Harderian, adrenal, and pituitary glands. Dose-response equations (linear and linear-quadratic) were fitted to the data for deaths from and occurrences of eight different individual or groups of tumors. Equations were constrained through the control intercepts and fitted separately for the two sexes, the two radiation qualities, and all exposure patterns for the two intervals of 600-799 days and 800-999 days from first exposure. RBE values were derived from the ratios of linear coefficients of dose-response curves. RBE values increased as dose was protracted, largely due to the reduced effectiveness of protracted gamma irradiation; however, about 28% of the increase can be attributed to the increase in neutron-induced injury caused by dose protraction. Highest RBE values were seen for tumors of epithelial tissue origin and the lowest for tumors of connective tissue origin. The range for significant values was from about 2 to over 50. Nonneoplastic diseases accounted for about 5% of all deaths, and 10% were classified as from unknown causes. Neither category responded to differences in radiation quality or exposure patterns.

Life shortening in mice exposed to fission neutrons and gamma rays II. Duration-of-life and long-term fractionated exposures.

Data are presented on the life shortening of

Dose-response modeling of life shortening in a retrospective analysis of the combined data from the JANUS program at Argonne National Laboratory.

{\rm B}6{\rm CF}_{1}

Effect of Daily Gamma-Irradiation on the Pigmentation of Mice'

mice given weekly exposures to 0.85-MeV fission neutrons (0.67, 1.67, 2.67 rad per weekly fraction) or60 Co γ rays (7, 17.4, 31.9 rad per weekly fraction) either for 60 exposures or for the duration of their lives. The life shortening produced by either the duration-of-life or the fractionated exposures was virtually identical, so the two series were treated as a single experiment. The relative biological effectiveness (RBE) for neutrons increased from 12 at 2.67 rad per weekly fraction to 21 at 0.67 rad per weekly fraction; over the dose ranges studied, the neutron RBE varied inversely with the -0.4 power of the dose. It is predicted that at 0.05 rad of neutrons per week, the RBE will approach 60 if weekly exposures to γ radiation are chosen as the reference; if continuous γ radiation is used as the reference, the RBE may be approximately twice as large. The data are generally consistent with those reported from othe...

Human Longevity: Nature vs. Nurture—Fact or Fiction

Life shortening was investigated in both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse exposed to fission neutrons and 60Co gamma rays. Three basic exposure patterns for both neutrons and gamma rays were compared: single exposures, 24 equal once-weekly exposures, and 60 equal once-weekly exposures. Ten different dose-response models were fitted to the data for animals exposed to neutrons. The response variable used for all dose-response modeling was mean after-survival. A simple linear model adequately described the response to neutrons for females and males at doses less than or equal to 80 cGy. At higher neutron dose levels a linear-quadratic equation was required to describe the life-shortening response. An effect of exposure pattern was observed prior to the detection of curvature in the dose response for neutrons and emerged as a potentially significant factor at neutron doses in the range of 40-60 cGy. Augmentation of neutron injury with dose protraction was observed in both sexes and began at doses as low as 60 cGy. The life-shortening response for all animals exposed to gamma rays (22-1918 cGy) was linear and inversely dependent upon the protraction period (1 day, 24 weeks, 60 weeks). Depending on the exposure pattern used for the gamma-ray baseline, relative biological effectiveness (RBE) values ranged from 6 to 43. Augmentation, because it occurred only at higher levels of neutron exposure, had no influence on the estimation of RBEm.

Life shortening in mice exposed to fission neutrons and gamma rays. V. Further studies with single low doses.

Ionizing radiations have been demonstrated to exert a dual action on mammalian melanocytes. They may bring about a selective destruction of melanocytes (1-3), or they may stimulate melanocytes either to begin melanin synthesis or to elaborate melanin at an increased rate (3, 4; H. B. Chase, personal communication). For the most part, previous studies of mammalian pigmentation have involved single exposures to Xor y-rays. Consequently, little is known concerning the effect that daily irradiation may have on mammalian melanocytes. During the course of survival studies it was observed that certain pigmented mice undergoing daily y-irradiation developed a marked hyperpigmentation of the extremities and, in some cases, a greying of the body hairs. Both phenomena are indicative of an underlying change at the cellular level-an alteration of melanocyte activity. The present paper deals with the fate of melanocytes during continued exposure to both Xand --rays, particularly with regard to the production of hyperpigmentation.

Life shortening in mice exposed to fission neutrons and. gamma. rays III. Neutron exposures of 5 and 10 rad

Genetic effects may have a greater influence on human longevity than biomedical intervention. An alternative perspective examines the heritability effects of genetic damage caused by free radicals within somatic cells, or genetic damage that accumulates over a lifetime.