Natural Lifespan Research Articles

Multiple Deletions Are Detectable in Mitochondrial DNA of Aging Mice

Mutational damage to human mitochondrial DNA (mtDNA) can cause disorders in oxidative phosphorylation; speculation that such damage is involved in degenerative diseases and aging is common. We have detected deletions in mouse mtDNA which resemble those found in elderly humans or patients with certain mtDNA disorders. Five different mtDNA deletions, predicted from the positions of short, direct DNA repeats, were present in aged, but not young, mice. Deleted regions were surrounded by either exact or inexact repeats and occurred in both the major and minor regions of the mtDNA genome. The abundance of a particular deletion was generally related to the thermodynamic stability of the bounding repeat sequence. Deletions in aged mice were present at low levels (less than 0.01% of total mtDNA). However, in contrast to results from aged humans, deletions were more abundant in liver than in brain, heart, or skeletal muscle. These results make it possible to predict the location and relative abundance of deletions in any sequenced mtDNA, including inbred mouse strains differing in inherent natural lifespan. The inbred mouse model will allow a critical examination of the relationship between the presence and abundance of mtDNA deletions and the aging process.

Reduced tumour incidence in mice with inherited seborrhoeic dermatitis.

121 mice homozygous for the gene seb (inherited seborrhoeic dermatitis) and their 142 unaffected heterozygous littermates were kept for their natural lifespan. Heterozygotes showed 84.1% total tumour incidence in males and 95.9% in females. The most common neoplasms were lymphomas, osteomas, lung tumours and neoplasms of the female genital tract. Homozygotes showed a tumour incidence of 36.1% in males and 45.0% in females. The reduction in incidence included all types of neoplasms except epithelial tumours of the skin: skin tumours were detected in 11 homozygous but only in one heterozygous animal. Life expectancy was not affected significantly by genotype. Homozygous mice showed rough and greasy fur and became alopecic with age. Energy intake was increased but growth and depository fat was reduced compared with heterozygous mice. Higher heat loss may incompletely be compensated by higher metabolic rate and thus 'dietary restriction' results in decreased tumour rates. As females show small gonads and a higher increase in food consumption hormonal factors may also be involved.

Genetic material donation: sperm, oocyte, pre-embryo

Genetic material donation has become an integral part of the management of infertility. Sperm, oocyte and pre-embryo donation are medical and technical successful procedures, undertaken to deliberately procure the creation of a child. By application of the modern assisted reproductive technologies (ART), it is the adult's interests which are upheld. This does not necessarily imply that those interests apply also to the resulting offspring. Therefore, practice of genetic material donation raises ethical, legal, religious and social issues, which are discussed. The practice of gametes and pre-embryo donation is opposed by the main religions. The medical problems are related mainly to selection of donors, evaluation of recipients and quality control of the genetic material. The relationship between the biological and social parents and safeguarding the interest of the offspring, may be resolved by legislation pertaining to the individual country. Sperm and pre-embryo banks should be subjected to licensing and should not be run by a commercial system. The donated genetic material should not be used to extend the natural reproductive life span. By practicing sperm, oocyte and pre-embryo donation the medical profession and society should consider not only the interests of the infertile couple but the interests of the offspring as well.

Facing limits: ethics and health care for the elderly

Proposals to limit care: intolerable necessity - limiting health care for the elderly, Daniel Callahan intergenerational equity in an age of limits, Richard D. Lamm. Philosophical foundations: a philosophy of finitude, ethics and the humanities in the allocation of resources, Edmund D. Pellegrino ethical options in the care of the elderly, J. Wesley Robb natural life span and natural law ethics, Anthony Battaglia. Clinical perspectives: surrogate decisions for nursing home patients, Jeanie Kayser-Jones the appropriateness of life-sustaining care for older people, Donald J. Murphy can we set limits and enhance autonomy?, Lawrence J. Schneiderman. Economics and public policy: is global budgeting the way to set limits on health care for the elderly, Michael D. Reagan counting the cost of lifesaving interventions for the elderly, Paul T. Menzel cost containment and conflicts of interest in the care of the elderly, Charles E. Begley changing the debate about health care for the elderly, Edward L. Schneider. Gender, equity, and distributive justice: achieving equity and setting limits - the importance of gender, Bethany Spielman ageism and sexism in the care of the elderly - why we need old women in power, Emily Erwin Culpepper how age should matter - justice as the basis for limiting care to the elderly, Gerald R. Winslow. Personal autonomy and social values: personal choice and public rationing, Judith Wilson Ross imposing limits or changing attitudes? - strategies for change, Marilyn Moon old age and euthanasia - a theological and personal perspective, John C. Bennett ethics and aging - Callahan and beyond, James W. Walters.

Death, suicide and the older adult.

Elderly people who are at high risk for suicide often have characteristics that are associated with reduced opportunity or inclination to communicate (e.g., male, living alone, residing in a low-income transient urban area, suffering from a depressive state). This paper attempts to provide converging perspectives on death and suicide from the standpoints of both the external observer and the elderly person. An interpretation of the statistical pattern is followed by a critique of current policy proposals for limiting society's response to the needs of vulnerable people on the basis of a "natural life span." Studies of elderly people themselves reveal a great diversity of attitudes toward death that is not well served by generalizations and stereotypes. However, it appears that stressful conditions of life arouse more anxiety among older people than does the prospect of death.

How to prevent the retiring brain from degenerating

In organs other than the brain, cell activation seems to increase “wear and tear”, e.g. by increased free-radical formation, and so to cause an increased rate of aging. However, activation of nerve cells within the physiological range seems to lead to maintenance of neurons during aging, possibly by preferentially stimulating the action of protective mechanisms such as DNA repair. This “use it or lose it” principle might explain why in aging and neurodegeaerative diseases certain neurons degenerate while others do not, and why recovery of various neuronal systems during aging has been obtained by restoration of the missing stimulus. Consequently, neuronal activation might provide a means of prolonging its optimal function for the full length of our natural life span, also following retirement.

Budget-constrained maintenance in the building industry

Given records of building component renewals which occurred during the year and also theage profile of the building stock, the theory of alternating renewal processes in discrete time is used to deduce the underlying probability mass functions of the natural lifespan of building components and of delay due to limited resource. In an investigation into the economics of renewal delay, the expected number of component renewals in each year of the life of a building is deduced from the convolutions of the probability mass function of natural lifespan: these expected numbers depend on the chosen delay. The nett present value of the expected cost associated with each specified delay is calculated, so that a judgement can be made as to the optimum delay (if any). These calculations are conveniently performed using a spreadsheet macro.

Aging: Setting Limits Within a Christian Vision: A Theology of the Paschal Mystery

ABSTRACT Daniel Callahan, in his provocative book Setting Limits, Medical Goals in an Aging Society, has affirmed that in a period of declining resources, it should be the function of medicine to help elderly to achieve a natural and fitting life span, and has invited the elderly to set limits to their demands. “To set limits” in a cultural context marked by frenzied consumerism, and a discriminatory attitude toward aging is to demand of the elderly what no one else is willing to do. What is needed for the “setting of limits” is a frame of reference where loss and negativity can be accepted without despair. In the Paschal Mystery Christianity provides us with a model of humanhood where the letting go of power and the acceptance of creatureliness are predominant characteristics. Disengagement is not simply for the end of the life cycle, but on-going from the beginning.

Old Age and New Policy

To the Editor.— The medical profession is well aware of governmental and societal needs to contain the cost of providing care to the American population. However, recent commentary by Dr Callahan1attempts to create new meaning for geriatric care under the guise of cost containment and allocation of resources. Franz Kafka could not have portrayed more ominous view of our society than Dr Callahan when he proposed a flat age limitation on the most expensive forms of life-extending care. We are not homogeneous society. Any physician actively participating in the care of our geriatric segment of the population can attest to the fact that some 85-year-olds are more productive and functional than some of our 60-year-olds, who may have reached the end of their natural life span in the sense of our common biographies. To follow Dr Callahan's train of thought, the next segment of

Interspecies Scaling of Risk for Radiation-induced Bone Cancer

The induction of bone cancer in mice, dogs and humans, due to protracted alpha-irradiation from skeletal burdens of radium, was found to be represented by a single dose-rate/time/response function, when time was normalized with respect to species natural life-span. In the absence of other causes of death, the median time to death from bone cancer after 226Ra intake is given by tm* = 790-d*-0.29, based on the dog data, with -d* the time-weighted average absorbed dose rate in cGy/mLSF to skeleton and where time is measured as milli-life-span-fraction. On the basis of life-span scaling of the time dimension, data on cancer induction from studies with laboratory animals can be scaled to estimate human risks in a three-step process involving a three-dimensional analysis. The overall cancer risk distribution is shown to be a mountain-like surface rising from a Euclidean plane formed by the dose rate and survival time co-ordinates. At lower dose rates the time required for cancer induction may exceed the natural life-span yielding a quasi-threshold for cancer risk. For intakes of 226Ra in young adults this quasi-threshold is predicted to occur at a cumulative life-time alpha-radiation dose to the skeleton of about 1 Gy.

RATIONING HEALTH CARE: Should it Be Done?

1. The utilitarian view supports allocation of goods to meet the needs of the greatest number of people; Lamm contends that the only just rationing would be according to age. 2. Some theorists assume that all individuals will live relatively healthily until the end of their natural lifespan; they do not distinguish between therapeutic medications and those that alleviate suffering. 3. According to intergenerational arguments, children should receive priority in funding, with the elderly at the lower end of the scale. 4. The Advisory Panel of the Office of Technology Assessment recommends rationing based on prognosis and quality of life; however, good prognostic skills are lacking and there is no consensus on quality of life.

Scaling of fatal cancer risks from laboratory animals to man.

The functionally injurious and carcinogenic responses after exposure to 226Ra in mice, beagles, and people are reviewed. The observed bone-cancer response ratios from beagle data are used for examples of scaling carcinogenic risks to man for inhaled 239PuO2 and, in a similar manner, those from rat data are used for ingestion of diethylnitrosamine. Scaling fatal cancer risks from laboratory animal data to human risk predictions is described as a three-step process involving a three-dimensional analysis. The three dimensions used in this study for chronic exposure to chemical toxicants or ionizing radiation are average dose rate to target tissue (proportional to tissue concentration), elapsed time, and risk. The first step involves determination of dose rate delivered to target tissues. The second step is evaluation of the independent dose-response relationships observed in animals and prediction of human risk distributions by normalizing time units with respect to species natural life span. The third step involves predicting induced cancer occurrence (dependent risk) using the convolution integral for each of the competing risks, including those associated with natural life span. The use of computer graphics in conjunction with three-dimensional models of dose-response relationships dramatically clarifies the separate and interactive roles of competing risks. Low dose rates result in spontaneous deaths from natural aging, yielding a quasi-threshold for fatal induced cancer.

Influence of age at exposure on concentrations of 239Pu in beagle gonads.

The influence of age at injection of 239Pu on the gonadal concentrations with time after injection in beagle dogs was determined. In addition, the distribution patterns of Pu within the organs were examined using fission track autoradiography. Beagles of different ages (juveniles approximately 90 d; young adults approximately 17 mo; aged approximately 5 y) were given a single injection of 239Pu(IV)-citrate and most were allowed to live out their natural lifespan. At times greater than 1,000 d after exposure, the concentrations of 239Pu (expressed as percent injected per gram organ weight) were higher in the testes and ovaries from animals injected as young adults (median 9.8 X 10(-4) and 15.4 X 10(-4%) g-1, respectively) when compared with the juveniles (median 2.8 X 10(-4) and 7.7 X 10(-4%) g-1, respectively) or aged (median 6.3 X 10(-4) and 17.2 X 10(-4%) g-1, respectively) animals. The lower concentrations found in the animals injected as juveniles can be attributed to the increase in gonadal size that occurs during organ maturation and puberty. Fission track autoradiographs from gonadal tissues at least 5 y after exposure confirm the nonuniform distribution of the nuclide in these organs. In the testis, Pu was found mostly in the interstitial tissues and in the ovary, was found in the stroma, particularly the medullary stroma.

Growth of the Eastern Atlantic squid, Loligo forbesi Steenstrup (Mollusca: Cephalopoda)

Abstract. Loligo forbesi Steenstrup is a commercially and biomedically important species raneing from Scotland to North Africa and from the Azores Islands in the central Atlantic east through the Mediterranean Sea and Red Sea. Eggs were collected from Plymouth. England and from the Azores and the hatchlings were reared to adult size in recirculating seawater systems. Growth data were obtained primarily from mortalities during the course of three culture experiments which lasted 360, 240 and 480 days. Loligo forbesi hatched at a size of 5–9mg (3.0–4.6mm mantle length, ML) and grew to a maximum size of 124g (155 mm ML) in 413 days. In all experiments, growth was exponential in form for at least the first 3 months at rales of 5.8, 5.1 and 3.6% body weight per day (BW/d) at mean temperatures of 14.1, 14.0 and 13.1°C respectively. In one short-term experiment, month-old squids grew at 8.0% BW/d at 17.4°C. Growth beyond 3 months was slower and either logarithmic (as described by the power function) or exponential in form. Growth rates gradually declined to 1–2% BW/d, Analyses of mantle length growth confirmed the wet weight results. There was no evidence of sexual dimorphism in the laboratory populations, which were of small size, and the length-weight (L-W) relationships were found to be similar to those of field populations. Growth rates during the exponential growth phase appeared very sensitive to temperature, with a 1°C difference changing growth rate by 2% BW/d and producing a three-fold difference in weight at 90 days post-hatching. These dramatic effects of temperature on adult size and lifespan in nature are discussed. It is hypothesized that the small size of mature laboratory-reared squids was due to low culture temperatures during the first 3 months.

Investigations into the genotoxic potential of loxtidine, a long-acting H2-receptor antagonist.

Loxtidine, a potent, non-competitive histamine H2-receptor antagonist was evaluated for genotoxic potential using a range of short-term mutagenicity assays. Unequivocally negative results were obtained in a Salmonella/plate incorporation assay and a liquid pre-incubation assay (using S. typhimurium strains TA1535, TA100, TA1537, TA1538 and TA98), a fluctuation assay [using Escherichia coli strains WP2, WP2 uvrA (R46) and 343/113 lys60 (R46)], a gene conversion assay (using Saccharomyces cerevisiae JD1) and a human peripheral lymphocyte cytogenetic assay. All of these in vitro tests were carried out in the presence and absence of rat liver S9 mix. In addition, the major metabolites of loxtidine in the rat were also negative in the same range of microbial mutagenicity assays. Loxtidine was inactive in the mouse micronucleus test after oral administration. The potential nitrosatability of loxtidine was investigated using an expanded version of the WHO Nitrosation Assay Procedure, and detectable quantities of mutagenic nitroso-species were not formed. The subsequent appearance of carcinoid tumours within the gastric fundus of rodents treated orally with loxtidine for most of their natural lifespan, led to additional assays being carried out on this compound to determine whether the tumorigenic effects were due to alternative mutagenic mechanisms. Negative results were obtained in an in vitro unscheduled DNA synthesis assay using primary rat hepatocytes, and an assay for spindle damaging agents using Muntjac skin fibroblasts. It can be concluded from these results that loxtidine is unlikely to be a genotoxic carcinogen. The increase in carcinoid tumour incidence observed in rats and mice after loxtidine treatment was probably related to the prolonged achlorhydria produced by this potent unsurmountable histamine H2-receptor antagonist.

Three-dimensional dose-response models of competing risks and natural life span

Three-dimensional dose-rate/time/response surfaces for chronic exposure to carcinogens, toxicants, and ionizing radiation dramatically clarify the separate and interactive roles of competing risks. The three dimensions are average dose rate, exposure time, and risk. An illustration with computer graphics shows the contributions with the passage of time of the competing risks of death from radiation pneumonitis/fibrosis, lung cancer, and natural aging consequent to the inhalation of plutonium-239 dioxide by beagles. These relationships are further evaluated by mathematical stripping with three-dimensional illustrations that graphically show the resultant separate contribution of each fatal effect. Radiation pneumonitis predominates at high dose rates and lung cancer at intermediate dose rates. Low dose rates result in spontaneous deaths from natural aging, yielding a type of practical threshold for lung cancer induction. Risk assessment is benefited by the insights that become apparent with these three-dimensional models. The improved conceptualization afforded by them contributes to the planning and evaluation of epidemiological analyses and experimental studies involving chronic exposure to toxicants.

Morphometric analysis of cardiac hypertrophy during development, maturation, and senescence in spontaneously hypertensive rats.

Hypertrophy of the mammalian heart, regardless of the initiating event, results in architectural remodeling of ventricular components that maintain structural and functional characteristics of this organ. Ventricular components that vary their morphology and morphometry in a hypertrophic state are the muscle cells, connective tissue elements, vasculature, or a combination of some or all of the above. Morphologic quantification of the progressive tissue changes occurring throughout the natural life span of the spontaneously hypertensive and normotensive Wistar-Kyoto rats has not been thoroughly documented. Using perfused-fixed tissue from both strains at 1, 6, 12, 18, and 24 months of age, we have determined the morphometric changes that occurred in the subepicardial and midwall regions of the left ventricle. Myocyte cell size, wall thickness, and arterial blood pressure were elevated in 1-month-old spontaneously hypertensive rats, reached significance by 6 months, and remained significantly greater throughout the 24 months examined. Tissue morphometry demonstrated significant tissue component volumetric differences at 6 months in the spontaneously hypertensive rat. Age-related morphometric tissue changes occurred in both strains yet were exacerbated (percent volume of myocytes) or diminished (percent volume interstitial space) in the mature and aging spontaneously hypertensive rat. Capillary density of SHR left ventricle showed a drastic decline so that 6-month-old SHR had the same density as a senescent Wistar-Kyoto. Tissue morphometry and capillary density data strongly support the hypothesis that tissue oxygenation is diminished in the spontaneously hypertensive rat, and as a result, tissue necrosis and myocyte cell death occur.

Three-Dimensional Dose–Response Models of Competing Risks and Natural Life Span

Three-Dimensional Dose–Response Models of Competing Risks and Natural Life Span. RAABE, O. G. (1987). Fundam. Appl. Toxicol. 8, 465–473. Three-dimensional dose-rate/time/response surfaces for chronic exposure to carcinogens, toxicants, and ionizing radiation dramatically clarify the separate and interactive roles of competing risks. The three dimensions are average dose rate, exposure time, and risk. An illustration with computer graphics shows the contributions with the passage of time of the competing risks of death from radiation pneumonitis/fibrosis, lung cancer, and natural aging consequent to the inhalation of plutonium-239 dioxide by beagles. These relationships are further evaluated by mathematical stripping with three-dimensional illustrations that graphically show the resultant separate contribution of each fatal effect. Radiation pneumonias predominates at high dose rates and lung cancer at intermediate dose rates. Low dose rates result in spontaneous deaths from natural aging, yielding a type of practical threshold for lung cancer induction. Risk assessment is benefited by the insights that become apparent with these three-dimensional models. The improved conceptualization afforded by them contributes to the planning and evaluation of epidemiological analyses and experimental studies involving chronic exposure to toxicants.

The histology and development of hepatic nodules in C3H/He mice following chronic administration of phenobarbitone

Male C3H/He mice were given 0 (control) or 85 mg/kg/day phenobarbitone (PB). Groups of five control and five treated animals were killed at 5, 10, 25, 40 and 55 weeks; additional animals were allowed to live out their natural life span or killed at the termination of the experiment at 100 weeks. Small nodules of basophilic cells were seen in control animals at 55 weeks. These increased both in size and number so that at term nodules were found in 17/35 animals examined. Animals given PB showed typical centrilobular hypertrophy. Basophilic nodules were also seen in the treated animals and these were similar in form and in number to those seen in control animals. The total number of liver nodules seen in animals given PB was, however, greater than the number seen in control animals. The increased nodule burden was a result of the development of a second nodule type that was first seen in animals killed at 40 weeks. These nodules were formed of large eosinophilic cells that had a similar appearance to the hypertrophied cells of the centrilobular region. In contrast the incidence of carcinoma in PB-treated animals was not increased over that of the control group.

Climacteric in women: An evolutionary defect?

This is a theoretical paper. Climacteric in women has two basic consequences: (i) Sterility, which is interpreted here as a positive feature, because it protects the older woman from the hardships of pregnancy. (ii) Hormonal deficiency, which is interpreted here as a negative feature, because it leads to deleterious changes in various parts of the body. Can these negative features be regarded as evolutionary defects? The answer is no, if the following points are considered. Through human innovations, women's natural lifespan of less than 30 years has been extended to almost 80 years. Had the lifespan not been manipulated, most women would not reach climacteric, which normally does not begin before the fourth decade of life. When interpreting climacteric as a phenomenon precipitated by man rather then by Nature, it follows that the negative features of climacteric should not be regarded as evolutionary defects.