Inconvenient Truths About Human Longevity.

The rise in human longevity is one of humanity's crowning achievements. Although advances in public health beginning in the 19th century initiated the rise in life expectancy, recent gains have been achieved by reducing death rates at middle and older ages. A debate about the future course of life expectancy has been ongoing for the last quarter century. Some suggest that historical trends in longevity will continue and radical life extension is either visible on the near horizon or it has already arrived; whereas others suggest there are biologically based limits to duration of life, and those limits are being approached now. In "inconvenient truths about human longevity" we lay out the line of reasoning and evidence for why there are limits to human longevity; why predictions of radical life extension are unlikely to be forthcoming; why health extension should supplant life extension as the primary goal of medicine and public health; and why promoting advances in aging biology may allow humanity to break through biological barriers that influence both life span and health span, allowing for a welcome extension of the period of healthy life, a compression of morbidity, but only a marginal further increase in life expectancy.

Cardiovascular effects of fission neutron or 60Co γ exposure in the B6CF1 mouse.

In this study, the B6CF1 mice from the JANUS program at the Argonne National Laboratory were analyzed for increased cardiovascular disease (CVD) mortality from 60Co γ ray or fission neutron exposures administered in either a single dose or protracted weekly doses. The data used for this study represent the last studies conducted at Argonne and have been archived for at least 15 years. CVD mortality increased in a dose-dependent manner from γ rays as well as from neutron exposures. The relative biological effectiveness (RBE) for neutrons is about 4 or 5. CVD mortality appeared to be enhanced when the dose was protracted, with a DDREF (dose and dose rate effectiveness factor) in the range of 0.4-0.45 for neutron and gamma ray exposure, respectively.

Primary Prevention with a Capital P.

The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine, but in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from chronic fatal diseases has declined, but even if it continues to do so in the future, the resulting longevity benefits are likely to diminish. It is even possible that unhealthy life expectancy could rise in the future as major fatal diseases wane. The reason for this is that the longer we live, the greater the influence of biological aging on the expression of fatal and disabling diseases. Research in gerontology has already demonstrated that aging is inherently modifiable, and that a therapeutic intervention that slows aging in people is a plausible target for science and public health. Given the speed with which population aging is progressing and chronic fatal and disabling conditions are challenging health-care costs across the globe, the case is now being made that delayed aging could be one of the most efficient and promising ways to combat disease, extend healthy life, compress morbidity, and reduce health-care costs.

Can Any Biomarker Predict the Temporal Behavior of Aging?

Journals are filled with articles describing the creation of physiological biomarkers whose temporal behavior is attributed to aging. This paper explores whether it is even possible to create a biomarker capable of describing the temporal mortality dynamics of aging. Just as Medawar referred to aging as an unsolved problem in biology in his classic 1951 lecture, this article suggests that aging remains an unresolved problem in gerontology. The argument is also made that biomarkers of any biological phenomenon must be derived from the logic of an evidence-based conceptual framework or paradigm. As such, the variables used to construct a dataset for quantitative analysis must be related to the subject of interest. It is, therefore, unclear whether a database designed to study disease contains the variables needed to study the mortality dynamics of aging and its biomedical consequences.

Genetic variation in the raptor gene is associated with overweight but not hypertension in American men of Japanese ancestry.

BACKGROUND: The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associated protein of mTOR complex I (Raptor) is a unique component of this pro-growth complex. The present study tested whether variation across the raptor gene (RPTOR) is associated with overweight and hypertension. METHODS: We tested 61 common (allele frequency ≥ 0.1) tagging single nucleotide polymorphisms (SNPs) that captured most of the genetic variation across RPTOR in 374 subjects of normal lifespan and 439 subjects with a lifespan exceeding 95 years for association with overweight/obesity, essential hypertension, and isolated systolic hypertension. Subjects were drawn from the Honolulu Heart Program, a homogeneous population of American men of Japanese ancestry, well characterized for phenotypes relevant to conditions of aging. Hypertension status was ascertained when subjects were 45-68 years old. Statistical evaluation involved contingency table analysis, logistic regression, and the powerful method of recursive partitioning. RESULTS: After analysis of RPTOR genotypes by each statistical approach, we found no significant association between genetic variation in RPTOR and either essential hypertension or isolated systolic hypertension. Models generated by recursive partitioning analysis showed that RPTOR SNPs significantly enhanced the ability of the model to accurately assign individuals to either the overweight/obese or the non-overweight/obese groups (P = 0.008 by 1-tailed Z test). CONCLUSION: Common genetic variation in RPTOR is associated with overweight/obesity but does not discernibly contribute to either essential hypertension or isolated systolic hypertension in the population studied.

How long must humans live?

Species are defined by biological criteria. This characterization, however, misses the most unique aspect of our species; namely, an ability to invent technologies that reduce mortality risks. Old animals are rare in nature, but survival to old age has become commonplace in humans. Science now asks how long can humans live, but we suggest a more appropriate question is: How long must humans live? Three lines of evidence are used to identify the biological equivalent of a warranty period for humans and why it exists. The effective end of reproduction, the age when the sex ratio is unity, and the acceleration of mortality reveal that approximately 50-55 years is sufficient time for our species to achieve its biological mandate-Darwinian fitness. Identifying this boundary is biomedically important because it represents a transition from expected health and vigor to a period when health and vigor become progressively harder to maintain.

Impact of climate change on elder health.

Demographers predict human life expectancy will continue to increase over the coming century. These forecasts are based on two critical assumptions: advances in medical technology will continue apace and the environment that sustains us will remain unchanged. The consensus of the scientific community is that human activity contributes to global climate change. That change will degrade air and water quality, and global temperature could rise 11.5°F by 2100. If nothing is done to alter this climatic trajectory, humans will be confronted by a broad spectrum of radical environmental challenges. Historically, children and the elderly adults account for most of the death toll during times of severe environmental stress. This article makes an assessment from a geriatric viewpoint of the adverse health consequences that global climate change will bring to the older segments of future populations in the United States.

Science fact versus SENS foreseeable.

Scientists in the various fields of aging share a common goal--the extension of healthy life. However, claiming that the only way to accomplish this is to treat the complications of aging rather than its causes requires more than declarations made by proponents of SENS--it requires empirical research based on the scientific method. As this paper illustrates, it will be difficult to prove that SENS interventions work because the primary result of interest, negligible senescence, is not an outcome variable in empirical tests of SENS.

Zeno's Paradox of Immortality.

Scientists who speculate on the future of human longevity have a broad range of views ranging from the promise of immortality, to radical life extension, to declines in life expectancy. Among those who contend that radical life extension is already here, or on the horizon, or immortality is forthcoming, elements of their reasoning appear surprisingly close, if not identical, to a famous mathematical paradox posed by the ancient Greek mathematician known as Zeno. Here we examine the underlying assumptions behind the views that much longer life expectancies are forthcoming or have already arrived, and place their line of reasoning within the context of a new Zeno paradox described here as The Paradox of Immortality.

Differences in life expectancy due to race and educational differences are widening, and many may not catch up.

It has long been known that despite well-documented improvements in longevity for most Americans, alarming disparities persist among racial groups and between the well-educated and those with less education. In this article we update estimates of the impact of race and education on past and present life expectancy, examine trends in disparities from 1990 through 2008, and place observed disparities in the context of a rapidly aging society that is emerging at a time of optimism about the next revolution in longevity. We found that in 2008 US adult men and women with fewer than twelve years of education had life expectancies not much better than those of all adults in the 1950s and 1960s. When race and education are combined, the disparity is even more striking. In 2008 white US men and women with 16 years or more of schooling had life expectancies far greater than black Americans with fewer than 12 years of education-14.2 years more for white men than black men, and 10.3 years more for white women than black women. These gaps have widened over time and have led to at least two "Americas," if not multiple others, in terms of life expectancy, demarcated by level of education and racial-group membership. The message for policy makers is clear: implement educational enhancements at young, middle, and older ages for people of all races, to reduce the large gap in health and longevity that persists today.

The delayed impact of parental age on offspring mortality in mice.

The certitude of death makes reproduction the foundation upon which all life-history strategies are based. Plasticity in the reproductive biology of organisms is an essential adaptive response to the capricious and hazardous environments of earth. In this article, we use data from a breeding colony for laboratory mice to examine the mortality risks of offspring born at the outer boundaries of their Dam's reproductive plasticity. Our results suggest that the mortality/survival characteristics of offspring are affected by both litter parity and offspring gender. Females born to young Dams have consistently longer life spans than females born to older Dams. Conversely, males are either not affected by parental age or have longer life spans when born to older Dams.

What is lifespan regulation and why does it exist?

The development of a unified conceptual framework for the field of biogerontology has been impeded by confusing and misleading terminology. Thus, distinctions and definitions are provided for key terms (and their concepts) used in the paper: senescence, lifespan, potential lifespan, essential lifespan, and lifespan regulation. An organismal perspective is then used to examine the relationships between reproduction, lifespan regulation and senescence. The principal conclusions drawn from this examination are: (1) the inevitability of death makes physiological investments in reproduction a higher priority than somatic maintenance, (2) the race between reproduction and death creates a probabilistic window of time (essential lifespan) within which reproduction must occur, (3) the integrated network of genetic processes responsible for achieving essential lifespan (lifespan regulation) must be evolutionarily conserved and extensively regulated, (4) senescence is a stochastic byproduct of these regulated processes rather than a direct target of natural selection, and (5) genomic instability (an important stochastic component of senescence) plays no active role in lifespan regulation.

Does senescence give rise to disease?

The distinctions between senescence and disease are blurred in the literature of evolutionary biology, biodemography, biogerontology and medicine. Theories of senescence that have emerged over the past several decades are based on the concepts that organisms are a byproduct of imperfect structural designs built with imperfect materials and maintained by imperfect processes. Senescence is a complex mixture of processes rather than a monolithic process. Senescence and disease have overlapping biological consequences. Senescence gives rise to disease, but disease does not give rise to senescence. Current data indicate that treatment of disease can delay the age of death but there are no convincing data that these interventions alter senescence. An understanding of these basic tenets suggests that there are biological limits to duration of life and the life expectancy of populations and reveal biological domains where the development of interventions and/or treatments may modulate senescence.

Senescence viewed through the lens of comparative biology.

Although mortality and longevity are inherently biological phenomena, their study has historically been the purview of demography and the actuarial sciences. An infusion of biological thinking into these disciplines transforms demography into biodemography and provides expectations and coherency to observations on age-determined mortality that would not be explainable otherwise. Comparative biology teaches us that reproduction is life's solution to the inevitability of death in the hostile environments of Earth. That solution, however, places a higher priority on investing physiological resources into reproduction that could otherwise have been used to maintain the soma (body) longer. As such, aging is an inescapable but inadvertent byproduct of imperfect maintenance and its attendant surveillance and repair. Biology also reveals that while bodies are not designed to fail, neither are they designed for extended operation. In other words, bodies are subject to biological warranty periods for normal operation. For sexually reproducing species, that warranty period includes the time from conception to sexual maturity, the production and nurturing of offspring, and a period of grand-parenting in some species. Humans are the only species capable of exploiting the loophole in the biological contract of life (bodies that are not designed to fail). Human ingenuity (science, medicine, public health) has produced interventions that manufacture survival time by delaying death, and in so doing, has created a phenomenon never before seen in the history of life-population aging (and all the societal and health consequences that go with it).

Mortality partitions and their relevance to research on senescence.

The reasons for classifying causes of death into aggregate groups are discussed and the impact of mortality partitions on analyses of mortality is described. Special emphasis is given to a mortality partition that distinguishes between intrinsic causes of death that arise primarily from the failure of biological processes that originate within an organism, and extrinsic causes of death that are primarily imposed on the organism by outside forces. Examples involving mortality data for mice, dogs, and humans are used to illustrate how this mortality partition infuses biological reasoning into mathematical models used to analyze and predict senescent-determined mortality, enhances the information content of the mortality schedules generated from these models, improves mortality comparisons between populations within species separated by time or geographic location, and provides a logical pathology endpoint for making interspecies comparisons of mortality. By bridging biology and the statistics of mortality, a mortality partition based on intrinsic and extrinsic causes of death provides both structure and direction for research on senescent-determined mortality.

Health promotion in older adults. Promoting successful aging in primary care settings.

The ultimate objective of the successful aging paradigm is to improve the quality of life among the elderly. Although the aging process is currently immutable, primary care providers can modify the pathology and mitigate the expression of disease through prevention and treatment. Avoiding disease and disability, maintaining mental function and maintaining physical function are cornerstones of this approach. Recommendations about eating right, eating less, and exercising more are to make , but they are not easy to adopt for geriatric patients. Our elderly patients need far more physician mentoring and guidance in order to attain the goal of a healthier and higher quality of life that is implied by strategies for successful aging.

Biodemographic perspectives for epidemiologists.

A new scientific discipline arose in the late 20th century known as biodemography. When applied to aging, biodemography is the scientific study of common age patterns and causes of death observed among humans and other sexually reproducing species and the biological forces that contribute to them. Biodemography is interdisciplinary, involving a combination of the population sciences and such fields as molecular and evolutionary biology. Researchers in this emerging field have discovered attributes of aging and death in humans that may very well change the way epidemiologists view and study the causes and expression of disease. In this paper, the biodemography of aging is introduced in light of traditional epidemiologic models of disease causation and death.