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.

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.

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.

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.

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.

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.

A potential decline in life expectancy in the United States in the 21st century.

Forecasts of life expectancy are an important component of public policy that influence age-based entitlement programs such as Social Security and Medicare. Although the Social Security Administration recently raised its estimates of how long Americans are going to live in the 21st century, current trends in obesity in the United States suggest that these estimates may not be accurate. From our analysis of the effect of obesity on longevity, we conclude that the steady rise in life expectancy during the past two centuries may soon come to an end.

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).

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.

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.

Misdirection on the road to Shangri-La.

Will life expectancy in the United States rise or fall in this century? The implications of either scenario are far reaching. We contend that the rise of childhood obesity in the United States in the past three decades has been so dramatic that it will soon lead to higher than expected death rates at middle ages and a possible decline in life expectancy by midcentury. The most detrimental health and longevity effects will not be seen for decades--a phenomenon that cannot be detected by current methods used to forecast life expectancy or estimate the number of deaths currently attributable to obesity. This scenario contrasts sharply with the views of mathematical demographers who generate forecasts by relying on the assumption that the U.S. pattern of longevity will follow that of other longer lived nations and on the extrapolation of historical trends in life expectancy into the future.

Misdirection on the road to Shangri-La.

Will life expectancy in the United States rise or fall in this century? The implications of either scenario are far reaching. We contend that the rise of childhood obesity in the United States in the past three decades has been so dramatic that it will soon lead to higher than expected death rates at middle ages and a possible decline in life expectancy by midcentury. The most detrimental health and longevity effects will not be seen for decades--a phenomenon that cannot be detected by current methods used to forecast life expectancy or estimate the number of deaths currently attributable to obesity. This scenario contrasts sharply with the views of mathematical demographers who generate forecasts by relying on the assumption that the U.S. pattern of longevity will follow that of other longer lived nations and on the extrapolation of historical trends in life expectancy into the future.

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.

Mortality of atomic bomb survivors predicted from laboratory animals.

Exposure, pathology and mortality data for mice, dogs and humans were examined to determine whether accurate interspecies predictions of radiation-induced mortality could be achieved. The analyses revealed that (1) days of life lost per unit dose can be estimated for a species even without information on radiation effects in that species, and (2) accurate predictions of age-specific radiation-induced mortality in beagles and the atomic bomb survivors can be obtained from a dose-response model for comparably exposed mice. These findings illustrate the value of comparative mortality analyses and the relevance of animal data to the study of human health effects.

Pathology effects at radiation doses below those causing increased mortality.

Mortality data from experiments conducted at the Argonne National Laboratory (ANL) on the long-term effects of external whole-body irradiation on B6CF(1) mice were used to investigate radiation-induced effects at intermediate doses of (60)Co gamma rays or fission-spectrum neutrons either delivered as a single exposure or protracted over 60 once-weekly exposures. Kaplan-Meier analyses were used to identify the lowest dose in the ANL data (within radiation quality, pattern of exposure, and sex) at which radiation-induced mortality caused by primary tumors could be detected (approximately 1-2 Gy for gamma rays and 10-15 cGy for neutrons). Doses at and below these levels were then examined for radiation-induced shifts in the spectrum of pathology detected at death. To do this, specific pathology events were pooled into larger assemblages based on whether they were cancer, cardiovascular disease or non-neoplastic diseases detected within the lungs and pleura, liver and biliary tract, reproductive organs, or urinary tract. Cancer and cardiovascular disease were further subdivided into categories based on whether they caused death, contributed to death, or were simply observed at death. Counts of how often events falling within each of these combined pathology categories occurred within a mouse were then used as predictor variables in logistic regression to determine whether irradiated mice could be distinguished from control mice. Increased pathology burdens were detected in irradiated mice at doses lower than those causing detectable shifts in mortality-22 cGy for gamma rays and 2 cGy for neutrons. These findings suggest that (1) models based on mortality data alone may underestimate radiation effects, (2) radiation may have adverse health consequences (i.e. elevated health risks) even when mortality risks are not detected, and (3) radiation-induced pathologies other than cancer do occur, and they involve multiple organ systems.

Position statement on human aging.

A large number of products are currently being sold by antiaging entrepreneurs who claim that it is now possible to slow, stop, or reverse human aging. The business of what has become known as antiaging medicine has grown in recent years in the United States and abroad into a multimillion-dollar industry. The products being sold have no scientifically demonstrated efficacy, in some cases they may be harmful, and those selling them often misrepresent the science upon which they are based. In the position statement that follows, 52 researchers in the field of aging have collaborated to inform the public of the distinction between the pseudoscientific antiaging industry, and the genuine science of aging that has progressed rapidly in recent years.

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.