Bruce A. Carnes

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.

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.

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.

Can Human Biology Allow Most of Us to Become Centenarians

Life span is a topic of great interest in science, medicine and among the general public. How long people live has a profound impact on medical costs, intergenerational interactions, and the solvency of age-based entitlement programs around the world. These challenges are already occurring and the magnitude of their impact is, in part, proportional to the fraction of a population that lives the longest. Some demographic forecasts suggest that most babies born since the year 2000 will survive to their 100th birthday. If these forecasts are correct, then there is reason to fear that the financial solvency of even the most prosperous countries are in jeopardy. We argue here that human biology will preclude survival to age 100 for most people.

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.

Senescence Viewed through the Lens of Comparative Biology

Abstract:u2002 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 lifes 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).

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.

A systems analysis of age-related changes in some cardiac aging traits

Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling—a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals.

Genetic Variation in the Raptor Gene Is Associated With Overweight But Not Hypertension in American Men of Japanese Ancestry

BACKGROUNDnThe 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.nnnMETHODSnWe 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.nnnRESULTSnAfter 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).nnnCONCLUSIONnCommon 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.

Old Age and Centenarians: The Human ‘Warranty Period’

More humans are surviving to older ages than ever before. The age structure of our species is shifting from young to old, a phenomenon referred to as population aging. It is global in nature, uniquely human, and has become one of the greatest challenges ever encountered by our species. The basis for this assertion is that biological function (homeostasis) declines with advancing age and at the same time pathologies, frailty, and disability increase. Given these biological realities, this article examines whether humans have a warranty period, when do we grow old, and what are the odds of becoming a centenarian.