7.3 未来之路和基本概念
In 1990, Caleb Finch described several plants and animal species, mostly invertebrates that did not seem to show signs of aging. Throughout his landmark book, Longevity, Senescence and the Genome, Finch provided several lines of evidence suggesting that genes regulating longevity in species with negligible senescence may have been carried forward into the human genome. Many biogerontologists interpreted Finch's writing to mean that aging is not an inevitable outcome of being alive and that it may be possible to genetically manipulate longevity. Further evidence supporting the possibility of extending maximal life span came when several researchers showed that the Gompertz Mortality Rate in the oldest cohorts of Caenorhabditis elegans and Drosophila flattened, decelerated, or both, a finding recently supported in studies of human centenarians. A deceleration in mortality rates means that maximal life span cannot be statistically predicted and that the oldest cohorts represent a sub-population with slightly different genomes (see Chapter 2, section titled, “Deceleration of mortality rate at end of life suggests possibility of longevity genes”). That is, genes must exist that regulate longevity. That genes regulate longevity was confirmed when several investigations were able to extend maximal longevity in invertebrate species by altering a single gene (see Chapter 5). The combined theoretical and experimental results leave little doubt that longevity genes do indeed exist and that genetic manipulation of human longevity may be possible.
Others have argued that similar extension of maximal life span in humans may not be so easy, if at all possible. The skepticism in the ability to genetically manipulate human longevity arises from two primary observations. First, the theoretical and experimental results from investigations testing the evolutionary theory of longevity suggest strongly that extending maximal life span in humans will negatively impact growth and reproduction. As discussed in Chapter 3, evolutionarily successful organisms are those that focus their cellular resources on the molecular fidelity of the DNA within the germ line (Chapter 3). The fidelity of molecules associated with maintenance of the soma is valuable to the organism only as long as needed for successful reproduction. Mortality is the price we pay for reproductive success—species without reproductive success are eliminated. This “trade-off” between reproduction and longevity has been demonstrated experimentally. In virtual every case where maximal life span has been extended in invertebrates and mice, reproduction success has been negatively impacted. Many have argued that human gene manipulation aimed at extending longevity will disrupt normal reproduction and lead to a decline in fitness.
The second observation suggesting that extension of human longevity may be difficult is that, unlike physiologically simpler organisms, hundreds of genes are involved in the mammalian regulation of longevity. These genes regulate functions as diverse as the development and maintenance of the cytostructure, apoptosis and autophagy, and intracellular metabolic signaling. Importantly, investigations using a systems biology approach to determine the critical genes determining maximal life span (Chapter 2) have shown that no single or even small group of genes appears to be more important than any other longevity gene. This means that all genes involved in human longevity must be altered simultaneously to safety extend maximal life span, a difficult if not impossible task to be sure. Altering only a few of the genes associated with longevity may result in the unintended consequence of disrupting the normal function of a biochemical or physiological process.
Although the road ahead to genetic manipulation of human longevity may seem impossible, recent advances in genetic engineering suggest that the technology to alter several genes simultaneously, needed for safe extension of human maximal life span, will someday exist (see discussion on CRISPR, Chapter 5). As such, questions and discussions surrounding the genetic manipulation of human longevity will need to transition from “can we genetically manipulate maximal life span?” to “should we genetically manipulate life span?” Extending human maximal life span through genetic manipulation will significantly increase the oldest segment of the population and bring social and health-care challenges never before experienced. Today's society has yet to deal effectively with the economic, environmental, and social issues associated with the increase in the elderly population brought about by the doubling of mean life span during the twentieth century (see Box 7.1 and Chapter 11). Genetic manipulation of maximal life span can only exacerbate these issues. There also exist significant ethical concerns associated with altering the human genome for enhancement of normal, non-disease-related functions such as maximal life span. Many prominent biologist and geneticists, including the discoverers of the CRISPR method, are calling for a moratorium on human genetic manipulation until international guidelines and standards are established. However, the decision to genetically manipulate longevity must not be left solely to a select few experts. All of us, especially the younger populations that will be most affected by a large older population, should begin now to discuss the implications of human genetic manipulation of longevity.
ESSENTIAL CONCEPTS
• Biodemography combines the classical techniques of demography—mortality analysis—with the biological principles of longevity. Biodemography is primarily a mathematical and theoretical science that constructs models predicting the origins of human longevity.
• Humans respond to environmental changes on the basis of cognitive reasoning and thus can change the environment to fit their needs, rather than instinctively allow the environment to control their longevity.
• A population contains many subpopulations with distinctive mortality rates, and such subpopulations have had a significant influence on the origins of human longevity. Biodemographers refer to human mortality rates as facultative.
• GWASs and deep sequencing use high-throughput technology to find rare gene variants that may be associated with human longevity.
• Biodemographers suggest that the different genotypes resulting in different mortality rates could have existed throughout evolutionary history and may have influenced the selection of genes that determine human longevity.
• The origin of longevity in Homo sapiens may result from our advanced intelligence, which allows us to adapt the environment to our genes and thus change mortality characteristics.
• Archeological evidence indicates that from the Neolithic period (∼5000 bce) to the Enlightenment (∼1600 ce), the average human life span remained fairly stable at 30–40 years.
• Widespread inoculation programs and the control of infectious diseases increased life expectancy dramatically in the early twentieth century.
• In the economically developed countries, the increase in life expectancy at birth after 1970 reflects improvements in care and treatment for noninfectious, life-threatening diseases in older age groups.
• Throughout the twentieth century, females born in developed countries had a greater life expectancy at birth than males. The gender gap in longevity is now narrowing, due to significantly greater gains in mean life span for men than for women.
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