Monday, August 25, 2008

The Quest for Longer Life

By: Mark P. Mattson, Ph.D.

In his review, Mark Mattson of the National Institute on Aging notes that the brain is mostly missing from David Haycock’s otherwise fascinating exploration of the history of prolonging life.

Human beings have long been fascinated and in many cases obsessed with the possibility of living forever, or even the less ambitious goal of living longer before experiencing disability and disease. Tales of individuals with exceptional longevity—including Methuselah and other characters in the Bible—have been passed from generation to generation throughout the history of modern man, despite a lack of substantive evidence. However, with the advent of actuarial and scientific methods it has become clear that, as with other biological variables, the life spans of individuals in populations throughout the world follow a bell curve, with the maximum attainable life span of approximately 120 years remaining largely unchanged for thousands of years.

In his new book, Mortal Coil, David Haycock, a historian and an authority on the history of medicine, provides a riveting account of the past four centuries of humans’ search for the explanation of their mortality and the possibility of achieving immortality. The book integrates religious, philosophical and scientific considerations of mortality, using well-researched accounts of the lives and contributions of key thinkers as well as of charlatans who have shaped our views of aging. Drawing upon his training as a historian and his knowledge of medicine, Haycock provides a unique view of a fundamental aspect of human existence, written in an easy-to-read yet thought-provoking manner—albeit with room for further insight about the brain.

Sir Francis Bacon recommended a diet that included plants known to contain poisonous substances, such as hemlock, mandrake and nightshade. Recently, accumulated scientific evidence has suggested that the health benefits of some of the chemicals in plants do indeed result from their noxious properties.The book begins in the early 1600s with the life and intellectual pursuits of Sir Francis Bacon, who made several major contributions that advanced knowledge of the causes of aging and the prospect of life span extension. In his essays on this subject Bacon describes how the aging process is unequal—some parts of the body age relatively fast and are not repaired (the arteries and bones, for example), whereas other parts, such as the skin and the blood, can be restored during aging. 

Interestingly, Bacon recommended a diet that included plants known to contain poisonous substances, such as hemlock, mandrake and nightshade. Recently, accumulated scientific evidence has suggested that the health benefits of some of the chemicals in plants do indeed result from their noxious properties; in a process called “hormesis,” low amounts of such potentially toxic substances induce a mild adaptive stress response in cells and organs, which results in increased resistance to disease. As described by Haycock, it was also in the 17th century that Rene Descartes emphasized the importance of dietary moderation, exercise and “peace and tranquility.” This section of the book provides an interesting and well-conceived account of how people viewed mortality from religious and philosophical perspectives at a time when the biological underpinnings of aging were completely unknown.

The era of alchemy and the search for the “elixir of life,” still in the 1600s, is the topic of the next section of Mortal Coil. Haycock describes the intermingling of the beginnings of medicine with the promulgation of anecdotal cases and outright witchcraft and quackery that was fueled by the hopes and fears of the sick and the aged. Claims of dramatic cures through treatments ranging from bloodletting to herbs and gonadal extracts were rampant. Despite the prevalence of false claims during this time period, however, valuable information and concepts were generated. For example, the Swiss alchemist and physician Paracelsus developed the idea that medicines are poisons that at low doses have beneficial effects. In England there was a growing interest in the prolongation of life among members of the Royal Society, and physicians commonly employed drastic measures to prolong the lives of people on their deathbeds. Robert Boyle espoused the “corpuscular theory”—the principle that life could be prolonged by replacing body fluids and cells in old individuals with fluids and cells from younger individuals.

Haycock describes the 18th century as the age of reason and optimism for the future of medicine, health and longevity. Claims of exceptional longevity continued—St. Germain claimed to be 300 years old, and even prominent physicians such as the Scottish doctor George Cheyne suggested that it was possible to live beyond 200 years by adopting a strict Spartan-like lifestyle. But this hope among intellectuals and medical professionals was in stark contrast to the reality of the times, for the average life span was actually decreasing; for example, average life expectancy in England in 1726 was 25 years.

 One lesson of the 1700s, however, was that with optimism comes energy and motivation, and, indeed, the belief that immortality might be eventually achieved through advances in science and medicine became an impetus for rigorous research in these fields. Even Napoleon Bonaparte expressed the opinion that science would find a way to prolong life indefinitely. And on the other side of the Atlantic Ocean in sprouting America, Benjamin Franklin was fascinated with the process of aging and the possibility of slowing it through dietary modifications—he found that his own health benefited by abstaining from meat. Also important among Interestingly, many of the environmental factors that were anecdotally linked to increased longevity in the 16th through the 18th centuries exert their beneficial effects by modifying neurotransmitter systems in the brain.the conceptual advances of the 1700s were the idea of the “power of the mind” forwarded by William Godwin and the appreciation of the role of inheritance as a determinant of one’s life span as voiced by the German physician Christof Hufeland. This section of the book touches on the influence of the brain on health and longevity, but could have benefited from specific examples of how chronic stress shortens life and engagement in intellectual and leisure activities promotes health. Interestingly, many of the environmental factors that were anecdotally linked to increased longevity in the 16th through the 18th centuries exert their beneficial effects by modifying neurotransmitter systems in the brain. For example, by increasing signaling by the neurotransmitters serotonin and glutamate, exercise and engagement in intellectual activities increase the production of neurotrophic factors, proteins that promote the growth and survival of nerve cells and thereby protect against disease.

Rigorous investigations of longevity and the aging process in which reliable data were systematically collected began and then grew exponentially during the 19th century. Data collected by the life insurance industry based on substantiated birth and death records definitively refuted claims that individuals were living beyond 120 years of age. Thomas Malthus’s analysis of population growth demonstrated the importance of competition for available resources in setting limits on survival, and predicted adverse consequences of continued exponential growth of the human population. At the same time, the meticulous research of the naturalists Alfred Wallace and Charles Darwin led to the realization that humans evolved over millions of years by the process of natural selection. These kinds of fully validated discoveries clearly suggested that longevity is largely predetermined by evolutionary history and that, accordingly, the death of the individual is important for the survival of the species. Elsewhere, Benjamin Gompertz developed an equation that describes the survival curves for populations of any animal from which two key values can be obtained: the average life span and the maximal life span. Coincident advances in medicine by famous scientists such as Louis Pasteur led to reduction in deaths caused by infectious agents, which resulted in increases in the average life span—but without an increase in the maximum life span, which remained at 100 to120 years.

Haycock concludes Mortal Coil by summarizing the many advances in aging research and in understanding the molecular and cellular basis of aging and age-related disease. This large body of knowledge, the vast majority of which has been obtained within the past hundred years, was bolstered by numerous major discoveries in the field of biology, including what cells are and how they divide and function; the structure and mechanism of replication of DNA; how proteins, which are made from amino acids, control the structure and function of cells; and the nature of oxygen free radicals and how they damage cells.

Though not overtly stated by Haycock, the title for his book presumably derives from the Shakespearean use of the phrase: Hamlet, in his famous soliloquy, ponders what happens once we have “shuffled off this mortal coil”—the troubles of life and the suffering in the world. But the title also invokes the double helix “coil” of DNA, inherited from our parents, which controls our life and also dooms us to death. Accordingly, included in the last section of the book are sketches of the work of several prominent scientists whose discoveries support the importance of the “mortal coil,” among them Thomas Kirkwood, who developed the “disposable soma theory of aging.” This theory focuses on the concept that evolution protects the germ cells while discarding the body through its programmed death. The discovery that dividing cells in the body, such as those in the skin, are capable of only a limited number of cell divisions, proportional to the life span of the species, strengthened the case for a genetically programmed life span. Haycock touches on key points concerning the mechanisms of aging, but leaves it to the reader to integrate this information with that covered in the previous sections of the book. The book would have been enhanced by the inclusion of examples of predictions made in the preceding centuries and whether they were or were not supported by emerging scientific findings.

Some of these examples are brain-related. Many centuries before the discoveries of nerve cells and neurotransmitters it was recognized that thought, mood and behavior could be affected by substances present in certain plants and animals. A culture of using traditional medicines that were mainly components (roots, leaves, bark, etc.) or extracts of plants became pervasive in societies throughout the world. In an increasing number of cases, the efficacy of such traditional medicines is being validated in controlled studies and the specific chemicals responsible for the medicinal actions are being identified. In several cases the active chemicals are actually toxins that at the low doses consumed activate adaptive cellular stress response pathways in neurons and other cells. The result is that the cells respond to the mild stress induced by the phytochemicals by increasing their ability to cope with more severe stress and resist disease. It would have been more informative if Haycock had included a description of the brain circuitry and neurotransmitters that control mood (serotonin, norepinephrine and dopamine) and how drugs used to treat depressed or otherwise abnormal mood act on these neurotransmitter systems. In modern societies mood-altering drugs, particularly antidepressants, are becoming widely used. It will be of considerable interest to know how views of longevity and life span are affected by From an evolutionary perspective, survival is paramount, and the brain is of fundamental importance in the critical decision-making processes that determine one’s fate.these drugs.

 Also missing from the book is discussion of the roles of the brain in the contemplation of mortality and in efforts to delay death. From an evolutionary perspective, survival is paramount, and the brain is of fundamental importance in the critical decision-making processes that determine one’s fate. As modern societies evolved, survival depended less on avoiding sudden violent death and more upon avoiding and properly treating diseases. Assimilation of scientific data and the development of drugs in pharmaceutical companies and universities required the coordinated efforts of individual scientists and physicians—a dramatic example of altruism. Higher cognitive functions were essential for these efforts to extend health span (the number of years lived in good health) and, with it, average life span. Because of the brain’s structural and chemical complexity, and the prevalence of psychiatric and neurological disorders such as schizophrenia, depression, epilepsy, Alzheimer’s disease and Parkinson’s disease, the brain was itself a major target for drug development. Together with basic research in animals and human subjects, the various neurotransmitters that control all behaviors and bodily functions were identified, and “neurochemical maps” of the nerve cell circuitry of the brain were established.

While great strides have been made in understanding what happens to the body’s molecules and cells during aging, the general “formula” for living longer and healthier that was first appreciated four centuries ago remains largely unchanged: eat in moderation, exercise regularly, keep the mind engaged in challenging intellectual pursuits and avoid chronic stress. In 2008 it is realistic to expect further incremental advances that increase average life span and extend health span, but as suggested by the history elegantly chronicled by Haycock in Mortal Coil, the prospect of major increases in maximum life span remains remote.

About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Helen Mayberg, M.D., Icahn School of Medicine at Mount Sinai 
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine
Charles Zorumski, M.D., Washington University School of Medicine

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