Authors: Sherwin B Nuland
How We Die (14 page)
The other of the two major theories of aging is the proposition that the entire process is predetermined by genetic factors. In this formulation, there exists within each living thing a genetic program whose function is to progressively shut down the physiological processes of normal life and eventually of any life at all. Among humans, different people do it in different ways, or at least its most prominent features vary in each of us. This allows for such separate phenomena as loss of immunity, wrinkling of the skin, the growth of malignancies, the onset of dementia, decreased elasticity in blood vessels, and many other events of senescence.
The genetic theory was given a huge boost almost thirty years ago when Dr. Leonard Hayflick showed that human cells cultured in the laboratory begin to slowly stop dividing after a while. In time, they quit altogether, and die. The maximum number of cell divisions was found always to be finite, and to be about fifty. The studies were conducted on a ubiquitous type of cell called the fibroblast, which makes up the basic structural framework of all tissues of the body, and the findings may be extrapolated to other cells as well. The seemingly endless capacity of the cancer cell to reproduce, of course, escapes the orderly finiteness of normal existence.
Such studies as Hayflick’s help to explain why each species exhibits a characteristic life span and why individuals within species tend to have life spans that correlate well with those of their parents—the best assurance of longevity is to choose the right mother and father.
A plethora of specific aging factors have pushed their way onto the scene of science, and my guess is that virtually all of them have some degree of validity. In other words, aging is very likely the result of all of them in combination, with the importance of individual components varying for each of us. Some of the factors are common to all living things. Among them are the changes that occur in molecules and organelles. Changes that occur in cells, tissues, and organs may be specific to a single species, like those that take place in the whole plant or animal. The evidence, as Dr. Hayflick puts it, “is strongly persuasive that those attributes of biological instability that by common belief are considered to be age changes have a multiplicity of causes.”
Some of the biological phenomena have already been described, such as the genetic program itself, the generating of free radicals, the instability of molecules, finite cell life, and accumulated genetic and metabolic errors. There are several other possible components that have found vigorous champions in the halls of science. Lipofuscin, for example, is thought by some researchers to be more than simply a bland product of intracellular breakdown that harmlessly discolors aging organs; they believe that its accumulation is lethal. Others place great emphasis on hormonal changes mediated through the nervous system; there are proponents of the theory that among the changes occurring in the immune system, one of the most fundamental is its decreasing ability to recognize its own host’s tissues, with the result that the degenerative diseases of the elderly are brought about by the body’s rejection of some of the very tissues of which it is made.
Yet another theory holds that the molecules in the structural tissue called collagen become cross-linked to one another. The aggregation of such linkages impedes the flow of nutrients and wastes while at the same time decreasing the space needed for vital processes to occur. Among its other effects, cross-linking may damage DNA, which in turn brings about mutations or cell death. And there is a relatively new theory that physiological systems and perhaps also the anatomic changes that may accompany them become less complex with age, and therefore less efficient; the decreased complexity may be the result of other more basic processes, perhaps including some of those already described.
Recently, moreover, there has been increasing interest in a phenomenon widespread among species, which seems to be a programmed form of cell death. This process, which researchers have named apoptosis (from the Greek, meaning “a falling away from”), is initiated by the activity of a protein called the myc gene, which starts a powerful series of genetic reactions under specific abnormal circumstances. For example, when nutrients are removed from certain types of cells growing in culture, the myc gene begins a process by which the cell undergoes an event that resembles an implosion, which in the course of about twenty-five minutes destroys it. It quite literally “falls away from” life. Such programmed death is important to the development of the mature organism, because it is a means whereby certain cells that are no longer useful in the developmental process can be replaced by those that belong to the next phase. Examples have also been found of apoptosis in fully mature individuals, triggered by various events in the environment of the affected cells.
Because apoptosis is a situation in which cell death occurs as a direct consequence of gene expression, it is tempting to ruminate over the possibility that the myc protein or something very like it can function as a “death gene.” This gene-directed death may be instigated by a variety of environmental and physiological factors, and it seems to provide a concordance between some of the different theories described in the foregoing paragraphs. This research pathway is made all the more promising by the demonstration of binding between the myc protein and another structure given the name max protein. When they bind, the cell is instructed in some not-yet-understood way to do one of three things—mature, divide, or self-destruct by apoptosis. Depending on how it expresses itself, therefore, the myc gene obviously plays a major role in development, in growth regulation, and finally in a programmed form of death. The implications of these new discoveries are obviously incalculable at the moment, not only for the understanding of normal processes but for pathological ones as well, particularly cancer.
The proponents of collegial compromise are exploring yet other avenues that may lead to clarification of seemingly disparate viewpoints. For example, the immune changes of senescence may be the result of hormonal influences determined by neurological events that are in turn genetic—or vice versa. There is no lack of theories, no lack of champions, and no lack of concordances among concepts. What emerges from all the experimental data and the speculations they provoke is the inevitability of aging, and therefore of life’s finiteness.
And what about those federally funded lists of formally named pathologies by which old people are supposed to die? Every group of lethal diseases of the elderly consists predominantly of the usual suspects. Of hundreds of known diseases and their predisposing characteristics, some 85 percent of our aging population will succumb to the complications of one of only seven major entities: atherosclerosis, hypertension, adult-onset diabetes, obesity, mental depressing states such as Alzheimer’s and other dementias, cancer, and decreased resistance to infection. Many of those elderly who die will have several of them. And not only that; the personnel of any large hospital’s intensive care unit can confirm the everyday observation that terminally ill people are not infrequently victims of all seven. These seven make up the posse that hunts down and kills the elderly among us. For the vast majority of those of us who live beyond middle age, they are the horsemen of death.
Autopsies are not as popular as they were a few decades ago. Given the meticulous accuracy with which diagnoses can nowadays be made before death, autopsy has become in the eyes of many bedside physicians a redundant exercise in academic pathology. Far fewer people die of a wrong diagnosis than did in an earlier era—the enormous majority succumb because of our inability to change the course of an accurately pinpointed disease. In the last decade or more, my own hospital’s so-called autopsy percentage has dwindled to a level that hovers around 20 percent, when for many years before then it stood consistently at well above twice that figure. The national rate is now about 13 percent.
During the heyday of the autopsy, I was able to obtain postmortem permission from the families of all but very few of my own patients who succumbed. I don’t try as hard these days, but when I do, I still make a point of being present to review the findings with the pathologist as he or she reveals them. After six years of residency training and thirty years of practice, I have witnessed a rather large number of autopsies. The wide extent of atherosclerosis and atrophy to be found in the bodies of old people is a commonplace, seemingly unworthy of comment when the dissector is seeking out the several sites to which a cancer may have spread or an infection lodged. Peering assiduously at tissues and into the insides of organs, both the dissector and the surgeon tend to ignore the familiar panorama of aging that gradually reveals itself with every added stroke of the knife. Remarking on it is as unusual as a motorist commenting on the leafiessness of a winter landscape when looking for the right street address—it’s just there, and that’s all there is to it.
And yet, when the autopsy report arrives in the surgeon’s—my—mailbox a few weeks later, I have often been astonished at the very advanced state of the barely noticed biological debris through which the pathologist and I have so recently made our way. In the detailed analysis of his findings, he has meticulously entered every one of his discovered divergences from normal health. As I read his summary, they all spring back to memory and take their place alongside the major clues we were so single-mindedly tracing. Only when this begins to happen do I fully appreciate the entire setting in which my patient has died.
Some of the autopsy findings have nothing to do with the circumstances of death. They are simply the results of the selfsame aging process out of which one or two particular kinds of pathology emerged to kill the patient. Such non-lethal findings may not directly contribute to the death, but they provide the background against which it occurs.
Recently, I sought out the help of a colleague at the Yale–New Haven Hospital. Dr. G. J. Walker Smith is the director of the autopsy service, an astute veteran of that marbled chamber in which the doctors of the dead strive mightily to answer the question framed more than two hundred years ago by the founder of their somber specialty, the Paduan anatomist Giovanni Battista Morgagni:
Ubi est morbus?
“Where is the disease?” Together, pathologist and newly deceased patient undertake the obligation promised by the time-honored avowal that stares down on them from plaques on the walls of hundreds of autopsy rooms all over the world:
Hic est locus ubi mors gaudet succurso vitae
—“This is the place where death rejoices to come to the aid of life.”
Ubi est morbus?
“Where is the disease?” Together, pathologist and newly deceased patient undertake the obligation promised by the time-honored avowal that stares down on them from plaques on the walls of hundreds of autopsy rooms all over the world:
Hic est locus ubi mors gaudet succurso vitae
—“This is the place where death rejoices to come to the aid of life.”
The autopsy room is Walker Smith’s domain, just as the operating room is mine. When I told him I was interested in confirming my long-standing impressions by seeing a few final reports on patients who had died in advanced age, he did me one better—he himself became interested, and before long was just as taken with the project as I. He found twenty-three records of patients whose studies had been done before today’s scarcity. Together, we reviewed the findings in twelve men and eleven women eighty-four years of age and older who had died in the sixteen-month period between December 1970 and April 1972. Their average age was eighty-eight, and the oldest was ninety-five.
Although there were variations in the distribution of such pathologies as atherosclerosis and microscopic deterioration of the central nervous system, when viewed en masse, there was nevertheless a sameness about the findings that was starkly impressive to both of us.
An individual’s specific kind of death seems to depend upon the order in which his tissues become involved in the process of degradation. The one common thread among the twenty-three patients, at least as it is reflected in the staccato multisyllables of a pathologist’s unique approach to obituary, was the loss of vitality that comes with starvation and suffocation—as the arteries narrow, so does the margin between life and death. There is less nutriment, there is less oxygen, and there is less resiliency after insult. Everything rusts and crusts until life is finally extinguished. What we call a terminal stroke, or a myocardial infarction, or sepsis is simply a choice made by physicochemical factors we do not yet comprehend, the purpose of which is to bring down the curtain on a performance already much closer to its conclusion than may have been realized, even in an old person who has till then appeared vibrantly healthy.
An octogenarian who dies of myocardial infarction is not simply a weather-beaten senior citizen with heart disease—he is the victim of an insidious progression that involves all of him, and that progression is called aging. The infarction is only one of its manifestations, which in his case has beaten out the rest, though any of the others may be ready to snap him up should some bright young doctor manage to rescue him in a cardiac intensive care unit. Seven of Walker Smith’s oldsters officially died of myocardial infarction; four others had strokes as part of their terminus; eight died of infection, including three who disappeared into eternity arm in arm with the old man’s friend, pneumonia; there were three far-advanced cancers in the group, although the final episode for one was pneumonia and for another was stroke. The single most striking observation was also the one most expected: Every one of these twenty-three people had advanced atheromatous disease in the vessels of the heart or the brain, and almost all had it in both, even if they exhibited no symptoms that required treatment until the terminal event. One or the other of these vital engines was close to quits in every one of the old persons studied.
Another finding that elicited no surprise was the frequency of nameable disease in the other organs of any individual, which played no part in the patient’s death. In the pathologists’ reports, such diseases are designated “incidental.” Thus, in addition to the three patients whose malignancies killed them, another three were found to harbor unsuspected “incidental” cancers—in the lung, prostate, and breast; two women and one man had the ballooning of the aorta or other large abdominal vessels called an aneurysm, caused by atherosclerotic weakening; eleven of the twenty whose brains were microscopically studied were found to have old infarcts, even though only one had a known history of stroke; fourteen were found to have major atherosclerotic changes in the arteries of the kidneys; several had active urinary-tract infections; and a man who died of extensive stomach cancer had gangrene of his leg.
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