10.1 MODULATING 生物学衰老
As you learned in earlier chapters, the causes of aging and longevity are now known. Aging is caused by random, stochastic damage to cellular molecules that leads to altered cell function. Longevity—here meaning the length of the life span, independent of aging—has arisen as a byproduct of genes selected for reproductive success. The biochemical and physiological mechanisms that underlie aging and longevity are not yet fully understood. Nonetheless, many biogerontologists agree on one point: the rate of aging and alterations in longevity reflect the intracellular accumulation of damaged 蛋白质.
In this section, we discuss why aging cannot be modulated, then look at what types of research might be needed to better understand the biological basis of aging.
10.1.1Aging cannot be modulated
We live. We grow old. We die. Although aging is something most of us would like to stop, or at least slow down, the simple truth is that aging cannot be modified. To understand why this is so, you must accept as fact three important principles of biological systems that we discussed in previous chapters: (1) aging did not evolve; (2) biological organisms are subject to the same laws of thermodynamics as inanimate objects; and (3) the second law of thermodynamics operates constantly and randomly. Since aging did not evolve, there are no genes that regulate the process. Aging must therefore be a random event. The randomness of aging arises because of the second law of thermodynamics. Millions of reactions take place in an organism, and each one must conform to the first and second laws of thermodynamics. This fact is nonnegotiable with the universe. Forces of the universe push every chemical reaction, even the minutest, toward increasing entropy and disorder. At some point, in every organism, one of these reactions will attempt to take place in a system where the entropy exceeds the free energy. There will be a loss in molecular fidelity and an accumulation of damaged 蛋白质. This will start a chain reaction that will end with the loss of cellular function. Over time, all the cells in the human body experience a loss of molecular fidelity. Humans are not able, and most likely never will be able, to alter this fundamental fact of the universe.
One can argue, however, that the laws of thermodynamics apply to a closed system, a system having no input from the environment. Organisms are open systems, constantly interacting with the environment, and perhaps we can intervene to offset the effect of the second law. Indeed, some suggest that, in the twentieth century, the human intervention that led to the unprecedented increase in life expectancy proves that biological systems can successfully combat the second law. A close inspection of the gains in life expectancy over the past 100 years, however, suggests only that we made headway against disease. Aging remains. As shown in Figure 10.1, there was indeed a rapid increase in life expectancy during the twentieth century and the first decade of the twenty-first century. But, the increased life expectancy between 1900 and 1950 was achieved by curtailing the infant mortality rate, reducing deaths due to childhood diseases, and reducing deaths due to infections that killed most people before the end of their reproductive period. The slower gains after 1960 were the result of advances in medical technology that reduced deaths from diseases that had been major killers of older people before they reached an advanced age. For example, individuals who would have died in their fifties or sixties from a heart attack are now living into their seventies and eighties because of technologies that diagnose and fix the problems before they become fatal. Thus, the increase in life span during the twentieth century was the result of modulating age-related disease, not aging.
Figure 10.1 Gain in life expectancy at birth by decade, 1910–2010. Note that 60% of the gain in life expectancy occurred during the first 50 years of the twentieth century, reflecting a decrease in infant mortality and improvements in disease control.
Some scientists suggest that the rapid advancements in biotechnology will lead to anti-aging therapies. These researchers point to advances in stem cell research that show great promise for restoring age-related functional loss. Others suggest that organs grown in vitro from our own cells will replace those damaged by age or disease. Both types of therapy will undoubtedly be realities in the future and will lead to increased life expectancy. But the question before us is, Will these interventions modulate aging? The answer is an unequivocal “no”; they will only postpone the inevitable. As soon as you fix one tissue or organ, another system will fail, and so on and so on. Knee replacement, a common surgery in the elderly population, has not stopped kidney cells from accumulating damage. Perpetual motion in humans is impossible, just as the nineteenth-century physicists who developed the laws of thermodynamics predicted.
10.1.2 Mechanisms that lead to loss of molecular fidelity may be modulated in the future
Since its beginning, biogerontological research has focused almost exclusively on trying to alter the process of aging by correcting damage that has already been done. This approach to modulating aging will never be successful: increasing entropy is a fundamental law of the universe, and all matter strives to reach energy equilibrium. We can, however, modulate the rate of aging by evaluating mechanisms that lead to the loss of molecular fidelity.
All age-related disease will be cured someday, and we will be left with nothing more than increasing entropy as the cause of death. If we are to modify the rate of aging, biogerontological research must focus on the mechanisms of aging, not on the mechanisms of age-related disease. Biogerontology should be evaluating why, given the laws of thermodynamics, organisms survive at all. In other words, biogerontologists need to stop asking “Why do we die?” and begin asking “Why do we live?”
It is not easy to predict what specific research will be undertaken when biogerontologists frame their research in the why-do-we-live context. With the rapid pace of discoveries in biology, any predictions made today will probably be outdated tomorrow. There are, however, some general areas of research that should be given greater focus if we are to modulate the rate of aging. These areas include genetics and gene regulatory systems.
Because evolution has selected all of our genes to ensure survival to reproductive age, it would seem appropriate to focus greater attention on genes and gene regulatory systems that maintain usable energy—that is, those genes that maintain molecular fidelity and cellular order. In general, these are the genes that regulate the repair of DNA and proteins and the removal of damaged cellular components.
The focus on genes that maintain molecular fidelity and cellular order will lead naturally to research that evaluates when systems, and what systems, are likely to be the most susceptible to the second law. Evolutionary theory provides the answer to the when: systems involved in repair and maintenance become susceptible to the second law after the organism reaches reproductive age. Thus, there needs to be a significant shift in the model generally used in aging research. Biogerontologists should begin investigations aimed at young, prereproductively active and reproductively active populations, without making comparisons with the aged (post-reproductive) population. Comparison with the aged population should occur only after achieving a clear understanding of genetic pathways or regulatory systems in younger populations that are most susceptible to the second law. Then, research can begin to test whether or not these systems affect the rate of aging.
Given the current state of biotechnology, answering the question of what system or systems are most susceptible to increasing entropy is made difficult by the randomness of the second law. Biogerontologists need significant advances in genomic research (a topic discussed in Chapter 5) before they can identify genetic pathways that are likely to be important to the rate of aging (some of this research has begun in invertebrates). This will undoubtedly require a greater use of mathematical models—a method almost nonexistent in biogerontology—to help predict outcomes of age-related functional loss resulting from gene expression (or non-expression) in young individuals.
Until general genomic research provides biogerontologists with the tools necessary for investigating the impact of increasing entropy on age-related functional loss, some areas of research might be helpful in the short term. General medical science and biogerontology have determined that the cardiovascular system tends to decay at a greater rate than other systems. Fatty streaks in arteries, precursors to an accumulation of damaged 蛋白质 that leads to narrowing of the vessel, can be found in children as young as six months old. Using the cardiovascular system as a model, researchers can begin to understand how a loss in molecular fidelity begins. The development of certain types of cancer, particularly those likely to occur in younger populations, may also provide some understanding of why genetic pathways regulating damage and repair become altered.
