Genetic Influences on Late-Life Diseases (2000)

Why do people differ so much in their patterns of aging? There are some unfortunate individuals who develop debilitating dementias by middle age, while others may be cognitively intact until their ninth decade, but then succumb to Alzheimer's disease. Still others may do well until their late 6os, when they suffer the first of a series of heart attacks. These examples are particularly important, but no body system is immune to the genetic lottery. Until relatively recently, only pediatricians and obstetricians had major concerns about hereditary disorders. Now geriatricians, family physicians, internists-in fact all practitioners-have begun to appreciate the importance of genetics to their practices. But we all know, of course, that genes do not tell the whole story. Environment also plays a big role, as do interactions between environment and genes and interactions between one gene and another. Even dumb luck has a lot to do with how well we do ! We do not understand why genetically identical organisms grown in apparently identical environments die at widely different times. Perhaps one factor has to do with random damage to DNA-damage that is either not repaired or improperly repaired. The role of chance in aging (and in development) is an important area of sudy (see Finch and Kirkwood, 2000). DIFFERENCES IN SUSCEPTIBILITY TO DISORDERS OP AGING In this issue, Kirkwood describes the evolutionary biological theory of why we age. In brief, the numerous declines in structure and function that unfold during the latter half of the lifespan occur because of the decline in the force of natural selection with respect to the age at which genes have their effects. Evolutionary theory predicts two categories of gene action that modulate differential susceptibility to disorders of aging-mutations and polymorphisms. Mutations. The first category of gene action involves rare mutations that are thought to have essentially neutral effects during the early part of our life course but deleterious effects late in life. Recent evidence from the Human Genome Project suggests that the earlier estimates of 80,000 to 100,000 genes of man may be an underestimate. Perhaps we have as many as 120,000 to 140,000 genes. Since all genes are subject to spontaneous and induced changes in either their coding or their regulatory sequences, we can immediately see the opportunities for an enormous variety of altered gene actions, many of which may well escape the force of natural selection and thus survive to influence patterns of aging, Mutations are rare and idiosyncratic events, with frequencies of the order of one out of a million copies of the usual (`wild type) variety of gene, and the particular types of mutations vary from pedigree (family genetic history) to pedigree. I therefore regard such constitutional heritable variations in genes as having the potential to lead to individual, or private, modulations of aging (Martin, I997). Such experiments of nature are of importance for at least three reasons. The first is that, while any individual mutation is rare, collectively they are numerous. The second is that the individual patient or family afflicted with an associated vulnerability is far from an abstract statistic and deserves the best medicine we can offer. (This is why the government has wisely instituted a program of private sector support for the development of orphan drugs; for treatment of rare disorders, the manufacture of which cannot otherwise be profitable.) The third, and perhaps most significant reason in terms of its ultimate impact on public health, is the likelihood that at least a proportion of these mutations may brightly illuminate fundamental mechanisms of aging and age-related diseases. Polymorphisms. The other relevant category of gene action involves polymorphisms-genetic variants that are much more frequent. A proportion of such polymorphisms are likely to fit the idea of a trade-off in gene action-good effects early in the lifespan, but deleterious effects late in life. …