Alleles and Aging: The Effects of Different Forms of Genes on Aging and Longevity

Article excerpt

The notion of aging as affecting particular tissues or organs versus the notion of an underlying aging process affecting all cells.

The natural human interest in longevity has been intensified in recent years by three interlocking and often discussed factors: the increasing age of the baby boomer generation, the progressive prolongation of active life, leading to increasing numbers of engaged nonagenerians and centenarians, and the narcissism and youth-worship of current society. In a scientific response to this interest, one can consider a number of theories about the basis for aging and longevity that are themselves venerable. For example, by the early 1960s, Hayflick and Moorhead (1961) had demonstrated the limited lifespan of fibroblast cells, and both that phenomenon and deficits from oxidative damage to macromolecules (among these are nucleic acids, which allow organisms to reproduce) were already lively topics of discussion as possible driving forces in aging.

But times have changed. The advances in human genetics and the harvest of genetic information from the Human Genome Project are combining to refine our questions about the genetics of aging-or more precisely about the relation or contribution of alleles--different forms of particular genes--to aging. In particular, one can note that the genome project is providing a complete catalogue of genes along with increasingly extensive assessments of all human variation. What prospects come into view for the understanding of aging?

VIEWS OF AGING AND ITS MECHANISM(S)

In attempting to define the role of alleles in human aging, it is useful to recall a fundamental distinction: the notion of aging as afFecting particular tissues or organs versus the notion of an underlying aging process affecting all cells. In a famously cogent formulation of the tissue- or organ-specific, or "segmental," view, Martin (1985) pointed out that premature aging (or "progeroid") syndromes may be relevant to multiple aspects of the senescent phenotype, and that "gene action in the domain of development . . . can set the stage for patterns of aging in the adult." His thinking underscored the experience of pathologists over many decades: that autopsies of those who died from causes unrelated to physical condition (for example, auto accidents) show enormous ranges in the differential aging of tissues and organs. For example, even among the very old, an individual might have a young heart but old kidneys.

The other type of thinking about senescence assumes a unitary, or general, rather than a segmental hypothesis. This view assumes that a fundamental process underlies overall aging, and segmental phenomena are accounted for by effects specific to a particular body system that reinforce or ameliorate the underlying process. The biological clock in modern versions of this proposal does not tick uniformly The ticking of the clock occurs not at a constant rate but rather with a probability that can vary over time but has a cumulative, inexorable trend.

The distinction between the two types of formulation can be seen in their view of death: For segmental aging, there will be a definable single or multifactored "cause" for death (for example, heart disease or renal failure), whereas for the general, underlying clock theory, death is considered the endpoint in a process that occurs even in the absence of overt, system-specific pathology.

Both segmental and general theories have distinguished histories in gerontology research, in humans as well as in animal models. An extensive summary is given by Johnson and colleagues (1999), and important topics are covered in other contributions in this volume. To orient this discussion toward genetic factors, Figure I gives a variant of the treatment of Johnson and colleagues that is general enough to encompass both views of aging and longevity. Homeostasis (the steady-state physiological condition) in adult organisms is represented as a balance of components. …