| HOME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
| ||||||||||||||||||||||
EDITORIAL |
College of Biological Sciences, University of Minnesota, St. Paul.
Address correspondence to Huber R. Warner, PhD, College of Biological Sciences, University of Minnesota, 123 Snyder Hall, 1475 Gortner Ave., St. Paul, MN 55108. E-mail: warne033{at}umn.edu
THE first experimental evidence that genetics plays a role in aging was provided by Luckinbill and colleagues (1) and Rose (2), who produced long-lived fruit fly lines by repeatedly selecting for progeny from the oldest females. Although it was also known that some human families have an unusual number of individuals who live a long time, only in the last 10 years has it been possible to elucidate some of the mechanisms by which this may occur. Richard Miller (3) provided a lot of clarity to this question in his 1998 Kleemeier lecture titled: "Are There Genes for Aging?" Whereas it is fairly obvious that the broad range of life spans among animals must be genetically determined, it is less clear why the longevity of individuals within a species is so variable, even in an apparently genetically homogeneous population. Environmental factors presumably are also important in longevity, and the relative contributions have been estimated to be about one third genetic and two thirds environmental (4).
A breakthrough in elucidating the biological mechanisms modulating longevity was made possible by the sequencing of the complete genomes of such organisms as Caenorhabditis elegans (C. elegans), fruit flies, and mice. Although long-lived mutants of C. elegans were described in the late 1980s and early 1990s by Friedman and Johnson (5) and Kenyon and colleagues (6), the proteins affected were not identified until Gary Ruvkun and his colleagues cloned and sequenced two of these mutant genes (7,8). By now a role for the insulin-signaling pathway in modulating aging in C. elegans, fruit flies, and mice has been firmly established as mutations reducing the activity of the insulin-like receptor, phosphatidyl inositol 3'-kinase, and mTor all increase longevity. Also, over-expression of genes coding for certain antioxidant enzymes can increase longevity, but reduction in the activity of other antioxidant genes gives mixed results, so the role of oxidative stress in mammals during aging seems more tenuous (9,10). Increasing the expression of stress response proteins promotes longevity in invertebrate organisms (11), but their role in mammalian aging also remains undefined as circulating levels of Hsp70 are low in centenarians and their offspring (12).
Success in this research area was greatly stimulated by a series of Requests for Applications (RFA) issued by the National Institute on Aging (NIA) in 1992, 1998, and 2003 to identify what were called "longevity assurance genes." While the research funded by these RFAs was primarily focused on short-lived animal models, this success encouraged investigators and funding agencies to begin to focus on human longevity as well. For example, the goal of the NIA-funded Longevity Consortium is to identify specific genes and pathways that modulate human longevity. Concurrently, there are many epidemiological studies underway to identify genes associated with exceptional longevity in humans, e.g., in New England (13), Louisiana, Georgia, and in Askenazi Jews (14,15), to name a few American studies. Insights are coming from these studies with the discovery of alleles that associate with increased longevity in humans, and not surprisingly, many of these occur in genes for proteins involved in lipoprotein metabolism. Supercentenarians have also recently become of interest in efforts to discover what factors have been responsible for their ability to live to 110 years or more (16) (www.supercentenaraian-research-foundation.org).
What follows are two articles discussing the genetic basis of aging. The first article is a summary of a meeting of the Longevity Consortium summarizing recent progress in a variety of areas related to longevity, including mitochondrial function, telomere biology, caloric restriction, stress response, nuclear proteins, cell senescence, and epigenetic changes. The second article is a call for sequencing genomes of particular interest to biogerontologists, as the "biology of longevity ... has been neglected" in previous decisions about which organisms to sequence. Thus, it is hoped that these varied approaches to identify genes and pathways that associate with human longevity, as well as genes that correlate with unusual longevity in long-lived species, will help to more precisely define the roles of genetic background in human aging and longevity, and perhaps also in the development of age-related pathology.
References
| ||||||||||||||||||||||
| HOME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
