Rates of mortality in populations of Caenorhabditis elegans.
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Aging↗
Biomedical subjects
G J Lithgow
Publications and source records attributed to G J Lithgow.
Mortality rates in a genetically heterogeneous population of Caenorhabditis elegans.
Age-specific mortality rates in isogenic populations of the nematode Caenorhabditis elegans increase exponentially throughout life. In genetically heterogeneous populations, age-specific mortality increases exponentially until about 17 days and then remains constant until the last death occurs at about 60 days. This period of constant age-specific mortality results from genetic heterogeneity. Subpopulations differ in mean life-span, but they all exhibit near exponential, albeit different, rates of increase in age-specific mortality. Thus, much of the observed heterogeneity in mortality rates later in life could result from genetic heterogeneity and not from an inherent effect of aging.
Aging↗
Thermotolerance of a long-lived mutant of Caenorhabditis elegans.
Age-synchronous cohorts of Caenorhabditis elegans were grown at 20 degrees C, then stressed at 30 degrees C or 35 degrees C. Intrinsic thermotolerance of wild type and age-1 mutant strains was assessed by measuring either progeny production or survival. In addition to increased life span (Age), mutation of age-1 results in a highly significant increased intrinsic thermotolerance (Itt) as measured by survival at 35 degrees C. Mean survival of Age strains is approximately 45% longer than that of non-Age strains for both sterile and nonsterile worms. Thermotolerance declines across the life span of both Age and non-Age strains, but Itt was observed at almost all ages. Unstressed age-1 animals showed a consistent and significant fertility deficit. Short thermal stresses can cause a dramatic reduction in progeny production for both Age and non-Age genotypes. Mutants of age-1 showed a small but consistent increased thermotolerance as measured by fertility. We propose that the enhanced ability of Age strains to cope with environmental stress may be mechanistically related to their lower age-specific mortality rates.
Aging↗
Comparing mutants, selective breeding, and transgenics in the dissection of aging processes of Caenorhabditis elegans.
The genetic analysis of aging processes has matured in the last ten years with reports that long-lived strains of both fruit flies and nematodes have been developed. Several attempts to identify mutants in the fruit fly with increased longevity have failed and the reasons for these failures are analyzed. A major problem in obligate sexual species, such as the fruit fly, is the presence of inbreeding depression that makes the analysis of life-history traits in homozygotes very difficult. Nevertheless, several successful genetic analyses of aging in Drosophila suggest that with careful design, fruitful analysis of induced mutants affecting life span is possible. In the nematode Caenorhabditis elegans, mutations in the age-1 gene result in a life extension of some 70%; thus age-1 clearly specifies a process involved in organismic senescence. This gene maps to chromosome II, well separated from a locus (fer-15) which is responsible for a large fertility deficit in the original stocks. There is no trade-off between either rate of development or fertility versus life span associated with the age-1 mutation. Transgenic analyses confirm that the fertility deficit can be corrected by a wild-type fer-15 transformant (transgene); however, the life span of these transformed stocks is affected by the transgenic array in an unpredictable fashion. The molecular nature of the age-1 gene remains unknown and we continue in our efforts to clone the gene.
Aging↗
The search for the genetic basis of aging: the identification of gerontogenes in the nematode Caenorhabditis elegans.
Study of C. elegans has provided much information for gerontologists. The influence of the genome on life span is clearly observable, and at least one gerontogene, age-1, has been defined. Data relating to important evolutionary questions has emerged and will continue to be used in testing current hypotheses. We are using an approach unbiased by theoretical constraints to delineate aging processes simultaneously at the molecular and organismal levels. Much remains to be discovered before fundamental questions posed in this article are answered to a satisfactory degree. The immediate agenda is the identification and isolation of gerontogenes which influence life span in invertebrate models. This work is well in hand and will lead to the unraveling of specific life-span-determining processes. At this point we may be able to predict whether analogous processes also limit life in mammals. If we are fortunate and aging processes exhibit evolutionary conservation, many exciting possibilities await. Molecular tools provided by the invertebrate system can then be used to isolate homologous mammalian gerontogenes that could be subsequently utilized in highly targeted attempts to intervene in mammalian aging. This offers the most direct strategy for identifying life-span prolongation genes in humans.
Aging↗
P13-kinase inhibition induces dauer formation, thermotolerance and longevity in C. elegans.
The effects of 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), an inhibitor of mammalian phosphatidylinositol 3-OH kinase, was tested on an insulin signaling-like pathway in the nematode Caenorhabditis elegans. Populations of C. elegans were treated with LY294002 at different stages of the life cycle, and its effects on development, thermotolerance and longevity were assessed. At concentrations of 160 microM and above, LY294002 significantly induced both dauer formation and thermotolerance. Treatment of adult worms also resulted in a small, but significant, increase in life span. The results presented are consistent with the view that a neuroendocrine signaling pathway functions in adult worms to determine stress resistance and longevity.
Animals↗