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Exp Gerontol 1997 Jan;32(1-2):11-22
Institute for Behavioral Genetics, University of Colorado, Boulder 80309, USA.
Genetics is an important tool for identifying key molecular events that are involved in specifying biological functions. Genetic approaches have been used repeatedly to understand diverse biological phenomena: oncogenesis, development, and the cell cycle, but have only recently been applied to the analysis of organismic aging and senescence. The power of the genetic approach stems from two facts. First, genetic analyses allow the integration of phenomena that are analyzed at many levels of observation from the molecule to the intact organism, and second, genetics has the real power to reveal causality by factors that are not dependent upon the prejudice of the investigator. I discuss several areas where genetics has been fruitfully applied to the study of the aging processes: human genes identified by "segmental progeroid" mutations, neurological diseases of the elderly, the limited proliferative life span of human somatic cells in tissue culture, studies on the life span of the mouse, and genetic analysis of life span in shorter lived metazoans (Drosophila melanogaster and Caenorhabditis elegans), and the yeast Saccharomyces cerevisiae.
Metabolism 1997 Aug;46(8):851-856
Abdenur JE, Brown WT, Friedman S, Smith M, Lifshitz F
Miami Children's Hospital, FL, USA.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition with an unknown molecular defect. Patients with HGP progressively develop failure to thrive (FTT), alopecia, loss of subcutaneous fat, scleroderma, stiffening of various joints, and severe atherosclerosis. The median life span is 13 years, and the main cause of death is cardiovascular complications. There are few reports of endocrine and metabolic studies because of the rarity of this condition, and the response to long-term growth hormone (GH) treatment has not been described. We report the results of endocrine and metabolic studies performed to investigate the etiology of growth failure in five patients with HGP. Additionally, the response to nutritional therapy (NT) and GH treatment in three of these patients is presented. Our results suggest that elevated GH levels are characteristic of this disease and that an elevated basal metabolic rate (BMR) could be the cause of the FTT seen in HGP. Nonaggressive NT slightly improved weight gain and growth velocity (GV). Combined NT and GH treatment in three patients improved the GV, increased the levels of growth factors, and paradoxically resulted in decreased BMRs. However, the response to these therapies decreased over time and did not seem to prevent the progression of atherosclerotic disease.
Exp Gerontol 1997 Jan;32(1-2):65-78
Harrison DE, Roderick TH
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
In both mice and men, during the adult life span, aging causes an exponential increase in vulnerability to almost all pathologies. Thus, aging is a serious public health problem. Altering the basic mechanisms that control normal aging would be a powerful approach to reduce damage from aging processes, so research identifying these mechanisms is of vital importance. Because life spans are determined by the first biological system to malfunction, it is likely that basic mechanisms are involved in life span extension of animals already having maximum normal life spans for the species. When life spans of a species are extended, all biological systems must function for unusually long times. If there are a limited number of genes for basic mechanisms that control aging rates in multiple biological systems, then life spans can be extended relatively easily. If not, extending maximum life spans would require changes in impractically large numbers of genes, all genes involved in functional life spans of every biological system. In fact, life spans appear to increase rapidly during evolution, suggesting that changes in only a few genes are required. These genes are likely to control underlying mechanisms timing aging in multiple biological systems. The purpose of selection for increased life span is to identify these genes. An important potential problem is that all species have many defective genetic alleles that can cause early disease and death. Selection studies must be designed to distinguish between altering basic mechanisms of aging, and simply avoiding early pathologies due to defective alleles. Animal models that are short lived for their species should be avoided, because their deaths almost always result from genetic defects unrelated to mechanisms of normal aging. During selection, alleles not causing early pathologies may appear to increase life spans by replacing defective alleles in genetic regions linked to early pathologies; however, these affect early disease, not basic mechanisms of aging. A more subtle potential problem is that caloric restriction increases life spans in mice. Selection for long lived mice should focus on more basic mechanisms than breeding mice that voluntarily consume fewer calories. The fact that aging rates in different biological systems are not necessarily coordinated in different individuals suggests that normal aging is timed by more than one mechanism. Thus, the objective in selection for maximum longevity is to capture the entire set of alleles that increase longevity in a species. Wild populations are not practical to use, despite some theoretical advantages, as genes retarding aging would be confounded with those reducing the stress of captivity. Currently we use four-way crosses of inbred strains that represent maximal genetic diversity. Genetic regions important in increasing longevity will be identified using microsatellite markers distinguishing each of the four starting strains over the entire genome. Other genetic techniques proven useful for studying characteristics that are quantitatively controlled by multiple genes may also be useful in studying mechanisms timing aging; these techniques include diallele crosses, recombinant inbred lines, bilineal congenic lines and correlated genetic markers.
Exp Gerontol 1997 Jan;32(1-2):111-116
Hosokawa M, Abe T, Higuchi K, Shimakawa K, Omori Y, Matsushita T, Kogishi K, Deguchi E, Kishimoto Y, Yasuoka K, Takeda T
Department of Senescence Biology, Kyoto University, Japan.
The Senescence-Accelerated Mouse (SAM) was established by inbreeding and pedigree selection based on the life span, degree of senescence, as well as the incidence and degree of several age-associated disorders. At first, SAM strains were developed under conventional conditions, but now some strains are also maintained under specific pathogen-free conditions. There are many methods used to maintain such strains of mice; our methods will be introduced as one example of how to develop and maintain strains of mice used in aging research.
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