Showing papers in "Science of Aging Knowledge Environment in 2002"

The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis

Abstract: Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stre...

Life-Span Study of SPF Fischer 344 Male Rats Fed Ad Libitum or Restricted Diets: Longevity, Growth, Lean Body Mass and Disease

Abstract: A life-span study was carried out on longevity, pathologic lesions, growth, lean body mass, and selected aspects of muscle of barrier-maintained SPF Fischer 344 rats fed either ad libitum (Group A)...

Aging: A Theory Based on Free Radical and Radiation Chemistry

Abstract: This 1956 paper describes a theory about mechanisms of aging that is based on free radical chemistry: "Aging and the degenerative diseases associated with it are attributed basically to the deleter...

Ovarian and Steroidal Influences on Neuroendocrine Aging Processes in Female Rodents

Abstract: Some mammalian aging processes involve effects of steroids on the brain and pituitary. An ovary-dependent, neuroendocrine aging syndrome of laboratory rats and mice is described in this article. Th...

Three Mutants That Extend Both Mean and Maximum Life Span of the Nematode, Caenorhabditis elegans, Define the age-1 Gene

Abstract: Long-lived mutants in the nematode Caenorhabditis elegans have been studied to determine if the mutations responsible for extended life were allelic. Three of four mutant strains studied (MK31, MK542, MK546) contain recessive mutations that significantly lengthen life; MK542 and MK546 consistently fail to complement the long life phenotype of age-1 and are therefore allelic. MK31, although longer lived than wild type, is equivocal, in some cases failing to complement age-1 but not in others. All three long-lived strains have reduced hermaphrodite self-fertility and also fail to complement for this presumed pleiotropic effect of the age-1 mutation. Each of these three strains also contains an independent mutation at unc-31 IV. Since the mutants were isolated in the same mutant hunt (Klass, 1983) using protocols that did not guarantee independence, the mutations cannot be assumed to be independently isolated.

Detection of Inactive Enzyme Molecules in Ageing Organisms

Abstract: Using immunochemical techniques, evidence is obtained that older nematodes (Turbatrix aceti) contain two populations of enzyme molecules—one active and the other totally inactive.

Murine Chromosomal Regions Correlated With Longevity

Abstract: In this longevity analysis of 360 BXD recombinant inbred female mice (20 different strains), 2 strains had very significantly shorter survival and 1 strain had very significantly longer survival than the other 17 strains; 4 other strains had less significant lengthening of survival compared to the other 13 strains in a proportional hazards model of survival. Mean survival on the shortest lived strain was 479 days; on the longest lived strain the mean survival was almost double (904 days). Ranges of survival within strain were very large (averaging 642 days), and strain accounted for only 29% of the variation in survival, showing that there are important environmental and/or special developmental effects on longevity even in this colony housed in a single room. Each strain had been typed for markers of 141 regions on 15 chromosomes; 101 of these markers had distinguishable distributions on the 20 strains. The two shortest lived strains had the same alleles for 63% of the markers. The single region most significantly correlated with survival (marked by P450, Coh, Xmmv-35 on chromosome 7) divided the mice into two groups with survival medians which differed by 153 days (755 days for mice with a B genotype; 602 days for mice with a D genotype). Evaluated individually, 44% of the genetic markers (including some markers on 11 of 15 chromosomes with any markers typed) were found to be significantly correlated with survival (P less than 0.05) although one would only expect 5% of the markers to be significant by chance. While studies of many markers should adjust for the multiple comparisons problem, one interpretation of these crude P values is that any experiment with only one of these "significant" markers typed would be likely to conclude that the marker was a significant predictor of survival. Two types of multiple regression models were used to examine the correlation with survival of groups of genes. When a proportional hazards model for survival was done in terms of genotype regions, a six genetic region model best correlated with survival: that marked by P450, Coh, Xmmv-35 on chromosome 7 (B allele lives longer), Ly-24 on chromosome 2 (B allele lives longer), beta 2M and H-3 on chromosome 2 (D allele lives longer) Lamb-2 on chromosome 1 (D allele lives longer), Ltw-4 on chromosome 1 (B allele lives longer), and the Igh area of chromosome 12 (Igh-Sa4, Igh-Sa2, Igh-Bgl, Igh-Nbp, Igh-Npid, Igh-Gte, Odc-8, and Ox-1; D allele lives longer).(ABSTRACT TRUNCATED AT 400 WORDS)

The Naked Mole Rat--A New Record for the Oldest Living Rodent

Abstract: We report a new record for the world's longest-lived rodent, a male naked mole rat (Heterocephalus glaber). On the basis of his weight at capture, this animal was approximately 1 year old when coll...

Innate immunity, local inflammation, and degenerative disease.

Abstract: The brain lesions associated with Alzheimer's disease (AD), which are referred to as neurofibrillary tangles and senile plaques, are characterized by the presence of a broad spectrum of inflammatory mediators. Surprisingly, these mediators, which include complement proteins, inflammatory cytokines, prostaglandins, and acute phase reactants such as C-reactive protein and amyloid P, are produced by resident brain cells, including neurons. Although secondary to the fundamental pathology caused by the presence of tangles and plaques, there is strong evidence that inflammation exacerbates the neuronal loss. In particular, AD lesions show evidence of self-attack by the complement system--a part of the immune system that normally functions to rid the body of invading pathogens. However, the lesions are devoid of significant T cell infiltration, a hallmark of an inflammatory immune response, and antibodies. We define this phenomenon as autotoxicity to distinguish it from classical autoimmunity, in which the body raises antibodies to normal endogenous macromolecules. Locally produced inflammatory mediators have also been identified in atherosclerotic plaques, along with evidence of complement self-attack. As was previously shown for heart attacks, epidemiological evidence indicates that extended use of nonsteroidal anti-inflammatory drugs (NSAIDs) results in a reduced risk of AD. NSAIDs inhibit the production of prostaglandin inflammatory mediators, but powerful new therapeutic agents might be developed by targeting more critical inflammatory mechanisms, especially the complement system.

Lipid peroxidation and the aging process.

Abstract: Consistent evidence supports the hypothesis that a progressive accumulation of oxidative damage to important cellular molecules is a fundamental mechanism involved in most senescence-associated alterations. Oxidative damage occurs when free radicals produced within an organism are not completely destroyed by the appropriate endogenous defense systems. Because lipids are a major component of living organisms and probably the first easy target of free radicals once they are produced, lipid peroxidation might play an important role in initiating and/or mediating some aspects of the aging process. It has been widely demonstrated that there is an age-associated increase in the steady-state concentrations of lipid peroxidation products. However, establishing the involvement of this phenomenon in the pathogenesis of the aging process has not been an easy task. The recent development of more reliable techniques to measure lipid peroxidation, together with more well-defined animal models of aging, should be of great help in future studies in this field. The current evidence for the presence and importance of lipid peroxidation in the aging process is discussed in this review.

Mitochondrial bioenergetics, aging, and aging-related disease.

Abstract: In this Perspective, the author discusses some of the bioenergetic consequences of the various alterations in mitochondrial function that have been hypothesized to be associated with human aging and aging-related disease. Special focus is afforded to neurodegenerative disease.

Effect of Dietary Restriction on Liver Protein Synthesis in Rats

Abstract: At 6 wk of age, male Fischer F344 rats were fed a purified, casein-based diet either ad libitum or in the amount of 60% of the diet consumed by the rats fed ad libitum (restricted diet). Hepatocyte...

Sailing to Byzantium

Abstract: An aged man is but a paltry thing, A tattered coat upon a stick, unless Soul clap its hands and sing, and louder sing For every tatter in its mortal dress, Nor is there singing school but studying Monuments of its own magnificence; And therefore I have sailed the seas and come To the holy city of Byzantium. O sages standing in God's holy fire As in the gold mosaic of a wall, Come from the holy fire, perne in a gyre, And be the singing‐masters of my soul. Consume my heart away; sick with desire And fastened to a dying animal It knows not what it is; and gather me Into the artifice of eternity.

No truth to the fountain of youth.

Abstract: The essay "No Truth to the Fountain of Youth" was published in the Scientific American special issue The Science of Staying Young in June 2002. In this article, the authors explain why it is import...

A Test of Evolutionary Theories of Senescence

Abstract: Senescence is the post-maturation decline in survivorship and fecundity that accompanies advancing age. Two main evolutionary theories have been proposed to account for senescence. (1) The mutation...

Cancer and aging: yin, yang, and p53.

Abstract: The author discusses a recent paper published in Nature that shows that a hyperactive allele of the tumor suppressor p53 leads to the development of some premature aging phenotypes in mice. This new discovery is discussed in light of previous findings related to mechanisms of aging.

The Werner Syndrome Helicase-Nuclease--One Protein, Many Mysteries

Abstract: Werner syndrome (WS) is an autosomal recessive condition characterized by an early onset of age-related symptoms that include ocular cataracts, premature graying and loss of hair, arteriosclerosis and atherosclerosis, diabetes mellitus, osteoporosis, and a high incidence of some types of cancers. A major motivation for the study of WS is the expectation that elucidation of its underlying mechanisms will illuminate the basis for "normal" aging. In 1996, the gene responsible for the syndrome was positionally cloned. This advance launched an explosion of experiments aimed at unraveling the molecular mechanisms that lead to the WS phenotype. Soon thereafter, its protein product, WRN, was expressed, purified, and identified as a DNA helicase-exonuclease, a bifunctional enzyme that both unwinds DNA helices and cleaves nucleotides one at a time from the end of the DNA. WRN was shown to interact physically and functionally with several DNA-processing proteins, and WRN transgenic and null mutant mouse strains were generated and described. The substantial number of excellent reviews on WRN and WS that were published in the past 2 years (1-7) reflects the rapid pace of advances made in the field. Unlike those comprehensive articles, this review focuses on the biochemistry of the WRN protein and some aspects of its cell biology. Also considered are the putative functions of WRN in normal cells and the consequences of the loss of these functions in WS.

Single-cell antisense RNA amplification and microarray analysis as a tool for studying neurological degeneration and restoration.

Abstract: Neurodegenerative diseases typically affect subpopulations of neurons. Characterizing these vulnerable cells and identifying the factors that make them susceptible to damage while neighboring cells remain resistant are essential to the understanding of molecular pathogenesis that underlies neurodegenerative diseases. Classically, molecular analysis of the central nervous system involves the identification and isolation of an anatomic region of interest; next, the relevant tissue is pulverized, and the resulting homogenate is analyzed. Although this method provides useful data, its effectiveness diminishes when used in areas of high cellular diversity or in instances in which one cell type is lost as a consequence of selective cell death or quiescence. A technique that affords the ability to assess molecular events in a very precise anatomical site would provide a powerful tool for this research discipline. In this review, we discuss the amplification of messenger RNA from single neural cells and the subsequent use of the RNA to probe DNA microarrays in an effort to create cell-specific molecular profiles. Specifically, recent work in single-cell expression profiling in Alzheimer's and Huntington's diseases is discussed. We also review some new work with neural stem cells and their application to restorative neurobiology. Finally, we discuss the use of cell-specific molecular profiles to better understand the basics of neuronal cell biology.

Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease

Abstract: An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD.

Hematopoietic Stem Cells and Aging

Abstract: Hematopoiesis is a process by which a single cell--called a hematopoietic stem cell (HSC)--has the proliferative potential to give rise to all of the major lineages of blood and immune cells. Stem ...

Position Statement on Human Aging

Abstract: Fifty-one top researchers in the field of aging collaborated to create this position paper. It describes what scientists know and do not know about intervening in human aging, and includes informat...

Genes, culture, and aging flies--what the lab can and cannot tell us about natural genetic variation for senescence.

Abstract: Model organisms cultured in the lab provide a powerful way to explore basic biological processes. However, lab culture can select for high early fecundity and dramatically shorten the life-span of lab organisms. Studies that use these short-lived organisms to identify aging-related genes might identify genes that simply restore the organism's original life-span. These results might not be fully relevant to wild populations. Experiments that reduce selection for shorter life-span or seek genes in naturally long-lived cohorts should lead to a more accurate understanding of aging.

Mitigating the tithonus error: genetic analysis of mortality phenotypes.

Abstract: Summarizing an organism's age at death in terms of the mean or maximum life-span is the most popular way to describe genetic effects on aging. In this Perspective, the author describes a new study with the fly Drosophila melanogaster, in which another type of measure is also used: the age-dependent risk of death, or age-specific mortality. Changes in age-specific mortality reflect the underlying physiological deterioration of an organism as it ages. Thus, the author argues that these changes provide a phenotype that is ideal for the genetic analysis of aging.

Subfield history: Caenorhabditis elegans as a system for analysis of the genetics of aging.

Abstract: This article reviews key events in the genetic analysis of aging in the worm. The events are presented in the form of a timeline and include landmark papers, key meetings, and the development of im...

Wake up and smell the maillard reaction.

Abstract: The chemical reactions that occur when foods are browned during processing at high temperature also occur in the body during the natural aging process. Such reactions proceed at an accelerated rate in certain pathologies, such as diabetes, renal disease, atherosclerosis, and neurodegenerative diseases. A study now reveals that the consumption of foods rich in browned and oxidized products (so-called glycotoxins) induces a chronic inflammatory state in diabetic individuals. The study reveals a novel aspect at the interface between nutrition and disease, which might be especially relevant for the elderly and those with impaired renal function.

Regulation of aging by germline stem cells.

Abstract: The author discusses a recent paper published in Science (see Arantes-Oliveira) that shows that germline stem cells in the worm Caenorhabditis elegans send a signal to a steroid hormone receptor an...

Deciphering the gene expression profile of long-lived snell mice.

Abstract: In a recent publication, gene expression profiling experiments for the long-lived Snell dwarf mouse were reported. In this Perspective, the author argues that although the authors have developed a ...