Showing papers in "Science of Aging Knowledge Environment in 2001"

Pleiotropy, Natural Selection, and the Evolution of Senescence

Abstract: A new individual entering a population may be said to have a reproductive probability distribution. The reproductive probability is zero from zygote to reproductive maturity. Later, perhaps shortly...

Selection for Delayed Senescence in Drosophila melanogaster

Abstract: Understanding the mechanism whereby the aging process is controlled has proven to be a uniquely difficult biological problem. Many theories have been put forth offering explanations for the phenomenon of senescence on a variety of different levels ranging from cellular, biochemical, and physiological to genetic and evolutionary. Many of these explanations are nonexclusive, which adds redundancy to confusion in considering the whole body of theory. Many of the cellular and/or biochemical mechanisms proposed amount to little more than detailed discussions of various possible gene end-products, which are themselves the subject of genetic and evolutionary theories. And even among these, no single theory predominates. J. B. S. Haldane (1941) and P. B. Medawar (1952) advanced the first theory of senescence incorporating a modem genetic and evolutionary perspective on the aging process. Their theory postulates the existence of specialized age-of-onset modifier genes which repress the action of other genes that are deleterious until an advanced age has been reached. Little harm results from the expression of the mutations then, however, and senescence gradually ensues with their derepression. In this theory, selection modifies life span by simply increasing or decreasing the period over which such modifiers are effective. Williams (19 57) later expanded on this, introducing the notion that the genes influencing senescence might themselves act pleiotropically with reciprocal effects at early and late ages. In this theory, the beneficial effects of genes early in life are weighed in evolution against their late life effects; youthful vigor must be accompanied by an early senescence and short life, while a delayed senescence and long life occur at the cost of youthful vitality. Apart from further extension of these ideas by Hamilton (1966) and Emlen (1 970), no new major theories of the evolution of senescence have arisen since Williams (1957). One reason for this may be that until recently, the few experimental tests performed contributed comparatively little substantiating information toward these theories. Early attempts at modifying life span through artificial selection include that of Glass (1960), who withheld mating in Drosophila to enforce an early versus late age-specific pattern of reproduction. This produced a slight increase in the longevity of late-reproducing lines. Wattiaux (1968) also found an increase in longevity in Drosophila under selection for an agespecific pattern of reproduction. This was followed by Sokal's (1970) study showing that continuous reproduction at an early age reduced median life span in Tribolium. Mertz (1975) found similar trends in an even later study. Taylor and Condra (1980) and Barclay and Gregory (1982) report changes in the longevity of Drosophila populations under rand K-selection or when exposed to predation. Concurrently with these, Lints and Hoste (1974, 1977) published the results of a well designed and extensive experiment that also selected for increased longevity in D. melanogaster through an early or late age-specific schedule of reproduction. But life span fluctuated wildly throughout the 13 generations of selection here, declining by 70% in the first few generations and then recovering. Further experiments (Lints et al., 1979)

Genetic Analysis of Life-Span in Caenorhabditis elegans

Abstract: Crosses between Bristol and Bergerac strains of the self-fertilizing hermaphroditic nematode Caenorhabditis elegans do not show the heterosis effects for life-span that complicate analysis of interstrain crosses with Drosophila or mice. Instead they yield F1 progeny with life-spans similar to those of the parent strains. By analysis of life-span variation among progeny F2 populations from such crosses and by two independent analyses of lifespans among recombinant inbred lines derived from F2 individuals by 18 rounds of self-fertilization, we estimate that the heritability of life-span in C. elegans is between 20% and 50%. Recombinant inbred lines show a range in mean life-spans of 10 days to 31 days compared to life-spans of about 18 days for each of the two parental strains. We conclude that life-span variation in C. elegans has a substantial genetic component and that this organism offers promising opportunities for selective breeding of longer-lived strains and genetic analysis of senescence. The extent to which genes determine life-span in animals remains controversial. For example, two recent studies suggest little or no genetic control of life-span in the Oregon R strain of Drosophila (1, 2). In contrast, another investigation led to estimates as high as 79% for heritability of life-span in mice (3). Direct genetic analysis of this question has been prevented so far by failure to identify specific life-span mutants. At the same time, selective breeding for naturally occurring life-span differences between laboratory strains of common experimental organisms has been hampered by heterosis effects: that is, the hybrid progeny from interstrain crosses live significantly longer than does either parent (3-5). An accepted explanation for the heterosis effects seen, for example, with Drosophila and mice is that being inbred, laboratory strains have become homozygous for recessive alleles that shorten life-span but are not selected against under laboratory conditions. Interbreeding of these strains restores heterozygosity in the F1 progeny, resulting in increased life-span. In hermaphroditic species that are predominantly or solely inbred, such as some snails (6) and nematodes (7), wild animals that are already homozygous at most or all loci might be expected to have evolved optimal life-spans. Therefore, maintenance of small laboratory populations should not markedly shorten life-span by inbreeding, and crosses between laboratory strains should show little or no heterosis effect. In this study we developed methods that improve the reproducibility of life-span determination in Caenorhabditis elegans. Using these methods we have demonstrated that no heterosis effects are observed in crosses between two strains, var. Bristol and var. Bergerac, which have been maintained as laboratory stocks since the 1940s. This characteristic simplifies estimation of life-span heritability, the component of life-span variation that is due to genetic rather than environmental facThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. ? 1734 solely to indicate this fact. tors. We have made heritability estimates from analysis of the increased variation in life-span among progeny F2 populations from interstrain crosses and from two separate analyses of lifespan in recombinant inbred (RI) lines derived from F2 individuals by repeated self-fertilization. The three analyses suggest that heritability of life-span is between 20% and 50%. The RI lines from these crosses include longer-lived strains that may be useful for further, more direct, genetic analysis of aging. MATERIALS AND METHODS Strains, Media, and General Techniques. Stocks of C. elegans were maintained at 20?C as described by Brenner (7) unless otherwise indicated. Wild-type strains included the N2 strain of var. Bristol (N7) and var. Bergerac (8) obtained from D. Hirsh. Escherichia coli strains used as food sources for C. elegans were OP50 (for growth on NGM agar plates) and B/r (for growth in liquid culture). Male and hermaphrodite master stocks were maintained for up to 8 months as dauerlarvae (9) on NGM plates sealed with Parafilm and kept at 16?C. Establishment of Survival Populations. Dauerlarvae were allowed to mature and reproduce for one generation on NGM agar plates, and at the fourth larval stage their F1 progeny were transferred to fresh NGM plates. Two days later these adult worms were used to start synchronous aging populations by transfer of appropriate parents (hermaphrodites and males for crosses; hermaphrodites alone for selfing) to fresh NGM plates preseeded with E. coli OP50. After 4-12 hr of egg laying, the adults were removed, and the synchronized F2 progeny were allowed to mature. This procedure was designed to eliminate possible effects of differences in parental age on progeny lifespan. After 3 days, F2 progeny in groups of 50 worms were suspended in S basal medium plus cholesterol (7) and transferred to Falcon plastic Petri plates containing 4 ml of the same medium with 109 E. coli B/r or OP50 per ml. Maintenance temperature and bacterial concentration were chosen to optimize fecundity (10). These survival populations were transferred daily for 5 successive days, by which time almost all worms are past reproductive age. Thereafter, populations were transferred thrice weekly until all worms had died. Criteria of Death. At each transfer of survival populations, the numbers of worms alive, dead, or lost were recorded. Criteria of death were: (a) lack of spontaneous movement, (b) no response when touched with a probe, (c) visible tissue degeneration, and (d) lack of osmotic turgor. Osmotic turgor was assayed by cutting worms that showed criteria a through C; cut living worms extrude body contents as a result of turgor pressure. The "lost" category included worms killed erroneously in checking for turgor pressure or unintentionally as a result of poor technique, worms killed by premature hatching of eggs Abbreviation: RI, recombinant inbred. t Current address: Dept. of Molecular Biology and Biochemistry, University of California, Irvine, CA 92717.

Effects of Food Restriction on Aging: Separation of Food Intake and Adiposity

Abstract: Restricted feeding of rodents increases longevity, but its mechanism of action is not understood. We studied the effects of lifelong food restriction in genetically obese and normal mice of the sam...

Evolution of Human Longevity and the Genetic Complexity Governing Aging Rate

Abstract: Genetic complexity of processes governing the aging rate of man was estimated by determining the maximum rate lifespan has evolved along the hominid ancestral-descendant sequence. Maximum lifespan potential was found to have increased approximately 2-fold over the past 3 million years, reaching a maximum rate of increase of 14 years per 100,000 years about 100,000 years ago. It is estimated that about 0.6% of the total functional genes have received substitutions leading to one or more adaptive amino acid changes during this 100,000-year time-period. This suggests that aging is not the result of an expression of a large number of independently acting processes. Instead, primary aging processes appear to exist where only a few genetic changes are necessary to decrease uniformly the aging rate of many different physiological functions.

Cortical basal ganglionic degeneration

Abstract: In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a retired mason's assistant with cortical basal ganglionic degeneration (CBGD). CBGD is an extremely rare neurodegenerative disease that is categorized under both Parkinsonian syndromes and frontal lobe dementias. It affects men and women nearly equally, and the age of onset is usually in the sixth decade of life. CBGD is characterized by Parkinson's-like motor symptoms and by deficits of movement and cognition, indicating focal brain pathology. Neuronal cell loss is ultimately responsible for the neurological symptoms.

The Maintenance of the Accuracy of Protein Synthesis and Its Relevance to Aging

Abstract: The ways in which the accumulation of mutations might contribute to the process of aging in higher organisms or in individual clones of cells has been discussed at length. No corresponding treatmen...

Using yeast to discover the fountain of youth.

Abstract: The budding yeast Saccharomyces cerevisiae has long served as a model organism for the study of basic cellular processes. Its short generation time, well-established molecular genetics, and fully sequenced genome have made this organism a favorite of researchers in diverse fields. Much of the information obtained has been shown to apply to higher eukaryotes, including humans. Recently, researchers have begun using yeast to tackle one of the outstanding questions in science: How and why do organisms age? The identification of individual genes in yeast that can affect the aging process itself has elevated this single-celled fungus to full contender status in the aging field. In this Perspective, we present two fundamentally different measures of aging in yeast: replicative life-span and stationary phase survival (chronological life-span). We describe the benefits and limitations of each and present models that attempt to explain these "aging" phenomena. Finally, we present compelling evidence that the use of yeast as a model system will ultimately prove beneficial to the study of human aging.

Biomarkers of aging.

Abstract: As a subgenre of biogerontology, biomarker research has developed a thoroughly tarnished reputation, and those who believe that biomarker studies should be a major focus in experimental aging research must now try to prove to their doubting colleagues that under the tarnish lies true metal, rather than more layers of tarnish. In this Perspective, the author argues that the discovery of biomarkers of aging is possible.

Does caloric restriction in the laboratory simply prevent overfeeding and return house mice to their natural level of food intake

Abstract: Some researchers have speculated that the senescence-retarding effect of caloric restriction on laboratory rodents is an artifact of overfeeding under captive conditions. The argument posits that mice in nature are chronically calorically restricted; therefore, the typical laboratory protocol of restricting animals to 60% of their ad lib food intake more realistically replicates life in the field: the conditions under which the animals' physiology has been designed by natural selection to thrive. The hypothesis concludes that instead of comparing control animals with restricted animals, we are in fact comparing overfed animals with adequately fed ones, and, not surprisingly, the overfed ones die younger. In this Perspective, the author discusses the merits and drawbacks of this hypothesis in light of energy consumption data for various types of mice.

The two faces of oxygen.

Abstract: Scientists have suspected for half a century that reactive oxygen species (ROS) are major instigators of aging. These byproducts of metabolism batter a wide variety of molecules within cells, and an organism's ability to repair the damage declines with age. Now, some researchers say they're wrapping up the case against ROS, at least for lower organisms. By counteracting this destruction with protective enzymes, researchers have extended the average lifetime of some invertebrates. But the verdict isn't in yet, because recent studies have revealed that ROS also make key contributions to normal cell signaling.

Aging Can Be Genetically Dissected Into Component Processes Using Long-Lived Lines of Caenorhabditis elegans

Abstract: The aging process has been dissected by analysis of genetic variants of the nematode Caenorhabditis elegans. Long-lived recombinant inbred lines were generated; some of these lines have mean and maximum life spans up to 70% longer than wild type. Longer life results from a slowing of the characteristic exponential increase in mortality rate that is typical of aging populations in all species. The length of developmental periods and the length of the reproductive period are unrelated to increased life span. Lengthened life is due entirely to an increase in postreproductive life span. Development, reproduction, and life span are each under independent genetic control. General motor activity decays linearly with chronological age in all genotypes. The decay in general motor activity is correlated with and a predictor of life span, suggesting that both share at least one common rate-determining component.

Correlation Between Deoxyribonucleic Acid Excision-Repair and Life-Span in a Number of Mammalian Species

Abstract: The ability of fibroblasts to perform unscheduled DNA synthesis (a measure of excision-repair) after UV irradiation was measured radioautographically for seven species at several times after several UV fluences. Both the initial rate and the maximum incorporation of [3H]dThd increased with the life-span of the species (shrew, mouse, rat, hamster, cow, elephant, man). Unscheduled DNA synthesis was approximately proportional to the logarithm of life-span.

Laboratory Evolution of Postponed Senescence in Drosophila melanogaster

Abstract: Evolutionary genetics seems to have found the fundamental cause of senescence: the decline in the sensitivity of natural selection to gene effects expressed at later ages in most populations of organisms with separate somatic and germline tissue. (Here "senescence" refers to decline in age-specific fitness-components after the onset of reproductive maturity.) This idea traces back to Haldane (1941) and Medawar (1946, 1952), with considerable elaboration and elucidation since then (Williams, 1957; Hamilton, 1966; Edney and Gill, 1968; Emlen, 1970; Charlesworth and Williamson, 1975; Charlesworth, 1980; Rose, 1983a). While there are still clear limitations to the mathematical formulation of this theory (cf. Hamilton, 1966; Charlesworth, 1980), the basic formal analysis leads to a straightforward conclusion: the first partial derivative of fitness with respect to appropriately scaled changes in age-specific life-history characters usually declines in magnitude with the age of these changes. The force of natural selection thus declines with age. This overall theory and its particular subsidiary variants lead to a number of empirically testable corollaries (Rose, 1983a, 1983b). Some of these corollaries are specific to the subsidiary variants of the theory (Rose and Charlesworth, 1980, 1981a, 1981b; Rose, 1983b), sothattests of them individually do not test the theory as a whole. Fortunately, there are two corollaries which follow from the general theory itself: the reproductive schedule of an outbred population will give rise to natural selection acting to (i) accelerate senescence in populations with a relatively earlier age of reproduction and (ii) postpone senescence in populations with a relatively later age of reproduction (Edney and Gill, 1968; Rose, 1983a). The former prediction has been corroborated by Sokal (1970) using Tribolium castaneum, while the latter has been corroborated by Wattiaux (1968a, 1968b) and by Rose and Charlesworth (1980, 198 lb), using Drosophila species. Once a theory has been well-developed mathematically and then empirically corroborated, attention turns to experiments in which the theory either is not clearly corroborated or is ostensibly refuted. It would be misleading to claim that all relevant experimental results directly corroborate the evolutionary theory of senescence. Sokal (1 970) and Mertz (1975) using Tribolium castaneum and Taylor and Condra (1980) using Drosophila pseudoobscura found heterogeneity between lines in experiments with replication, such that some lines did not exhibit the predicted response to the imposed selective regime. Taylor and Condra (1980) also found a difference in the response of the sexes which was later attributed to the pattern of female mating preference (Taylor et al., 1981). More problematic still are the studies from the Lints laboratory, one of which failed to obtain a direct response to artificial selection for longevity (Lints et al., 1979), while another gave puzzling fluctuations in life-history attributes (Lints and Hoste, 1974, 1977). Lints (1978, 1983) has made a great deal of these problems, contending that they cast doubt on all proposed evolutionary theories of senescence. While it can be argued that these puzzling results are due to technical artifacts such as inbreeding, genetic disequilibrium, and inadequate controls (cf. Rose and Charlesworth, 1981b), the only ef-

Identifying differentially expressed genes in cDNA microarray experiments authors.

Abstract: H. Bengtsson is in the Department of Mathematical Statistics, Centre for Mathematical Sciences, Lund University, Sweden. B. Calder is at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. I. S. Mian is in the Department of Radiation Biology and Environmental Toxicology, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. M. Callow and E. Rubin are in the Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. T. P. Speed is in the Department of Statistics, University of California, Berkeley, CA, USA,. and the Division of Genetics and Bioinformatics, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. E-mail: SMian@lbl.gov

More than a sum of our cells.

Abstract: Cells in the body grow and die, cells in lab dishes grow and die, and individual organisms grow and die. The parallels seem maddeningly obvious, but scores of scientists still labor to draw the correct connections, to uncover the mechanisms that underlie aging in cell culture flasks and in whole animals. Do our cells stop growing, quit working, cease dividing, or start dying as we age? Do we die when our cells do, or are we somehow more than the sum of our cells? For decades, scientists have searched for evidence that links changes in cell growth, cell function, cell division, and cell death to the phenomenon we call aging. Although definitive proof eludes them, researchers continue to conduct experiments in tissue culture and in animal models, amassing information that points us toward a greater understanding of what aging is--and is not.

Aging research grows up.

Abstract: Long viewed as an insoluble enigma, aging is shedding its cloak of mystery as scientists start to understand why and how we age. Many studies support the theoretical argument that aging occurs because natural selection weakens with age, leaving us vulnerable to harmful, late-acting genes. As for what causes aging, scientists have narrowed the pack of candidates to a handful, including free radicals and reactions between glucose and proteins. In recent decades, many mechanisms for lengthening life in animals have come to light. By extending this research, scientists may be closing in on ways to lengthen the human life-span.

Detangling Alzheimer's disease.

Abstract: Alzheimer's disease (AD) afflicts 4 million people in the United States and is expected to strike 14 million by the year 2050, as the population ages. Researchers are scrambling to find genetic risk factors, decipher disease mechanisms, and develop reliable diagnostic tests that detect the illness at its earliest, potentially most treatable stage. Using these findings, they hope to devise new therapeutic approaches. Current clinical trials are testing novel techniques that stall or reverse AD-like neuropathology in mice.

The hunt for a cure for Parkinson's disease.

Abstract: Several exciting new scientific advances have been made in the past decade toward both understanding the causes of and finding a cure for Parkinson's disease. Heartened by an acceleration in research findings in the past several years, the government has recently called for an infusion of funds from both the National Institutes of Health and private foundations into this burgeoning area of biomedical research. Most currently available conventional treatments for the disease only temporarily delay symptom presentation while doing nothing to halt disease progression. However, the rapidly accelerating pace of research in this field has left researchers hopeful that Parkinson's will be the first major age-related neurodegenerative disease for which we have a viable cure. In this article, advances in various areas of Parkinson's disease research are reviewed.

Life extension--our salvation or our ruin?

Abstract: Extending the human life-span will have far-reaching political and sociological implications and presents countless ethical conundrums. In an economy based on scarcity, who will receive life-extens...

Alzheimer's Disease: A two-hit wonder?

Abstract: The accumulation of senile plaques and neurofibrillary tangles in the brain marks the onset of Alzheimer's Disease (AD) (see "Detangling Alzheimer's Disease") But researchers aren't sure what caus

Bye-bye Birdie: Short-lived fryers less resistant to molecular pecking than long-lived fliers

Abstract: Our feathered friends might be hiding a few antiaging tricks under their wings: New results suggest that long-lived birds withstand damage caused by reactive oxygen molecules better than either mam...