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1 Louisiana State University Health Sciences Center, New Orleans.
2 National Institute on Aging, Bethesda, Maryland.
3 University of Connecticut Health Center, Farmington.
4 Rutgers University, New Brunswick, New Jersey.
5 University of Michigan, Ann Arbor.
6 Albert Einstein College of Medicine, Bronx, New York.
7 University of Salzburg, Austria.
8 The Pennsylvania State University, State College.
9 Institute for Basic Research, Staten Island, New York.
10 Virginia Commonwealth University, Richmond.
11 University of Alabama, Birmingham.
12 University of Illinois, Chicago.
Note: The original corresponding author is S. Michal Jazwinski, PhD, Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido St., Box P7-2, New Orleans, LA 70112. E-mail: sjazwi{at}lsuhsc.edu, but please address correspondence to: Huber R. Warner, PhD, College of Biological Sciences, 1475 Gortner Ave., University of Minnesota, St. Paul, MN 55108. E-mail: warne033{at}umn.edu
THE Biological Sciences Section (BSS) program was organized around the theme of the 57th Annual Meeting of The Gerontological Society of America: "Promoting the Health of an Aging Population." This article provides a brief summary of the 12 BSS symposia. The organizer of this program was Dr. Michal Jazwinski, Louisiana State University Health Sciences Center, New Orleans.
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BIOLOGY FOR NON-BIOLOGISTS: USE OF MODEL ORGANISMS TO STUDY AGING |
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 Top Biology for Non-Biologists: Use... Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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This symposium, targeted to an audience of non-biologists, briefly described how animal models are used to elucidate aging mechanisms that might also apply to humans. It also documented the observation that manipulations that increase longevity often extend health span as well. A variety of genetic and environmental interventions that extend life span in fruit flies have been identified, and changes in gene expression patterns as a result of these interventions scale to the mean life span of the flies. These changes during aging encompass 80% of the genes, suggesting that gene expression patterns may be a useful biomarker of the physiological age of fruit flies. Reducing the uptake of citric acid cycle intermediates from the gut by mutations in a protein (indy) that transports them into the blood stream can increase the life span of the flies by up to 100% without reducing fertility, metabolism, or physical activity, perhaps mimicking calorie restriction.
So far, more than 200 mutations that positively influence longevity have been identified in nematodes. A variety of aging phenotypes are seen as nematodes grow older. The first life-extending single gene mutation isolated, age-1, delays muscle wasting and nuclear deterioration, but not some other aging phenotypes such as yolk protein accumulation.
The discovery in the 1990s that dwarf mice are long-lived created a new model for aging research. These dwarf mice are produced by mutations that either block pituitary development and therefore the production of growth hormone, or inactivate the growth hormone receptor. Both kinds of mutations reduce cancer incidence, improve retention of learning ability, and increase insulin sensitivity. Thus, although dwarf mice might not do well "in the wild," they appear to be healthier animals than normal mice when maintained in a laboratory environment.
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NATURE, NURTURE, AND LONGEVITY: WHAT MOST OF THE WORLD'S ORGANISMS CAN TELL US |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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This symposium elaborated in greater depth on the recent contributions that model organisms have made to our understanding of the aging process (see above). A good deal of attention was devoted to the role of sirtuins in life-span regulation. An increase in Sir2 levels increases life span in fruit flies, just as it does in yeast and nematodes. The requirement for Sir2 in the life-span-extending pathway of calorie restriction was demonstrated. Work on 18 small polyphenols has been shown to increase human SIRT1 activity. These include resveratrol, butein, and piceatannol, all of which come from plants and have similar chemical structures. They are the first molecules shown to extend life span in diverse species such as yeast, worms, and flies. Importantly, the Sir2 gene is necessary for this life extension, and these compounds appear to work by mimicking calorie restriction. In the case of resveratrol, treatment with the polyphenol was shown to actually increase the activity of Sir2 in the fly and extend life span. In mice, it was shown that nicotinamide dinucleotide (NAD) biosynthesis regulates the Sir2 NAD-dependent deacetylase.
Work on the nematode has provided great insight into the mechanisms by which the insulin-signaling pathway leads to life-span extension. Data from whole-genome microarray studies were used to document the changes in gene expression seen with DAF-16 life-span extension. The insulin-like peptides INS-7 and INS-18 act as agonists and antagonists, respectively, of the DAF-2/DAF-16 life-span pathway. INS-7 and INS-18 may coordinate and amplify the activity of the DAF-2/DAF-16 pathway allowing all the cells in the animal to coordinate their physiological systems. A connection to insulin-signaling was made through the discussion of the role of Sir2 in regulating insulin secretion of the pancreatic beta cell, insulin-signaling, and glucose metabolism in mice.
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PATHOBIOLOGY AND DEGENERATIVE DISORDERS OF AGING—A MODEL SYSTEMS PERSPECTIVE |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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In this session the exciting advances in understanding fundamental processes that contribute to age-related decline and underlie late-onset neurodegenerative conditions were highlighted. Modeling of late-onset neurodegenerative diseases by over-expressing wild-type or human mutant variants of genes that cause polyglutamine aggregation disease and Parkinson's disease in Drosophila recapitulates fundamental aspects of the human diseases (for example, late-onset neurodegeneration of specific neuronal types). A pivotal role for the molecular chaperones has been demonstrated, using fly models in which human disease proteins aggregate (a feature of human disease) to become toxic to eye neurons. Up-regulation of chaperone activity dramatically suppresses the disease phenotypes in flies, while interference with chaperones accelerates neurodegeneration.
A triple-transgenic mouse model is being used to study yet another neurodegenerative disorder, Alzheimer's disease. This transgenic mouse expresses mutant human amyloid precursor protein (APPSwe), mutant human presenilin (PS1M146V), thus enhancing 
-secretase activity and Aß1-42 production, and a tauP301L isoform, thereby promoting plaque and tangle formation and behavioral dysfunction. The pathology in this mouse closely parallels human Alzheimer's disease. Anti-Aß antibodies reversed both extracellular and intracellular Aß load via a proteasome-dependent process, with associated reversal of tau pathology as well (as long as tau had not advanced to a highly hyperphosphorylated end state). Analysis of memory deficits in these triple-transgenic mice indicated that cognitive impairment precedes extensive neuropathology and demonstrated that clearance of intraneuronal Aß rescues spatial reference memory deficits. These findings suggest that Aß immunization is a viable option for early intervention in treating Alzheimer's disease.
Flies and nematodes age with features remarkably similar to those that occur in higher organisms. For example, in C. elegans, muscle undergoes substantial cellular degradation including reduction of sarcomere number and structure, much like human sarcopenia. Genetic studies of the decline in nematode muscle have shown that reduced insulin-signaling can dramatically delay sarcopenia onset. Another biomarker of aging is the accumulation of lipofuscin and advanced glycation endproducts (age pigments), that increase with age in invertebrates and vertebrates. Interestingly, age pigment scores correlate directly with how well an animal has aged (lowest in those that appear youthful), rather than its exact chronological age. These characterized biomarkers are being used to identify genetic conditions that extend health span—the period of youthful vigor that precedes age-related decline.
Another common feature of aging cells is that damaged and abnormal proteins accumulate in the cytosol over time. Semifunctional and aggregated proteins are thought to interfere with normal cell function. Rodent models and tissue culture cells have been used to demonstrate that a selective mechanism for the degradation of cytosolic proteins in lysosomes, known as chaperone-mediated autophagy (CMA), is activated under conditions of mild oxidative stress to contribute to the removal of the oxidized proteins. CMA activity decreases with age and in some familial forms of Parkinson's disease. Decreased CMA activity leads to the accumulation of damaged proteins and deregulation of the stress response.
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PROFILES OF HEALTHY AGING: QUANTIFYING BIOLOGICAL AGE AND FUNCTION |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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While a person's actual life span can be easily determined, it has become clear that chronological age is not equivalent to biological age. There is no universally accepted definition or "gold standard" of successful aging, nor is there a definitive measurement instrument. This symposium reviewed concepts of biological aging and provided insights on the measurement of frailty.
Older adults display a spectrum of functionality, ranging from individuals that are fully active and seemingly resistant to injury, to those susceptible to future decline, to those who are impaired in their activities of daily living and are at high risk of subsequent disability. Frailty may be defined as an increased vulnerability and decreased resilience to stress. By assessing criteria indicative of weight loss, exhaustion, weakness, slow walking speed, and low physical activity, it is possible to define a syndrome of frailty that may help predict survival and risk of subsequent disability independent of current disease and disability. However, the importance of frailty on future outcomes does not diminish the contribution of disability and comorbidity to biological age. Indeed, disability and disease burden is predictive of the same outcomes used to validate frailty. A prime example of the utility of these measures is the demonstration that a variety of interventions can result in a greater reduction in disability than in mortality, suggesting changes in biological age independent of survival. Further, it was shown that the accumulation of deficits correlates better with survival than does chronological age.
Biological age is a complex entity. This was evident on both the physiological and clinical levels. The search for biomarkers of aging demonstrates the complexity of biological age; numerous investigations have failed to provide a single measure that consistently performs well in quantifying biological age. A better approach may be the use of weighted, multicomponent scores, an example of which was presented. Likewise, a clinically based assessment of frailty or biological age needs to avoid oversimplification. Complex, multisystem dysregulation involving numerous pathways leads to declining functionality. As similarly frail individuals may suffer impairment in disparate areas of functionality, surveying multiple domains of disability gains importance.
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NATHAN SHOCK CENTER SYMPOSIUM ON MICROARRAYS IN AGING RESEARCH: CURRENT STATUS AND FUTURE DIRECTIONS |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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The gene expression profiles in transgenic mice expressing catalase in mitochondria were discussed. These mice showed a 5-month increase in median and maximum life span. Future studies will determine what function the gene expression changes observed perform in these mice, and in other models of life-span extension, as a function of age. Gene expression changes occurring within the vulnerable midbrain dopamine region were analyzed in two mouse models of Parkinson's disease and human postmortem brain tissue. The data presented illustrated a common pathogenic pathway and revealed new insights in the early, early-mid, and mid-late stages of Parkinson's disease. A mutant mouse model (SOD2+/–) with a 20% decrease in life span demonstrated multiple pathologies and accelerated aging in a number of tissues. These observations are associated with gene expression profiles that suggest a decline in genome maintenance functions. Methodological questions in microarray studies were also discussed. Issues discussed included hardware problems, inappropriate hypothesis testing, low statistical power, overlapping gene sets in two models of extended longevity, and challenges for the future.
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THE PARADOX OF THE INSULIN SIGNALING PATHWAY AND LONGEVITY |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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Down-regulation of the insulin/IGF-1-signaling pathway is associated with significant longevity in nematodes and flies. However, similar alterations in the insulin-signaling pathway and decline in insulin action are associated with variety of age-related diseases leading to death in humans. This symposium aimed to understand this paradox. One major difference between mammals and lower species such as the nematode is the different regulation of the insulin/IGF-1-signaling pathway. For example, a genetic attenuation of insulin-signaling in nematodes causes a decrease in the expression of the major agonist ins-7, while insulin resistance in humans causes a compensatory increase in insulin production to overcome this resistance and maintain normal blood glucose levels.
Another reason for differences between species is the fact that the attenuation of the insulin-signaling pathway can elicit opposing downstream phenotypes. For example, while the daf-2 mutant nematode accumulates intra-intestinal fat, the FIRKO mouse (fat insulin receptor knock-out) has a decrease in fat mass. Expression of the nematode apolipoprotein gene, and the vitellogenin genes vit-2 and vit-5, is lower in daf-16 mutants, while in mammalian insulin resistance apolipoprotein levels are increased. If insulin resistance in humans causes improvement in lipoproteins levels, perhaps longevity would be increased.
In mammals, IGF-1 and insulin have distinct and largely independent signaling pathways. It has been hypothesized that a decrease in IGF-1-signaling is what is important for mammalian longevity. Indeed, increased longevity is characteristic of Ames dwarf mice and GH-resistant GHR-KO mice, and in female mice heterozygous for a knockout of the IGF-1 receptor. Because rodents seem to die with tumors, but not from cardiovascular diseases, the comparative biology of IGF-1 among mammalian species is also important to consider. Increased plasma IGF-1 is a risk factor for several kinds of tumors in humans. On the other hand, increased IGF-1 levels are also associated with decreased frequency of impaired glucose tolerance, diabetes mellitus, cardiovascular disease, and osteoporosis. Thus, while high IGF-1 may decrease most causes of death in humans, it may increase the death from cancer, in contrast to the demonstrated benefit in rodents. An interesting phenotype in some of these IGF-1-deficient models is the net physiological increase in insulin action. Thus, it is not clear if these models are long-lived because of IGF-1 deficiency or enhanced insulin sensitivity, which is the opposite of the physiological state of long-lived lower species.
The initial assessment of humans with exceptional longevity has demonstrated that enhanced insulin sensitivity is one of their major characteristics, and also obtains in their offspring. The first longevity assurance genes that have been described in humans (cholesterol ester transfer protein, apolipoprotein 3, and microsomal transfer protein) modulate the metabolism of lipoproteins. These long-lived humans are not dwarfs as a group, and neither they nor their offspring exhibit a decrease in IGF-1 levels. This suggests that a decline in the insulin/IGF-1-signaling pathway may not be beneficial to human longevity. Rather, downstream effects resulting in alteration of this pathway may be common in long-lived lower species and mammals. Alternatively, it is possible that a set point for the action of the insulin/IGF-1- signaling pathway is necessary for all species. In such a case, to attain longevity in lower species insulin action has to be decreased, while in humans it has to be increased.
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MITOCHONDRIA AND AGING: CAUSE OR EFFECT? |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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Chronic exposure of heart muscle to oxidants originating from mitochondria leads to an increase of oxidatively damaged protein with age as shown by oxyblot (immune blot using an antiserum raised against carbonylated proteins). However, mitochondria age differently depending on the tissue and the "mitotype." Heart muscle contains two types of mitochondria which are morphologically and physiologically distinct; these are the subsarcolemmal mitochondria (SSM) and the interfibrillar mitochondria (IFM). Superoxide dismutase activity in mitochondria (MnSOD) increases with age, which can be viewed as an adaptation to increased oxidative stress.
The functional analysis of two yeast genes, YGR076c (a putative mitochondrial ribosomal protein) and YKL056c (the yeast homolog of human translationally controlled tumor protein [TCTP]) was presented. In a global transcription study of yeast aging, YGR076c was found to be down-regulated in senescent yeast mother cells. The corresponding deletion mutation showed respiratory deficiency, resistance to oxidative stress, and a substantial increase in life span. The green fluorescent protein (GFP)-tagged YGR076c protein localized to mitochondria in both young and old cells. The protein encoded by YKL056c is very highly conserved in eukaryotic cells and was shown by mitochondrial proteomics and by GFP tagging to relocalize from the cytoplasm to the mitochondria after a mild oxidative stress. The function of this latter protein is unknown at present.
Fruit flies expressing the human uncoupling protein 2 gene (UCP2) in mitochondria are long-lived. This is consistent with the current view of UCP function. UCP2 is widely expressed in human cells and has a role in reducing hyperpolarization of the mitochondrial inner membrane, thus avoiding the excessive production of superoxide radicals and their follow-up products. Expression of UCP2 in neurons was sufficient to elongate the life span of flies, although not to the same extent as by expression in all adult tissues. Thus, the role of mitochondria in aging is like the chicken and egg problem. It is not known where things begin, but they are intimately intertwined.
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WHOLE ANIMAL ENERGY METABOLISM IN LAB AND FIELD: IS THERE A LINK TO AGING? |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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The metabolic rates of approximately 4000 individual flies of various ages from different recombinant inbred fly lines (RI) have been measured to determine the relationship between metabolic rate and longevity in Drosophila melanogaster. There was a wide range of longevities among the lines, but no evidence of an inverse relationship between the average metabolic rate of a line, or an individual in the line, and its longevity. In contrast, rearing flies at different temperatures showed a near-perfect inverse relationship between longevity and metabolic rate. It is apparent from this that metabolic rate can be an important factor regulating longevity. As such it is premature to dismiss any connection between metabolic rate and longevity. This point was emphasized in studies of non-human primates, in which the relevance of total versus resting energy expenditure during lifelong calorie restriction was studied. Decreased oxidative damage in skeletal muscle during calorie restriction was found; resting energy expenditure was reduced during calorie restriction, as well.
In other studies, the total daily energy expenditure (TEE) of male F344 rats and C57BL/6 mice was measured over their entire life span. Control animals (A) were fed ad libitum and experimental animals (R) were fed 40% less than ad libitum from 6 weeks of age onward. Animals were sedentary or had voluntary exercise wheels provided throughout the life span. All R animals exhibited a striking decrease in mass specific metabolic rate (SMR) upon initiation of calorie restriction. However, from 6 months of age onwards, the SMRs of sedentary A and R animals were not significantly different over most of the life span. Exercised R animals (running approximately 4 km/day over their life span) had a SMR significantly greater than A and sedentary R animals. The maximum life span (measured at 10% survival) of animals was significantly increased by calorie restriction and was not influenced by altered SMR or physical activity, regardless of the method of normalization (organ mass, analysis of covariance, etc.). It was concluded that decreased intensity of whole body metabolic rate is neither necessary nor sufficient to explain the age-retarding effects of calorie restriction.
During the past hundred or so years, during which mice have been domesticated for use in the laboratory, they have become much fatter than mice living in the wild. In addition, recent studies have suggested that mice taken from the wild live longer than domesticated strains. This raises the distinct possibility that when we calorically restrict small rodents we do not prolong their life spans, as much as give them back the life that was taken away by 100 years of domestication. To test this idea, the energy expenditure of wild mice was compared with the energy intakes of ad libitum-fed mice in the laboratory. Data from the literature for daily energy expenditure collected on wild mice using the doubly-labeled water method were reviewed. On average, food intake levels of mice in the laboratory were 20% greater than predicted. This magnitude of effect is far too large to account for the obesity in laboratory mice, indicating they must also have significantly elevated energy expenditure as well—probably on physical activity. Calorie restriction, between ad libitum feeding down to 80% of this level, includes many effects that appear to mimic the differences between wild and laboratory rodents: The mice under restriction are less active, have lowered expenditure of energy matching their lowered intake, and have substantially reduced body fatness. Most of the effect on longevity over this range of restriction may be generated by the reduced body fatness. However, the life-promoting effects of calorie restriction are evident at lower levels of restriction, and this continued effect is probably a direct consequence of the restriction. This analysis suggests that discussion of the roles of calorie restriction or fat depletion should not occur in a vacuum relative to the levels of restriction.
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RECENT BREAKTHROUGHS IN UNDERSTANDING PROGERIA AND PREMATURE AGING SYNDROMES |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease of childhood with striking features resembling premature aging. Important clues about aging may result from understanding the pathogenic mechanisms involved in HGPS. Recently, it was discovered that a spontaneous mutation in the gene LMNA encoding the lamin A/C nuclear envelope proteins causes HGPS. Mutations in LMNA have been found in eight other disorders, including several atypical Werner syndrome patients. This symposium provided an overview of the latest research on HGPS, as well as a discussion of funding opportunities.
A comparison of the HGPS phenotype with other laminopathies and premature aging syndromes was provided. The mutation responsible for HGPS (G608G) creates a cryptic splice site that causes the deletion of 50 amino acids near the C terminus of lamin A. This removes a site where internal cleavage of the protein normally occurs by the action of the enzyme ZMPSTE24, following removal of a lipid farnesyl group at the terminal CAAX box. This lack of cleavage may account for the nuclear mislocalization of lamin A leading to nuclear membrane abnormalities. Such nuclear abnormalities are also associated with aging pathologies and may indicate a common origin. Single nucleotide polymorphisms related to the LMNA locus are being screened in a study of centenarians to determine if LMNA may be one of the genes associated with longevity.
Prospects for therapy of HGPS and the role of the Progeria Research Foundation (PRF) in supporting research were discussed. PRF was established to stimulate and fund research to find a cure for HGPS. The PRF was instrumental in coordinating an effort that resulted in the discovery of the HGPS gene mutation. The Foundation recently co-sponsored a symposium exploring the prospects for bone marrow transplantation as a potential treatment. Also being explored are the potential use of drugs that may inhibit the removal of the lipid group from the terminal CAAX end. Two Program Announcements have also been issued by the National Institute on Aging to encourage studies on this progeroid syndrome.
Some late breaking research into mouse models of HGPS and related disorders was presented. Transgenic mice with the HGPS mutation showed aging-related pathologies. Heterozygosity for LMNA deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. It was clear that further work in understanding the pathogenesis of HGPS and related disorders may also provide a deeper understanding of the genetic basis of aging.
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CHANCE EVENTS IN AGING: FINDINGS FROM TWIN STUDIES |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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This was the BSS Student Symposium. A discussion of the chance events of aging as they correlate to the "non-shared" environment and developmental factors that are not controlled by genotype was presented. It focused on answering the question of how cell numbers can vary between genetically identical organisms. Background data were presented on differences relating to fertility cycles of inbred mice and irreversible ovarian cell loss throughout the aging process. For example, fibroblast daughter cells have unequal potential for proliferation, and identical twins have variations in neuron numbers affecting overall cerebrum and cerebellum size.
Genetic and environmental influences on normative cognitive change were discussed in the context of whether environmental variance increases over age relative to genetic variance, and if so, is this due to some gene-environment interaction. Data were presented from the Swedish Adoption/Twin Study of Aging, both on twins separated before age 10 and reared apart, as well as twins reared together, matched for sex, year, and county of birth. It was concluded that there is decreasing influence from heritable components, and increasing influence from environmental components after age 65, which is consistent with stochastic theories, and provides a possible base to build on for investigating gene-environment interactions. In studying concordant and discordant twin pairs in the Swedish Twin Study on Aging with respect to dementia onset a number of characteristics have been studied, including: years of education, APOE genotype, height, significant tooth loss, engagement in mentally stimulating leisure activities, social class, and stroke. Most of these characteristics proved statistically significant when correlated to dementia onset in twin pairs.
Findings from the OCTO-Twin study looking into origins of variance in the oldest-old were presented in an effort to address the genetics of complex behaviors in aging. Phenotypic domains that have been studied include health and functioning capacity, cognitive functioning, personality and personal control, psychological well-being, and interpersonal functioning. Perhaps the most interesting finding from the research presented was not the effect of environment on aging and development, but the role that genetics plays in limiting the impact of the environment.
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THE CELLULAR AND MOLECULAR MECHANISMS OF IMMUNOSENESCENCE |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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A description of the age-related defect in the development of CD8 T cells that react with an influenza type specific nucleoprotein (NP) antigen was presented. There was a developmental delay and a lower peak number of flu-specific CD8 T cells after primary infection with influenza virus in aged mice compared to young mice. A defect was observed in both the number of NP-specific CD8 T cells and the cytotoxic capacity of the cytotoxic T lymphocytes (CTLs). This lowered CD8 T-cell response appears to be due primarily to limited expansion of NP-specific cells, rather than decreased activity per CD8 T cell. Infection with E55+MULV and poly I:C can deplete T cells in young mice within hours of inoculation through apoptosis, whereas T cells of aged mice are resistant to this depletion. This resistance to depletion of T cells in aged mice is associated with decreased induction of caspase 3. Adoptive transfer of CD8 T cells from young and aged mice into young and aged recipients indicates that factors both intrinsic and extrinsic to the T cell play a role in the defect. Thus, an age-related reduction in apoptosis may restrict the immunologic space necessary for a potent CD8 response in aged mice.
The production of novel T cells during T-cell senescence was also discussed. An age-related contraction of the T-cell repertoire was described. The frequency of naïve T cells decreased 100-fold. A similar contraction in diversity was observed in memory T cells. Memory CD4 T cells exhibited abnormal expression of natural killer group 2D (NKG2D), killer cell immunoglobulin-like receptor (KIR), immunoglobulin-like transcripts (ILT-2), and CXCR3, with loss of normal CD28 and CD40L expression. Loss of CD28 could be prevented by IL-12, and this process is blocked by TNF-
. TNF- could down-regulate CD28 promoter transcription, whereas IL-12 can induce CD28 expression by CD4+ CD28 null T cells. Inhibitory KIRs suppressed signaling through the T-cell receptor, whereas signaling through stimulatory KIRs provided co-stimulatory signals. Co-expression of DNAX-activation protein 12 (DAP-12) enhanced CTL activity, even in the absence of T-cell receptor stimulation. It was proposed that such autocrine activation in vivo of these abnormal senescent CD4 cells can lead to cytotoxic activity, tissue damage and autoimmunity.
CD8 T-cell replicative senescence in human T cells correlates with telomere shortening. decreased telomerase activity, and reduced apoptosis in response to several signaling pathways induced by any of the following: anti-Fas, galactin-1 and anti-CD3, a decrease in stress proteins, including HSP70 and an increase in TNF-. Further, these changes were shown to be relevant to age-related pathologies, including a loss of antiviral cytotoxicity and suppression of other immune cell functions and production of TNF- that can stimulate osteoclast differentiation and contribute to osteoporosis.
The relationship between activation and activation-induced cell death (AICD) was discussed. Young (2-month-old) mice exhibit high T-cell activation and rapid entry into the cell cycle, as well as subsequent high rate of apoptosis. In contrast, aged mice, while capable of exhibiting high T-cell activation, exhibit delayed entry into the cell cycle and low apoptosis. These results indicate that the defect in activation and AICD are distinct, and the initial T-cell defect during aging is a defect in AICD. The ratio of proliferation on day 2 divided by proliferation on day 6 exhibited a 100-fold range in different strains of recombinant-inbred mice. Strains that exhibited both high T-cell activation and AICD also displayed a long life span.
In humans, there appears to be an accumulation of senescent memory T cells limiting the available "immunologic space" for naïve T cells. The age-related accumulation of CD28– Fas+ T cells was associated with a resistance to activation and AICD. In contrast, the CD28+ Fas– T cells could up-regulate Fas and could undergo AICD. A defect in up-regulation of Fas on CD28+ T cells, which correlated with a defect in AICD, was most evident in the early old age group, but was partially eliminated in humans living past 90 years of age. The defect in AICD after stimulation with PHA and IL-2, does not steadily increase with age, but a more normal phenotype is preserved in individuals that exhibit successful aging in late-old age.
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ANTI-AGING MEDICINE: THE HYPE AND THE REALITY |
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This session was devoted to a sampling of articles that were published in two special sections of the June and July issues of the Journal of Gerontology: Biological Sciences during the summer of 2004 under the same title as this session. Current debates about the future of human longevity rest on two premises: one is that duration of life is limited by fundamental biological forces that are related to a species' life history such as reproduction, and the other is the suggestion that the history of limit theories have been proven wrong by observed trends in life expectancy. A third way of looking at the forces that influence duration of life is that pharmacological interventions may become available to delay the onset of senescence. Nevertheless, the term "anti-aging" makes no sense in the absence of measures of biological aging or in light of the fact that aging is a fundamental property of all matter. It is important to understand the clear distinction between the biological forces that influence duration of life (longevity determination), and those that influence aging itself.
The treatment of non-elderly GH-deficient adults with recombinant human GH (rhGH) improves body composition, muscle strength, physical function, and bone density, and reduces blood cholesterol and cardiovascular disease risk, but is often accompanied by carpal tunnel syndrome, peripheral edema, joint pain and swelling, gynecomastia, glucose intolerance, and possibly increased cancer risk. Furthermore, clinically significant functional benefits, prolongation of youth, and life extension have not been demonstrated, casting some doubt about this highly touted anti-aging intervention. This prompted an exploration of the anti-aging industry from the perspective of the United States Federal Food, Drug, and Cosmetic Act and its amendments, particularly as it pertains to dietary supplements and human growth hormone. The time has come for Congress to reassess the wisdom of the current law regarding dietary supplements. In the case of growth hormone, non-physicians who distribute rhGH could be prosecuted as narcotic dealers under the Controlled Substances Act, and even off-label administration of rhGH by physicians is illegal in the United States because of the very narrowly defined circumstances under which its use is allowed under the law. Congress should reassess the wisdom of the 1994 Dietary Supplements Health and Education Act.
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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TopBiology for Non-Biologists: Use...Nature, Nurture, and Longevity:...Pathobiology and Degenerative...Profiles of Healthy Aging:...Nathan Shock Center Symposium...The Paradox of the...Mitochondria and Aging: Cause...Whole Animal Energy Metabolism...Recent Breakthroughs in...Chance Events in Aging:...The Cellular and Molecular...Anti-Aging Medicine: The Hype... |
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Received March 21, 2005
Accepted June 1, 2005
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