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MEETING REPORT |
California Pacific Medical Center Research Institute, San Francisco.
Address correspondence to Arnold Kahn, PhD, California Pacific Medical Center Research Institute, San Francisco Coordinating Center, 185 Berry Street, Lobby 4, San Francisco, CA 94107. E-mail: arnold.kahn{at}ucsf.edu
The Longevity Consortium is a multi-investigator, multi-institutional National Institute on Aging-sponsored research group the ultimate mission of which is to identify genes involved in human aging and longevity. The Consortium funds several research projects in human participants and in animal models, provides core statistical and genotyping support to Consortium-associated investigators, and holds symposia at intervals of 6–8 months as a framework for information exchange, project updates, and discussion. The most recent meeting, held in May 2007, included sessions on the biological determinants of frailty, the aging brain, biological rhythms and aging, and aging in model organisms. What follows is a summary of the scientific sessions of the meeting.
Steven Austad (University of Texas Health Science Center at San Antonio) opened the Symposium with a plenary presentation on the general theme of the comparative biology of aging, an approach that is always represented in program content but is not usually discussed explicitly. Two important and provocative points were made. First, whereas data from animal models consistently suggest that reducing the level of insulin/insulin-like growth factor-1 (IGF-I) activity increases longevity, the situation appears to be the opposite in humans, because humans carrying a mutation in the growth hormone receptor do not show the same life extension as that seen in mice with a similar receptor deficiency. Indeed, if anything, the life span of affected humans is shortened. Whether this is because the animal models differ fundamentally from humans in the physiology of aging or represent an artifact of laboratory breeding is not clear. Second, smaller size within a given mammalian species is associated with longer life. However, in apparent contrast to other reports, this increased longevity is not consistently associated with increased stress resistance at the cellular level in fibroblasts, although it correlates with an increased rate of repair of DNA strand breaks.
THE BIOLOGICAL DETERMINANTS OF LONGEVITY
Frailty appears to be a highly conserved phenomenon in aging animals and people that is characterized, in part, by altered body composition, a reduction in mass of many tissues, a loss of strength, diminished mobility and responsiveness to external stimulation, and increased vulnerability to injury and illness. As noted by Marco Pahor (University of Florida, Gainesville), some features associated with the frailty phenotype are due to sarcopenia, the steady loss of skeletal muscle mass and strength that occurs throughout most of adult life. The problems associated with sarcopenia are further exacerbated in people who are also obese. The two conditions act together to increase the risk of age-related disease and mortality. Additionally, sarcopenic–obese individuals also have high circulating levels of cytokines associated with inflammation. However, unlike exercise, anti-inflammatory drugs are not effective in combating disability.
Tamara Harris (National Institutes of Health [NIH], Bethesda, MD) also emphasized the effects of sarcopenia on frailty, as reflected in the loss of lean body mass (especially in the upper body) and reductions in skeletal muscle strength. For example, lower handgrip strength is predictive of all-cause mortality in elderly men and women, as are slower walking speed and a lessened ability to climb steps. The factors behind the sarcopenia and reductions in muscle strength are incompletely known but, as noted here and in the presentation by Bret Goodpaster (University of Pittsburgh, PA), may be associated with lipid and fat accumulation in muscle and reduced mitochondrial function. As men and women lose lean body mass with age, they also accumulate fat in the connective tissue surrounding the muscle fiber and lipid within the myofiber. One small study suggests that moderate aerobic physical activity, which does not curtail the loss of muscle mass, does reduce the accumulation of muscle fat and improve muscle strength. In another study, the loss of muscle mass associated with diet-induced weight loss could be ameliorated by exercise, which also reduced fat accumulation.
Apoptosis may also be involved in age-related sarcopenia (Christiaan Leewenburgh, University of Florida, Gainesville). In rats, caloric restriction (CR) attenuates the age-related loss in muscle strength. This effect is partially accounted for by a reduction in apoptotic potential. Even moderate (8%) CR, which increases mean but not maximum life span, is effective at preserving muscle strength in rats, especially when combined with exercise. The combination of CR and exercise extends the ability of treated animals to run well at older ages, diminishes the muscle loss associated with apoptosis, and counteracts age-related reductions in myofiber diameter and increases in extracellular (endomysium-associated) connective tissue. Iron accumulation associated with increased oxidative stress (as evidenced, for example, by RNA oxidation) may also contribute to sarcopenia and a diminution in muscle mass and strength.
Although invertebrates are not commonly used for research on frailty, Catherine Wolkow (NIH, Baltimore, MD) showed that aging Caenorhabditis elegans do exhibit aging-related loss of motor functions. For example, previous work from her laboratory indicates that the nematode pharynx shows an age-related deterioration in function (represented by pumping action) and structure (deterioration reminiscent of sarcopenia). A novel image analysis technique has now been developed to observe the pharynx in vivo, as well as pattern recognition algorithms to analyze changes in structure and function. There is now evidence that serotonin deficiency accelerates pharyngeal aging in C. elegans and that pharyngeal function at midlife is related to structural and functional decline. Initial RNA interference (RNAi) screening to identify genes involved in pharyngeal aging has focused on six genes expressed in the pharynx or that are associated with longevity or calcium binding. One of these, goa-1, is a G-protein 
subunit that is expressed in neurons and many muscles.
THE AGING BRAIN
Naftali Raz (Wayne State University, Detroit, MI) provided a brief overview of the literature on brain aging using findings from magnetic resonance (MR) imaging, spectroscopy, and postmortem examinations. He followed by presenting a more detailed account of the current understanding of the changes in the aging human brain. As in other organs and tissues, there is substantial inter-individual variation in the extent, time of onset, and rate of brain aging. Even within the brain, different regions show discrepant patterns of age-related change. For example, the volume of white matter declines nonlinearly with age, showing accelerated shrinkage at the 6th and 7th decades, whereas most of the cortical regions show a linear decline. The greatest shrinkage is observed in tertiary association cortices (lateral prefrontal and inferior parietal cortex). The microstructure of brain white matter also changes with age, showing increased anisotropy (as observed by diffusion tension imaging) and accumulation of macrostructural changes reflected in increased burden of white matter hyperintensities noted on MR images. These hyperintensities, which have been associated with a number of vascular risk factors and conditions, such as stroke and atherosclerosis, are more common in people with hypertension and elevated blood levels of C-reactive protein and homocysteine. Aerobic fitness exercise may slow age-related brain shrinkage and possibly reduce the loss of brain tissue.
Superoxide has apparently conflicting roles in the brain, serving both as a signaling molecule involved in long-term potentiation (LTP) and hippocampus-dependent learning and memory and as a potential mediator of oxidative damage in the brain during aging. To clarify the involvement of this reactive oxygen species (ROS) in the aging brain, Eric Klann (New York University) used transgenic mice overexpressing extracellular superoxide dismutase (EC-SOD) or mitochondrial superoxide dismutase (SOD-2). EC-SOD overexpression in aged mice results in increased LTP in the hippocampus and significantly better cerebellum-dependent motor learning and hippocampus-dependent spatial learning. The latter improvements are associated with reduced superoxide levels in the hippocampus and may therefore enhance neuronal function by reducing oxidative stress. In contrast, SOD-2–overexpressing mice exhibit LTP and memory similar to normal controls. However, when introduced into the Alzheimer's disease-model Tg2576 mice, SOD-2 overexpression decreases the deposition of amyloid plaque deposits and improves spatial and contextual memory. Collectively, the data suggest that superoxide is an ROS that normally contributes to age-related impairments in LTP and hippocampus-dependent memory. In wild-type animals, increased expression of EC-SOD but not SOD-2 helps limit these superoxide-induced, senescent changes. In contrast, SOD-2 expression is effective in ameliorating some of the deficits in the Alzheimer's disease mouse, underscoring the complex role of superoxide in brain function, pathology, and aging.
BIOLOGICAL RHYTHMS AND AGING
The potential effects of biological rhythms on the aging process are not widely discussed or well appreciated. However, as shown in the work of Roman Kondratov (Cleveland State University, OH) and his collaborators, and Katie Stone and her colleagues (see below), this view needs revision. The BMAL1 protein is a transcription factor involved in regulating circadian rhythms. Kondratov and his associates found that when the BMAL1 gene is deleted in the mouse, BMAL-1 knockout animals express a segmental progeria, with premature death and a phenotype that includes slow growth, weight loss, sarcopenia, osteopenia, and subcapsular cataracts. BMAL-1 mice show elevated levels of ROS in the kidneys, spleen, and heart. When mouse L929 fibroblasts are treated with anti-BMAL inhibitory RNAi, they become markedly more sensitive to oxidative damage induced by exogenous peroxide. Kondratov postulates that the circadian system coordinates antioxidative defense through BMAL1, a possibility supported by the finding that there are BMAL-1–responsive sites in the promoter region of a group of antioxidant genes including catalase, PRDX1 (peroxiredoxin) and GPX1 (glutathione peroxidase).
Katie Stone (California Pacific Medical Center Research Institute, San Francisco) presented additional direct evidence of the effects of circadian rhythms in aging. Several human biological systems display circadian rhythmicity, including the sleep–activity cycle, body temperature, bone remodeling, immune function, and cardiovascular system-related activities such as blood pressure and heart rate. About one third of older persons have disruptions of circadian rhythmicity (sleep–activity cycles). Such disruption has been previously linked to decreased survival (in demented nursing home residents and breast cancer patients) and increased cognitive impairment. More recently, data on actigraphically assessed sleep–activity rhythms have been collected from a cohort of community-dwelling elderly women (average age 84 years) and used to determine whether deviations from normal in such rhythms are associated with increases in mortality and cognitive dysfunction and exacerbation of physical function deficits and frailty. The results show that a decrease in amplitude (peak to nadir changes in level of activity) and robustness of the rhythm are associated with increased mortality, in addition to decreases in cognition, physical function, and energy levels. Moreover, deviation from the typical acrophase (time of day of peak activity) in either direction is linked to greater mortality. As noted by Stone, these findings should prompt the search for interventions to regulate sleep–activity rhythms in older adults with the goal of improving survival and successful aging.
AGING IN MODEL ORGANISMS
Steroid hormones have pivotal roles throughout the lifetime of mammals, and details of the pathways and mode of action for most of these mediators are well established. However, although C. elegans expresses 248 nuclear (putative steroid) receptors, much less is known about steroid hormones in these and other invertebrates. Recently, Adam Antebi (Baylor Medical College, Houston, TX) and his associates identified the ligands for DAF-12, a nuclear receptor involved in many components of the C. elegans life cycle, including dauer formation and longevity. The ligands are 3-keto bile acid-like steroids, called dafachronic acids, that are capable of rescuing the dauer-constitutive phenotype associated with the hormone-deficient mutants daf-9/cytochrome p450 and daf-36/Rieske oxygenase. In his presentation, Antebi showed that dafachronic acid supplementation shortens the life span of long-lived daf-9 mutants and abolishes their resistance to stress, indicating that the ligand is ‘pro-aging’ in response to signals from the dauer pathways. Moreover, the ligand also extends the life span of germline-ablated daf-9 and daf-36/Rieske mutants, showing that it is also ‘anti-aging’ in the germline longevity pathway. Thus, dafachronic acid regulates C. elegans life span according to signaling state.
Taste and olfaction are among the more surprising factors that appear to regulate life span, at least in invertebrates. As reviewed by Marta Gaglia (University of California, San Francisco), as early as 1999, the Cynthia Kenyon laboratory showed that chemosensory mutants in C. elegans have extended longevity. The laboratory also reported that this sensory-regulated extension depends largely on the insulin/IGF-I pathway, including the downstream transcription factor daf-16/Forkhead (FOXO). Given this, it is not surprising that ablation of a particular odorant receptor, STR-2, and some specific neurons (e.g., chemosensory neurons designated ASI) also increase C. elegans longevity. Current work is focused on how diet, olfaction, and taste interact to affect longevity and on the role of specific neurotransmitters in movement and, potentially, life span.
Cell-autonomous circadian regulatory pathways, which are conserved from yeast to humans, control cycles of gene expression, metabolism, and detoxification. These cycles involve retrograde signaling from mitochondria to the nucleus in response to cellular redox status and ROS. Moreover, they can be synchronized by central nervous system pacemakers in response to light, temperature, and food. John Tower (University of Southern California, Los Angeles) reported that conditional overexpression of mitochondrial manganese SOD (MnSOD) in adult Drosophila increases the expression of Phase II-like detoxification genes, stimulates circadian activity, and extends life span. Phase II-like genes share DNA-sequence motifs, suggesting the existence of conserved redox-sensitive signaling pathways and transcription factors that may also coordinate detoxification, circadian rhythms, and life span in higher organisms. Current work by Tower and colleagues focuses on the use of a real-time analysis system to monitor and characterize the effects of aging and longevity-promoting interventions on the behavior and rhythm activity of groups of flies. Circadian rhythms are known to deteriorate during aging in both flies and humans, resulting in sleep fragmentation and suppression of behavior cycle amplitudes. Tower suggests that this deterioration of rhythm leads to increased oxidative stress and age-related, senescent changes. If true, then interventions that restore or stimulate circadian rhythms might be efficacious in the treatment of human aging-related disorders (cf. Stone above in ‘Biological Rhythms and Aging’).
Rong Yuan (The Jackson Laboratory, Bar Harbor, ME) discussed an extensive, broad effort to use 32 different inbred strains of mice to quantify age-related changes in these animals and to link the findings on differences in phenotype to high-density (quantitative trait locus) QTL analysis and, ultimately, gene identification. At intervals of 6 months, the mice are phenotyped using measures that include body weight; urine chemistry, blood chemistry, and hormone assays; metabolic rate; sleep–activity patterns; and neuromuscular function. In addition, 6-, 12-, and 20-month-old mice are being compared for-age-related and strain differences in body composition, the ability to repair DNA, and stem cell function. Necropsy data are expected to provide information on chronic disease status as a function of strain and age. The findings from these studies are to be made available to the scientific community on the Mouse Phenome Database (http://www.jax.org/phenome). Data collected to date indicate, for example, that glucose levels are strongly linked to one block (haplotype) containing three genes. In addition, lower IGF-I levels in young animals correlate with life span, but the relationship does not hold in older animals.
SUMMARY
Although many biological gerontologists continue to study the effects of the insulin/IGF-I pathway on aging and longevity, as noted by Steve Austad, a pressing issue remains to demonstrate the applicability of the findings to humans. For example, individuals carrying a Laron or Laron-like growth hormone receptor mutation do not show the extended longevity and health characteristics of dwarf mice carrying similar gene defects.
Frailty is a major and apparently ubiquitous feature of old age, observed in elderly humans, as well as in vertebrate and invertebrate animals. (e.g., see Wolkow above on aging C. elegans). Its defining features include slow movement, a reduction in muscle strength, and the loss of muscle mass or sarcopenia (Pahor, Harris, Goodpasture, and Leewenburgh). Although these age-related changes can be accounted for by a number of different mechanisms, two received particular attention at this meeting—accumulation of fat and lipids in muscle that occurs along with losses in mass and strength (Pahor, Goodpasture) and increased apoptosis in skeletal myofibers (Leewenburgh). In addition, iron accumulation is associated with the loss of muscle mass and strength and increased oxidative stress (Leewenburgh).
Age-related changes in the normal human brain have received less attention than those associated with pathology (e.g., Alzheimer's disease, Parkinson's disease), so comprehensive documentation of what happens to the brain in the absence of disease is very welcome. As noted by Raz, losses in the quantity and quality of brain tissue with age show substantial variation in timing, rate of occurrence, and region of the brain affected. Significant individual differences in brain shrinkage patterns are also noted, with some of the variance attributable to identifiable genetic factors. Linking structural alterations in the aging brain to changes in function are even more challenging. Some insight into identifying the mechanisms that underlie brain aging was provided by Klann, who showed that transgene-mediated, overexpression of extracellular SOD was effective in mitigating age-related losses in hippocampus-dependent learning and memory. Whereas such changes were not realized in normal animals transgenic for mitochondrial SOD, expression of the latter in a mouse model of Alzheimer's disease did decrease amyloid deposition and improve spatial memory. Both findings underscore the importance of oxidative damage in brain aging and the potential for antioxidant-based interventions to help reverse or delay senescent changes in brain structure and function.
The brain, of course, is not only a target of aging but also a likely contributor to age-related changes in other tissues and organs. Thus, the brain's suprachiasmatic nucleus helps establish and maintain circadian rhythms in mammals and, as illustrated in the presentations of Stone, Kondratov, and Tower, changes in these rhythms may be central to the aging process in humans and model organisms. Thus, Stone showed that disruption in the normal amplitude and timing of sleep–activity (circadian) rhythms in elderly women is associated with increases in all-cause mortality, cognitive dysfunction, and frailty. One mechanism by which this might occur was suggested by the findings of Kondratov—that genetic inactivation of a transcription factor (BMAL-1) involved in regulating circadian rhythms in mice results in accelerated, progeria-like aging, with animals dying at 9 months. Elevated levels of ROS can be detected in many organs in knockout mice and this finding, coupled with the presence of putative BMAL-1 binding sites in the promoter region of several antioxidant genes, suggests that the circadian system may coordinate antioxidant defenses through the BMAL-1 transcription factor. Tower and associates found that flies overexpressing mitochondrial SOD live longer, sustain stronger circadian rhythms, and show increased expression of Phase-II detoxification genes. These detoxification genes, like the target genes identified by Kondratov, share DNA-sequence motifs and therefore would be candidates for coordinate regulation by transcription factors involved in circadian rhythms and life-span determination.
Caloric restriction is the best established environmental intervention for slowing the aging process and extending longevity. Although it is almost certain that it is the dietary change that is responsible for the latter effects, data from several laboratories, including the Kenyon Laboratory, indicate that olfactory input, originating from odorants in food, may play a role. For example, Gaglia (Kenyon Laboratory) showed that mutations affecting chemosensory function/olfaction in C. elegans also extend life span. Moreover, ablation of select neurons downstream of chemosensory input similarly increase longevity.
Neurons, of course, are only one modality by which biological processes are controlled centrally. "Downstream" there are other mediators through which the aging of cells and tissues is modulated. Perhaps the most important of these are the hormones, some of which are, in fact, produced by neurons or neuroendocrine cells. As shown by Antebi, dafachronic acids, operating through the DAF-12 nuclear receptor play important roles in mediating dauer formation and aging in C. elegans. Dafachronic acids are bile acid-like steroids that have been shown to act as hormones in mammals. Interestingly, the dafachronic acid/DAF-12 pathway, like the downstream elements of the insulin/IGF-I pathway, helps regulate the DAF-16/FOXO transcription factor. Thus, the network of interactions involving insulin/IGF-I and longevity is still further enlarged.
A
The activities of the Longevity Consortium including these meetings are supported by National Institutes of Health, National Institute on Aging Grant U19 AG032122 entitled "A Consortium to Study the Genetics of Longevity."
For further information about the Consortium and Consortium-sponsored events, please contact the Project Director Alicia Whittington at awhittington{at}sfcc-cpmc.net
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