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MEETING REPORT |
California Pacific Research Institute, San Francisco.
Address correspondence to Arnold Kahn, PhD, California Pacific Research Institute, San Francisco Coordinating Center, 185 Berry St., Lobby 4, San Francisco, CA 94107. E-mail: arnold.kahn{at}ucsf.edu
THE Longevity Consortium (LC) is a National Institute on Aging (NIA)-supported multi-institutional research group that has been hosting once- or twice-yearly symposia since 2001. The overall goal of the LC is to identify genes and genetic pathways important in human aging and longevity using data collected from human studies and animal models. The symposia are held to assure ongoing, open dialogue among member and nonmember scientists in an environment also intended to stimulate the development of new collaborations and lines of research. Each meeting includes progress reports from LC-supported investigators and scientific sessions involving speakers new to our symposia and, on occasion, new to the field of biological gerontology. This report summarizes the presentations and core themes presented at the Napa, California, meeting of the LC held in November 2006. In general, the research presented supports the central role of DNA maintenance, modification, and variation in longevity and aging.
TELOMERES AND AGING
Telomere shortening, DNA methylation, and nuclear protein regulation of gene expression are epigenetic mechanisms believed to function in aging and age-related structural and functional changes. The most topical, if not the best established of the latter is telomere shortening. In an overview lecture, Tim Spector (St. Thomas Hospital, London, U.K.) presented data on a variety of age-associated phenotypes in twins. He began with the basic finding that, in general, telomeres (specifically telomere length restriction fragments) in proliferating somatic cells (white blood cells in this instance) become progressively shorter with age. However, the rate at which this loss occurs appears to be influenced by both intrinsic and extrinsic factors including male sex, obesity, a history of cigarette smoking, osteoarthritis (possible chronic inflammation), and low socioeconomic status. Each of these factors is associated with shorter telomeres as well as shortened life span. The precise meaning of these associations remains elusive, in part, because the studies were cross-sectional in nature. Moreover, there also remains the fundamental difficulty in distinguishing cause from effect in association studies: Are shortened telomeres a consequence of or the cause of reduced life expectancy?
THE ROLE OF MITOCHONDRIA IN AGING
Mitochondria are involved in the aging process, although the mechanism remains elusive. The complexity and elusiveness of the situation was well illustrated in a presentation by Tom Prolla (University of Wisconsin, Madison). Using transgenic (TG) mice carrying a defective gene for mitochondrial DNA (mtDNA) polymerase 
(an enzyme necessary for mtDNA proliferation), Prolla and coworkers found that the genetically modified animals have much greater frequencies of mtDNA mutations and an overall phenotype consistent with accelerated aging including shortened life spans, sarcopenia, osteopenia, and the graying of hair. However, and somewhat surprisingly, the engineered animals do not show evidence of oxidative damage in proteins, lipids, or nucleic acids, a frequent explanation for how mitochondria promote aging. In contrast, the TG mice do express elevated levels of cleaved caspase-3, and show premature activation of apoptosis in many tissues. These findings led to the hypothesis that the premature aging observed in the polymerase mutant animals is the result of the apoptotic loss of irreplaceable cells (e.g., stem cells) and the resulting tissue dysfunction. Precisely how increased mitochondrial mutation leads to increased apoptosis remains to be established.
A different approach to the issue of mtDNA alteration and apoptosis was presented by Janine Santos (University of Medicine and Dentistry, New Jersey (UMDNJ), Newark). Fibroblasts stressed with peroxide have increased mtDNA damage but an even greater relative increase in apoptotic cell death (cf. Prolla above). These effects are dependent upon the catalytic activity of human telomerase reverse transcriptase (hTERT), are genotoxin-specific (etoposide but not methylmethanesulfate is an effective stressor) and hTERTs localization in the mitochondrion. The latter result was obtained by using targeted mutations to the mitochondrial leader sequence of hTERT to block the movement of the protein into the mitochondrial matrix. Thus, telomerase localization within mitochondria is essential to modulating responses to genotoxic stress and increasing or, at a minimum, permitting mtDNA damage. Santos and colleagues hypothesize that the latter may help to cull dysfunctional mitochondria from the cell, thereby identifying telomerase as part of a mitochondrial quality control mechanism.
David Rand (Brown University, Providence, RI) presented still another innovative approach to assessing the role of mitochondria in aging and longevity based on the hypothesis that mitochondrially-produced free radicals drive the aging process by damaging essential proteins, nucleic acids, and lipids. Because mitochondrial proteins are encoded by both nuclear DNA (90%) and mtDNA (10%), it follows that, by disrupting the natural relationship in the origin of these proteins (and presumably mitochondrial function), effects might be seen in physiology and longevity. This disruption was achieved by introducing mitochondria from Drosophila simulans into the nuclear genetic background of D. melanogaster, thereby creating, as a consequence of epistasis, hypomorphic mitochondrial genotypes (sim-mel strains). These genotypes showed significantly reduced performance in fitness and physiological assays, but relatively small changes in longevity when fed normal diets. However, under conditions of partial dietary restriction (achieved by reducing only the amount of yeast) that promote life-span extension, the presence of D. simulans mtDNA in the sim-mel animals does reduce longevity, indicating that mitochondrial genes are part of the pathway(s) through which dietary restriction extends longevity. It is interesting that no mitochondrial effect on life span is seen when the animals are raised on complete caloric restriction (CR; reduced yeast plus nutrients). In another exploration of the possible involvement of mtDNA in longevity, D. simulans mitochondria were introduced into flies carrying the chico mutation, an insulin-signaling pathway hypomorph that increases longevity. The presence of the chico gene reversed the longevity-limiting effects of D. simulans mitochondria in animals raised on 2% yeast, a result that places mitochondrial genes in both the dietary restriction and insulin pathways that influence life span.
CALORIC RESTRICTION
In animal models, CR is by far the best-established environmental manipulation to extend longevity and curtail the onset of age-related chronic disease. However, it remains uncertain whether the same effects can be achieved in humans. Recently, a carefully controlled study of CR was conducted in humans (CALERIE; Comprehensive Assessment of Long Term Effects of Reducing Intake of Energy). As described by Eric Ravussin (Pennington Biomedical Research Center, Baton Rouge, LA), besides feasibility and safety, the study was intended to address two main hypotheses: first, that chronic CR (resulting in loss of weight and maintenance of energy balance at a lower body mass) is associated with lower rates of energy expenditure, lower body temperature, and evidence of lower tissue oxidative stress and second, that chronic CR ameliorates risk factors for chronic diseases commonly associated with aging, including cardiovascular disease and type 2 diabetes. To test these hypotheses, 48 healthy overweight men and women (25 < body mass index < 30 kg/m2; age range 25–50 years) were enrolled. Persons who smoked; exercised more than twice a week; were pregnant, lactating, or postmenopausal; or had a personal history of obesity were excluded. The participants were randomized into four groups: controls (healthy diet, weight maintenance), CR (equaling 25% of baseline energy requirements), CREX (equaling 12.5% CR plus structured exercise to increase energy expenditure by 12.5%), or LCD (low calorie diet until a stable 15% weight loss was achieved). Measurements were taken at baseline and after 3 and 6 months. The data show that prolonged CR by diet or a combination of diet plus exercise (CREX) resulted in reductions in weight, fat mass, fasting serum insulin level, and body core temperatures. The findings of decreased body temperature and decreased insulin concentration are notable because they are consistent with the possibility that these measures are potential biomarkers of aging and longevity. In addition, the data show that the CR intervention, alone or in combination with exercise, reduced oxygen consumption (normalized on the basis of fat-free mass), improved insulin and ß-cell sensitivity, and produced a decline in DNA but not protein damage. The results also support the concept that insulin resistance is related to an abnormal partitioning of fat between adipose (the appropriate place for storage) and other tissues such as hepatic, muscle, and pancreatic tissues. To confirm and extend these findings, additional collaborative studies are being established using a total of 240 participants recruited from the Pennington Biomedical Research Center, Washington University and Tufts University. The participants will be randomized to a 25% CR or a control group for 2 years. This longer study will allow a differentiation between the effects of CR during weight loss versus CR at weight maintenance.
MOLECULAR CHAPERONES IN AGING AND LONGEVITY
Molecular chaperones, including the heat shock proteins, affect stress resistance, aging, and the development of at least some of the age-related diseases involving the nervous system. Illustrative of the latter are the polyglutamine (polyQ) expansion neurodegenerative disorders of which Huntington's disease is an example. In Huntington's disease, the disease gene (huntingtin) has variable numbers of trinucleotide CAG repeats, giving rise to polyQ tracts of differing lengths in the protein. If the number of repeats in the protein exceeds 35–40, the disease becomes manifest functionally and by the appearance of protein aggregates. Cindy Voisine (Northwestern University, Evanston, IL) presented experimental approaches and results showing how Caenorhabditis elegans can be used to model such disorders and to provide important insights into the mechanisms controlling protein turnover and homeostasis. For example, TG nematodes that produce tissue-specific polyQ repeats carrying the Yellow Fluorescence Protein (YFP) marker permit localization of the repeats in muscle and neurons and visualization of the formation of aggregates. At the same time, documentation of the effects on worm behavior (e.g., motility) can also be recorded. Thus, for example, a threshold of 29–40 polyQ repeats expressed in the muscle of young animals results in the formation of aggregates and a 
10-fold reduction in motility. The effect of polyQ repeat expression varies as a function of worm age, with smaller polyQ tracts aggregating in older animals. Additionally, the action of polyQ is delayed in longer-lived age-1 mutants and dependent on daf-16 (a downstream transcription factor in the insulin/insulin-like growth factor 1 [IGF-1] pathway), strongly linking polyQ toxicity to life-span-determining pathways. Some naturally occurring proteins (e.g., paramyosin) with temperature-sensitive mutations, misfold and aggregate at a nonpermissive temperature when coexpressed with the polyQ protein. Moreover, the aggregation of polyQ itself is enhanced strongly by expression of a single temperature-sensitive protein. Thus, whether protein folding will occur normally or result in misfolding (and aggregation) is sensitive to the environment in which the activity is occurring. Moreover, the cellular folding environment can be influenced by both life-span-modifying genes (e.g., age-1) and proteins serving as molecular chaperones. An example of the latter is the heat shock protein 70 (Hsp 70) family that works with cochaperones to modulate the protein-folding cycle as part of a chaperone network regulating protein folding and homeostasis.
That HSPs are of major importance in stress resistance and longevity was further documented in the presentation by Gordon Lithgow (Buck Institute, Novato, CA). Hormesis is a phenomenon in which exposure to a moderate level of stress (e.g., heat) elicits protection against the original stressing agent (thermotolerance) and often against stresses of other kinds, and is usually associated with increased longevity. Using more than one treatment with heat (at least in C. elegans) results in even further increases in life span. Heat shock-induced hormesis depends upon the expression of HSPs. The induced expression of these molecular chaperones declines with age. HSPs function in an integrated fashion with components of the insulin/IGF-1, Jun N-terminal Kinase (JNK) signaling, and heat shock factor (HSF) pathways. For example, the regulation of induced HSP expression by elements of the insulin/IGF-1 pathway does not depend on transcriptional regulation by HSF-1 but appears to be under translational control. More recently, still other classes of genes have been identified that function in the stress (heat) tolerance/longevity pathway(s), notably members of the caffeine-induced death-resistant (CID-1; checkpoint protein) protein pathway including Check Point Kinase (CHK)-1 and cell division cycle-related (CDC)-25. Knockdown of the latter as well as of CID-1 using RNA interference (RNAi) increase both life span and thermotolerance in C. elegans.
Ionizing radiation is another stress-evoking agent that has hormetic action. As noted by Judy Campisi (Lawrence Berkeley Laboratories, Berkeley, CA), the priming, hormesis-stimulating action of radiation improves repair of the double-stranded (ds) DNA breaks that result, at least in part, from high doses of irradiation and result in cellular senescence. However, somewhat surprisingly, such repair does not appear to depend on telomerase activity or p53 and DNA damage kinases, but is linked to the expression of the WRN gene. WRN is a member of the recQ-like helicase family which when mutated causes Werner's syndrome, a disorder characterized by premature aging (segmental progeria) and early death. The WRN protein is localized primarily in nucleoli and telomeres, where it helps to suppress recombination and may participate in transcription. To be effective in hormesis, however, cells must go through at least one cell division (S phase), suggesting that the long-term action of irradiation is chromatin mediated.
Other presentations at the meeting also called attention to the issue of DNA damage and repair and how they may affect the aging process. Ben Van Houten (National Institute of Environmental Health Sciences [NIEHS], Research Triangle Park, NC) presented further insights into this relationship using the C. elegans model. As nematodes age, they show a diminished capacity for nucleotide excision repair (NER), a phenomenon also seen in GLP-1, Germ Line-Proliferation defective worms. GLP-1 animals do not produce oocytes, so measures of NER activity are limited to somatic tissue. The degree of age-related decline in NER is associated with the relative transcriptional activity of the target gene and is most evident in low activity genes. Not surprisingly, C. elegans carrying a mutation in the XPA-1 gene (encoding a DNA-binding protein required for NER) show greatly diminished DNA repair capacity and are particularly sensitive to exposure to chronic ultraviolet light; an effect that results in diminished longevity and the inhibition of growth in adult animals. The reason for the age-related reduction in DNA repair is not clear, but bioinformatic analysis comparing gene expression in old versus young worms suggests that the reduction may relate to diminished oxidative phosphorylation. Aging nematodes have fewer mitochondria (reduced amounts of mtDNA) and lower levels of adenosine triphosphate (ATP).
Michelle Boehm (Yale University, New Haven, CT) discussed findings on the role of microRNAs in development, aging, and longevity. MicroRNAs are small, well-conserved RNAs that function by binding to messenger RNA and regulating gene expression at the level of translation. In C. elegans, the microRNA (Abnormal Cell LINeage) lin-4 helps to determine the fate choices of cells and the timing of development by interacting with lin-14, a gene encoding a transcription factor. When lin-14 expression is repressed, worm life span is extended, stress resistance is increased, and aging measured by lipofuscin accumulation is slowed. The reverse is observed with the loss of lin-4: shortened longevity, increased stress sensitivity, and accelerated tissue aging. The lin-14 life-extending effect is seen when its function is curtailed in adults as well as in larval animals. The life-span-increasing actions of lin-4 and lin-14 are also dependent on the activity of the aAbnormal Dauer Formation (DAF)-16 and HSF-1 transcription factors, and on DAF-2, a homologue of the insulin/IGF-1 receptor. Therefore, the lin-4 and lin-14 sequence is somehow coupled to a pathway already known to be important in stress resistance and longevity. How this interaction takes place is still unresolved. Lin-14, for example, does not affect the entry of DAF-16 into the nucleus or the expression of sod-3, a downstream target of daf-16. One possible point of interaction is Fourteen-Three-Three (FTT)-2, a protein that can bind LIN-14 as well as Sirtuin (SIR)-2 and activate DAF-16. SIR-2 is a protein deacytlase previously implicated in the life-extending response to CR and stress.
NUCLEAR PROTEINS AND THE REGULATION OF LONGEVITY
Transcription factors are intimately involved in the regulation of gene expression. A single transcription factor may affect multiple genes, most of which have not been identified. Thus, it is not possible to assess which functions might be affected by the binding of a particular transcription factor or how such functions might be coordinately regulated at the transcription level. As noted, DAF-16 is a transcription factor that works downstream in the insulin/IGF-1 pathway and has been shown to be involved in stress responses, fat storage, dauer formation, and life-span determination in C. elegans. Heidi Tissenbaum (University of Massachusetts, Waltham) took advantage of chromatin immunoprecipitation (ChIP) assays, previously shown to be effective in cloning novel target genes in mammals, to identify target genes for the DAF-16 transcription factor in C. elegans. After validating the assay with sod-3, a known target of DAF-16, 103 genes were identified that contained a consensus binding sequence for the transcription factor. Of these putative targets, 33 with binding sequences in the promoter region were shown to bind to DAF-16 with varying degrees of intensity. When functionally assayed for gene expression in DAF-16 null animals, some putative target genes were found to be upregulated, others downregulated, but many showed no change at all relative to wild-type worms. Thus, DAF-16 can function as both as an activator and repressor of target gene function.
Control of transcriptional activity is most often viewed within the context of transcription factors (e.g., DAF-16) or proteins associated with chromatin structure and conformation (e.g., histones). However, as illustrated by Colin Stewart (National Cancer Institute [NCI], Bethesda, MD), proteins that were first identified as defining the nuclear matrix (particularly in the lamina layer located beneath the nuclear envelope) also contribute to the functionality of cells and, ultimately, to the phenotype of the whole organism. The nuclear lamins are the intermediate filaments that form a meshlike structure in the nuclear lamina. They serve as a scaffold for other proteins including the emerins, prostaglandin E2 (PGE2) and cyclooxygenase 2 (Cox-2), within the nucleus. Mutations in lamins cause a number of diseases (the laminopathies) that can affect striated and cardiac muscle (most commonly), cartilage, and skin, and cause lipid accumulation. Knockout of the lamin gene in mouse leads to growth retardation and an early death from atrophy of skeletal and heart muscle. In humans, a mutation in the lamin A gene, LMNA, results in Hutchinson–Gilford progeria syndrome, a disease characterized by multiple anomalies and death early in life. A mouse gene deletion that yields a farnesylated lamin A derivative, an improperly formed and functional nuclear lamina, produces a phenotype that shows many of the characteristics of progeria including slow growth, early death, heart defects, and alopecia. As with fibroblasts cultured from progeroid children, fibroblasts from postnatal mutant mice show defective cell proliferation and a susceptibility to stress-induced apoptosis. Curiously, other changes often associated with diminished proliferation, such as alterations in telomerase levels and (sister) chromatid exchange, are not seen in mutant mouse cells. However, microarray and real-time polymerase chain reaction (PCR) analyses of mutant cells reveal major differences in the expression of messenger RNAs associated with extracellular matrix (ECM) and signaling molecules including transforming growth factor-beta (TGF-ß), fibroblast growth factors (FGFs), and Wingless and Integrin-Like WNTs. Consistent with the involvement of the ECM is the observation that mutant fibroblasts cultured in ECM-coated dishes appear normal. What, then, is the connection between the ECM and the nuclear lamins? The answer appears to be in proteins, like nesprin, that physically link the nucleus, the cytoskeleton, and the cell surface. Such protein "networks" provide an explanation of how the extracellular environment (beyond cytokines and growth factors) and mechanotransduction may affect cell structure and function. Indeed, loss or mutation of A-type lamins makes cells more susceptible to mechanical stress-induced apoptosis.
Judy Campisi also discussed the effects of the extracellular environment on cell structure and function in aging. Cellular senescence, an age-associated cellular phenotype, may serve as both a means to keep cells from becoming cancerous (by making them less available for transformation) and at the same time and to the contrary, promote cancer development. This latter cancer-promoting activity may occur because senescent cells are secretory and express elevated levels of inflammatory cytokines (e.g., interleukin-6 [IL-6], IL-8) and vascular endothelial growth factor (VEGF), which stimulate the migration and invasion into tumors of endothelial cells (i.e., blood vessels), an event necessary if tumors are to grow above the size of small nodules. The importance of senescent cell secretory activity relative to carcinogenesis was demonstrated by showing that co-injection of pretumor cells with senescent cells into nude mice leads to tumor formation; this result was not seen when pretumor cells alone are injected. In vitro experiments paralleling this in vivo study indicate that the stimulus to tumor formation probably results, at least in part, from the IL-6 and IL-8 produced by the senescent cells.
EPIGENETIC CHANGE IN AGING AND CANCER FORMATION
Another mechanism for controlling gene action is via secondary modifications of DNA as, for example, in DNA methylation. DNA methylation plays an important regulatory role during development and is also potentially involved in the cellular and tissue changes seen during carcinogenesis and aging. Hypermethylation in the gene promoter region is associated with transcriptional silencing; hypomethylation results in increased expression. As documented by Jean-Pierre Issa (M.D. Anderson Cancer Center, Houston, TX), DNA methylation usually increases with age, but within a tissue (e.g., the mucosa of the colon) there is both individual-to-individual variation and variation between tissues. Moreover, the degree of hypermethylation is increased or at least associated with chronic inflammatory disorders including ulcerative colitis, gastritis, and smoking. In the cancer epigenome, hundreds of genes may be hypermethylated; these structural modifications are much more common than are mutations and chromosomal abnormalities, and they give rise to the hypothesis that spontaneous carcinogenesis is principally an epigenetic, rather than genetic disease. In this hypothesis, various risk factors including aging, diet, and exposure to environmental agents (carcinogens, epimutagens) give rise to patches within a tissue of epigenetically modified (methylated) cells that exhibit altered or faulty gene expression. Such patches or fields, although not initially diminishing normal tissue function, are potentially precancerous in nature. Upon further aging, dietary variation or exposure to environmental agents that can affect the level of hypermethylation such precancerous tissue may become truly cancerous. Support for the "cancer as an epigenetic phenomenon" hypothesis comes from studies of methylation of the DNA repair gene MGMT in the normal mucosal tissue adjacent to hypermethylated tumor tissue. Here, the levels of hypermethylation are much higher than levels found in similar tissue harvested from areas adjacent to normal tissue or tumor tissue that is not hypermethylated, reinforcing the idea that tumors derive from cells in which increased methylation has already occurred.
WHOLE GENOME SCANNING
Ultimately, the major goal of the LC is to identify genes important in human aging and life-span determination. The whole genome scan is one of the more promising new direct approaches to obtaining this information. Preliminary data from applying this technology were presented by Kathryn Lunetta and Joanne Murabito (Boston University, MA) using 1345 individuals drawn from the largest 330 Framingham Heart Study families (258 original cohort and 1087 offspring participants) and the Affymetrix 100K (100,000) single nucleotide polymorphism (SNP) GeneChip. This initial analysis focused on age at death, morbidity-free survival, physical performance, and age at menopause, as well as several other measures of successful aging (all results will be available as "dbGaP" on the National Center for Biotechnology Information (NCBI) Web site (http://www.ncbi.nlm.nih.gov/) in 2007. Family-based association tests (FBAT) and generalized estimating equations (GEE) were used to determine genetic associations. Two strategies for 100K SNP associations were presented: (i) a simple low-p-value SNP ranking strategy; and (ii) SNP associations within candidate genes and regions previously reported to be associated with longevity in model organisms or humans. None of the associations achieved genome-wide significance. For age at death, in FBAT models, there were eight SNPs in two regions 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73,527,652) with strong associations (p < 10–5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for GEE tests of association with age at death included two SNPs (p <.001) intronic to forkhead box 1A (FOXO1A). FBAT and GEE models identified SNPs associated with both age at death and morbidity-free survival at age 65 years including an SNP near paraoxonase 1 (PON1). FOXO 1 is the homolog of DAF 16, a transcription factor in the insulin/IGF-1 pathway; a gene that has been repeatedly implicated in aging and longevity in model systems. PON-1 is thought to affect atherosclerosis, cardiovascular disease, and Alzheimer's disease. Some PON-1 polymorphisms are more common in the oldest old. In the analysis of selected candidate genes identified from the NCBI, Science of Aging Knowledge Environment (SAGKE), and GenAge Web sites, SNP associations (FBAT or GEE p <.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. As noted above, mutations in WRN are responsible for Werner's syndrome. Alleles of WRN have also been associated with successful aging as assessed by cognitive function. These data are hypothesis-generating and serve as a resource for replication of findings from other population-based samples. Future plans include a high-density 550K Affymetrix scan on 9000 Framingham participants with available DNA.
PROGRESS REPORTS
Each meeting of the LC includes brief presentations covering the most recent, largely preliminary findings by investigators funded by the Consortium. Thus, Michael Masternak and Andrez Bartke (Southern Illinois University, Carbondale) reported on the variable expression of IGF-1 and insulin signaling-pathway genes in calorically restricted and ad libitum-fed long-lived Ames and growth hormone receptor knockout (GHR-KO) dwarf mice. On a similar theme, Elad Ziv (University of California, San Francisco) presented data on the association between SNPs in genes in the insulin/IGF-1 pathway and all-cause mortality and oldest survivorship in two human cohorts. Wen-Chi Hsueh (University of California, San Francisco) and Richard Cawthon (University of Utah, Salt Lake City) reported on the role of telomeres in human aging and longevity, including heretofore unreported evidence suggesting possible associations between telomere length and a number of potentially important biological and physiological markers of the aging process. Finally, Richard Miller (University of Michigan, Ann Arbor) presented findings on the possible role in mice of smaller body size, IGF-1 levels, and stress resistance at the cellular level in determining life span. An update was also given on the status of research on the genetics and age-related functionality of hybrid animals produced by breeding shorter-lived B6 laboratory mice and longer-lived field-captured Idaho mice.
SUMMARY
Although the findings were diverse in technique and model systems, it appears that much of the research presented supports the central role of DNA maintenance, modification, and variation in longevity and aging. Thus, for example, Tom Prolla's research emphasized the role of mtDNA mutation in premature aging and apoptosis in a mouse model, whereas Janine Santos's observations linked the intramitochondrial localization of the DNA repair enzyme, hTERT, to stress-related mtDNA damage and cell apoptosis. There was also David Rand's presentation on the dynamic relationship between nuclear and mtDNA in establishing the contribution of mitochondria to longevity under different physiological and dietary conditions.
Other examples of the centrality of DNA to much of the meeting's scientific content included work done by Judy Campisi on the Werner's gene (a recQ-like DNA helicase involved in segmental progeria) and the findings of Ben Van Houten on the role of DNA nucleotide excision repair in contributing to life-span determination in C. elegans. The involvement of still other, in these instances, nonenzymatic proteins in relationship to DNA function and aging was also illustrated in Heidi Tissenbaum's presentation on transcription factor binding to DNA and Colin Stewart's observations on the multiple roles potentially played by nuclear matrix proteins in nuclear structure and function, including the possibility that such proteins serve as a link between exogenous mechanical force, DNA, and gene expression. The latter represents a relatively underappreciated example of the great importance the environment plays in regulating DNA function and gene expression. A much more fully investigated and discussed aspect of gene (i.e., DNA)–environment interaction as it affects aging and longevity is, of course, the impact of diet (CR) on the latter processes. Eric Ravussin's presentation on CR in humans focused on this issue, albeit indirectly with regard to molecular mechanisms, but it was Jean-Pierre Issa's references to the role of environment, notably diet, in modulating DNA methylation (and, in turn, gene expression) that concretely illustrated the linkage between intracellular change and the environment.
A
The activities of the Consortium, including meetings, are supported by National Institutes of Health, National Institute on Aging Grant U19 AG023122 entitled "A Consortium to Study the Genetics of Longevity."
For further information about the Longevity Consortium and the Consortium-sponsored symposia, contact Alicia Whittington (awhittington{at}sfcc-cpmc.net) or Cindy Kim (ckim{at}sfcc-cpmc.net).
F
Decision Editor: Huber R. Warner, PhD
Received April 6, 2007
Accepted April 14, 2007
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