Lee SJ et al. (1990) J Infect Dis "Changes in antibody profile after treatment of human onchocerciasis."

Ottesen EA, Lee SJ, Francis HL, Awadzi K, Nutman TB

[J Infect Dis, 1990]

To define the changes in antibody response to Onchocerca volvulus antigens after treatment of patients with onchocerciasis, IgG and IgE antibodies were examined quantitatively and qualitatively in 21 patients and 3 control individuals before and sequentially for 14 days after treatment with diethylcarbamazine. The quantitative levels of IgE and IgG responses (both polyclonal and O. volvulus-specific) remained essentially unchanged for all patients, but 9 of the 21 patients showed intensified responses to one or more parasite-specific antigens, and 8 of 21 developed antibodies to previously undetected antigens. There was a significant correlation between the intensities of infection and the development of newly recognized anti-O. volvulus antibodies. These studies demonstrate that O. volvulus-specific IgE and IgG antibody responses are, at least transiently, enhanced by treatment with diethylcarbamazine and that after treatment, parasites possibly release antigens previously hidden from the host's immune response.

Lee SJ et al. (2009) Curr Biol "Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans."

Lee SJ, Kenyon C

[Curr Biol, 2009]

BACKGROUND: Many ectotherms, including C. elegans, have shorter life spans at high temperature than at low temperature. High temperature is generally thought to increase the "rate of living" simply by increasing chemical reaction rates. In this study, we questioned this view and asked whether the temperature dependence of life span is subject to active regulation. RESULTS: We show that thermosensory neurons play a regulatory role in the temperature dependence of life span. Surprisingly, inhibiting the function of thermosensory neurons by mutation or laser ablation causes animals to have even shorter life spans at warm temperature. Thermosensory mutations shorten life span by decreasing expression of daf-9, a gene required for the synthesis of ligands that inhibit the DAF-12, a nuclear hormone receptor. The short life span of thermosensory mutants at warm temperature is completely suppressed by a daf-12(-) mutation. CONCLUSIONS: Our data suggest that thermosensory neurons affect life span at warm temperature by changing the activity of a steroid-signaling pathway that affects longevity. We propose that this thermosensory system allows C. elegans to reduce the effect that warm temperature would otherwise have on processes that affect aging, something that warm-blooded animals do by controlling temperature itself.

Lee SJ et al. (2009) Cell Metab "Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression."

Lee SJ, Kenyon C, Murphy CT

[Cell Metab, 2009]

Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the downregulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the life span-shortening effect of glucose and that aqp-1 may act cell nonautonomously as a feedback regulator in the insulin/IGF-1-signaling pathway. Insulin downregulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.

Lee SJ et al. (2010) Curr Biol "Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity."

Kenyon C, Hwang AB, Lee SJ

[Curr Biol, 2010]

A mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice, but the underlying mechanism is unknown. One environmental condition that reduces rates of respiration is hypoxia (low oxygen). Thus, it is possible that mechanisms that sense oxygen play a role in the longevity response to reduced respiration. The hypoxia-inducible factor HIF-1 is a highly conserved transcription factor that activates genes that promote survival during hypoxia. In this study, we show that inhibition of respiration in C. elegans can promote longevity by activating HIF-1. Through genome-wide screening, we found that RNA interference (RNAi) knockdown of many genes encoding respiratory-chain components induced hif-1-dependent transcription. Moreover, HIF-1 was required for the extended life spans of clk-1 and isp-1 mutants, which have reduced rates of respiration. Inhibiting respiration appears to activate HIF-1 by elevating the level of reactive oxygen species (ROS). We found that ROS are increased in respiration mutants and that mild increases in ROS can stimulate HIF-1 to activate gene expression and promote longevity. In this way, HIF-1 appears to link respiratory stress in the mitochondria to a nuclear transcriptional response that promotes longevity.

Lee SJ et al. (2010) PLoS Genet "The Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks."

Koo HS, Hyun M, Gartner A, Ahn B, Lee SJ

[PLoS Genet, 2010]

WRN-1 is the Caenorhabditis elegans homolog of the human Werner syndrome protein, a RecQ helicase, mutations of which are associated with premature aging and increased genome instability. Relatively little is known as to how WRN-1 functions in DNA repair and DNA damage signaling. Here, we take advantage of the genetic and cytological approaches in C. elegans to dissect the epistatic relationship of WRN-1 in various DNA damage checkpoint pathways. We found that WRN-1 is required for CHK1 phosphorylation induced by DNA replication inhibition, but not by UV radiation. Furthermore, WRN-1 influences the RPA-1 focus formation, suggesting that WRN-1 functions in the same step or upstream of RPA-1 in the DNA replication checkpoint pathway. In response to ionizing radiation, RPA-1 focus formation and nuclear localization of ATM depend on WRN-1 and MRE-11. We conclude that C. elegans WRN-1 participates in the initial stages of checkpoint activation induced by DNA replication inhibition and ionizing radiation. These functions of WRN-1 in upstream DNA damage signaling are likely to be conserved, but might be cryptic in human systems due to functional redundancy.

Lee SJ et al. (2004) Development "A Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint."

Han SM, Lee SJ, Yook JS, Koo HS

[Development, 2004]

A Werner syndrome protein homolog in C. elegans (WRN-1) was immunolocalized to the nuclei of germ cells, embryonic cells, and many other cells of larval and adult worms. When wrn-1 expression was inhibited by RNA interference (RNAi), a slight reduction in C elegans life span was observed, with accompanying signs of premature aging, such as earlier accumulation of lipofuscin and tissue deterioration in the head. In addition, various developmental defects, including small, dumpy, ruptured, transparent body, growth arrest and bag of worms, were induced by RNAi. The frequency of these defects was accentuated by gamma-irradiation, implying that they were derived from spontaneous or induced DNA damage. wrn-1(RNAi) worms showed accelerated larval growth irrespective of gamma-irradiation, and pre-meiotic germ cells had an abnormal checkpoint response to DNA replication blockage. These observations suggest that WRN-1 acts as a checkpoint protein for DNA damage and replication blockage. This idea is also supported by an accelerated S phase in wrn-1(RNAi) embryonic cells. wrn-1(RNAi) phenotypes similar to those of Werner syndrome, such as premature aging and short stature, suggest wrn-1-deficient C. elegans as a useful model organism for Werner syndrome.

Lees, Hayley et al. (2013) International Worm Meeting "Investigating the role of the wrn-1 helicase in the nematode worm, C. elegans."

Cox, Lynne, Lees, Hayley, Woollard, Alison

[International Worm Meeting, 2013]

In order to ameliorate the deleterious consequences of old age, the biology of human ageing must be understood. The study of human progeroid disorders which recapitulate many of the features of normal ageing have helped to contribute to our understanding of normal human ageing. Werner syndrome is a canonical progeroid disorder, caused by mutation of the WRN gene. WRN encodes both RecQ helicase and exonuclease activities, and is known to participate in DNA replication, repair, recombination and telomere maintenance. In addition, although many interacting partners have been identified, the exact molecular functions of the WRN gene remain largely unknown. In order to dissect the roles of WRN helicase in ageing, we use mutants of the WRN homologue and interacting partners in the nematode worm, C. elegans. Reduction of function by RNA interference of the C. elegans WRN homologue wrn-1 leads to ageing phenotypes and shortened lifespan 1. We have shown that mutation of wrn-1 leads to genomic instability: interestingly, this phenotype is enhanced in a mutant cep-1 background (the C. elegans p53 homologue). Notably, lifespan also shows significant modulation, while brood size remains unchanged from that of either single mutant. Therefore we suggest that cep-1 status has a significant effect upon the role of wrn-1 helicase in longevity and germline maintenance in worms. References 1.Lee, SJ; Yook, JS; Han, SM; Koo, HS. A Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint. Development, 2004. 131(11): p. 2565-2575.

Onken, Brian D. et al. (2011) International Worm Meeting "Insulin Signaling and Dietary Restriction Differentially Regulate Glucose Metabolism to Impact C. elegans Healthspan."

Onken, Brian D., Driscoll, Monica

[International Worm Meeting, 2011]

A major goal of aging research is to understand the underlying relationship between nutritional intake, metabolism, and healthy aging. Low-glycemic index diets have been shown to reduce risk of age-related metabolic diseases such as diabetes and cardiovascular disease, and reduced caloric intake via dietary restriction increases healthspan across species. One potential approach for supporting healthy aging is via interventions that engage healthspan-promoting metabolism. In Caenorhabditis elegans, adding excess glucose to the growth medium shortens lifespan [1, 2], while inhibiting the glycolytic enzyme hexokinase with the glucose analog 2-deoxyglucose increases lifespan [1]. We have shown that disrupting genes encoding two other glycolytic enzymes that catalyze unidirectional, irreversible reactions lengthens C. elegans median lifespan, induces large gains in youthful locomotory ability, and triggers a fluorescent biomarker that distinguishes a healthy metabolic state. Conversely, disrupting counterpart gluconeogenic genes decreases nematode healthspan. In investigating potential longevity-related pathways that might impinge upon glucose metabolism, we found that disrupting glycolytic genes increases healthspan through the FOXO transcription factor DAF-16, which is also required for the increased lifespan seen with lowered levels of insulin signaling, and which is downregulated by increased glucose availability [2]. Strikingly, we also found that gluconeogenic activity is absolutely and specifically required for increased healthspan under dietary restriction. These results provide evidence for an intriguing new paradigm: breakdown of glucose via glycolysis negatively impacts healthy aging through insulin signaling and DAF-16, while dietary restriction engages the reciprocal gluconeogenic pathway to promote healthspan. Our observations support that healthspan might be optimized via dietary, pharmacological, or genetic interventions that increase gluconeogenic activity or decrease glycolysis. 1. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, et al. (2007). Cell Metab 6: 280-293. 2. Lee SJ, Murhpy CT, Kenyon C (2009). Cell Metab 10: 379-391.

Abate JP et al. (2009) Cell Metab "Life is short, if sweet."

Blackwell TK, Abate JP

[Cell Metab, 2009]

Insulin is essential for glucose homeostasis, but reducing its activity delays the aging process in model organisms. In this issue of Cell Metabolism, Lee et al. (2009) show how these effects of insulin signaling intersect when glucose is fed to C. elegans.

Hwang AB et al. (2011) Aging (Albany NY) "Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection."

Hwang AB, Lee SJ

[Aging (Albany NY), 2011]

A mild reduction in mitochondrial respiration extends the life span of many species, including C. elegans. We recently showed that hypoxia-inducible factor 1 (HIF-1) is required for the acquisition of a long life span by mutants with reduced respiration in C. elegans. We suggested that increased levels of reactive oxygen species (ROS) produced in the respiration mutants increase HIF-1 activity and lead to this longevity. In this research perspective, we discuss our findings and recent advances regarding the roles of ROS and HIF-1 in aging, focusing on the longevity caused by reduced respiration.