Elisabeth M van Leeuwen, Jennifer E Huffman, Joshua C Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A Brody, Mary F Feitosa, Qing Duan, Katharina E Schraut, Pau Navarro, Jana V van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka Lyytikäinen, Joris Deelen, Ilja M Nolte, Sander W van der Laan, Gail Davies, Andrea JM Vermeij-Verdoold, Andy ALJ van Oosterhout, Jeannette M Vergeer-Drop, Dan E Arking, Holly Trochet, Generation Scotland, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G Uitterlinden, Abbas Dehghan, Oscar H Franco, Eric J Sijbrands, Albert Hofman, Charles C White, Josyf C Mychaleckyj, Gina M Peloso, Morris A Swertz, LifeLines Cohort Study, Gonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda WJH Penninx, Ian Ford, Brendan M Buckley, Anton JM de Craen, John M Starr, Ian J Deary, Gerard Pasterkamp, Albertine J Oldehinkel, Harold Snieder, P Eline Slagboom, Kjell Nikus, Mika Kähönen, Terho Lehtimäki, Jorma S Viikari, Olli T Raitakari, Pim van der Harst, J Wouter Jukema, Jouke-Jan Hottenga, Dorret I Boomsma, John B Whitfield, Grant Montgomery, Nicholas G Martin, CHARGE Lipids Working Group, Ozren Polasek, Veronique Vitart, Caroline Hayward, Ivana Kolcic, Alan F Wright, Igor Rudan, Peter K Joshi, James F Wilson, Leslie A Lange, James G Wilson, Vilmundur Gudnason, Tamar B Harris, Alanna C Morrison, Ingrid B Borecki, Stephen S Rich, Sandosh Padmanabhan, Bruce M Psaty, Jerome I Rotter, Blair H Smith, Eric Boerwinkle, L Adrienne Cupples, Cornelia van Duijn
Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C. Newly discovered variants of the cholesteryl ester transfer protein (CETP) gene are associated with levels of “good” cholesterol. One version of the CETP gene is known to lead to higher concentrations of high-density lipoprotein (HDL) cholesterol, the type that helps protect against heart disease. However, other beneficial variants remain undiscovered. An international research team led by Cornelia van Duijn from Erasmus Medical Center in Rotterdam, The Netherlands, conducted a meta-analysis of previous studies that collectively compiled data from close to 60,000 people. They identified five novel variants linking CETP with HDL levels. Four of these were single letter differences and one was an insertion of a chunk of DNA. The researchers validated the findings in an independent cohort of around 48,000 people. People who carry these genetic variants may live longer and experience healthier aging.
{"title":"Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C","authors":"Elisabeth M van Leeuwen, Jennifer E Huffman, Joshua C Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A Brody, Mary F Feitosa, Qing Duan, Katharina E Schraut, Pau Navarro, Jana V van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka Lyytikäinen, Joris Deelen, Ilja M Nolte, Sander W van der Laan, Gail Davies, Andrea JM Vermeij-Verdoold, Andy ALJ van Oosterhout, Jeannette M Vergeer-Drop, Dan E Arking, Holly Trochet, Generation Scotland, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G Uitterlinden, Abbas Dehghan, Oscar H Franco, Eric J Sijbrands, Albert Hofman, Charles C White, Josyf C Mychaleckyj, Gina M Peloso, Morris A Swertz, LifeLines Cohort Study, Gonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda WJH Penninx, Ian Ford, Brendan M Buckley, Anton JM de Craen, John M Starr, Ian J Deary, Gerard Pasterkamp, Albertine J Oldehinkel, Harold Snieder, P Eline Slagboom, Kjell Nikus, Mika Kähönen, Terho Lehtimäki, Jorma S Viikari, Olli T Raitakari, Pim van der Harst, J Wouter Jukema, Jouke-Jan Hottenga, Dorret I Boomsma, John B Whitfield, Grant Montgomery, Nicholas G Martin, CHARGE Lipids Working Group, Ozren Polasek, Veronique Vitart, Caroline Hayward, Ivana Kolcic, Alan F Wright, Igor Rudan, Peter K Joshi, James F Wilson, Leslie A Lange, James G Wilson, Vilmundur Gudnason, Tamar B Harris, Alanna C Morrison, Ingrid B Borecki, Stephen S Rich, Sandosh Padmanabhan, Bruce M Psaty, Jerome I Rotter, Blair H Smith, Eric Boerwinkle, L Adrienne Cupples, Cornelia van Duijn","doi":"10.1038/npjamd.2015.11","DOIUrl":"10.1038/npjamd.2015.11","url":null,"abstract":"Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C. Newly discovered variants of the cholesteryl ester transfer protein (CETP) gene are associated with levels of “good” cholesterol. One version of the CETP gene is known to lead to higher concentrations of high-density lipoprotein (HDL) cholesterol, the type that helps protect against heart disease. However, other beneficial variants remain undiscovered. An international research team led by Cornelia van Duijn from Erasmus Medical Center in Rotterdam, The Netherlands, conducted a meta-analysis of previous studies that collectively compiled data from close to 60,000 people. They identified five novel variants linking CETP with HDL levels. Four of these were single letter differences and one was an insertion of a chunk of DNA. The researchers validated the findings in an independent cohort of around 48,000 people. People who carry these genetic variants may live longer and experience healthier aging.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2015-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain-derived neurotrophic factor (BDNF) and its receptor (tropomyosin-related kinase B: TrkB, also known as Ntrk2) have a key role in central regulation of the energy balance. BDNF and TrkB are also expressed in the peripheral tissues, including adipose tissue, but their peripheral role has been unclear. Here we report on the functional significance of the adipose tissue BDNF/TrkB axis in metabolic homeostasis. To examine the role of the BDNF/TrkB axis in the central nervous system and in adipose tissue, we generated adipocyte-specific or neuron-specific BDNF/TrkB conditional knockout (CKO) mice. Then we compared the feeding behavior and metabolic profile between each type of CKO mouse and their littermates. Bdnf expression was significantly increased in the adipose tissue of mice receiving a high-calorie diet, whereas Ntrk2 expression was decreased. The Bdnf/Ntrk2 expression ratio of adipose tissue was higher in female mice than male mice. Fabp4-Cre mice are widely used to establish adipocyte-specific CKO mice. However, we found that Fabp4-Cre-induced deletion of Bdnf or Ntrk2 led to hyperphagia, obesity, and aggressiveness, presumably due to ectopic Fabp4-Cre mediated gene recombination in the brain. Next, we attempted to more specifically delete Bdnf or Ntrk2 in adipocytes using Adipoq-Cre mice. Expression of Ntrk2, but not Bdnf, in the adipose tissue was reduced by Adipoq-Cre mediated gene recombination, indicating that adipocytes only expressed TrkB. No phenotypic changes were detected when Adipoq-Cre TrkB CKO mice were fed a normal diet, whereas female CKO mice receiving a high-calorie diet showed a decrease in food intake and resistance to obesity. The adipose tissue BDNF/TrkB axis has a substantial influence on the feeding behavior and obesity in female mice. A signaling pathway that inhibits appetite in the brain plays an opposite role in fat tissue, with a particularly strong effect in females. Within the brain, the interaction between brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) promotes weight loss and reduced eating. Researchers led by Tohru Minamino at Niigata University in Japan have demonstrated that these proteins exhibit a different activity in fat. Whereas mice lacking BDNF or TrkB in the brain were prone to overeating and obesity, these traits were absent when this pathway was disrupted in fat. Intriguingly, female mice lacking TrkB in their fat cells proved less prone to obesity when fed a high-fat diet, while little change was seen in males. This may result from interactions with estrogen signaling, and the researchers see a potential target for treating female obesity.
{"title":"Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation","authors":"Atsushi Nakagomi, Sho Okada, Masataka Yokoyama, Yohko Yoshida, Ippei Shimizu, Takashi Miki, Yoshio Kobayashi, Tohru Minamino","doi":"10.1038/npjamd.2015.9","DOIUrl":"10.1038/npjamd.2015.9","url":null,"abstract":"Brain-derived neurotrophic factor (BDNF) and its receptor (tropomyosin-related kinase B: TrkB, also known as Ntrk2) have a key role in central regulation of the energy balance. BDNF and TrkB are also expressed in the peripheral tissues, including adipose tissue, but their peripheral role has been unclear. Here we report on the functional significance of the adipose tissue BDNF/TrkB axis in metabolic homeostasis. To examine the role of the BDNF/TrkB axis in the central nervous system and in adipose tissue, we generated adipocyte-specific or neuron-specific BDNF/TrkB conditional knockout (CKO) mice. Then we compared the feeding behavior and metabolic profile between each type of CKO mouse and their littermates. Bdnf expression was significantly increased in the adipose tissue of mice receiving a high-calorie diet, whereas Ntrk2 expression was decreased. The Bdnf/Ntrk2 expression ratio of adipose tissue was higher in female mice than male mice. Fabp4-Cre mice are widely used to establish adipocyte-specific CKO mice. However, we found that Fabp4-Cre-induced deletion of Bdnf or Ntrk2 led to hyperphagia, obesity, and aggressiveness, presumably due to ectopic Fabp4-Cre mediated gene recombination in the brain. Next, we attempted to more specifically delete Bdnf or Ntrk2 in adipocytes using Adipoq-Cre mice. Expression of Ntrk2, but not Bdnf, in the adipose tissue was reduced by Adipoq-Cre mediated gene recombination, indicating that adipocytes only expressed TrkB. No phenotypic changes were detected when Adipoq-Cre TrkB CKO mice were fed a normal diet, whereas female CKO mice receiving a high-calorie diet showed a decrease in food intake and resistance to obesity. The adipose tissue BDNF/TrkB axis has a substantial influence on the feeding behavior and obesity in female mice. A signaling pathway that inhibits appetite in the brain plays an opposite role in fat tissue, with a particularly strong effect in females. Within the brain, the interaction between brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) promotes weight loss and reduced eating. Researchers led by Tohru Minamino at Niigata University in Japan have demonstrated that these proteins exhibit a different activity in fat. Whereas mice lacking BDNF or TrkB in the brain were prone to overeating and obesity, these traits were absent when this pathway was disrupted in fat. Intriguingly, female mice lacking TrkB in their fat cells proved less prone to obesity when fed a high-fat diet, while little change was seen in males. This may result from interactions with estrogen signaling, and the researchers see a potential target for treating female obesity.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2015-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer’s disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD.
{"title":"The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease","authors":"Joshua S Talboom, Ramon Velazquez, Salvatore Oddo","doi":"10.1038/npjamd.2015.8","DOIUrl":"10.1038/npjamd.2015.8","url":null,"abstract":"Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer’s disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2015-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elderly individuals have an eroded immune system but whether immune senescence is implicated with the development of frailty is unknown. The underlying immune mechanisms and the link between markers of senescence and physical frailty is not well established. We explored the association of specific T-cell subset markers of immune differentiation and senescence on CD4+ and CD8+ cells (CD28−, CD27− and CD57+) and the immune risk profile (inverted CD4/CD8 ratio <1) with physical frailty among 421 participants who were frail (N=32), prefrail (N=187) and robust (N=202) in the Singapore Longitudinal Ageing Study cohort. In ordinal logistic regression models relating tertile category rank scores of immune biomarker with frailty status (robust, prefrail and frail), CD8+CD28−CD27+ (odds ratio (OR)=1.35, P=0.013), CD4+CD28−CD27+ (OR=1.29, P=0.025), CD8+CD28− (OR=1.31, P=0.022), and CD4/CD8 ratio (OR=1.27, P=0.026) were positively associated with frailty, controlling for age, sex and multimorbidity. CD4/CD8 ratio less than one was not associated with frailty (OR=0.84, P=0.64). In stepwise multinomial logistic regression controlling for age, sex and comorbidity, only CD8+CD28−CD27+ was the independent predictor of prefrailty: highest tertile of the immune marker significantly predicted prefrailty (versus low tertile, OR=1.72, P=0.037) and frailty (OR=2.56, P=0.06). The study supports the hypothetical role of immune senescence in physical frailty, particularly in regard to the observed loss of CD28 expression from both CD8+ cells and CD4+ cells, but not for CD27 or CD4/CD8 ratio as a marker of senescence. The potential of CD8+CD28−CD27+ as a biological marker of frailty should be further investigated in prospective studies. Declining function in a subset of immune cells may render certain elderly individuals especially weak and prone to hospitalization. As we age, a process called immunosenescence undermines the body''s ability to fight infection and recover from injury. Researchers led by Tze Pin Ng at the National University of Singapore have now found evidence that this process contributes to the increased weakness and overall physiological decline observed among the ''frail'' elderly. The researchers analyzed immune cells collected from 421 elderly Singaporeans, and found that T cells from frail patients tended to lack CD28. This protein is associated with immune function, and its absence is a signature of immunosenescence. Importantly, T-cells from patients who subsequently developed frailty also showed reduced CD28. This suggests a link between immunosenescence and frailty, and may offer a useful predictor for unhealthy aging.
{"title":"Markers of T-cell senescence and physical frailty: insights from Singapore Longitudinal Ageing Studies","authors":"Tze Pin Ng, Xavier Camous, Ma Shwe Zin Nyunt, Anusha Vasudev, Crystal Tze Ying Tan, Liang Feng, Tamas Fulop, Keng Bee Yap, Anis Larbi","doi":"10.1038/npjamd.2015.5","DOIUrl":"10.1038/npjamd.2015.5","url":null,"abstract":"Elderly individuals have an eroded immune system but whether immune senescence is implicated with the development of frailty is unknown. The underlying immune mechanisms and the link between markers of senescence and physical frailty is not well established. We explored the association of specific T-cell subset markers of immune differentiation and senescence on CD4+ and CD8+ cells (CD28−, CD27− and CD57+) and the immune risk profile (inverted CD4/CD8 ratio <1) with physical frailty among 421 participants who were frail (N=32), prefrail (N=187) and robust (N=202) in the Singapore Longitudinal Ageing Study cohort. In ordinal logistic regression models relating tertile category rank scores of immune biomarker with frailty status (robust, prefrail and frail), CD8+CD28−CD27+ (odds ratio (OR)=1.35, P=0.013), CD4+CD28−CD27+ (OR=1.29, P=0.025), CD8+CD28− (OR=1.31, P=0.022), and CD4/CD8 ratio (OR=1.27, P=0.026) were positively associated with frailty, controlling for age, sex and multimorbidity. CD4/CD8 ratio less than one was not associated with frailty (OR=0.84, P=0.64). In stepwise multinomial logistic regression controlling for age, sex and comorbidity, only CD8+CD28−CD27+ was the independent predictor of prefrailty: highest tertile of the immune marker significantly predicted prefrailty (versus low tertile, OR=1.72, P=0.037) and frailty (OR=2.56, P=0.06). The study supports the hypothetical role of immune senescence in physical frailty, particularly in regard to the observed loss of CD28 expression from both CD8+ cells and CD4+ cells, but not for CD27 or CD4/CD8 ratio as a marker of senescence. The potential of CD8+CD28−CD27+ as a biological marker of frailty should be further investigated in prospective studies. Declining function in a subset of immune cells may render certain elderly individuals especially weak and prone to hospitalization. As we age, a process called immunosenescence undermines the body''s ability to fight infection and recover from injury. Researchers led by Tze Pin Ng at the National University of Singapore have now found evidence that this process contributes to the increased weakness and overall physiological decline observed among the ''frail'' elderly. The researchers analyzed immune cells collected from 421 elderly Singaporeans, and found that T cells from frail patients tended to lack CD28. This protein is associated with immune function, and its absence is a signature of immunosenescence. Importantly, T-cells from patients who subsequently developed frailty also showed reduced CD28. This suggests a link between immunosenescence and frailty, and may offer a useful predictor for unhealthy aging.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2015-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Aging science comes of age","authors":"Kazuo Tsubota","doi":"10.1038/npjamd.2015.7","DOIUrl":"10.1038/npjamd.2015.7","url":null,"abstract":"","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2015-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alaattin Kaya, Siming Ma, Brian Wasko, Mitchell Lee, Matt Kaeberlein, Vadim N Gladyshev
The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in a laboratory setting often have severe fitness disadvantages in the wild. To obtain an unbiased view on longevity regulation, we analyzed how a replicative lifespan is shaped by transcriptional, translational, metabolic, and morphological factors across 22 wild-type Saccharomyces cerevisiae isolates. We observed significant differences in lifespan across these strains and found that their longevity is strongly associated with up-regulation of oxidative phosphorylation and respiration and down-regulation of amino- acid and nitrogen compound biosynthesis. As calorie restriction and TOR signaling also extend the lifespan by adjusting many of the identified pathways, the data suggest that the natural plasticity of yeast lifespan is shaped by the processes that not only do not impose cost on fitness, but also are amenable to dietary intervention. A new study pinpoints a consistent set of genes and pathways underlying variations in yeast lifespan. Vadim Gladyshev at Harvard Medical School and co-workers analyzed 22 Saccharomyces cerevisiae yeast strains with diverse lifespans and habitats, looking to identify genomic signatures associated with natural variations in longevity. They observed a number of factors that characterized the longest-lived strains, including the upregulation of aerobic respiration, and found that interactions between genes and the environment were key. They also showed that factors associated with increased longevity in yeast strains do not necessarily degrade the fitness of those strains in the wild, and that longevity can be influenced through diet. The study thus paints a more complete picture of how environmental factors trigger changes—some hard–wired in the genome—that have real consequences on aging and longevity.
在衰老研究中，芽殖酵母是一种有用的模式生物，它导致了长寿遗传决定因素的鉴定，其中许多因素在高等真核生物中是保守的。然而，在实验室环境中促进长寿的因素在野生环境中往往具有严重的适应性缺点。为了获得有关长寿调控的公正观点，我们分析了 22 个野生型酿酒酵母分离物的转录、翻译、代谢和形态因素是如何影响复制寿命的。我们观察到这些菌株的寿命存在显著差异，并发现它们的寿命与氧化磷酸化和呼吸的上调以及氨基酸和氮化合物生物合成的下调密切相关。由于卡路里限制和 TOR 信号转导也会通过调整许多已确定的通路来延长寿命，这些数据表明，酵母寿命的自然可塑性是由那些不仅不会对适应性造成代价，而且适合饮食干预的过程形成的。一项新研究确定了酵母寿命变化所依赖的一组一致的基因和途径。哈佛大学医学院的瓦迪姆-格拉迪舍夫（Vadim Gladyshev）及其合作者分析了22个具有不同寿命和栖息地的酿酒酵母菌株，希望找出与自然寿命变化相关的基因组特征。他们观察到最长寿菌株的一些特征因素，包括有氧呼吸的上调，并发现基因与环境之间的相互作用是关键。他们还发现，与酵母菌株寿命延长有关的因素并不一定会降低这些菌株在野生环境中的适应性，而且饮食也会影响它们的寿命。因此，这项研究更全面地描绘了环境因素如何引发变化--有些是基因组中的硬连接--从而对衰老和长寿产生真正的影响。
{"title":"Defining molecular basis for longevity traits in natural yeast isolates","authors":"Alaattin Kaya, Siming Ma, Brian Wasko, Mitchell Lee, Matt Kaeberlein, Vadim N Gladyshev","doi":"10.1038/npjamd.2015.1","DOIUrl":"10.1038/npjamd.2015.1","url":null,"abstract":"The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in a laboratory setting often have severe fitness disadvantages in the wild. To obtain an unbiased view on longevity regulation, we analyzed how a replicative lifespan is shaped by transcriptional, translational, metabolic, and morphological factors across 22 wild-type Saccharomyces cerevisiae isolates. We observed significant differences in lifespan across these strains and found that their longevity is strongly associated with up-regulation of oxidative phosphorylation and respiration and down-regulation of amino- acid and nitrogen compound biosynthesis. As calorie restriction and TOR signaling also extend the lifespan by adjusting many of the identified pathways, the data suggest that the natural plasticity of yeast lifespan is shaped by the processes that not only do not impose cost on fitness, but also are amenable to dietary intervention. A new study pinpoints a consistent set of genes and pathways underlying variations in yeast lifespan. Vadim Gladyshev at Harvard Medical School and co-workers analyzed 22 Saccharomyces cerevisiae yeast strains with diverse lifespans and habitats, looking to identify genomic signatures associated with natural variations in longevity. They observed a number of factors that characterized the longest-lived strains, including the upregulation of aerobic respiration, and found that interactions between genes and the environment were key. They also showed that factors associated with increased longevity in yeast strains do not necessarily degrade the fitness of those strains in the wild, and that longevity can be influenced through diet. The study thus paints a more complete picture of how environmental factors trigger changes—some hard–wired in the genome—that have real consequences on aging and longevity.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2015-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"57528183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
‘Purpose in Life’ (Purpose) is associated with healthy aging, but it is unknown whether this association is causal. Conceptualizing Purpose as a form of psychosocial resource, one mechanism promoting health could be the regulation of stress hormones. To test this hypothesis, we recruited 44 older community-dwelling adults to examine the association between Purpose and cortisol at baseline, in response to, and recovery from, an acute social laboratory stressor. Purpose did not predict cortisol baseline or reactivity, but did predict a faster recovery to pre-stress baseline levels. The health benefits of Purpose in aging may therefore reflect the combination of a normal stress response, which serves an adaptive benefit of allostasis, with an accelerated stress recovery, which reduces the burden of allostatic load. This model should be tested in future studies using larger samples, multiple related constructs, and longitudinal designs that include participants’ health records.
{"title":"‘Purpose in Life’ as a psychosocial resource in healthy aging: an examination of cortisol baseline levels and response to the Trier Social Stress Test","authors":"Nia Fogelman, Turhan Canli","doi":"10.1038/npjamd.2015.6","DOIUrl":"10.1038/npjamd.2015.6","url":null,"abstract":"‘Purpose in Life’ (Purpose) is associated with healthy aging, but it is unknown whether this association is causal. Conceptualizing Purpose as a form of psychosocial resource, one mechanism promoting health could be the regulation of stress hormones. To test this hypothesis, we recruited 44 older community-dwelling adults to examine the association between Purpose and cortisol at baseline, in response to, and recovery from, an acute social laboratory stressor. Purpose did not predict cortisol baseline or reactivity, but did predict a faster recovery to pre-stress baseline levels. The health benefits of Purpose in aging may therefore reflect the combination of a normal stress response, which serves an adaptive benefit of allostasis, with an accelerated stress recovery, which reduces the burden of allostatic load. This model should be tested in future studies using larger samples, multiple related constructs, and longitudinal designs that include participants’ health records.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2015-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Idiopathic late-onset dementia (ILOD) describes impairments of memory, reasoning and/or social abilities in the elderly that compromise their daily functioning. Dementia occurs in several major prototypical neurodegenerative disorders that are currently defined by neuropathological criteria, most notably Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and hippocampal sclerosis of aging (HSA). However, people who die with ILOD commonly exhibit mixed pathologies that vary within and between brain regions. Indeed, many patients diagnosed with probable AD exhibit only modest amounts of disease-defining amyloid β-peptide plaques and p-Tau tangles, and may have features of FTD (TDP-43 inclusions), Parkinson’s disease (α-synuclein accumulation), HSA and vascular lesions. Here I argue that this ‘mosaic neuropathological landscape’ is the result of commonalities in aging-related processes that render neurons vulnerable to the entire spectrum of ILODs. In this view, all ILODs involve deficits in neuronal energy metabolism, neurotrophic signaling and adaptive cellular stress responses, and associated dysregulation of neuronal calcium handling and autophagy. Although this mosaic of neuropathologies and underlying mechanisms poses major hurdles for development of disease-specific therapeutic interventions, it also suggests that certain interventions would be beneficial for all ILODs. Indeed, emerging evidence suggests that the brain can be protected against ILOD by lifelong intermittent physiological challenges including exercise, energy restriction and intellectual endeavors; these interventions enhance cellular stress resistance and facilitate neuroplasticity. There is also therapeutic potential for interventions that bolster neuronal bioenergetics and/or activate one or more adaptive cellular stress response pathways in brain cells. A wider appreciation that all ILODs share age-related cellular and molecular alterations upstream of aggregated protein lesions, and that these upstream events can be mitigated, may lead to implementation of novel intervention strategies aimed at reversing the rising tide of ILODs.
{"title":"Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle","authors":"Mark P Mattson","doi":"10.1038/npjamd.2015.3","DOIUrl":"10.1038/npjamd.2015.3","url":null,"abstract":"Idiopathic late-onset dementia (ILOD) describes impairments of memory, reasoning and/or social abilities in the elderly that compromise their daily functioning. Dementia occurs in several major prototypical neurodegenerative disorders that are currently defined by neuropathological criteria, most notably Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and hippocampal sclerosis of aging (HSA). However, people who die with ILOD commonly exhibit mixed pathologies that vary within and between brain regions. Indeed, many patients diagnosed with probable AD exhibit only modest amounts of disease-defining amyloid β-peptide plaques and p-Tau tangles, and may have features of FTD (TDP-43 inclusions), Parkinson’s disease (α-synuclein accumulation), HSA and vascular lesions. Here I argue that this ‘mosaic neuropathological landscape’ is the result of commonalities in aging-related processes that render neurons vulnerable to the entire spectrum of ILODs. In this view, all ILODs involve deficits in neuronal energy metabolism, neurotrophic signaling and adaptive cellular stress responses, and associated dysregulation of neuronal calcium handling and autophagy. Although this mosaic of neuropathologies and underlying mechanisms poses major hurdles for development of disease-specific therapeutic interventions, it also suggests that certain interventions would be beneficial for all ILODs. Indeed, emerging evidence suggests that the brain can be protected against ILOD by lifelong intermittent physiological challenges including exercise, energy restriction and intellectual endeavors; these interventions enhance cellular stress resistance and facilitate neuroplasticity. There is also therapeutic potential for interventions that bolster neuronal bioenergetics and/or activate one or more adaptive cellular stress response pathways in brain cells. A wider appreciation that all ILODs share age-related cellular and molecular alterations upstream of aggregated protein lesions, and that these upstream events can be mitigated, may lead to implementation of novel intervention strategies aimed at reversing the rising tide of ILODs.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2015-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35114795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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