Volume 9, Issue 9

September 2017
pp 1941—2009

About the Cover

The cover for issue 9 of Aging features Figure 3A "G-quadruplex-stabilizing drugs upregulate γH2A.X" from Moruno-Manchon et al.

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Table of Contents

Editorials

Rapamycin in mice

William R. Swindell,

https://doi.org/10.18632/aging.101289 pp 1941—1942

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Non-coding transcriptome in brain aging

Thomas Arendt, Uwe Ueberham, Michael Janitz,

https://doi.org/10.18632/aging.101290 pp 1943—1944

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AURKA inhibition mimics BRCAness

Jeff Hirst, Andrew K. Godwin,

https://doi.org/10.18632/aging.101291 pp 1945—1946

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Autophagic responses compensate mitochondrial impairments

Vanessa Henkel, Verena Warnsmann, Heinz D. Osiewacz,

https://doi.org/10.18632/aging.101292 pp 1947—1948

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Aging: Cancer – an unlikely couple

Antja-Voy Hartley, Matthew Martin, Tao Lu,

https://doi.org/10.18632/aging.101295 pp 1949—1950

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Targeting neuroinflammation - a potential for anti-aging interventions

Gillian Cady, Marianna Sadagurski,

https://doi.org/10.18632/aging.101296 pp 1951—1952

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Inhibition of neuronal autophagy mediates longevity

Jonathan Byrne, Thomas Wilhelm, Holger Richly,

https://doi.org/10.18632/aging.101297 pp 1953—1954

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BubR1 and brain aging

Syed Mohammed Qasim Hussaini, Mi-Hyeon Jang,

https://doi.org/10.18632/aging.101300 pp 1955—1956

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Research Papers

The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons

Jose F. Moruno-Manchon, Edward C. Koellhoffer, Jayakrishnan Gopakumar, Shashank Hambarde, Nayun Kim, Louise D. McCullough, Andrey S. Tsvetkov,

https://doi.org/10.18632/aging.101282 pp 1957—1970

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Moruno-Manchon JF, Koellhoffer EC, Gopakumar J, Hambarde S, Kim N, McCullough LD, Tsvetkov AS, . The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons. . 9:1957-1970. https://doi.org/10.18632/aging.101282

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                TY  - JOUR
                AU  - Moruno-Manchon, Jose F. 
                AU  - Koellhoffer, Edward C. 
                AU  - Gopakumar, Jayakrishnan 
                AU  - Hambarde, Shashank 
                AU  - Kim, Nayun 
                AU  - McCullough, Louise D. 
                AU  - Tsvetkov, Andrey S. 
                TI  - The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons
                JO  - 
                JA  - 
                VL  - 9
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101282
                DO  - 10.18632/aging.101282
                SP  - 1957
                EP  - 1970
                PY  - 
                AB  - The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double–strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G-quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G-quadruplexes could represent a new avenue for neurodegeneration and brain aging research.
                ER  -

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Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging

Amiya K. Ghosh, Martin O’Brien, Theresa Mau, Raymond Yung,

https://doi.org/10.18632/aging.101288 pp 1971—1982

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Ghosh AK, O’Brien M, Mau T, Yung R, . Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging. . 9:1971-1982. https://doi.org/10.18632/aging.101288

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                TY  - JOUR
                AU  - Ghosh, Amiya K. 
                AU  - O’Brien, Martin 
                AU  - Mau, Theresa 
                AU  - Yung, Raymond 
                TI  - Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging
                JO  - 
                JA  - 
                VL  - 9
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101288
                DO  - 10.18632/aging.101288
                SP  - 1971
                EP  - 1982
                PY  - 
                AB  - Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A &amp; TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.
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Leukocyte telomere length, T cell composition and DNA methylation age

Brian H. Chen, Cara L. Carty, Masayuki Kimura, Jeremy D. Kark, Wei Chen, Shengxu Li, Tao Zhang, Charles Kooperberg, Daniel Levy, Themistocles Assimes, Devin Absher, Steve Horvath, Alexander P. Reiner, Abraham Aviv,

https://doi.org/10.18632/aging.101293 pp 1983—1995

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Chen BH, Carty CL, Kimura M, Kark JD, Chen W, Li S, Zhang T, Kooperberg C, Levy D, Assimes T, Absher D, Horvath S, Reiner AP, et al, . Leukocyte telomere length, T cell composition and DNA methylation age. . 9:1983-1995. https://doi.org/10.18632/aging.101293

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                TY  - JOUR
                AU  - Chen, Brian H. 
                AU  - Carty, Cara L. 
                AU  - Kimura, Masayuki 
                AU  - Kark, Jeremy D. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Zhang, Tao 
                AU  - Kooperberg, Charles 
                AU  - Levy, Daniel 
                AU  - Assimes, Themistocles 
                AU  - Absher, Devin 
                AU  - Horvath, Steve 
                AU  - Reiner, Alexander P. 
                AU  - Aviv, Abraham 
                TI  - Leukocyte telomere length, T cell composition and DNA methylation age
                JO  - 
                JA  - 
                VL  - 9
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101293
                DO  - 10.18632/aging.101293
                SP  - 1983
                EP  - 1995
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Chen, Brian H. 
                AU  - Carty, Cara L. 
                AU  - Kimura, Masayuki 
                AU  - Kark, Jeremy D. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Zhang, Tao 
                AU  - Kooperberg, Charles 
                AU  - Levy, Daniel 
                AU  - Assimes, Themistocles 
                AU  - Absher, Devin 
                AU  - Horvath, Steve 
                AU  - Reiner, Alexander P. 
                AU  - Aviv, Abraham 
                TI  - Leukocyte telomere length, T cell composition and DNA methylation age
                JO  - 
                JA  - 
                VL  - 9
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101293
                DO  - 10.18632/aging.101293
                SP  - 1983
                EP  - 1995
                PY  - 
                AB  - Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8+ T cells, memory CD8+ T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (r=-0.16, p=3.1x10-6). This finding was replicated in the FHS (r=-0.09, p=6.5x10-3) and the BHS (r=-0.07, p=3.8x 10-2). LTL was also inversely related to proportions of memory CD8+ T cells (p=4.04x10-16) and positively related to proportions of naive CD8+ T cells (p=3.57x10-14). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8+ T cells and less naive CD8+ T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.
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Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population

Yan Zhang, Qiuming He, Ruizhong Zhang, Hong Zhang, Wei Zhong, Huimin Xia,

https://doi.org/10.18632/aging.101294 pp 1996—2009

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Zhang Y, He Q, Zhang R, Zhang H, Zhong W, Xia H, . Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population. . 9:1996-2009. https://doi.org/10.18632/aging.101294

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                TY  - JOUR
                AU  - Zhang, Yan 
                AU  - He, Qiuming 
                AU  - Zhang, Ruizhong 
                AU  - Zhang, Hong 
                AU  - Zhong, Wei 
                AU  - Xia, Huimin 
                TI  - Large-scale replication study identified multiple independent SNPs in <i>RET</i> synergistically associated with Hirschsprung disease in Southern Chinese population
                JO  - 
                JA  - 
                VL  - 9
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101294
                DO  - 10.18632/aging.101294
                SP  - 1996
                EP  - 2009
                PY  - 
                AB  - Hischsprung disease (HSCR) is an intestinal disorder with strong genetic components. RET was considered as the strongest contributor. Multiple single nucleotide polymorphisms (SNP) were demonstrated as associated with HSCR in different populations. However, whether the associations of reported SNPs derived from one causal variants or congregations of multiple variants were still not clear. In this study, we successfully genotyped 16 SNPs in RET with a largest case-control study to date, totaling 1470 HSCR and 1473 control subjects in South Chinese population. Multiple independent contributors were identified through pairwise and stepwise logistic regression. The intragenic synergistic effect among these SNPs were further explored and cross validated by logistic regression and multifactor dimensionality reduction (MDR). Noteworthy, in further subclinical manifestation analysis, the six potential independent contributors in RET were more essential for the patients with short-segment aganglionosis (S-HSCR). Although functional evaluations are required, our comprehensive analysis for RET gene integrating detailed disease subphenotypes might facilitate improved understanding for the genetic understanding of HSCR etiology.
                ER  -

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