Volume 8, Issue 5

Patrick A, Seluanov M, Hwang C, Tam J, Khan T, Morgenstern A, Wiener L, Vazquez JM, Zafar H, Wen R, Muratkalyeva M, Doerig K, Zagorulya M, et al, . Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan. . 8:841-847. https://doi.org/10.18632/aging.100958

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                TY  - JOUR
                AU  - Patrick, Alison 
                AU  - Seluanov, Michael 
                AU  - Hwang, Chaewon 
                AU  - Tam, Jonathan 
                AU  - Khan, Tanya 
                AU  - Morgenstern, Ari 
                AU  - Wiener, Lauren 
                AU  - Vazquez, Juan M.
                AU  - Zafar, Hiba 
                AU  - Wen, Robert 
                AU  - Muratkalyeva, Malika 
                AU  - Doerig, Katherine 
                AU  - Zagorulya, Maria 
                AU  - Cole, Lauren 
                AU  - Catalano, Sophia 
                AU  - Lobo Ladd, Aliny AB
                AU  - Coppi, A. Augusto
                AU  - Coşkun, Yüksel 
                AU  - Tian, Xiao 
                AU  - Ablaeva, Julia 
                AU  - Nevo, Eviatar 
                AU  - Gladyshev, Vadim N.
                AU  - Zhang, Zhengdong D.
                AU  - Vijg, Jan 
                AU  - Seluanov, Andrei 
                AU  - Gorbunova, Vera 
                TI  - Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100958
                DO  - 10.18632/aging.100958
                SP  - 841
                EP  - 847
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Patrick, Alison 
                AU  - Seluanov, Michael 
                AU  - Hwang, Chaewon 
                AU  - Tam, Jonathan 
                AU  - Khan, Tanya 
                AU  - Morgenstern, Ari 
                AU  - Wiener, Lauren 
                AU  - Vazquez, Juan M.
                AU  - Zafar, Hiba 
                AU  - Wen, Robert 
                AU  - Muratkalyeva, Malika 
                AU  - Doerig, Katherine 
                AU  - Zagorulya, Maria 
                AU  - Cole, Lauren 
                AU  - Catalano, Sophia 
                AU  - Lobo Ladd, Aliny AB
                AU  - Coppi, A. Augusto
                AU  - Coşkun, Yüksel 
                AU  - Tian, Xiao 
                AU  - Ablaeva, Julia 
                AU  - Nevo, Eviatar 
                AU  - Gladyshev, Vadim N.
                AU  - Zhang, Zhengdong D.
                AU  - Vijg, Jan 
                AU  - Seluanov, Andrei 
                AU  - Gorbunova, Vera 
                TI  - Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100958
                DO  - 10.18632/aging.100958
                SP  - 841
                EP  - 847
                PY  - 
                AB  - Differences in the way human and mouse fibroblasts experience senescence in culture had long puzzled researchers. While senescence of human cells is mediated by telomere shortening, Parrinello et al. demonstrated that senescence of mouse cells is caused by extreme oxygen sensitivity. It was hypothesized that the striking difference in oxygen sensitivity between mouse and human cells explains their different rates of aging. To test if this hypothesis is broadly applicable, we cultured cells from 16 rodent species with diverse lifespans in 3% and 21% oxygen and compared their growth rates. Unexpectedly, fibroblasts derived from laboratory mouse strains were the only cells demonstrating extreme sensitivity to oxygen. Cells from hamster, muskrat, woodchuck, capybara, blind mole rat, paca, squirrel, beaver, naked mole rat and wild-caught mice were mildly sensitive to oxygen, while cells from rat, gerbil, deer mouse, chipmunk, guinea pig and chinchilla showed no difference in the growth rate between 3% and 21% oxygen. We conclude that, although the growth of primary fibroblasts is generally improved by maintaining cells in 3% oxygen, the extreme oxygen sensitivity is a peculiarity of laboratory mouse strains, possibly related to their very long telomeres, and fibroblast oxygen sensitivity does not directly correlate with species' lifespan.
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Aging of immune system: immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults

Ling Qin, Xie Jing, Zhifeng Qiu, Wei Cao, Yang Jiao, Jean-Pierre Routy, Taisheng Li,

https://doi.org/10.18632/aging.100894 pp 848—859

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Qin L, Jing X, Qiu Z, Cao W, Jiao Y, Routy J, Li T, . Aging of immune system: immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults. . 8:848-859. https://doi.org/10.18632/aging.100894

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                TY  - JOUR
                AU  - Qin, Ling 
                AU  - Jing, Xie 
                AU  - Qiu, Zhifeng 
                AU  - Cao, Wei 
                AU  - Jiao, Yang 
                AU  - Routy, Jean-Pierre 
                AU  - Li, Taisheng 
                TI  - Aging of immune system: immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100894
                DO  - 10.18632/aging.100894
                SP  - 848
                EP  - 859
                PY  - 
                AB  - Aging is a major risk factor for several conditions including neurodegenerative, cardiovascular diseases and cancer. Functional impairments in cellular pathways controlling genomic stability, and immune control have been identified. Biomarker of immune senescence is needed to improve vaccine response and to develop therapy to improve immune control. To identify phenotypic signature of circulating immune cells with aging, we enrolled 1068 Chinese healthy volunteers ranging from 18 to 80 years old. The decreased naïve CD4+ and CD8+ T cells, increased memory CD4+ or CD8+ T cells, loss of CD28 expression on T cells and reverse trend of CD38 and HLA-DR, were significant for aging of immune system. Conversely, the absolute counts and percentage of NK cells and CD19+B cells maintained stable in aging individuals. The Chinese reference ranges of absolute counts and percentage of peripheral lymphocyte in this study might be useful for future clinical evaluation.
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Exercise: a “new drug” for elderly patients with chronic heart failure

Roberto Antonicelli, Liana Spazzafumo, Simonetta Scalvini, Fabiola Olivieri, Maria Vittoria Matassini, Gianfranco Parati, Donatella Del Sindaco, Raffaella Gallo, Fabrizia Lattanzio,

https://doi.org/10.18632/aging.100901 pp 860—872

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Antonicelli R, Spazzafumo L, Scalvini S, Olivieri F, Matassini MV, Parati G, Del Sindaco D, Gallo R, Lattanzio F, . Exercise: a “new drug” for elderly patients with chronic heart failure. . 8:860-872. https://doi.org/10.18632/aging.100901

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                TY  - JOUR
                AU  - Antonicelli, Roberto 
                AU  - Spazzafumo, Liana 
                AU  - Scalvini, Simonetta 
                AU  - Olivieri, Fabiola 
                AU  - Matassini, Maria Vittoria
                AU  - Parati, Gianfranco 
                AU  - Del Sindaco, Donatella 
                AU  - Gallo, Raffaella 
                AU  - Lattanzio, Fabrizia 
                TI  - Exercise: a “new drug” for elderly patients with chronic heart failure
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100901
                DO  - 10.18632/aging.100901
                SP  - 860
                EP  - 872
                PY  - 
                AB  - Patients with chronic heart failure (CHF) experience progressive deterioration of functional capacity and quality of life (QoL). This prospective, randomized, controlled trial assesses the effect of exercise training (ET) protocol on functional capacity, rehospitalization, and QoL in CHF patients older than 70 years compared with a control group. A total of 343 elderly patients with stable CHF (age, 76.90±5.67, men, 195, 56.9%) were randomized to ET (TCG, n=170) or usual care (UCG, n=173). The ET protocol involved supervised training sessions for 3 months in the hospital followed by home-telemonitored sessions for 3 months. Assessments, performed at baseline and at 3 and 6 months, included: ECG, resting echocardiography, NT-proBNP, 6-minute walk test (6MWT), Minnesota Living with Heart Failure Questionnaire, and comprehensive geriatric assessment with the InterRAI-HC instrument. As compared to UCG, ET patients at 6 months showed: i) significantly increased 6MWT distance (450±83 vs. 290±97 m, p&lt;0.001); ii) increased ADL scores (5.00±2.49 vs. 6.94±5.66, p=0.037); iii) 40% reduced risk of rehospitalisation (hazard ratio=0.558, 95%CI, 0.326-0.954, p=0.033); and iv) significantly improved perceived QoL (28.6±12.3 vs. 44.5±12.3, p&lt;0.001). In hospital and home-based telemonitored exercise confer significant benefits on the oldest CHF patients, improving functional capacity and subjective QoL and reducing risk of rehospitalisation.
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Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart

Yuan Xing, Wanqing Sun, Yishi Wang, Feng Gao, Heng Ma,

https://doi.org/10.18632/aging.100933 pp 873—888

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Xing Y, Sun W, Wang Y, Gao F, Ma H, . Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart. . 8:873-888. https://doi.org/10.18632/aging.100933

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                TY  - JOUR
                AU  - Xing, Yuan 
                AU  - Sun, Wanqing 
                AU  - Wang, Yishi 
                AU  - Gao, Feng 
                AU  - Ma, Heng 
                TI  - Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100933
                DO  - 10.18632/aging.100933
                SP  - 873
                EP  - 888
                PY  - 
                AB  - Insulin protects cardiomyocytes from myocardial ischemia/reperfusion (MI/R) injury through activating Akt. However, phosphatase PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) dephosphorylates and inactivates Akt. The balanced competitive interaction of insulin and PHLPP-1 has not been directly examined. In this study, we have identified the effect of mutual inhibition of insulin signaling and PHLPP-1 on the cardioprotective efficiency of Akt in aged heart. Young (3 mon) and aged (20 mon) Sprague Dawley (SD) rats were subjected to MI/Rin vivo. The PHLPP-1 level was higher in aged vs. young hearts at base. But, insulin treatment failed to decrease PHLPP-1 level during reperfusion in the aged hearts. Consequently, the cardioprotection of insulin-induced Akt activation was impaired in aged hearts, resulting in more susceptible to MI/R injury. In cultured rat ventricular myocytes, PHLPP-1 knockdown significantly enhanced insulin-induced Akt phosphorylation and reduced simulated hypoxia/reoxygenation-induced apoptosis. Contrary, PHLPP-1 overexpression terminated Akt phosphorylation and deteriorated myocytes apoptosis. Using in vivo aged animal models, we confirmed that cardiac PHLPP-1 knockdown or enhanced insulin sensitivity by exercise training dramatically increased insulin-induced Akt phosphorylation. Specifically, MI/R-induced cardiomyocyte apoptosis and infarct size were decreased and cardiac function was increased. More importantly, we found that insulin regulated the degradation of PHLPP-1 and insulin treatment could enhance the binding between PHLPP-1 and β-transducin repeat-containing protein (β-TrCP) to target for ubiquitin-dependent degradation. Altogether, we have identified a new mechanism by which insulin suppresses PHLPP-1 to enhance Akt activation. But, aged heart possesses lower insulin effectiveness and fails to decrease PHLPP-1 during MI/R, which subsequently limited Akt activity and cardioprotection. PHLPP-1 could be a promising therapeutic interventional target for elderly ischemic heart disease patients.
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Autofluorescence as a measure of senescence in C. elegans: look to red, not blue or green

Zachary Pincus, Travis C Mazer, Frank J Slack,

https://doi.org/10.18632/aging.100936 pp 889—898

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Pincus Z, Mazer TC, Slack FJ, . Autofluorescence as a measure of senescence in C. elegans: look to red, not blue or green. . 8:889-898. https://doi.org/10.18632/aging.100936

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                TY  - JOUR
                AU  - Pincus, Zachary 
                AU  - Mazer, Travis C
                AU  - Slack, Frank J
                TI  - Autofluorescence as a measure of senescence in <i>C. elegans</i>: look to red, not blue or green
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100936
                DO  - 10.18632/aging.100936
                SP  - 889
                EP  - 898
                PY  - 
                AB  - In C. elegans, intestinal autofluorescence (sometimes referred to as lipofuscin or “age pigment”) accumulates with age and is often used as a marker of health or the rate of aging. We show that this autofluorescent material is spectrally heterogeneous, and that materials that fluoresce under different excitation wavelengths have distinct biological properties. Red autofluorescence (visible with a TRITC filterset) correlates well with an individual's remaining days of life, and is therefore a candidate marker of health. In contrast, blue autofluorescence (via a DAPI filterset) is chiefly an indicator of an individual's incipient or recent demise. Thus, population averages of blue fluorescence essentially measure the fraction of dead or near-dead individuals. This is related to but distinct from the health of the living population. Green autofluorescence (via a FITC or GFP filterset) combines both properties, and is therefore ill suited as a marker of either death or health. Moreover, our results show that care must be taken to distinguish GFP expression near the time of death from full-body green autofluorescence. Finally, none of this autofluorescence increases after oxidative stress, suggesting that the material, or its biology in C. elegans, is distinct from lipofuscin as reported in the mammalian literature.
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Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet

Michel Bernier, Devin Wahl, Ahmed Ali, Joanne Allard, Shakeela Faulkner, Artur Wnorowski, Mitesh Sanghvi, Ruin Moaddel, Irene Alfaras, Julie A. Mattison, Stefano Tarantini, Zsuzsanna Tucsek, Zoltan Ungvari, Anna Csiszar, Kevin J. Pearson, Rafael de Cabo,

https://doi.org/10.18632/aging.100942 pp 899—916

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Bernier M, Wahl D, Ali A, Allard J, Faulkner S, Wnorowski A, Sanghvi M, Moaddel R, Alfaras I, Mattison JA, Tarantini S, Tucsek Z, Ungvari Z, et al, . Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet. . 8:899-916. https://doi.org/10.18632/aging.100942

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                TY  - JOUR
                AU  - Bernier, Michel 
                AU  - Wahl, Devin 
                AU  - Ali, Ahmed 
                AU  - Allard, Joanne 
                AU  - Faulkner, Shakeela 
                AU  - Wnorowski, Artur 
                AU  - Sanghvi, Mitesh 
                AU  - Moaddel, Ruin 
                AU  - Alfaras, Irene 
                AU  - Mattison, Julie A.
                AU  - Tarantini, Stefano 
                AU  - Tucsek, Zsuzsanna 
                AU  - Ungvari, Zoltan 
                AU  - Csiszar, Anna 
                AU  - Pearson, Kevin J.
                AU  - de Cabo, Rafael 
                TI  - Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100942
                DO  - 10.18632/aging.100942
                SP  - 899
                EP  - 916
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Bernier, Michel 
                AU  - Wahl, Devin 
                AU  - Ali, Ahmed 
                AU  - Allard, Joanne 
                AU  - Faulkner, Shakeela 
                AU  - Wnorowski, Artur 
                AU  - Sanghvi, Mitesh 
                AU  - Moaddel, Ruin 
                AU  - Alfaras, Irene 
                AU  - Mattison, Julie A.
                AU  - Tarantini, Stefano 
                AU  - Tucsek, Zsuzsanna 
                AU  - Ungvari, Zoltan 
                AU  - Csiszar, Anna 
                AU  - Pearson, Kevin J.
                AU  - de Cabo, Rafael 
                TI  - Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100942
                DO  - 10.18632/aging.100942
                SP  - 899
                EP  - 916
                PY  - 
                AB  - Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.
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The effects of graded levels of calorie restriction: VII. Topological rearrangement of hypothalamic aging networks

Davina Derous, Sharon E Mitchell, Cara L Green, Yingchun Wang, Jing Dong J Han, Luonan Chen, Daniel E.L Promislow, David Lusseau, John R Speakman, Alex Douglas,

https://doi.org/10.18632/aging.100944 pp 917—932

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Derous D, Mitchell SE, Green CL, Wang Y, Han JD, Chen L, Promislow DE, Lusseau D, Speakman JR, Douglas A, . The effects of graded levels of calorie restriction: VII. Topological rearrangement of hypothalamic aging networks. . 8:917-932. https://doi.org/10.18632/aging.100944

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                TY  - JOUR
                AU  - Derous, Davina 
                AU  - Mitchell, Sharon E
                AU  - Green, Cara L
                AU  - Wang, Yingchun 
                AU  - Han, Jing Dong J
                AU  - Chen, Luonan 
                AU  - Promislow, Daniel E.L
                AU  - Lusseau, David 
                AU  - Speakman, John R
                AU  - Douglas, Alex 
                TI  - The effects of graded levels of calorie restriction: VII. Topological rearrangement of hypothalamic aging networks
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100944
                DO  - 10.18632/aging.100944
                SP  - 917
                EP  - 932
                PY  - 
                AB  - Connectivity in a gene-gene network declines with age, typically within gene clusters. We explored the effect of short-term (3 months) graded calorie restriction (CR) (up to 40 %) on network structure of aging-associated genes in the murine hypothalamus by using conditional mutual information. The networks showed a topological rearrangement when exposed to graded CR with a higher relative within cluster connectivity at 40CR. We observed changes in gene centrality concordant with changes in CR level, with Ppargc1a, and Ppt1 having increased centrality and Etfdh, Traf3 and Abcc1 decreased centrality as CR increased. This change in gene centrality in a graded manner with CR, occurred in the absence of parallel changes in gene expression levels. This study emphasizes the importance of augmenting traditional differential gene expression analyses to better understand structural changes in the transcriptome. Overall our results suggested that CR induced changes in centrality of biological relevant genes that play an important role in preventing the age-associated loss of network integrity irrespective of their gene expression levels.
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MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma

Luca Falzone, Rossella Salemi, Salvatore Travali, Aurora Scalisi, James A. McCubrey, Saverio Candido, Massimo Libra,

https://doi.org/10.18632/aging.100951 pp 933—944

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Falzone L, Salemi R, Travali S, Scalisi A, McCubrey JA, Candido S, Libra M, . MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. . 8:933-944. https://doi.org/10.18632/aging.100951

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                TY  - JOUR
                AU  - Falzone, Luca 
                AU  - Salemi, Rossella 
                AU  - Travali, Salvatore 
                AU  - Scalisi, Aurora 
                AU  - McCubrey, James A.
                AU  - Candido, Saverio 
                AU  - Libra, Massimo 
                TI  - MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100951
                DO  - 10.18632/aging.100951
                SP  - 933
                EP  - 944
                PY  - 
                AB  - Tumor spreading is associated with the degradation of extracellular matrix proteins, mediated by the overexpression of matrix metalloproteinase 9 (MMP-9). Although, such overexpression was linked to epigenetic promoter methylation, the role of intragenic methylation was not clarified yet. Melanoma was used as tumor model to investigate the relationship between the DNA intragenic methylation ofMMP9 gene and MMP-9 overexpression at transcriptional and protein levels. Computational analysis revealed DNA hypermethylation within the intragenic CpG-2 region of MMP9 gene in melanoma samples with high MMP-9 transcript levels. In vitro validation showed that CpG-2 hotspot region was hypermethylated in the A375 melanoma cell line with highest mRNA and protein levels of MMP-9, while low methylation levels were observed in the MEWO cell line where MMP-9 was undetectable. Concordant results were demonstrated in both A2058 and M14 cell lines. This correlation may give further insights on the role of MMP-9 upregulation in melanoma.
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Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells

Sandy S.C Hung, Nicole J Van Bergen, Stacey Jackson, Helena Liang, David A. A Mackey, Damián Hernández, Shiang Y Lim, Alex W Hewitt, Ian Trounce, Alice Pébay, Raymond C.B Wong,

https://doi.org/10.18632/aging.100950 pp 945—957

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Hung SS, Van Bergen NJ, Jackson S, Liang H, Mackey DA, Hernández D, Lim SY, Hewitt AW, Trounce I, Pébay A, Wong RC, . Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells. . 8:945-957. https://doi.org/10.18632/aging.100950

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                TY  - JOUR
                AU  - Hung, Sandy S.C
                AU  - Van Bergen, Nicole J
                AU  - Jackson, Stacey 
                AU  - Liang, Helena 
                AU  - Mackey, David A. A
                AU  - Hernández, Damián 
                AU  - Lim, Shiang Y
                AU  - Hewitt, Alex W
                AU  - Trounce, Ian 
                AU  - Pébay, Alice 
                AU  - Wong, Raymond C.B
                TI  - Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100950
                DO  - 10.18632/aging.100950
                SP  - 945
                EP  - 957
                PY  - 
                AB  - Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mtDNA mutations and subsequent oxidative phosphorylation (OXPHOS) defects in reprogramming. We obtained fibroblasts from a total of 6 LHON patients and control subjects, and showed a significant defect in complex I respiration in LHON fibroblasts by high-resolution respiratory analysis. Using episomal vector reprogramming, our results indicated that human induced pluripotent stem cell (hiPSC) generation is feasible in LHON fibroblasts. In particular, LHON-specific OXPHOS defects in fibroblasts only caused a mild reduction and did not significantly affect reprogramming efficiency, suggesting that hiPSC reprogramming can tolerate a certain degree of OXPHOS defects. Our results highlighted the induction of genes involved in mitochondrial biogenesis (TFAM, NRF1), mitochondrial fusion (MFN1, MFN2) and glycine production (GCAT) during reprogramming. However, LHON-associated OXPHOS defects did not alter the kinetics or expression levels of these genes during reprogramming. Together, our study provides new insights into the effects of mtDNA mutation and OXPHOS defects in reprogramming and genes associated with various aspects of mitochondrial biology.
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Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

Ilenia Segatto, Samuele Massarut, Robert Boyle, Gustavo Baldassarre, David Walker, Barbara Belletti,

https://doi.org/10.18632/aging.100954 pp 958—977

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Segatto I, Massarut S, Boyle R, Baldassarre G, Walker D, Belletti B, . Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer. . 8:958-977. https://doi.org/10.18632/aging.100954

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                TY  - JOUR
                AU  - Segatto, Ilenia 
                AU  - Massarut, Samuele 
                AU  - Boyle, Robert 
                AU  - Baldassarre, Gustavo 
                AU  - Walker, David 
                AU  - Belletti, Barbara 
                TI  - Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100954
                DO  - 10.18632/aging.100954
                SP  - 958
                EP  - 977
                PY  - 
                AB  - Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC50 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse.Summary StatementOur results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments.
                ER  -

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Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis

Guibin Xu, Fei Yue, Hai Huang, Yongzhong He, Xun Li, Haibo Zhao, Zhengming Su, Xianhan Jiang, Wenjiao Li, Jing Zou, Qi Chen, Leyuan Liu,

https://doi.org/10.18632/aging.100957 pp 977—985

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Xu G, Yue F, Huang H, He Y, Li X, Zhao H, Su Z, Jiang X, Li W, Zou J, Chen Q, Liu L, . Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. . 8:977-985. https://doi.org/10.18632/aging.100957

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                TY  - JOUR
                AU  - Xu, Guibin 
                AU  - Yue, Fei 
                AU  - Huang, Hai 
                AU  - He, Yongzhong 
                AU  - Li, Xun 
                AU  - Zhao, Haibo 
                AU  - Su, Zhengming 
                AU  - Jiang, Xianhan 
                AU  - Li, Wenjiao 
                AU  - Zou, Jing 
                AU  - Chen, Qi 
                AU  - Liu, Leyuan 
                TI  - Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100957
                DO  - 10.18632/aging.100957
                SP  - 977
                EP  - 985
                PY  - 
                AB  - Excessive deposition of extracellular matrix proteins in renal tissues causes renal fibrosis and renal function failure. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles. MAP1S is an autophagy activator and promotes the biogenesis and degradation of autophagosomes. Previously, we reported that MAP1S suppresses hepatocellular carcinogenesis in a mouse model and predicts a better prognosis in patients suffering from clear cell renal cell carcinomas. Furthermore, we have characterized that MAP1S enhances the turnover of fibronectin, and mice overexpressing LC3 but with MAP1S deleted accumulate fibronectin and develop liver fibrosis because of the synergistic impact of LC3-induced over-synthesis of fibronectin and MAP1S depletion-caused impairment of fibronectin degradation. Here we show that a suppression of MAP1S in renal cells caused an impairment of autophagy clearance of fibronectin and an activation of pyroptosis. Depletion of MAP1S in mice leads to an accumulation of fibrosis-related proteins and the development of renal fibrosis in aged mice. The levels of MAP1S were dramatically reduced and levels of fibronectin were greatly elevated in renal fibrotic tissues from patients diagnosed as renal atrophy and renal failure. Therefore, MAP1S deficiency may cause the accumulation of fibronectin and the development of renal fibrosis.
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Inverse correlation between longevity and developmental rate among wild C. elegans strains

Yujin Lee, Wooseon Hwang, Juyoung Jung, Sangsoon Park, Josephine Jill T. Cabatbat, Pan-Jun Kim, Seung-Jae V Lee,

https://doi.org/10.18632/aging.100960 pp 986—994

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Lee Y, Hwang W, Jung J, Park S, Cabatbat JJ, Kim P, Lee SV, . Inverse correlation between longevity and developmental rate among wild C. elegans strains. . 8:986-994. https://doi.org/10.18632/aging.100960

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                TY  - JOUR
                AU  - Lee, Yujin 
                AU  - Hwang, Wooseon 
                AU  - Jung, Juyoung 
                AU  - Park, Sangsoon 
                AU  - Cabatbat, Josephine Jill T.
                AU  - Kim, Pan-Jun 
                AU  - Lee, Seung-Jae V
                TI  - Inverse correlation between longevity and developmental rate among wild <i>C. elegans</i> strains
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100960
                DO  - 10.18632/aging.100960
                SP  - 986
                EP  - 994
                PY  - 
                AB  - Genetic studies using model organisms have shown that many long-lived mutants display impaired fitness, such as reduced fecundity and delayed development. However, in several wild animals, the association between longevity and fitness does not seem to be inevitable. Thus, the relationship between longevity and fitness in wild organisms remains inconclusive. Here, we determined the correlation between lifespan and fitness, developmental rate and brood size, by using 16 wild-derived C. elegans strains originated from various geographic areas. We found a negative correlation between lifespan and developmental rate. In contrast, we did not find such negative correlation between longevity and developmental rate among the individuals of C. elegans strains. These data imply that polymorphic genetic variants among wild isolates determine resource allocation to longevity and developmental rate.
                ER  -

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Metabolic drift in the aging brain

Julijana Ivanisevic, Kelly L Stauch, Michael Petrascheck, H Paul Benton, Adrian A Epstein, Mingliang Fang, Santhi Gorantla, Minerva Tran, Linh Hoang, Michael E Kurczy, Michael D Boska, Howard E Gendelman, Howard S Fox, Gary Siuzdak,

https://doi.org/10.18632/aging.100961 pp 1000—1020

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Ivanisevic J, Stauch KL, Petrascheck M, Benton HP, Epstein AA, Fang M, Gorantla S, Tran M, Hoang L, Kurczy ME, Boska MD, Gendelman HE, Fox HS, et al, . Metabolic drift in the aging brain. . 8:1000-1020. https://doi.org/10.18632/aging.100961

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                TY  - JOUR
                AU  - Ivanisevic, Julijana 
                AU  - Stauch, Kelly L
                AU  - Petrascheck, Michael 
                AU  - Benton, H Paul
                AU  - Epstein, Adrian A
                AU  - Fang, Mingliang 
                AU  - Gorantla, Santhi 
                AU  - Tran, Minerva 
                AU  - Hoang, Linh 
                AU  - Kurczy, Michael E
                AU  - Boska, Michael D
                AU  - Gendelman, Howard E
                AU  - Fox, Howard S
                AU  - Siuzdak, Gary 
                TI  - Metabolic drift in the aging brain
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100961
                DO  - 10.18632/aging.100961
                SP  - 1000
                EP  - 1020
                PY  - 
                AB  - Brain function
                    is highly dependent upon controlled energy metabolism whose loss heralds
                    cognitive impairments. This is particularly notable in the aged individuals
                    and in age-related neurodegenerative diseases. However, how metabolic
                    homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic
                    analyses across different anatomical regions of mouse brain at different
                    stages of its adult lifespan. Interestingly, while severe proteomic
                    imbalance was absent, global-untargeted metabolomics revealed an energymetabolic
                    drift or significant imbalance in core metabolite levels in aged mouse
                    brains. Metabolic imbalance was characterized by compromised cellular
                    energy status (NAD decline, increased AMP/ATP, purine/pyrimidine
                    accumulation) and significantly altered oxidative phosphorylation and
                    nucleotide biosynthesis and degradation. The central energy metabolic drift
                    suggests a failure of the cellular machinery to
                    restore metabostasis (metabolite homeostasis) in the aged brain and
                    therefore an inability to respond properly to external stimuli, likely
                    driving the alterations in signaling activity and thus in neuronal function
                    and communication.
                ER  -

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Deep biomarkers of human aging: Application of deep neural networks to biomarker development

Evgeny Putin, Polina Mamoshina, Alexander Aliper, Mikhail Korzinkin, Alexey Moskalev, Alexey Kolosov, Alexander Ostrovskiy, Charles Cantor, Jan Vijg, Alex Zhavoronkov,

https://doi.org/10.18632/aging.100968 pp 1021—1033

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Putin E, Mamoshina P, Aliper A, Korzinkin M, Moskalev A, Kolosov A, Ostrovskiy A, Cantor C, Vijg J, Zhavoronkov A, . Deep biomarkers of human aging: Application of deep neural networks to biomarker development. . 8:1021-1033. https://doi.org/10.18632/aging.100968

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                TY  - JOUR
                AU  - Putin, Evgeny 
                AU  - Mamoshina, Polina 
                AU  - Aliper, Alexander 
                AU  - Korzinkin, Mikhail 
                AU  - Moskalev, Alexey 
                AU  - Kolosov, Alexey 
                AU  - Ostrovskiy, Alexander 
                AU  - Cantor, Charles 
                AU  - Vijg, Jan 
                AU  - Zhavoronkov, Alex 
                TI  - Deep biomarkers of human aging: Application of deep neural networks to biomarker development
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100968
                DO  - 10.18632/aging.100968
                SP  - 1021
                EP  - 1033
                PY  - 
                AB  - One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. The best performing DNN in the ensemble demonstrated 81.5 % epsilon-accuracy r = 0.90 with R2 = 0.80 and MAE = 6.07 years in predicting chronological age within a 10 year frame, while the entire ensemble achieved 83.5% epsilon-accuracy r = 0.91 with R2 = 0.82 and MAE = 5.55 years. The ensemble also identified the 5 most important markers for predicting human chronological age: albumin, glucose, alkaline phosphatase, urea and erythrocytes. To allow for public testing and evaluate real-life performance of the predictor, we developed an online system available at http://www.aging.ai. The ensemble approach may facilitate integration of multi-modal data linked to chronological age and sex that may lead to simple, minimally invasive, and affordable methods of tracking integrated biomarkers of aging in humans and performing cross-species feature importance analysis.
                ER  -

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Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures

Monika Eipel, Felix Mayer, Tanja Arent, Marcelo R.P. Ferreira, Carina Birkhofer, Uwe Gerstenmaier, Ivan G. Costa, Stefanie Ritz-Timme, Wolfgang Wagner,

https://doi.org/10.18632/aging.100972 pp 1034—1048

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Eipel M, Mayer F, Arent T, Ferreira MR, Birkhofer C, Gerstenmaier U, Costa IG, Ritz-Timme S, Wagner W, . Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures. . 8:1034-1048. https://doi.org/10.18632/aging.100972

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                TY  - JOUR
                AU  - Eipel, Monika 
                AU  - Mayer, Felix 
                AU  - Arent, Tanja 
                AU  - Ferreira, Marcelo R.P.
                AU  - Birkhofer, Carina 
                AU  - Gerstenmaier, Uwe 
                AU  - Costa, Ivan G.
                AU  - Ritz-Timme, Stefanie 
                AU  - Wagner, Wolfgang 
                TI  - Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100972
                DO  - 10.18632/aging.100972
                SP  - 1034
                EP  - 1048
                PY  - 
                AB  - Aging is reflected by highly reproducible DNA methylation (DNAm) changes that open new perspectives for estimation of chronological age in legal medicine. DNA can be harvested non-invasively from cells at the inside of a person's cheek using buccal swabs - but these specimens resemble heterogeneous mixtures of buccal epithelial cells and leukocytes with different epigenetic makeup. In this study, we have trained an age predictor based on three age-associated CpG sites (associated with the genesPDE4C, ASPA, and ITGA2B) for swab samples to reach a mean absolute deviation (MAD) between predicted and chronological age of 4.3 years in a training set and of 7.03 years in a validation set. Subsequently, the composition of buccal epithelial cells versus leukocytes was estimated by two additional CpGs (associated with the genes CD6 and SERPINB5). Results of this "Buccal-Cell-Signature" correlated with cell counts in cytological stains (R2 = 0.94). Combination of cell type-specific and age-associated CpGs into one multivariate model enabled age predictions with MADs of 5.09 years and 5.12 years in two independent validation sets. Our results demonstrate that the cellular composition in buccal swab samples can be determined by DNAm at two cell type-specific CpGs to improve epigenetic age predictions.
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Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice

Joshua Crapser, Rodney Ritzel, Rajkumar Verna, Venugopal R. Venna, Fudong Liu, Anjali Chauhan, Edward Koellhoffer, Anita Patel, Austin Ricker, Kendra Maas, Joerg Graf, Louise D. McCullough,

https://doi.org/10.18632/aging.100952 pp 1049—1063

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Crapser J, Ritzel R, Verna R, Venna VR, Liu F, Chauhan A, Koellhoffer E, Patel A, Ricker A, Maas K, Graf J, McCullough LD, . Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. . 8:1049-1063. https://doi.org/10.18632/aging.100952

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                TY  - JOUR
                AU  - Crapser, Joshua 
                AU  - Ritzel, Rodney 
                AU  - Verna, Rajkumar 
                AU  - Venna, Venugopal R.
                AU  - Liu, Fudong 
                AU  - Chauhan, Anjali 
                AU  - Koellhoffer, Edward 
                AU  - Patel, Anita 
                AU  - Ricker, Austin 
                AU  - Maas, Kendra 
                AU  - Graf, Joerg 
                AU  - McCullough, Louise D.
                TI  - Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100952
                DO  - 10.18632/aging.100952
                SP  - 1049
                EP  - 1063
                PY  - 
                AB  - Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke.
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SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Suowen Xu, Meimei Yin, Marina Koroleva, Michael A. Mastrangelo, Wenbo Zhang, Peter Bai, Peter J. Little, Zheng Gen Jin,

https://doi.org/10.18632/aging.100975 pp 1064—1082

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Xu S, Yin M, Koroleva M, Mastrangelo MA, Zhang W, Bai P, Little PJ, Jin ZG, . SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. . 8:1064-1082. https://doi.org/10.18632/aging.100975

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                TY  - JOUR
                AU  - Xu, Suowen 
                AU  - Yin, Meimei 
                AU  - Koroleva, Marina 
                AU  - Mastrangelo, Michael A.
                AU  - Zhang, Wenbo 
                AU  - Bai, Peter 
                AU  - Little, Peter J.
                AU  - Jin, Zheng Gen
                TI  - SIRT6 protects against endothelial dysfunction and atherosclerosis in mice
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100975
                DO  - 10.18632/aging.100975
                SP  - 1064
                EP  - 1082
                PY  - 
                AB  - SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE-/- mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/- haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/-; ApoE-/- mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease.
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Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging

Matilde Cescon, Peiwen Chen, Silvia Castagnaro, Ilaria Gregorio, Paolo Bonaldo,

https://doi.org/10.18632/aging.100924 pp 1083—1101

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Cescon M, Chen P, Castagnaro S, Gregorio I, Bonaldo P, . Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging. . 8:1083-1101. https://doi.org/10.18632/aging.100924

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                TY  - JOUR
                AU  - Cescon, Matilde 
                AU  - Chen, Peiwen 
                AU  - Castagnaro, Silvia 
                AU  - Gregorio, Ilaria 
                AU  - Bonaldo, Paolo 
                TI  - Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100924
                DO  - 10.18632/aging.100924
                SP  - 1083
                EP  - 1101
                PY  - 
                AB  - Collagen VI is an extracellular matrix (ECM) protein with a broad distribution in different tissues and mostly deposited at the close periphery of the cell surface. Previous studies revealed that collagen VI protects neurons from the toxicity of amyloid-βpeptides and from UV-induced damage. However, the physiological role of this protein in the central nervous system (CNS) remains unknown. Here, we established primary neural cultures from murine cortex and hippocampus, and carried out in vitro and in vivo studies in wild-type and collagen VI null (Col6a1-/-) mice. Col6a1-/- neural cultures displayed an increased incidence of spontaneous apoptosis and higher vulnerability to oxidative stress, accompanied by altered regulation of autophagy with increased p62 protein levels and decreased LC3 lipidation. Analysis of brain sections confirmed increased apoptosis and abnormal regulation of autophagy in the CNS of collagen VI-deficient animals. To investigate the in vivo physiological consequences of these CNS defects, we carried out functional studies and found that motor and memory task performances were impaired in aged Col6a1-/- mice. These findings indicate that lack of collagen VI leads to spontaneous apoptosis and defective autophagy in neural cells, and point at a protective role for this ECM protein in the CNS during physiological aging.
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Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway

Zhifeng Gu, Wei Tan, Juan Ji, Guijian Feng, Yan Meng, Zhanyun Da, Genkai Guo, Yunfei Xia, Xinhang Zhu, Guixiu Shi, Chun Cheng,

https://doi.org/10.18632/aging.100925 pp 1102—1114

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Gu Z, Tan W, Ji J, Feng G, Meng Y, Da Z, Guo G, Xia Y, Zhu X, Shi G, Cheng C, . Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. . 8:1102-1114. https://doi.org/10.18632/aging.100925

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                TY  - JOUR
                AU  - Gu, Zhifeng 
                AU  - Tan, Wei 
                AU  - Ji, Juan 
                AU  - Feng, Guijian 
                AU  - Meng, Yan 
                AU  - Da, Zhanyun 
                AU  - Guo, Genkai 
                AU  - Xia, Yunfei 
                AU  - Zhu, Xinhang 
                AU  - Shi, Guixiu 
                AU  - Cheng, Chun 
                TI  - Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100925
                DO  - 10.18632/aging.100925
                SP  - 1102
                EP  - 1114
                PY  - 
                AB  - We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1x106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.
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Transgenerational programming of longevity and reproduction by post-eclosion dietary manipulation in Drosophila

Brian Xia, Steven de Belle,

https://doi.org/10.18632/aging.100932 pp 1115—1134

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Xia B, de Belle S, . Transgenerational programming of longevity and reproduction by post-eclosion dietary manipulation in Drosophila. . 8:1115-1134. https://doi.org/10.18632/aging.100932

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                TY  - JOUR
                AU  - Xia, Brian 
                AU  - de Belle, Steven 
                TI  - Transgenerational programming of longevity and reproduction by post-eclosion dietary manipulation in Drosophila
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100932
                DO  - 10.18632/aging.100932
                SP  - 1115
                EP  - 1134
                PY  - 
                AB  - Accumulating
                    evidence suggests that early-life diet may program one's health status by
                    causing permanent alternations in specific organs, tissues, or metabolic or
                    homeostatic pathways, and such programming effects may propagate across
                    generations through heritable epigenetic modifications. However, it remains
                    uninvestigated whether postnatal dietary changes may program longevity
                    across generations. To address this question of important biological and
                    public health implications, newly-born flies (F0) were collected
                    and subjected to various post-eclosion dietary manipulations (PDMs) with different
                    protein-carbohydrate (i.e., LP, IP or HP for low-, intermediate- or
                    high-protein) contents or a control diet (CD). Longevity and fecundity
                    analyses were performed with these treated F0 flies and their F1, F2 and F3
                    offspring, while maintained on CD at all times. The LP and HP PDMs shortened
                    longevity, while the IP PDM extended longevity significantly up to the F3
                    generation. Furthermore, the LP reduced while the IP PDM increased lifetime
                    fecundity across the F0-F2 generations. Our
                    observations establish the first animal model for studying
                    transgenerational inheritance of nutritional programming of longevity,
                    making it possible to investigate the underlying epigenetic mechanisms and
                    identify gene targets for drug discovery in future studies.
                ER  -

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Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake

Ruth McClelland, Kelly Christensen, Suhaib Mohammed, Dagmara McGuinness, Josephine Cooney, Andisheh Bakshi, Evangelia Demou, Ewan MacDonald, Muriel Caslake, Peter Stenvinkel, Paul G. Shiels,

https://doi.org/10.18632/aging.100948 pp 1135—1149

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McClelland R, Christensen K, Mohammed S, McGuinness D, Cooney J, Bakshi A, Demou E, MacDonald E, Caslake M, Stenvinkel P, Shiels PG, . Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake. . 8:1135-1149. https://doi.org/10.18632/aging.100948

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Provider: 
                TY  - JOUR
                AU  - McClelland, Ruth 
                AU  - Christensen, Kelly 
                AU  - Mohammed, Suhaib 
                AU  - McGuinness, Dagmara 
                AU  - Cooney, Josephine 
                AU  - Bakshi, Andisheh 
                AU  - Demou, Evangelia 
                AU  - MacDonald, Ewan 
                AU  - Caslake, Muriel 
                AU  - Stenvinkel, Peter 
                AU  - Shiels, Paul G.
                TI  - Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100948
                DO  - 10.18632/aging.100948
                SP  - 1135
                EP  - 1149
                PY  - 
                AB  - Background: We have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health. Results: We observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption. Conclusions: Accelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status.
                ER  -

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Bonnie and Clyde: Vitamin C and iron are partners in crime in iron deficiency anaemia and its potential role in the elderly

Darius J.R Lane, Patric J Jansson, Des R Richardson,

https://doi.org/10.18632/aging.100966 pp 1150—1152

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Lane DJ, Jansson PJ, Richardson DR, . Bonnie and Clyde: Vitamin C and iron are partners in crime in iron deficiency anaemia and its potential role in the elderly. . 8:1150-1152. https://doi.org/10.18632/aging.100966

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Mir 145/143: tumor suppressor, oncogenic microenvironmental factor or ...both?

Mario Cioce, Sabrina Strano, Paola Muti, Giovanni Blandino,

https://doi.org/10.18632/aging.100965 pp 1153—1155

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Cioce M, Strano S, Muti P, Blandino G, . Mir 145/143: tumor suppressor, oncogenic microenvironmental factor or ...both?. . 8:1153-1155. https://doi.org/10.18632/aging.100965

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Erratum: Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles

Sylvia Weilner, Verena Keider, Melanie Winter, Eva Harreither, Benjamin Salzer, Florian Weiss, Elisabeth Schraml, Paul Messner, Peter Pietschmann, Florian Hildner, Christian Gabriel, Heinz Redl, Regina Grillari-Voglauer, Johannes Grillari,

https://doi.org/10.18632/aging.100917 pp 1156—1157

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Weilner S, Keider V, Winter M, Harreither E, Salzer B, Weiss F, Schraml E, Messner P, Pietschmann P, Hildner F, Gabriel C, Redl H, Grillari-Voglauer R, et al, . Erratum: Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles. . 8:1156-1157. https://doi.org/10.18632/aging.100917

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                TY  - JOUR
                AU  - Weilner, Sylvia 
                AU  - Keider, Verena 
                AU  - Winter, Melanie 
                AU  - Harreither, Eva 
                AU  - Salzer, Benjamin 
                AU  - Weiss, Florian 
                AU  - Schraml, Elisabeth 
                AU  - Messner, Paul 
                AU  - Pietschmann, Peter 
                AU  - Hildner, Florian 
                AU  - Gabriel, Christian 
                AU  - Redl, Heinz 
                AU  - Grillari-Voglauer, Regina 
                AU  - Grillari, Johannes 
                TI  - Erratum: Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100917
                DO  - 10.18632/aging.100917
                SP  - 1156
                EP  - 1157
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Weilner, Sylvia 
                AU  - Keider, Verena 
                AU  - Winter, Melanie 
                AU  - Harreither, Eva 
                AU  - Salzer, Benjamin 
                AU  - Weiss, Florian 
                AU  - Schraml, Elisabeth 
                AU  - Messner, Paul 
                AU  - Pietschmann, Peter 
                AU  - Hildner, Florian 
                AU  - Gabriel, Christian 
                AU  - Redl, Heinz 
                AU  - Grillari-Voglauer, Regina 
                AU  - Grillari, Johannes 
                TI  - Erratum: Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles
                JO  - 
                JA  - 
                VL  - 8
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100917
                DO  - 10.18632/aging.100917
                SP  - 1156
                EP  - 1157
                PY  - 
                AB  - 
                ER  -

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Erratum: Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of β-amyloid

Yuanyuan Li, Xing Yuan, Yunheng Shen, Jing Zhao, Rongcai Yue, Fang Liu, Weiwei He, Rui Wang, Lei Shan, Weidong Zhang,

https://doi.org/10.18632/aging.100956 pp 1158

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Li Y, Yuan X, Shen Y, Zhao J, Yue R, Liu F, He W, Wang R, Shan L, Zhang W, . Erratum: Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of β-amyloid. . 8:1158-1158. https://doi.org/10.18632/aging.100956

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Volume 8, Issue 5

About the Cover

Editorials

Uma Gaur, Xiaolan Fan, Mingyao Yang,

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Vi K. Chiu, Anne-France Le Rolle,

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Gerald Krystal, Melisa J Hamilton, Kevin L Bennewith,

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Susan E. Erdman,

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Research Papers

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Ling Qin, Xie Jing, Zhifeng Qiu, Wei Cao, Yang Jiao, Jean-Pierre Routy, Taisheng Li,

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Roberto Antonicelli, Liana Spazzafumo, Simonetta Scalvini, Fabiola Olivieri, Maria Vittoria Matassini, Gianfranco Parati, Donatella Del Sindaco, Raffaella Gallo, Fabrizia Lattanzio,

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Yuan Xing, Wanqing Sun, Yishi Wang, Feng Gao, Heng Ma,

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Zachary Pincus, Travis C Mazer, Frank J Slack,

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Michel Bernier, Devin Wahl, Ahmed Ali, Joanne Allard, Shakeela Faulkner, Artur Wnorowski, Mitesh Sanghvi, Ruin Moaddel, Irene Alfaras, Julie A. Mattison, Stefano Tarantini, Zsuzsanna Tucsek, Zoltan Ungvari, Anna Csiszar, Kevin J. Pearson, Rafael de Cabo,

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Davina Derous, Sharon E Mitchell, Cara L Green, Yingchun Wang, Jing Dong J Han, Luonan Chen, Daniel E.L Promislow, David Lusseau, John R Speakman, Alex Douglas,

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Luca Falzone, Rossella Salemi, Salvatore Travali, Aurora Scalisi, James A. McCubrey, Saverio Candido, Massimo Libra,

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Sandy S.C Hung, Nicole J Van Bergen, Stacey Jackson, Helena Liang, David A. A Mackey, Damián Hernández, Shiang Y Lim, Alex W Hewitt, Ian Trounce, Alice Pébay, Raymond C.B Wong,

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Ilenia Segatto, Samuele Massarut, Robert Boyle, Gustavo Baldassarre, David Walker, Barbara Belletti,

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Guibin Xu, Fei Yue, Hai Huang, Yongzhong He, Xun Li, Haibo Zhao, Zhengming Su, Xianhan Jiang, Wenjiao Li, Jing Zou, Qi Chen, Leyuan Liu,

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Yujin Lee, Wooseon Hwang, Juyoung Jung, Sangsoon Park, Josephine Jill T. Cabatbat, Pan-Jun Kim, Seung-Jae V Lee,

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Julijana Ivanisevic, Kelly L Stauch, Michael Petrascheck, H Paul Benton, Adrian A Epstein, Mingliang Fang, Santhi Gorantla, Minerva Tran, Linh Hoang, Michael E Kurczy, Michael D Boska, Howard E Gendelman, Howard S Fox, Gary Siuzdak,

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Evgeny Putin, Polina Mamoshina, Alexander Aliper, Mikhail Korzinkin, Alexey Moskalev, Alexey Kolosov, Alexander Ostrovskiy, Charles Cantor, Jan Vijg, Alex Zhavoronkov,

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Monika Eipel, Felix Mayer, Tanja Arent, Marcelo R.P. Ferreira, Carina Birkhofer, Uwe Gerstenmaier, Ivan G. Costa, Stefanie Ritz-Timme, Wolfgang Wagner,

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Joshua Crapser, Rodney Ritzel, Rajkumar Verna, Venugopal R. Venna, Fudong Liu, Anjali Chauhan, Edward Koellhoffer, Anita Patel, Austin Ricker, Kendra Maas, Joerg Graf, Louise D. McCullough,