Volume 5, Issue 3

SIRT1 Activators: The Evidence STACks up

Sita Kugel, Raul Mostoslavsky,

https://doi.org/10.18632/aging.100534 pp 142—143

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Kugel S, Mostoslavsky R, . SIRT1 Activators: The Evidence STACks up. Aging (Albany NY). 5:142-143. https://doi.org/10.18632/aging.100534

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The sirtuins, oxidative stress and aging: an emerging link

Philip I. Merksamer, Yufei Liu, Wenjuan He, Matthew D. Hirschey, Danica Chen, Eric Verdin,

https://doi.org/10.18632/aging.100544 pp 144—150

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Merksamer PI, Liu Y, He W, Hirschey MD, Chen D, Verdin E, . The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY). 5:144-150. https://doi.org/10.18632/aging.100544

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                TY  - JOUR
                AU  - Merksamer, Philip I. 
                AU  - Liu, Yufei 
                AU  - He, Wenjuan 
                AU  - Hirschey, Matthew D. 
                AU  - Chen, Danica 
                AU  - Verdin, Eric 
                TI  - The sirtuins, oxidative stress and aging: an emerging link
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100544
                DO  - 10.18632/aging.100544
                SP  - 144
                EP  - 150
                PY  - 
                AB  - Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.
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Sirt1 activation by resveratrol is substrate sequence-selective

Mahadevan Lakshminarasimhan, David Rauh, Mike Schutkowski, Clemens Steegborn,

https://doi.org/10.18632/aging.100542 pp 151—154

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Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C, . Sirt1 activation by resveratrol is substrate sequence-selective. Aging (Albany NY). 5:151-154. https://doi.org/10.18632/aging.100542

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                TY  - JOUR
                AU  - Lakshminarasimhan, Mahadevan 
                AU  - Rauh, David 
                AU  - Schutkowski, Mike 
                AU  - Steegborn, Clemens 
                TI  - Sirt1 activation by resveratrol is substrate sequence-selective
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100542
                DO  - 10.18632/aging.100542
                SP  - 151
                EP  - 154
                PY  - 
                AB  - Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays. Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects. One Sentence Summary Testing 6802 acetylation sites reveals that resveratrol effects on Sirt1-dependent deacetylation depend on substrate sequence and suggests substrates relevant for in vivo effects.
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Protease-sensitive prions with 144-bp insertion mutations

Xiangzhu Xiao, Ignazio Cali, Zhiqian Dong, Gianfranco Puoti, Jue Yuan, Liuting Qing, Heming Wang, Qingzhong Kong, Pierluigi Gambetti, Wen-Quan Zou,

https://doi.org/10.18632/aging.100543 pp 155—173

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Xiao X, Cali I, Dong Z, Puoti G, Yuan J, Qing L, Wang H, Kong Q, Gambetti P, Zou W, . Protease-sensitive prions with 144-bp insertion mutations. Aging (Albany NY). 5:155-173. https://doi.org/10.18632/aging.100543

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                TY  - JOUR
                AU  - Xiao, Xiangzhu 
                AU  - Cali, Ignazio 
                AU  - Dong, Zhiqian 
                AU  - Puoti, Gianfranco 
                AU  - Yuan, Jue 
                AU  - Qing, Liuting 
                AU  - Wang, Heming 
                AU  - Kong, Qingzhong 
                AU  - Gambetti, Pierluigi 
                AU  - Zou, Wen-Quan 
                TI  - Protease-sensitive prions with 144-bp insertion mutations
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100543
                DO  - 10.18632/aging.100543
                SP  - 155
                EP  - 173
                PY  - 
                AB  - Insertion of 144-base pair (bp) containing six extra octapeptide repeats between residues 51 and 91 of prion protein (PrP) gene is associated with inherited prion diseases. Most cases linked to this insertion examined by Western blotting showed detectable proteinase K-resistant PrPSc (rPrPSc) resembling PrPSc type 1 and type 2 in sporadic Creutzfeldt-Jakob disease (sCJD), or PrP7-8 in Gerstmann-Sträussler-Scheinker disease. However, cases lacking detectable rPrPSc also have been reported. Which PrP conformer is associated with neuropathological changes in the cases without detectable rPrPSc remains to be determined. Here we report that while all six but one subjects with the 144-bp insertion mutations examined display the pathognomonic PrP patches in the cerebellum, one of them exhibits no detectable typical rPrPSc even in PrPSc-enriched preparations. Instead, a large amount of abnormal PrP is captured from this case by gene 5 protein and sodium phosphotungstate, reagents that have been proved to specifically capture abnormal PrP. All captured abnormal PrP from the cerebellum and other brain regions is virtually sensitive to PK-digestion (termed sPrPSc). The presence of the predominant sPrPSc but absence of rPrPSc in this 144-bp insertion-linked inherited CJD case suggests that mutant sPrPSc is the main component of the PrP deposit patches and sPrPSc is sufficient to cause neurotoxicity and prion disease.
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Identification of a small molecule activator of SIRT1 gene expression

Si-Young Cho, Miook Cho, Dae Bang Seo, Sang Jun Lee, Yousin Suh,

https://doi.org/10.18632/aging.100539 pp 174—182

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Cho S, Cho M, Seo DB, Lee SJ, Suh Y, . Identification of a small molecule activator of SIRT1 gene expression. Aging (Albany NY). 5:174-182. https://doi.org/10.18632/aging.100539

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                TY  - JOUR
                AU  - Cho, Si-Young 
                AU  - Cho, Miook 
                AU  - Seo, Dae Bang 
                AU  - Lee, Sang Jun 
                AU  - Suh, Yousin 
                TI  - Identification of a small molecule activator of <i>SIRT1</i> gene expression
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100539
                DO  - 10.18632/aging.100539
                SP  - 174
                EP  - 182
                PY  - 
                AB  - Increased SIRT1 expression exerts beneficial effects in transgenic animal models, ameliorating the onset and progression of aging-related disease phenotypes in various organs including the heart. The potential beneficial effects of SIRT1 have made SIRT1 a prime therapeutic target for age-related diseases and considerable efforts led to the identification of small molecule activator of SIRT1 protein. Thus far, however, a small molecule activator of SIRT1 gene expression has not been reported. Here, we report that syringaresinol, isolated from Panax ginseng berry pulp, is an activator of SIRT1 gene expression. Using human umbilical endothelial cells (HUVECs), we show that syringaresinol treatment induced binding of FOXO3 to the SIRT1 promoter in a sequence-specific manner, leading to induction of SIRT1 expression. Increased SIRT1 expression in HUVECs by syringaresinol treatment delayed cellular senescence and improved various markers of endothelial functions in a FOXO3 dependent manner. Collectively, these findings bring to light a new transcription activator of SIRT1 that may have therapeutic potential.
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Personality, self-rated health, and cognition in centenarians: Do personality and self-rated health relate to cognitive function in advanced age?

Kaori Kato, Richard Zweig, Clyde B. Schechter, Joe Verghese, Nir Barzilai, Gil Atzmon,

https://doi.org/10.18632/aging.100545 pp 183—191

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Kato K, Zweig R, Schechter CB, Verghese J, Barzilai N, Atzmon G, . Personality, self-rated health, and cognition in centenarians: Do personality and self-rated health relate to cognitive function in advanced age?. Aging (Albany NY). 5:183-191. https://doi.org/10.18632/aging.100545

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                TY  - JOUR
                AU  - Kato, Kaori 
                AU  - Zweig, Richard 
                AU  - Schechter, Clyde B. 
                AU  - Verghese, Joe 
                AU  - Barzilai, Nir 
                AU  - Atzmon, Gil 
                TI  - Personality, self-rated health, and cognition in centenarians: Do personality and self-rated health relate to cognitive function in advanced age?
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100545
                DO  - 10.18632/aging.100545
                SP  - 183
                EP  - 191
                PY  - 
                AB  - Personality and self-rated health have been linked previously to cognitive outcome in late life. However, these associations have not been shown among the oldest old. This study examined relationships between personality, self-rated health, and cognitive function in a selected sample of Ashkenazi Jewish centenarians (n = 68, 59% female) aged 95 to 106 who lived independently in the community. Personality was measured using the Personality Outlook Profile Scale (POPS), a brief measure that was validated in this population. Self-rated health was assessed by participants’ subjective rating of their present health, and Mini-Mental Status Examination was used to determine cognitive function. Results showed positive associations of the Positive Attitude Towards Life domain of the POPS and self-rated health with participants’ current cognitive function. These associations remained significant even after adjusting for the effects of participants'age, gender, marital status, education, and history of medical illnesses. Further exploratory analysis using structural equations modeling showed significant associations among the three variables, but demonstrated a borderline significant level of mediating effect of personality on the relationship between self-rated health and cognition. These results reemphasized the independent roles of personality and self-rated health on centenarians’ cognitive outcomes. Future studies will further elucidate the impact of personality and self-rated health on cognitive outcomes in the oldest old.
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A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging

Morten Scheibye-Knudsen, Karsten Scheibye-Alsing, Chandrika Canugovi, Deborah L. Croteau, Vilhelm A. Bohr,

https://doi.org/10.18632/aging.100546 pp 192—208

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Scheibye-Knudsen M, Scheibye-Alsing K, Canugovi C, Croteau DL, Bohr VA, . A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging. Aging (Albany NY). 5:192-208. https://doi.org/10.18632/aging.100546

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                TY  - JOUR
                AU  - Scheibye-Knudsen, Morten 
                AU  - Scheibye-Alsing, Karsten 
                AU  - Canugovi, Chandrika 
                AU  - Croteau, Deborah L. 
                AU  - Bohr, Vilhelm A. 
                TI  - A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100546
                DO  - 10.18632/aging.100546
                SP  - 192
                EP  - 208
                PY  - 
                AB  - 
                        The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.
                      
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B cell responses to the 2011/12-influenza vaccine in the aged

Raj K. Kurupati, Senthil Kannan, Xiang, Zhi Xiang, Susan Doyle, Sarah Ratcliffe, Kenneth E. Schmader, Hildegund CJ Ertl,

https://doi.org/10.18632/aging.100541 pp 209—226

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Kurupati RK, Kannan S, Xiang , Xiang Z, Doyle S, Ratcliffe S, Schmader KE, Ertl HC, . B cell responses to the 2011/12-influenza vaccine in the aged. Aging (Albany NY). 5:209-226. https://doi.org/10.18632/aging.100541

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                TY  - JOUR
                AU  - Kurupati, Raj K. 
                AU  - Kannan, Senthil 
                AU  - Xiang,  
                AU  - Xiang, Zhi 
                AU  - Doyle, Susan 
                AU  - Ratcliffe, Sarah 
                AU  - Schmader, Kenneth E. 
                AU  - Ertl, Hildegund CJ 
                TI  - B cell responses to the 2011/12-influenza vaccine in the aged
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 5
                IS  - 3
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100541
                DO  - 10.18632/aging.100541
                SP  - 209
                EP  - 226
                PY  - 
                AB  - Antibody and B cell responses to influenza A viruses were measured over a period of 2 months in 30 aged and 15 middle-aged individuals following vaccination with the 2011/12 trivalent inactivated influenza vaccine by micro-neutralization assays, ELISAs, ELISpot assays and cell surface staining with lineage-defining antibodies followed by multicolor flow cytometry. Both cohorts developed comparable antibody responses to the H3N2 virus of the vaccine while responses to the H1N1 virus were compromised in the aged. ELISpot assays of peripheral blood mononuclear cells (PBMCs) gave comparable results for the two cohorts. Analysis by flow cytometry upon staining of CD19+IgD-CD20- PBMCs with antibodies to CD27 and CD38 showed markedly reduced increases of such cells following vaccination in the aged. Additional analysis of cells from a subset of 10 younger and 10 aged individuals indicated that in the aged a portion of IgG producing cells lose expression of CD27 and reduce expression of CD38.
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Volume 5, Issue 3

Editorial

SIRT1 Activators: The Evidence STACks up

Sita Kugel, Raul Mostoslavsky,

Research Perspective

The sirtuins, oxidative stress and aging: an emerging link

Philip I. Merksamer, Yufei Liu, Wenjuan He, Matthew D. Hirschey, Danica Chen, Eric Verdin,

Research Papers

Sirt1 activation by resveratrol is substrate sequence-selective

Mahadevan Lakshminarasimhan, David Rauh, Mike Schutkowski, Clemens Steegborn,

Protease-sensitive prions with 144-bp insertion mutations

Xiangzhu Xiao, Ignazio Cali, Zhiqian Dong, Gianfranco Puoti, Jue Yuan, Liuting Qing, Heming Wang, Qingzhong Kong, Pierluigi Gambetti, Wen-Quan Zou,

Identification of a small molecule activator of SIRT1 gene expression

Si-Young Cho, Miook Cho, Dae Bang Seo, Sang Jun Lee, Yousin Suh,

Personality, self-rated health, and cognition in centenarians: Do personality and self-rated health relate to cognitive function in advanced age?

Kaori Kato, Richard Zweig, Clyde B. Schechter, Joe Verghese, Nir Barzilai, Gil Atzmon,

A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging

Morten Scheibye-Knudsen, Karsten Scheibye-Alsing, Chandrika Canugovi, Deborah L. Croteau, Vilhelm A. Bohr,

B cell responses to the 2011/12-influenza vaccine in the aged

Raj K. Kurupati, Senthil Kannan, Xiang, Zhi Xiang, Susan Doyle, Sarah Ratcliffe, Kenneth E. Schmader, Hildegund CJ Ertl,

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