Volume 6, Issue 6

Ribonucleoprotein Therapy in Alzheimer's Disease?

Je-Hyun Yoon, Myriam Gorospe,

https://doi.org/10.18632/aging.100672 pp 428—429

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Yoon J, Gorospe M, . Ribonucleoprotein Therapy in Alzheimer's Disease?. . 6:428-429. https://doi.org/10.18632/aging.100672

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CaMKII in Cardiometabolic Disease

Lale Ozcan, Ira Tabas,

https://doi.org/10.18632/aging.100675 pp 430—431

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Aging and DNA damage in humans: a meta-analysis study

Jorge Pinto Soares, António Cortinhas, Teresa Bento, José Carlos Leitão, Andrew R. Collins, Isabel Gaivã, Maria Paula Mota,

https://doi.org/10.18632/aging.100667 pp 432—439

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Soares JP, Cortinhas A, Bento T, Leitão JC, Collins AR, Gaivã I, Mota MP, . Aging and DNA damage in humans: a meta-analysis study. . 6:432-439. https://doi.org/10.18632/aging.100667

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Provider: 
                TY  - JOUR
                AU  - Soares, Jorge Pinto 
                AU  - Cortinhas, António 
                AU  - Bento, Teresa 
                AU  - Leitão, José Carlos 
                AU  - Collins, Andrew R. 
                AU  - Gaivã, Isabel 
                AU  - Mota, Maria Paula 
                TI  - Aging and DNA damage in humans: a meta-analysis study
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100667
                DO  - 10.18632/aging.100667
                SP  - 432
                EP  - 439
                PY  - 
                AB  - Age-related DNA damage is regarded as one of the possible explanations of aging. Although a generalized idea about the accumulation of DNA damage with age exists, results found in the literature are inconsistent. To better understand the question of age-related DNA damage in humans and to identify possible moderator variables, a meta-analysis was conducted. Electronic databases and bibliographies for studies published since 2004 were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for age-related DNA damage were calculated in a random-effects model. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found (r = 0.230, p = 0.000; 95% confidence interval = 0.111 - 0.342). The test for heterogeneity of variance indicates that the study´s results are significantly high (Q (75) = 1754.831, p = 0.000). Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age-related DNA damage (p=0.026; p=0.000; p=0.000, respectively). Nevertheless, sex did not show any influence on this relation (p=0.114). In conclusion, this meta-analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age-related DNA damage.
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Age-related increase of VGF-expression in T lymphocytes

Stefan Busse, Johann Steiner, Justus Micheel, Henrik Dobrowolny, Christian Mawrin, Tim J. Krause, Michael Adamaszek, Bernhard Bogerts, Ursula Bommhardt, Roland Hartig, Mandy Busse,

https://doi.org/10.18632/aging.100656 pp 440—453

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Busse S, Steiner J, Micheel J, Dobrowolny H, Mawrin C, Krause TJ, Adamaszek M, Bogerts B, Bommhardt U, Hartig R, Busse M, . Age-related increase of VGF-expression in T lymphocytes. . 6:440-453. https://doi.org/10.18632/aging.100656

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                TY  - JOUR
                AU  - Busse, Stefan 
                AU  - Steiner, Johann 
                AU  - Micheel, Justus 
                AU  - Dobrowolny, Henrik 
                AU  - Mawrin, Christian 
                AU  - Krause, Tim J. 
                AU  - Adamaszek, Michael 
                AU  - Bogerts, Bernhard 
                AU  - Bommhardt, Ursula 
                AU  - Hartig, Roland 
                AU  - Busse, Mandy 
                TI  - Age-related increase of VGF-expression in T lymphocytes
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100656
                DO  - 10.18632/aging.100656
                SP  - 440
                EP  - 453
                PY  - 
                AB  - VGF is a protein expressed by neurons and processed into several peptides. It plays a role in energy homeostasis and promotes growth and survival. Recently, VGF mRNA was detected in peripheral leukocytes. Since it is known that aging is associated with a decrease in the development and function of neuronal as well as immune cells, we addressed the question whether a peripheral expression of VGF by CD3+ T cells and CD56+ NK cells is correlated with age. Therefore, the frequency of VGF+CD3+ and VGF+CD56+ cells was determined in mentally healthy volunteers aged between 22 and 88. We found an age-dependent increase in the number of VGF+CD3+ T cells that correlated with HbA1c and the body mass index (BMI). VGF-expression by NK cells was age-independent. Blockade of VGF reduced proliferation and secretion of cytokines such as IL-2, IL-17A, IL-1β, IL-10 and TNF by CD3+ T cells and PBMCs. Rapamycin-mediated T cell blockade significantly reduced the frequency of VGF-expressing T cells. We conclude that VGF contributes to survival and function of peripheral T cells. The age-dependent increase in VGF-expression could serve as mechanism that counterregulates the decrease in functionality of T lymphocytes.
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Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing

Cristina Giuliani, Chiara Barbieri, Mingkun Li, Laura Bucci, Daniela Monti, Giuseppe Passarino, Donata Luiselli, Claudio Franceschi, Mark Stoneking, Paolo Garagnani,

https://doi.org/10.18632/aging.100661 pp 454—467

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Giuliani C, Barbieri C, Li M, Bucci L, Monti D, Passarino G, Luiselli D, Franceschi C, Stoneking M, Garagnani P, . Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing. . 6:454-467. https://doi.org/10.18632/aging.100661

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                TY  - JOUR
                AU  - Giuliani, Cristina 
                AU  - Barbieri, Chiara 
                AU  - Li, Mingkun 
                AU  - Bucci, Laura 
                AU  - Monti, Daniela 
                AU  - Passarino, Giuseppe 
                AU  - Luiselli, Donata 
                AU  - Franceschi, Claudio 
                AU  - Stoneking, Mark 
                AU  - Garagnani, Paolo 
                TI  - Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100661
                DO  - 10.18632/aging.100661
                SP  - 454
                EP  - 467
                PY  - 
                AB  - The role that mtDNA heteroplasmy plays in healthy aging, familial longevity and the heritability patterns of low levels heteroplasmy in the elderly are largely unknown. We analyzed the low levels of mtDNA heteroplasmy in blood in a cohort of centenarians, their offspring and a group of offspring of non long-lived parents, characterized by a less favorable health phenotype. The aims of this study are to: (i) investigate the transmission of low level heteroplasmies in the elderly; (ii) explore the association of heteroplasmy with age and longevity and (iii) investigate heteroplasmy patterns in these three groups. We sequenced a 853 bp mtDNA fragment in 88 individuals to an average coverage of 49334-fold, using quality control filtering and triplicate PCR analysis to reduce any methodological bias, and we detected 119 heteroplasmic positions with a minor allele frequency ≥ 0.2%. The results indicate that low-level heteroplasmies are transmitted and maintained within families until extreme age. We did not find any heteroplasmic variant associated with longevity and healthy aging but we identified an unique heteroplasmy profile for each family, based on total level and positions. This familial profile suggests that heteroplasmy may contribute to familial longevity.
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The age related markers lipofuscin and apoptosis show different genetic architecture by QTL mapping in short-lived Nothobranchius fish

Enoch Ng'oma, Kathrin Reichwald, Alexander Dorn, Michael Wittig, Tobias Balschun, Andre Franke, Matthias Platzer, Allesandro Cellerino,

https://doi.org/10.18632/aging.100660 pp 468—480

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Ng'oma E, Reichwald K, Dorn A, Wittig M, Balschun T, Franke A, Platzer M, Cellerino A, . The age related markers lipofuscin and apoptosis show different genetic architecture by QTL mapping in short-lived Nothobranchius fish. . 6:468-480. https://doi.org/10.18632/aging.100660

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                TY  - JOUR
                AU  - Ng'oma, Enoch 
                AU  - Reichwald, Kathrin 
                AU  - Dorn, Alexander 
                AU  - Wittig, Michael 
                AU  - Balschun, Tobias 
                AU  - Franke, Andre 
                AU  - Platzer, Matthias 
                AU  - Cellerino, Allesandro 
                TI  - The age related markers lipofuscin and apoptosis show different genetic architecture by QTL mapping in short-lived Nothobranchius fish
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100660
                DO  - 10.18632/aging.100660
                SP  - 468
                EP  - 480
                PY  - 
                AB  - Annual fish of the genus Nothobranchius show large variations in lifespan and expression of age-related phenotypes between closely related populations. We studied N. kadleci and its sister species N. furzeri GRZ strain, and found that N.kadleci is longer-lived than the N. furzeri. Lipofuscin and apoptosis measured in the liver increased with age in N. kadleci with different profiles: lipofuscin increased linearly, while apoptosis declined in the oldest animals. More lipofuscin (P &lt; 0.001) and apoptosis (P &lt; 0.001) was observed in N. furzeri than in N. kadleci at 16w age. Lipofuscin and apoptotic cells were then quantified in hybrids from the mating of N. furzeri to N. kadleci. F1 individuals showed heterosis for lipofuscin but additive effects for apoptosis. These two age-related phenotypes were not correlated in F2 hybrids. Quantitative trait loci analysis of 287 F2 fish using 237 markers identified two QTL accounting for 10% of lipofuscin variance (P &lt; 0.001) with overdominance effect. Apoptotic cells revealed three significant- and two suggestive QTL explaining 19% of variance (P &lt; 0.001), showing additive and dominance effects, and two interacting loci. Our results show that lipofuscin and apoptosis are markers of different age-dependent biological processes controlled by different genetic mechanisms.
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Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells

Aleksandra Borodkina, Alla Shatrova, Polina Abushik, Nikolay Nikolsky, Elena Burova,

https://doi.org/10.18632/aging.100673 pp 481—495

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Borodkina A, Shatrova A, Abushik P, Nikolsky N, Burova E, . Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. . 6:481-495. https://doi.org/10.18632/aging.100673

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                TY  - JOUR
                AU  - Borodkina, Aleksandra 
                AU  - Shatrova, Alla 
                AU  - Abushik, Polina 
                AU  - Nikolsky, Nikolay 
                AU  - Burova, Elena 
                TI  - Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100673
                DO  - 10.18632/aging.100673
                SP  - 481
                EP  - 495
                PY  - 
                AB  - Human endometrium-derived mesenchymal stem cells (hMESCs) enter the premature senescence under sublethal oxidative stress, however underlying mechanism remains unknown. Here, we showed that exogenous H2O2 induces a rapid phosphorylation and co-localization of ATM, H2A.X, 53BP1 leading to DNA damage response (DDR) activation. DDR was accompanied with nuclear translocation of p-p53 followed by up-regulation of p21Waf1 and the permanent hypophosphorylation of pRb. Additionally, the increased p38MAPK/MAPKAPK-2 activation persisted in H2O2-treated cells. We suggest that both p53/p21/pRb and p38MAPK/MAPKAPK-2 pathways are responsible for establishing an irreversible cell cycle arrest that is typical of senescence. The process of further stabilization of senescence required prolonged DDR signaling activation that was provided by the permanent ROS production which in turn was regulated by both p38MAPK and the increased functional mitochondria. To reverse senescence, the pharmacological inhibition of p38MAPK was performed. Cell treatment with SB203580 was sufficient to recover partially senescence phenotype, to block the ROS elevation, to decrease the mitochondrial function, and finally to rescue proliferation. Thus, suppression of the p38MAPK pathway resulted in a partial prevention of H2O2-induced senescence of hMESCs. The current study is the first to reveal the molecular mechanism of the premature senescence of hMESCs in response to oxidative stress.
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DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

Maarja Laos, Tommi Anttonen, Anna Kirjavainen, Taija af Hällström, Marikki Laiho, Ulla Pirvola,

https://doi.org/10.18632/aging.100668 pp 496—510

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Laos M, Anttonen T, Kirjavainen A, Hällström Ta, Laiho M, Pirvola U, . DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells. . 6:496-510. https://doi.org/10.18632/aging.100668

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                TY  - JOUR
                AU  - Laos, Maarja 
                AU  - Anttonen, Tommi 
                AU  - Kirjavainen, Anna 
                AU  - Hällström, Taija af 
                AU  - Laiho, Marikki 
                AU  - Pirvola, Ulla 
                TI  - DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100668
                DO  - 10.18632/aging.100668
                SP  - 496
                EP  - 510
                PY  - 
                AB  - Supporting cells (SCs) of the cochlear (auditory) and vestibular (balance) organs hold promise as a platform for therapeutic regeneration of the sensory hair cells. Prior data have shown proliferative restrictions of adult SCs forced to re-enter the cell cycle. By comparing juvenile and adult SCs in explant cultures, we have here studied how proliferative restrictions are linked with DNA damage signaling. Cyclin D1 overexpression, used to stimulate cell cycle re-entry, triggered higher proliferative activity of juvenile SCs. Phosphorylated form of histone H2AX (γH2AX) and p53 binding protein 1 (53BP1) were induced in a foci-like pattern in SCs of both ages as an indication of DNA double-strand break formation and activated DNA damage response. Compared to juvenile SCs, γH2AX and the repair protein Rad51 were resolved with slower kinetics in adult SCs, accompanied by increased apoptosis. Consistent with the in vitro data, in a Rb mutant mouse model in vivo, cell cycle re-entry of SCs was associated with γH2AX foci induction. In contrast to cell cycle reactivation, pharmacological stimulation of SC-to-hair-cell transdifferentiation in vitro did not trigger γH2AX. Thus, DNA damage and its prolonged resolution are critical barriers in the efforts to stimulate proliferation of the adult inner ear SCs.
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The Dynamic Exome: acquired variants as individuals age

Jasmin H. Bavarva, Hongseok Tae, Lauren McIver, Enusha Karunasena, Harold R. Garner,

https://doi.org/10.18632/aging.100674 pp 511—521

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Bavarva JH, Tae H, McIver L, Karunasena E, Garner HR, . The Dynamic Exome: acquired variants as individuals age. . 6:511-521. https://doi.org/10.18632/aging.100674

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                TY  - JOUR
                AU  - Bavarva, Jasmin H. 
                AU  - Tae, Hongseok 
                AU  - McIver, Lauren 
                AU  - Karunasena, Enusha 
                AU  - Garner, Harold R. 
                TI  - The Dynamic Exome: acquired variants as individuals age
                JO  - 
                JA  - 
                VL  - 6
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100674
                DO  - 10.18632/aging.100674
                SP  - 511
                EP  - 521
                PY  - 
                AB  - A singular genome used for inference into population-based studies is a standard method in genomics. Recent studies show that spontaneous genomic variants can propagate into new generations and these changes can contribute to individual cell aging with environmental and evolutionary elements contributing to cumulative genomic variation. However, the contribution of aging to genomic changes in tissue samples remains uncharacterized. Here, we report the impact of aging on individual human exomes and their implications. We found the human genome to be dynamic, acquiring a varying number of mutations with age (5,000 to 50,000 in 9 to 16 years). This equates to a variation rate of 9.6×10−7 to 8.4×10−6 bp−1 year−1 for nonsynonymous single nucleotide variants and 2.0×10−4 to 1.0×10−3 locus−1 year−1 for microsatellite loci in these individuals. These mutations span across 3,000 to 13,000 genes, which commonly showed association with Wnt signaling and Gonadotropin releasing hormone receptor pathways, and indicated for individuals a specific and significant enrichment for increased risk for diabetes, kidney failure, cancer, Rheumatoid arthritis, and Alzheimer's disease– conditions usually associated with aging. The results suggest that “age” is an important variable while analyzing an individual human genome to extract individual-specific clinically significant information necessary for personalized genomics.
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Volume 6, Issue 6

Editorials

Ribonucleoprotein Therapy in Alzheimer's Disease?

Je-Hyun Yoon, Myriam Gorospe,

CaMKII in Cardiometabolic Disease

Lale Ozcan, Ira Tabas,

Review

Aging and DNA damage in humans: a meta-analysis study

Jorge Pinto Soares, António Cortinhas, Teresa Bento, José Carlos Leitão, Andrew R. Collins, Isabel Gaivã, Maria Paula Mota,

Research Papers

Age-related increase of VGF-expression in T lymphocytes

Stefan Busse, Johann Steiner, Justus Micheel, Henrik Dobrowolny, Christian Mawrin, Tim J. Krause, Michael Adamaszek, Bernhard Bogerts, Ursula Bommhardt, Roland Hartig, Mandy Busse,

Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing

Cristina Giuliani, Chiara Barbieri, Mingkun Li, Laura Bucci, Daniela Monti, Giuseppe Passarino, Donata Luiselli, Claudio Franceschi, Mark Stoneking, Paolo Garagnani,

The age related markers lipofuscin and apoptosis show different genetic architecture by QTL mapping in short-lived Nothobranchius fish

Enoch Ng'oma, Kathrin Reichwald, Alexander Dorn, Michael Wittig, Tobias Balschun, Andre Franke, Matthias Platzer, Allesandro Cellerino,

Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells

Aleksandra Borodkina, Alla Shatrova, Polina Abushik, Nikolay Nikolsky, Elena Burova,

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

Maarja Laos, Tommi Anttonen, Anna Kirjavainen, Taija af Hällström, Marikki Laiho, Ulla Pirvola,

The Dynamic Exome: acquired variants as individuals age

Jasmin H. Bavarva, Hongseok Tae, Lauren McIver, Enusha Karunasena, Harold R. Garner,

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