Aging-US

BUFFALO, NY- October 16, 2023 – A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 19, entitled, “BMAL1 modulates senescence programming via AP-1.”

Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are coordinately regulated has not been thoroughly studied. In this new study, researchers Sarah K. Jachim, Jian Zhong, Tamas Ordog, Jeong-Heon Lee, Aditya V. Bhagwate, Nagaswaroop Kengunte Nagaraj, Jennifer J. Westendorf, João F. Passos, Aleksey V. Matveyenko, and Nathan K. LeBrasseur from the Mayo Clinic in Rochester, Minnesota, hypothesized that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program.

“Here, we demonstrate BMAL1 is significantly upregulated in senescent cells and has altered rhythmicity compared to non-senescent cells.”

Through BMAL1-ChIP-seq, they showed that BMAL1 is uniquely localized to genomic motifs associated with AP-1 in senescent cells. Integration of BMAL1-ChIP-seq data with RNA-seq data revealed that BMAL1 presence at AP-1 motifs is associated with active transcription. Finally, the researchers showed that BMAL1 contributes to AP-1 transcriptional control of key features of the senescence program, including altered regulation of cell survival pathways, and confers resistance to drug-induced apoptosis.

“Overall, these results highlight a previously unappreciated role of the core circadian clock component BMAL1 on the molecular phenotype of senescent cells.”

DOI - https://doi.org/10.18632/aging.205112

Corresponding authors - Nathan K. LeBrasseur - [email protected]

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Keywords - aging, AP-1, circadian clock, cellular senescence, senolytic, transcription regulation

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Sleep is vital for our health and well-being, but as we age, we tend to experience less and less of it. In particular, we lose some of the deep sleep stages, known as slow wave sleep (SWS), that are crucial for memory consolidation and brain maintenance. This can affect cognitive performance and increase our risk of developing dementia.

Not everyone is equally vulnerable to the negative effects of poor sleep quality. Some people seem to be more resilient and able to cope with less SWS without compromising their mental abilities. What makes them different? One possible factor is cognitive reserve (CR).

CR is a concept that refers to the brain’s ability to adapt and compensate for age-related changes or brain damage. It is influenced by various aspects of our life experiences, such as education, occupation, leisure activities, social interactions, and mental stimulation. People with higher CR are thought to have more efficient brain networks, more cognitive strategies, and more brain reserve (i.e., more neurons and connections) that can buffer the impact of aging or pathology on cognition.

In a new study, researchers Valentin Ourry, Stéphane Rehel, Claire André, Alison Mary, Léo Paly, Marion Delarue, Florence Requier, Anne Hendy, Fabienne Collette, Natalie L. Marchant, Francesca Felisatti, Cassandre Palix, Denis Vivien, Vincent de la Sayette, Gaël Chételat, Julie Gonneaud, and Géraldine Rauchs from Normandie University, UNI – ULB Neuroscience Institute, University of Liege, University College London, and CHU de Caen aimed to identify individuals in whom sleep disturbances might have greater behavioral consequences. On September 28, 2023, their research paper was published in Aging’s Volume 15, Issue 18, entitled, “Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.”

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Paper DOI -https://doi.org/10.18632/aging.204943

Corresponding author - Géraldine Rauchs - [email protected]

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Keywords - aging, sleep, cognitive reserve, cognition

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- October 11, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 18, entitled, “Pathways explaining racial/ethnic and socio-economic disparities in dementia incidence: the UK Biobank study.”

Pathways explaining racial/ethnic disparities in dementia risk are under-evaluated. In their new study, researchers May A. Beydoun, Hind A. Beydoun, Marie T. Fanelli-Kuczmarski, Jordan Weiss, Michael F. Georgescu, Osorio Meirelles, Donald M. Lyall, Michele K. Evans, and Alan B. Zonderman from the National Institute on Aging, Fort Belvoir Community Hospital, Stanford University, and the University of Glasgow examined those disparities and their related pathways among UK Biobank study respondents (50–74 y, N = 323,483; 3.6% non-White minorities) using a series of Cox proportional hazards and generalized structural equations models (GSEM).

“The present study examines pathways that might explain racial, ethnic, and socio-economic disparities in AD or all-cause dementia in a large cohort study, the UK Biobank. Our study used several methodologies, including structural equation modeling coupled with survival analysis techniques to examine complex mediating effects between race, ethnicity, socioeconomic status, and dementia or AD [Alzheimer’s disease] risk in a sex-specific manner focusing on lifestyle, biological and cognitive pathways. It is also an attempt at replicating a previous study conducted among US older adults [24].”

Results: After ≤15 years, 5,491 all-cause dementia cases were diagnosed. Racial minority status (RACE_ETHN, Non-White vs. White) increased dementia risk by 24% (HR = 1.24, 95% CI: 1.07–1.45, P = 0.005), an association attenuated by socio-economic status (SES), (HR = 1.12, 95% CI: 0.96–1.31). Total race-dementia effect was mediated through both SES and Life’s Essential 8 lifestyle sub-score (LE8LIFESTYLE), combining diet, smoking, physical activity, and sleep factors. SES was inversely related to dementia risk (HR = 0.69, 95% CI: 0.67, 0.72, P < 0.001). Pathways explaining excess dementia risk among racial minorities included ‘RACE_ETHN(−) → SES(−) → DEMENTIA’, ‘RACE_ETHN(−) → SES(−) → Poor cognitive performance, COGN(+) → DEMENTIA’ and ‘RACE_ETHN(−) → SES(+) → LE8LIFESTYLE(−) → DEMENTIA’.

“Pending future interventions, lifestyle factors including diet, smoking, physical activity, and sleep are crucial for reducing racial and socio-economic disparities in dementia.”

DOI - https://doi.org/10.18632/aging.205058

Corresponding author - May A. Beydoun - [email protected]

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Keywords - aging, dementia, Alzheimer’s disease, health disparities, socio-economic status, structural equations modeling

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- October 10, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 18, entitled, “High-throughput single-cell profiling of B cell responses following inactivated influenza vaccination in young and older adults.”

Seasonal influenza contributes to a substantial disease burden, resulting in approximately 10 million hospital visits and 50 thousand deaths in a typical year in the United States. 70 - 85% of the mortality occurs in people over the age of 65. Influenza vaccination is the best protection against the virus, but it is less effective for the elderly, which may be in part due to differences in the quantity or type of B cells induced by vaccination. In their new study, researchers Meng Wang, Ruoyi Jiang, Subhasis Mohanty, Hailong Meng, Albert C. Shaw, and Steven H. Kleinstein from Yale University / Yale School of Medicine investigated this possibility.

“[...] we sorted pre- and post-vaccination peripheral blood B cells from three young and three older adults with strong antibody responses to the inactivated influenza vaccine and employed single-cell technology to simultaneously profile the gene expression and the B cell receptor (BCR) of the B cells.”

Prior to vaccination, the researchers observed a higher somatic hypermutation frequency and a higher abundance of activated B cells in older adults than in young adults. Following vaccination, young adults mounted a more clonal response than older adults. The expanded clones included a mix of plasmablasts, activated B cells, and resting memory B cells in both age groups, with a decreased proportion of plasmablasts in older adults. Differential abundance analysis identified additional vaccine-responsive cells that were not part of expanded clones, especially in older adults.

“To summarize, we showed a quantitative difference in B cell response following vaccination between age groups, with expansion dominated by plasmablasts in the young, and activated B cells in older adults. [...] Overall, this study provides insights into the B cell vaccine response differences between young and older adults and may be beneficial to design more effective vaccines in the older age groups.”

DOI - https://doi.org/10.18632/aging.204778

Corresponding authors - Albert C. Shaw - [email protected], and Steven H. Kleinstein - [email protected]

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Keywords - aging, B cell receptor, repertoire, clonal expansion, single-cell RNA-seq

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- October 4, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 18, entitled, “Biomedical generative pre-trained based transformer language model for age-related disease target discovery.”

Target discovery is crucial for the development of innovative therapeutics and diagnostics. However, current approaches often face limitations in efficiency, specificity, and scalability, necessitating the exploration of novel strategies for identifying and validating disease-relevant targets. Advances in natural language processing have provided new avenues for predicting potential therapeutic targets for various diseases.

In their new study, researchers Diana Zagirova, Stefan Pushkov, Geoffrey Ho Duen Leung, Bonnie Hei Man Liu, Anatoly Urban, Denis Sidorenko, Aleksandr Kalashnikov, Ekaterina Kozlova, Vladimir Naumov, Frank W. Pun, Ivan V. Ozerov, Alex Aliper, and Alex Zhavoronkov from Insilico Medicine present a novel approach for predicting therapeutic targets using a large language model (LLM).

“We trained a domain-specific BioGPT model on a large corpus of biomedical literature consisting of grant text and developed a pipeline for generating target prediction.”

This study demonstrates that pre-training of the LLM model with task-specific texts improves its performance. Applying the developed pipeline, the researchers retrieved prospective aging and age-related disease targets and showed that these proteins are in correspondence with the database data. Moreover, they propose CCR5 and PTH as potential novel dual-purpose anti-aging and disease targets which were not previously identified as age-related but were highly ranked in their approach.

“Overall, our work highlights the high potential of transformer models in novel target prediction and provides a roadmap for future integration of AI approaches for addressing the intricate challenges presented in the biomedical field.”

DOI - https://doi.org/10.18632/aging.205055

Corresponding author - Alex Zhavoronkov - [email protected]

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Keywords - aging, transformers, deep learning, therapeutic target discovery, aging biomarkers, human aging

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- October 2, 2023 – A new priority research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 18, entitled, “Gene expression signatures of human senescent corneal and conjunctival epithelial cells.”

In this new study, researchers Koji Kitazawa, Akifumi Matsumoto, Kohsaku Numa, Yasufumi Tomioka, Zhixin A. Zhang, Yohei Yamashita, Chie Sotozono, Pierre-Yves Desprez, and Judith Campisi from the Buck Institute for Research on Aging, Kyoto Prefectural University of Medicine and Lawrence Berkeley National Laboratory aimed to investigate the senescent phenotypes of human corneal and conjunctival epithelial cells.

“Here, we induced cellular senescence in human corneal and conjunctival epithelium using X-irradiation, and analyzed gene expression profiles of each cell type to determine the characteristics of senescent ocular surface cells.”

The team examined cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation, and expression of senescence markers (p16 and p21). RNA sequencing analysis was conducted to compare gene expression profiles between senescent and non-senescent cells. Finally, the potential involvement of senescent cells in the pathogenesis of ocular surface diseases was investigated.

X-irradiated corneal and conjunctival epithelial cells exhibited typical senescence phenotypes, i.e., flattened morphologies, increased SA-β-gal activity, decreased cell proliferation, and increased expression of senescence markers, p16 and p21. RNA-seq analysis revealed substantial differences in gene expression profiles between senescent corneal (SCo) and conjunctival epithelial cells (SCj). Moreover, SCj were detected in pathological conjunctival tissues associated with limbal stem cell deficiency (LSCD) due to Stevens-Johnson syndrome or chemical burns, potentially being involved in abnormal differentiation.

“This study highlights the cellular and molecular characteristics of senescent ocular surface cells, particularly in SCj that show abnormal keratin expression, and their potential roles in severe ocular surface diseases and pathology.”

DOI - https://doi.org/10.18632/aging.205113

Corresponding authors - Koji Kitazawa - [email protected], and Judith Campisi - [email protected]

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Keywords - aging, cellular senescence, cornea, conjunctiva, Stevens-Johnson syndrome, limbal stem cell deficiency

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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R-loops are structures that form when the nascent RNA hybridizes with the template DNA strand, displacing the non-template strand. Nascent RNA refers to the newly synthesized RNA molecule that is produced during the process of transcription. Transcription is the first step in gene expression where the information in a DNA sequence is used to create an RNA molecule. In addition to transcription, R-loops are involved in various biological processes, such as splicing, DNA repair and chromatin remodeling. However, when R-loop homeostasis is disrupted, they can also cause transcriptional impairment, genome instability and cellular dysfunction.

"R-loops have been shown and studied in a wide range of organisms and while they have important regulatory roles, persistent R-loops can be detrimental to cell function and survival, having been closely linked to both gene expression dysregulation and increased genome instability."

In a new editorial paper, researcher Hana Hall from the Purdue Institute for Integrative Neuroscience at Purdue University, discusses the role of R-loops in neuronal aging and neurodegeneration. On September 13, 2023, her editorial was published in Aging’s Volume 15, Issue 17, and entitled, “R-loops in neuronal aging.” Hall summarizes her recent study and the current knowledge on how R-loop levels change during aging, how they affect gene expression and neuronal function, and how they are regulated by different factors.

Full blog - https://aging-us.org/2023/09/the-role-of-r-loops-in-neuronal-aging/

Paper DOI - https://doi.org/10.18632/aging.205070

Corresponding author - Hana Hall - [email protected]

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Keywords - aging, R-loops, neuron, transcription, genome instability, neurodegeneration

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- September 27, 2023 – A new editorial paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 17, entitled, “Promising trends in lung cancer care, but are we overlooking the majority?”

In their new editorial, researchers Bhavina Sharma and Apar Kishor Ganti from the University of Nebraska Medical Center discuss challenges and opportunities for better lung cancer care for the elderly. Lung cancer is the third most common cancer in the United States, after female breast cancer and prostate cancer. It accounts for more cancer-related deaths in both men and women than any other types of cancer.

The incidence of new lung cancer has decreased between 1999-2019, mirroring the fall in tobacco use in the past few decades. Lung cancer-related mortality has also decreased with the recent advances in screening techniques and treatment strategies. However, the incidence of lung cancer and lung cancer mortality is still disproportionately higher among older patients (65 years and older).

Multiple studies have shown that older patients are more likely to be undertreated because of their chronological age, even after accounting for their comorbidities and socioeconomic status. Common reasons for this disparity are insufficient study evidence, lack of appropriate resources and support, patient factors such as socioeconomic status, as well as variations in individual physician practices and preferences. Even though the median age of lung cancer diagnosis is 71 years, and more than two-thirds of patients are older than 65 years, older patients are less likely to be enrolled in clinical trials.

“Although there is now increasing effort and guidance by major cancer societies and regulatory groups to increase inclusion of older patients, better conscious collaboration between the stakeholders is necessary for effective implementation of the strategies discussed and to enhance enrollment and retention of older cancer patients.”

DOI - https://doi.org/10.18632/aging.204662

Corresponding author - Apar Kishor Ganti - [email protected]

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Keywords - aging, lung cancer, clinical trials

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- September 26, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 17, entitled, “Availability of living donor optimizes timing of liver transplant in high-risk waitlisted cirrhosis patients.”

Liver transplant (LT) candidates have become older and frailer. Growing non-alcoholic steatohepatitis (NASH) and comorbid disease burden in recent years is also predisposing them for poor waitlist outcomes. In this new study, researchers Fakhar Ali Qazi Arisar, Shiyi Chen, Catherine Chen, Noorulsaba Shaikh, Ravikiran Sindhuvalada Karnam, Wei Xu, Sumeet K. Asrani, Zita Galvin, Gideon Hirschfield, Keyur Patel, Cynthia Tsien, Nazia Selzner, Mark Cattral, Leslie Lilly, and Mamatha Bhat from the University Health Network, University of Toronto, Baylor University Medical Center, and Dow University of Health Sciences aimed to evaluate the impact of access to living donor liver transplantation (LDLT) in waitlisted patients at highest risk of dropout.

“We reviewed all adult patients with decompensated cirrhosis listed for LT from November 2012 to December 2018.”

Patients with a potential living donor (pLD) available were identified. Survival analyses with Cox Proportional Hazards models and time to LT with Competing risk models were performed followed by prediction model development. Out of 860 patients who met inclusion criteria, 360 (41.8%) had a pLD identified and 496 (57.6%) underwent LT, out of which 170 (34.2%) were LDLT. The benefit of pLD was evident for all, but patients with moderate to severe frailty at listing (interaction p = 0.03), height <160 cm (interaction p = 0.03), and Model for end-stage liver disease (MELD)-Na score <20 (interaction p < 0.0001) especially benefited.

“Our study identifies that certain patient subgroups (short stature, MELD <20, and moderate to severe frailty) are at the highest risk for waitlist mortality with prolonged waiting time for a deceased donor organ offer. These patient subgroups, which represent a growing share of the waitlist population in recent years, would be especially protected against death or delisting if they had access to living donation at the time of listing. Certainly, LDLT is beneficial to all, with improved waitlist mortality and post-transplant outcomes.”

DOI - https://doi.org/10.18632/aging.204982

Corresponding author - Mamatha Bhat - [email protected]

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Keywords - aging, living donor liver transplant, frailty, old age, short-statured, MELD score, prediction model

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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BUFFALO, NY- September 20, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 17, entitled, “Development of a DNA damage-induced senescence model in osteoarthritic chondrocytes.”

Senescent cells (SnCs) have been described to accumulate in osteoarthritis (OA) joint tissues in response to injury, thereby participating in OA development and progression. However, clinical therapeutic approaches targeting SnCs using senolysis, although promising in preclinical OA models, have not yet proven their efficacy in patients with knee OA. This pitfall may be due to the lack of understanding of the mechanisms underlying chondrocyte senescence.

In their new study, researchers Mélina Georget, Anaïs Defois, Romain Guiho, Nina Bon, Sophie Allain, Cécile Boyer, Boris Halgand, Denis Waast, Gaël Grimandi, Alban Fouasson-Chailloux, Jérôme Guicheux, and Claire Vinatier from Nantes Université aimed to generate models of chondrocyte senescence.

“In this context, our study aims to develop in vitro models of chondrocyte senescence by investigating the ability of etoposide and IL-1β treatments to produce a reliable chondrocyte senescent model.”

This study used etoposide, to induce DNA damage-related senescence or chronic exposure to IL-1β to entail inflammation-related senescence in human OA chondrocytes. Several hallmarks of cellular senescence, such as cell cycle arrest, expression of cyclin-dependent kinase inhibitors, DNA damages, and senescence-associated secretory profile were evaluated. Chronic exposure to IL-1β induces only partial expression of senescence markers and does not allow us to conclude on its ability to induce senescence in chondrocytes. On the other hand, etoposide treatment reliably induces DNA damage-related senescence in human articular chondrocytes evidenced by loss of proliferative capacity, DNA damage accumulation, and expression of some SASP components.

“Etoposide-induced senescence model may help investigate the initiation of cellular senescence in chondrocytes, and provide a useful model to develop therapeutic approaches to target senescence in OA.”

DOI - https://doi.org/10.18632/aging.204881

Corresponding author - Claire Vinatier - [email protected]

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Keywords - aging, senescence, osteoarthritis, etoposide, chondrocytes

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