bims-minfam 2023-06-11 papers

Issue of 2023–06–11
eight papers selected by
Ayesh Seneviratne, Western University

J Cardiovasc Aging. 2023 ;pii: 24. [Epub ahead of print]3(3):

The mTOR signaling pathway in cardiac aging.

The mammalian target of rapamycin (mTOR) is one of the most important signaling pathways that regulate nutrient sensing, cell growth, metabolism, and aging. The mTOR pathway, particularly mTOR complex 1 (mTORC1), has been shown to control aging, lifespan, and healthspan through the regulation of protein synthesis, autophagy, mitochondrial function, and metabolic health. The mTOR pathway also plays critical roles in the heart, from cardiac development, growth and maturation, and maintenance of cardiac homeostasis. Hyperactivation of mTORC1 signaling is well documented in aging and many age-related pathologies, including age-related cardiac dysfunction and heart failure. Suppression of mTORC1 by calorie restriction or rapamycin not only extends lifespan but also restores youthful phenotypes in the heart. In this article, we review model organisms of cardiac aging and highlight recent advances in the impact of the mTORC1 pathway on organismal and cardiac aging, particularly in Drosophila and mice. We focus on the downstream signaling pathways S6 kinase and 4EBP1, which regulates protein synthesis, as well as ULK1 and its related pathway that regulates autophagy. The interaction with mTOR complex 2 (mTORC2) and its potential role in cardiac aging are also discussed.

Keywords: aging; caloric restriction; cardiac aging; heart failure; mTOR; rapamycin

DOI: https://doi.org/10.20517/jca.2023.10

Science. 2023 Jun 09. 380(6649): 1010-1011

Taurine linked with healthy aging.

Joseph McGaunn, Joseph A Baur.

Reversing age-associated taurine loss improves mouse longevity and monkey health.

DOI: https://doi.org/10.1126/science.adi3025

Science. 2023 Jun 09. 380(6649): eabn9257

Taurine deficiency as a driver of aging.

Parminder Singh, Kishore Gollapalli, Stefano Mangiola, Daniela Schranner, Mohd Aslam Yusuf, Manish Chamoli, Sting L Shi, Bruno Lopes Bastos, Tripti Nair, Annett Riermeier, Elena M Vayndorf, Judy Z Wu, Aishwarya Nilakhe, Christina Q Nguyen, Michael Muir, Michael G Kiflezghi, Anna Foulger, Alex Junker, Jack Devine, Kunal Sharan, Shankar J Chinta, Swati Rajput, Anand Rane, Philipp Baumert, Martin Schönfelder, Francescopaolo Iavarone, Giorgia di Lorenzo, Swati Kumari, Alka Gupta, Rajesh Sarkar, Costerwell Khyriem, Amanpreet S Chawla, Ankur Sharma, Nazan Sarper, Naibedya Chattopadhyay, Bichitra K Biswal, Carmine Settembre, Perumal Nagarajan, Kimara L Targoff, Martin Picard, Sarika Gupta, Vidya Velagapudi, Anthony T Papenfuss, Alaattin Kaya, Miguel Godinho Ferreira, Brian K Kennedy, Julie K Andersen, Gordon J Lithgow, Abdullah Mahmood Ali, Arnab Mukhopadhyay, Aarno Palotie, Gabi Kastenmüller, Matt Kaeberlein, Henning Wackerhage, Bhupinder Pal, Vijay K Yadav.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

DOI: https://doi.org/10.1126/science.abn9257

medRxiv. 2023 May 17. pii: 2023.05.16.23290051. [Epub ahead of print]

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2 -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2 -CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2 -CHIP mice and Tet2 -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

DOI: https://doi.org/10.1101/2023.05.16.23290051

Signal Transduct Target Ther. 2023 Jun 08. 8(1): 239

Inflammation and aging: signaling pathways and intervention therapies.

Xia Li, Chentao Li, Wanying Zhang, Yanan Wang, Pengxu Qian, He Huang.

Aging is characterized by systemic chronic inflammation, which is accompanied by cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there is an urgent need for a systematic organization of inflammaging through dimensionality reduction. Factors secreted by senescent cells, known as the senescence-associated secretory phenotype (SASP), promote chronic inflammation and can induce senescence in normal cells. At the same time, chronic inflammation accelerates the senescence of immune cells, resulting in weakened immune function and an inability to clear senescent cells and inflammatory factors, which creates a vicious cycle of inflammation and senescence. Persistently elevated inflammation levels in organs such as the bone marrow, liver, and lungs cannot be eliminated in time, leading to organ damage and aging-related diseases. Therefore, inflammation has been recognized as an endogenous factor in aging, and the elimination of inflammation could be a potential strategy for anti-aging. Here we discuss inflammaging at the molecular, cellular, organ, and disease levels, and review current aging models, the implications of cutting-edge single cell technologies, as well as anti-aging strategies. Since preventing and alleviating aging-related diseases and improving the overall quality of life are the ultimate goals of aging research, our review highlights the critical features and potential mechanisms of inflammation and aging, along with the latest developments and future directions in aging research, providing a theoretical foundation for novel and practical anti-aging strategies.

DOI: https://doi.org/10.1038/s41392-023-01502-8

Immun Ageing. 2023 Jun 08. 20(1): 25

Aging and chronic inflammation: highlights from a multidisciplinary workshop.

Danay Saavedra, Ana Laura Añé-Kourí, Nir Barzilai, Calogero Caruso, Kyung-Hyun Cho, Luigi Fontana, Claudio Franceschi, Daniela Frasca, Nuris Ledón, Laura J Niedernhofer, Karla Pereira, Paul D Robbins, Alexa Silva, Gisela M Suarez, Wim Vanden Berghe, Thomas von Zglinicki, Graham Pawelec, Agustín Lage.

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed "inflammaging". After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop "Aging and Chronic Inflammation" to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.

Keywords: Aging; Biomodulina T; Cell senescence; Chronic inflammation; Immunosenescence; Inflammaging; Metformin; SASP; Senolytic

DOI: https://doi.org/10.1186/s12979-023-00352-w

Nature. 2023 Jun 07.

How screenwriting can help your grant writing.

Christine W Hartmann.

Keywords: Careers; Funding; Research management

DOI: https://doi.org/10.1038/d41586-023-01881-6