bims-agimec 2024-09-01 papers

bims-agimec

Biomed News

on Aging mechanisms

Issue of 2024–09–01
seven papers selected by
Metin Sökmen, Ankara Üniversitesi

T-Cell Senescence in Human Metabolic Diseases.
Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle.
Molecular Mechanisms of Autophagy Decline during Aging.
Quiescence-Origin Senescence: A New Paradigm in Cellular Aging.
mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes.
Metformin: From diabetes to cancer to prolongation of life.

Diabetes Metab J. 2024 Aug 28.

T-Cell Senescence in Human Metabolic Diseases.

Ha Thi Nga, Thi Linh Nguyen, Hyon-Seung Yi.

  Immunosenescence denotes a state of dysregulated immune cell function characterized by a confluence of factors, including arrested cell cycle, telomere shortening, markers of cellular stress, mitochondrial dysfunction, loss of proteostasis, epigenetic reprogramming, and secretion of proinflammatory mediators. This state primarily manifests during the aging process but can also be induced in various pathological conditions, encompassing chronic viral infections, autoimmune diseases, and metabolic disorders. Age-associated immune system alterations extend to innate and adaptive immune cells, with T-cells exhibiting heightened susceptibility to immunosenescence. In particular, senescent T-cells have been identified in the context of metabolic disorders such as obesity, diabetes, and cardiovascular diseases. Recent investigations suggest a direct link between T-cell senescence, inflammation, and insulin resistance. The perturbation of biological homeostasis by senescent T-cells appears intricately linked to the initiation and progression of metabolic diseases, particularly through inflammation-mediated insulin resistance. Consequently, senescent T-cells are emerging as a noteworthy therapeutic target. This review aims to elucidate the intricate relationship between metabolic diseases and T-cell senescence, providing insights into the potential roles of senescent T-cells in the pathogenesis of metabolic disorders. Through a comprehensive examination of current research findings, this review seeks to contribute to a deeper understanding of the complex interplay between immunosenescence and metabolic health.

Keywords:  Aging; Diabetes mellitus; Metabolic diseases; T-cell senescence

DOI:  https://doi.org/10.4093/dmj.2024.0140
Aging Cell. 2024 Aug 26. e14296

Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?

Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano.

  The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.

Keywords:  aging; mitochondria; organelle contacts; protein targeting; structure

DOI:  https://doi.org/10.1111/acel.14296
Semin Cancer Biol. 2024 Aug 26. pii: S1044-579X(24)00061-0. [Epub ahead of print]

Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle.

Abdol-Hossein Rezaeian, Wenyi Wei.

  It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also block cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.

Keywords:  aging; cancer; hypoxia; senescence; therapeutic strategies

DOI:  https://doi.org/10.1016/j.semcancer.2024.08.003
Cells. 2024 Aug 16. pii: 1364. [Epub ahead of print]13(16):

Molecular Mechanisms of Autophagy Decline during Aging.

Shaun H Y Lim, Malene Hansen, Caroline Kumsta.

  Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.

Keywords:  aging; autophagy; lysosomes; proteolysis; proteostasis

DOI:  https://doi.org/10.3390/cells13161364
Biomedicines. 2024 Aug 13. pii: 1837. [Epub ahead of print]12(8):

Quiescence-Origin Senescence: A New Paradigm in Cellular Aging.

Guang Yao.

  Cellular senescence, traditionally viewed as a consequence of proliferating and growing cells overwhelmed by extensive stresses and damage, has long been recognized as a critical cellular aging mechanism. Recent research, however, has revealed a novel pathway termed "quiescence-origin senescence", where cells directly transition into senescence from the quiescent state, bypassing cell proliferation and growth. This opinion paper presents a framework conceptualizing a continuum between quiescence and senescence with quiescence deepening as a precursor to senescence entry. We explore the triggers and controllers of this process and discuss its biological implications. Given that the majority of cells in the human body are dormant rather than proliferative, understanding quiescence-origin senescence has significant implications for tissue homeostasis, aging, cancer, and various disease processes. The new paradigm in exploring this previously overlooked senescent cell population may reshape our intervention strategies for age-related diseases and tissue regeneration.

Keywords:  Rb–E2F switch threshold; dormancy state continuum; geroconversion; quiescence; quiescence deepening; senescence

DOI:  https://doi.org/10.3390/biomedicines12081837
Int J Mol Sci. 2024 Aug 08. pii: 8676. [Epub ahead of print]25(16):

mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes.

Dario Troise, Silvia Mercuri, Barbara Infante, Vincenzo Losappio, Luciana Cirolla, Giuseppe Stefano Netti, Elena Ranieri, Giovanni Stallone.

  The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence.

Keywords:  SGLT-2 inhibitors; aging; inflammaging; mTOR inhibitors; senescence; senomorphic compounds; senotherapeutic strategies

DOI:  https://doi.org/10.3390/ijms25168676
Pharmacol Res. 2024 Aug 25. pii: S1043-6618(24)00312-8. [Epub ahead of print]208 107367

Metformin: From diabetes to cancer to prolongation of life.

Cesare R Sirtori, Sofia Castiglione, Chiara Pavanello.

  The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.

Keywords:  aging; cancer; diabetes; metformin

DOI:  https://doi.org/10.1016/j.phrs.2024.107367