bims-caglex 2024-12-15 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–12–15
23 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

The heat of longevity: sex differences in lifespan and body temperature.
Telomerase reverse transcriptase gene knock-in unleashes enhanced longevity and accelerated damage repair in mice.
Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
The dominance of old blood, and age-related increase in protein production and noise.
Arginase-II gene deficiency reduces skeletal muscle aging in mice.
Nuclear lipid droplets: a novel regulator of nuclear homeostasis and ageing.
Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions.
Climbing the longevity pyramid: overview of evidence-driven healthcare prevention strategies for human longevity.
Lifelong Glutathione Deficiency in Mice Increased Lifespan and Delayed Age-Related Motor Declines.
MicroRNA‑21‑5p expression in extracellular vesicles is increased in the blood of aging mice and in vascular endothelial cells induced by ionizing radiation.
IL-23R is a senescence-linked circulating and tissue biomarker of aging.
Aging and cell expansion enhance microRNA diversity in small extracellular vesicles produced from human adipose-derived stem cells.
Regenerative Potential Nanomedicine of Adipocyte Stem Cell-Derived Exosomes in Senescent Skin Tissue.
Betaine and aging: A narrative review of findings, possible mechanisms, research perspectives, and practical recommendations.
Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.
Biological function of EPHB4 in the aging process of vascular endothelial cells: mtDNA molecular mechanism and MAPK/PGC-1/TFAM signaling pathway.
Harnessing BDNF Signaling to Promote Resilience in Aging.
Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.
Cellular senescence as a key contributor to secondary neurodegeneration in traumatic brain injury and stroke.
Senescence of endothelial cells increases susceptibility to Kaposi's sarcoma-associated herpesvirus infection via CD109-mediated viral entry.
Differential effects of short-term and long-term ketogenic diet on gene expression in the aging mouse brain.
Autologous Cell-Free Fat Extract: A Novel Approach for Infraorbital Rejuvenation-A Pilot Study.
The CALERIE Genomic Data Resource.

Front Pharmacol. 2024 ;15 1512526

The heat of longevity: sex differences in lifespan and body temperature.

Chiara Ruocco, Maurizio Ragni, Enzo Nisoli.

  Dietary restriction (DR) has long been recognized as a powerful intervention for extending lifespan and improving metabolic health across species. In laboratory animals, DR-typically a 30%-40% reduction in caloric intake-delays aging and enhances mitochondrial function, oxidative defense, and anti-inflammatory pathways. In humans, findings from the CALERIE™ trial confirm DR's potential benefits, with a 25% caloric reduction over 2 years resulting in reduced visceral fat, improved cardiometabolic health, and favorable gene expression changes linked to proteostasis, DNA repair, and inflammation. However, recent research in genetically diverse mouse populations reveals that the impact of DR on lifespan is substantially modulated by genetic background, underscoring the importance of individual variability. Additionally, emerging evidence challenges previous assumptions that lower body temperature universally benefits lifespan extension, with data indicating complex relationships between thermoregulation, sex, and longevity. These findings underscore the need for nuanced approaches to DR in both research and potential therapeutic applications, with considerations for genetic and sex-specific factors to maximize healthspan and lifespan outcomes.

Keywords:  age-related disease; ageing markers; dietary restriction; genetic variability; lifespan; mitochondrial biogenesis; sex differences; thermoregulation

DOI:  https://doi.org/10.3389/fphar.2024.1512526
Aging Cell. 2024 Dec 11. e14445

Telomerase reverse transcriptase gene knock-in unleashes enhanced longevity and accelerated damage repair in mice.

Tian-Yi Zhu, Po Hu, Yu-Hui Mi, Jun-Li Zhang, An-Na Xu, Ming-Tong Gao, Ying-Ying Zhang, San-Bing Shen, Guang-Ming Yang, Yang Pan.

  While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.

Keywords:  Tert knock‐in; damage repair; lifespan extension; telomerase reverse transcriptase; transgenic mice

DOI:  https://doi.org/10.1111/acel.14445
bioRxiv. 2024 Nov 27. pii: 2024.11.25.625252. [Epub ahead of print]

Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.

Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
Key Points: Age-related attrition of the megakaryocytic niche and associated PF4 downregulation is a central mechanism in HSC aging.PF4 supplementation, acting on LDLR and CXCR3 receptors, rejuvenates the function of aged HSCs.

DOI: https://doi.org/10.1101/2024.11.25.625252
Ageing Res Rev. 2024 Dec 11. pii: S1568-1637(24)00459-8. [Epub ahead of print] 102641

The dominance of old blood, and age-related increase in protein production and noise.

Alexandra Sviercovich, Xiaoyue Mei, Grace Xie, Michael J Conboy, Irina M Conboy.

  This concise review provides new perspectives on systemic reduction of tissue aging by comparing different strategies, such as heterochronic parabiosis, injections of young blood plasma, neutral blood exchange (NBE) and therapeutic plasma exchange (TPE). Unlike previous literature that primarily discusses the need for young blood factors, we emphasize the potential of diluting age-elevated proteins as the way to re-calibrate systemic proteome to its younger state without donor blood. Furthermore, we introduce modulation of proteome noise, as an important part of understanding tissue aging and as a critical mechanism for tissue rejuvenation. We discuss studies on the dominance of aged systemic milieu in promoting progeric phenotypes in young cells, in vitro, and in multiple tissues of young animals, in vivo. We support our arguments with evidence showing a significant age-related increase in protein synthesis, in noise of newly synthesized proteomes, and in the rapid induction of these aging phenotypes in young muscle by exposure to aged tissue. We summarize the significance of these findings for future research on aging and longevity.

Keywords:  aging; de-novo synthesis; noise; proteome

DOI:  https://doi.org/10.1016/j.arr.2024.102641
Aging (Albany NY). 2024 Dec 12. null

Arginase-II gene deficiency reduces skeletal muscle aging in mice.

Matteo Caretti, Duilio Michele Potenza, Guillaume Ajalbert, Urs Albrecht, Xiu-Fen Ming, Andrea Brenna, Zhihong Yang.

  Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males. The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.

Keywords:  aging; arginase-II; cellular senescence; fibrosis; physical activity; skeletal muscle

DOI:  https://doi.org/10.18632/aging.206173
Aging (Albany NY). 2024 Dec 09. undefined

Nuclear lipid droplets: a novel regulator of nuclear homeostasis and ageing.

Konstantinos Palikaras, Nektarios Tavernarakis.

  Aging is a fundamental driver of numerous life-threatening diseases, significantly compromising cellular structures and functions, including the integrity of the nucleus. A consistent feature of aging across diverse species is the progressive accumulation of lipid droplets (nLDs) within the nuclear compartment, which disrupts nuclear architecture and functionality. Notably, aging is accompanied by a marked increase in nLD accumulation at the nuclear envelope. Interventions known to extend lifespan, such as caloric restriction and reduced insulin signaling, significantly reduce both the rate of accumulation and the size of nLDs. The triglyceride lipase ATGL-1, which localizes to the nuclear envelope, plays a critical role in limiting nLD buildup and maintaining nuclear lipid balance, especially in long-lived mutant worms. These findings establish excessive nuclear lipid deposition as a key hallmark of aging, with profound implications for nuclear processes such as chromatin organization, DNA repair, and gene regulation. In addition, ATGL-1 emerges as a promising therapeutic target for preserving nuclear health, extending organismal healthspan, and combating age-related disorders driven by lipid dysregulation.

Keywords:  ATGL-1; HLH-30/TFEB; aging; lipid droplet; non-linear optical phenomena; nucleus

DOI:  https://doi.org/10.18632/aging.206175
Geroscience. 2024 Dec 12.

Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions.

Ahmed M Elmansi, Abraham Kassem, Rafael M Castilla, Richard A Miller.

  Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions.

Keywords:  Inflammation; Longevity; NCoR1; NF-kB; P65

DOI:  https://doi.org/10.1007/s11357-024-01466-9
Front Aging. 2024 ;5 1495029

Climbing the longevity pyramid: overview of evidence-driven healthcare prevention strategies for human longevity.

Anđela Martinović, Matilde Mantovani, Natalia Trpchevska, Eva Novak, Nikolay B Milev, Leonie Bode, Collin Y Ewald, Evelyne Bischof, Tobias Reichmuth, Rebecca Lapides, Alexander Navarini, Babak Saravi, Elisabeth Roider.

  Longevity medicine is an emerging and iterative healthcare discipline focusing on early detection, preventive measures, and personalized approaches that aim to extend healthy lifespan and promote healthy aging. This comprehensive review introduces the innovative concept of the "Longevity Pyramid." This conceptual framework delineates progressive intervention levels, providing a structured approach to understanding the diverse strategies available in longevity medicine. At the base of the Longevity Pyramid lies the level of prevention, emphasizing early detection strategies and advanced diagnostics or timely identification of potential health issues. Moving upwards, the next step involves lifestyle modifications, health-promoting behaviors, and proactive measures to delay the onset of age-related conditions. The Longevity Pyramid further explores the vast range of personalized interventions, highlighting the importance of tailoring medical approaches based on genetic predispositions, lifestyle factors, and unique health profiles, thereby optimizing interventions for maximal efficacy. These interventions aim to extend lifespan and reduce the impact and severity of age-related conditions, ensuring that additional years are characterized by vitality and wellbeing. By outlining these progressive levels of intervention, this review offers valuable insights into the evolving field of longevity medicine. This structured framework guides researchers and practitioners toward a nuanced strategic approach to advancing the science and practice of healthy aging.

Keywords:  aging; healthcare; lifestyle; longevity; personalized medicine; preventive medicine

DOI:  https://doi.org/10.3389/fragi.2024.1495029
Aging Dis. 2024 Dec 03.

Lifelong Glutathione Deficiency in Mice Increased Lifespan and Delayed Age-Related Motor Declines.

J Thomas Mock, Paapa Mensah-Kane, Delaney L Davis, Jessica M Wong, Philip H Vann, Michael J Forster, Nathalie Sumien.

Glutathione (GSH) is a crucial redox scavenger, essential for maintaining cellular redox balance. This study explores the long-term effects of chronic GSH deficiency on lifespan, motor function, cognitive performance, redox status and inflammation. GCLM-/- mice, with a 70-90% reduction in GSH levels, were compared to GCLM+/+ controls across their lifespan (5, 10 and 20 months). We assessed lifespan, motor performance using balance and coordination tests, cognitive function through anxiety and memory tests, redox markers, and inflammation markers, particularly TNF-α and IL-6. Biochemical analyses of GSH levels in peripheral tissues and brain regions were conducted to evaluate redox state changes. GCLM-/- mice displayed extended lifespans and improved motor function at young and adult stages, with a delayed onset of motor decline with age. Cognitive function remains largely unaffected, although there are reductions in anxiety-related behaviors and minor deficits in fear-associated memory. Age-related increases in TNF-α, an inflammatory marker, are observed in both genotypes, with GCLM-/- mice showing a less pronounced increase, particularly in females. There were significant GSH reductions in peripheral tissues, with sporadic changes in brain regions. This stress likely triggers compensatory antioxidant responses, modulating inflammation and redox-sensitive pathways. The data suggests that lifelong GSH deficiency provides protective effects against inflammation and motor decline in younger animals but exacerbates these issues in older mice. The study offers insights into potential therapeutic strategies that leverage mild oxidative stress to promote healthy aging, emphasizing the importance of redox state and antioxidant defenses in the aging process.

DOI: https://doi.org/10.14336/AD.2024.1077
Exp Ther Med. 2025 Feb;29(2): 22

MicroRNA‑21‑5p expression in extracellular vesicles is increased in the blood of aging mice and in vascular endothelial cells induced by ionizing radiation.

Keisuke Yamamoto, Mitsuru Chiba.

  In recent years, the Japanese population has been aging and the risk of contracting various age-related diseases has increased. Thus, there is a need to analyze components that are characteristic of aging and examine their association with diseases to detect age-related diseases at an early stage. In the present study, microRNAs (miRNAs/miRs) in serum extracellular vesicles (EVs) of 82-102-week-old mice were analyzed to identify miRNAs characteristic of aging. Increased expression of mmu-miR-21a-5p was observed. These miRNAs may be derived from senescent vascular endothelial cells, and RNA-sequencing data (GSE130727) of HUVECs induced to senesce by 4 Gy of radiation revealed that the miRNAs were involved in the cell cycle and DNA repair. Annotations to senescence-related pathways were also identified. Reduced expression of the miR-21-5p target gene, which has an identical sequence in humans and mice, was confirmed. In HUVECs induced to age under similar conditions, increased senescence-associated β-galactosidase activity and increased intracellular miR-21-5p expression were observed. A portion of the miR-21-5p was secreted extracellularly by internalizing tetraspanin-positive EVs, and miR-21-5p was secreted into the extracellular space. The present study also demonstrated that miR-21-5p expression was upregulated and extracellular secretion of miR-21-5p was enhanced during vascular endothelial cell senescence. These findings suggested that increased serum miR-21-5p represents a biomarker for vascular endothelial cell senescence.

Keywords:  RNA-sequencing; gene expression; microRNA; microRNA-21-5p; microarray; senescence; serum

DOI:  https://doi.org/10.3892/etm.2024.12772
Nat Aging. 2024 Dec 10.

IL-23R is a senescence-linked circulating and tissue biomarker of aging.

Chase M Carver, Sonia L Rodriguez, Elizabeth J Atkinson, Andrew J Dosch, Niels C Asmussen, Paul T Gomez, Ethan A Leitschuh, Jair M Espindola-Netto, Karthik B Jeganathan, Madison G Whaley, Theodore M Kamenecka, Darren J Baker, Andrew J Haak, Nathan K LeBrasseur, Marissa J Schafer.

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

DOI: https://doi.org/10.1038/s43587-024-00752-7
Cytotechnology. 2025 Feb;77(1): 15

Aging and cell expansion enhance microRNA diversity in small extracellular vesicles produced from human adipose-derived stem cells.

Toshiya Tsubaki, Ryota Chijimatsu, Taiga Takeda, Maki Abe, Takahiro Ochiya, Shinsaku Tsuji, Keita Inoue, Tokio Matsuzaki, Yasuhide Iwanaga, Yasunori Omata, Sakae Tanaka, Taku Saito.

  Adipose-derived stem cells (ASCs) and their small extracellular vesicles (sEVs) hold significant potential for regenerative medicine due to their tissue repair capabilities. The microRNA (miRNA) content in sEVs varies depending on ASC status; however, the effects of aging and cell passage on miRNA profiles remain unclear. In this study, we examined the effects of donor age and cell expansion on ASC characteristics and transcriptome using ASCs obtained from three young and three old donors. Cell expansion significantly impaired stem cell properties, notably reducing proliferation and differentiation capacities. In contrast, donor age had minimal effects on ASCs. RNA sequencing (RNA-seq) revealed differences in gene expression related to stemness, phagocytosis, and metabolic processes influenced by cell expansion. To investigate miRNA variability, we performed small RNA-seq on sEVs collected from ASCs of all six donors. The miRNA profiles were influenced by donor age and cell passage. Interestingly, functional enrichment analysis indicated that advanced donor age and increased cell passage may enhance the production of miRNAs associated with organ development through various pathways. These findings suggest that donor age and cell expansion differentially influence ASC characteristics and sEV miRNA content, highlighting the need for disease-specific conditioning of ASCs to optimize the therapeutic effects of sEVs in clinical applications.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-024-00675-6.

Keywords:  Adipose-derived stem cells; Extracellular vesicles; Regenerative therapy; microRNA

DOI:  https://doi.org/10.1007/s10616-024-00675-6
Int J Nanomedicine. 2024 ;19 13149-13163

Regenerative Potential Nanomedicine of Adipocyte Stem Cell-Derived Exosomes in Senescent Skin Tissue.

An-Na Li, Jing-Hua Sun, Syafiqah Saidin, Jee Syuen Cheah, Chia-Hung Kuo, Ling Li, Jia-Shen Li, Ru-Yu Bai, Yong Diao, Hui-Min David Wang.

   Introduction: Skin is the first-line barrier defense against infection, irradiation, and toxins, but is prone to natural aging (intrinsic aging) and environmental factors (extrinsic aging). Hence, there is an increasing urgency to explore an effective treatment for aging skin. This study was focused on testing the potential of utilizing adipocyte stem cell derived exosomal as nanomedicine to regenerate the dermal layer and counteract signs of skin aging.
Methods: The harvested stem cells from adipose tissues were isolated, cultured, and then starved. The centrifugation of cell cultures medium yielded the human adipose-derived stem cells conditional medium (HADSCs-CM). Collagen secretion and fibroblast viability of human fibroblasts (Hs68) were measured in the presence of HADSCs-CM. The dermal layer, vascular endothelial growth factor (VEGF), and collagen levels were evaluated on the mice animal models between the treatments with and without HADSCs-CM.
Results: Western blotting, transmission electron microscopy (TEM), and dynamic light scattering (DLS) confirmed that the functional particles in HADSCs-CM were exosomes. When Hs68 fibroblasts were treated with HADSCs-CM, both cell viability and collagen secretion increased in a dose-dependent manner. Following the post-ultraviolet A (post-UVA) exposure, the mice exposed to the HADSCs-CM have decreased dermal thickness and VEGF expression and increased collagen volume compared to the non-HADSCs-CM exposed mice (control group).
Conclusion: HADSCs-CM significantly alleviated signs of skin senescence, including reduced dermal thickness, decreased VEGF expression, and enhanced collagen production. Exosomes, identified in the HADSCs-CM, are the functional component of these regenerative effects. This study highlights that the exosomal nanomedicine found in HADSCs-CM could regenerate skin, boost collagen production, improve fibroblast cell viability, and contain functional exosomes.

Keywords:  adipocyte stem cells; collagen; dermal regeneration; exosomal nanomedicine; skin aging

DOI:  https://doi.org/10.2147/IJN.S470225
Ageing Res Rev. 2024 Dec 06. pii: S1568-1637(24)00452-5. [Epub ahead of print]104 102634

Betaine and aging: A narrative review of findings, possible mechanisms, research perspectives, and practical recommendations.

Emilia Zawieja, Agata Chmurzynska.

  The rapid aging of the global population necessitates addressing age-related conditions through innovative strategies. Nutritional supplements have emerged as potential interventions for preventing or slowing age-related changes, with betaine being a promising candidate. This systematic review aims to provide a comprehensive analysis of current literature on the impact of betaine on the aging process. Specifically, we summarize the mechanisms through which betaine is proposed to affect aging, we integrate existing findings, we identify gaps in the literature, and we discuss practical implications for promoting healthy aging. Evidence suggests that betaine may counteract aging-related changes in methylation potential by increasing concentration of S-adenosylmethionine, a key methyl donor. Additionally, betaine reduces homocysteine concentrations, potentially mitigating vascular, neurodegenerative, and oxidative damage. Betaine has also been shown to enhance mitochondrial function, to reduce oxidative stress, and to attenuate inflammation. It may serve as a preventive agent against sarcopenia by promoting anabolic signaling pathways and improving muscle strength in younger adults. Betaine may also exert an effect on bone remodeling and adipose tissue metabolism, with animal studies indicating enhanced fat oxidation and reduced fat synthesis. Although certain limited studies have suggested betaine's potential in mitigating age-related neurodegenerative diseases, the currently available evidence does not establish a clear link between dietary betaine intake and the incidence of cardiovascular diseases or type-2 diabetes. In conclusion, emerging evidence highlights the potential of betaine in attenuating age-related changes. However, further research is required to elucidate the efficacy and safety of betaine supplementation in older populations.

Keywords:  Aging; Betaine; Homocysteine; Methylation; Neurodegeneration; One-carbon metabolism

DOI:  https://doi.org/10.1016/j.arr.2024.102634
Front Aging Neurosci. 2024 ;16 1503336

Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells.

Helena Borland Madsen, Claudia Navarro, Emilie Gasparini, Jae-Hyeon Park, Zhiquan Li, Deborah L Croteau, Vilhelm A Bohr.

   Introduction: During aging, many cellular processes, such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses, become compromised. Urolithin A (UA) and Nicotinamide Riboside (NR) are two naturally occurring compounds known for their anti-inflammatory and mitochondrial protective properties, yet the effects of these natural substances on microglia cells have not been thoroughly investigated. As both UA and NR are considered safe dietary supplements, it is equally important to understand their function in normal cells and in disease states.
Methods: This study investigates the effects of UA and NR on immune signaling, mitochondrial function, and microglial activity in a human microglial cell line (HMC3).
Results: Both UA and NR were shown to reduce DNA damage-induced cellular senescence. However, they differentially regulated gene expression related to neuroinflammation, with UA enhancing cGAS-STING pathway activation and NR displaying broader anti-inflammatory effects. Furthermore, UA and NR differently influenced mitochondrial dynamics, with both compounds improving mitochondrial respiration but exhibiting distinct effects on production of reactive oxygen species and glycolytic function.
Discussion: These findings underscore the potential of UA and NR as therapeutic agents in managing neuroinflammation and mitochondrial dysfunction in neurodegenerative diseases.

Keywords:  aging; innate immune signaling; microglia; mitochondrial health; nicotinamide riboside; urolithin A

DOI:  https://doi.org/10.3389/fnagi.2024.1503336
Int J Biol Macromol. 2024 Dec 07. pii: S0141-8130(24)09347-4. [Epub ahead of print] 138536

Biological function of EPHB4 in the aging process of vascular endothelial cells: mtDNA molecular mechanism and MAPK/PGC-1/TFAM signaling pathway.

Yanyan Lin, Minzhen Zhan, Xiangqi Chen, Xuemin Xiao.

  Previous studies have shown that EPHB4 is also involved in regulating the proliferation, migration, and apoptosis of endothelial cells. In this study, we found a close relationship between EPHB4 and aging. Therefore, in-depth research on the relationship between EPHB4 and aging can help reveal the molecular mechanisms of aging and provide new ideas and methods for developing anti-aging drugs and treating vascular aging-related diseases. In addition, in our current study, we found a close relationship between EPHB4, cellular senescence, and CM-AVM. The MAPK/PGC-1/TFAM signaling axis mediated by EPHB4 may also be involved in the process of CM-AVM, laying a solid foundation for future in-depth studies on the relationship between EPHB4 and CM-AVM. Our findings revealed a decrease in mitochondrial membrane potential associated with EPHB4 deficiency, suggesting that EPHB4 loss may contribute to mitochondrial dysfunction. Additionally, EPHB4 deficiency led to an elevation in mitochondrial ROS levels, which was confirmed using mitochondrial-specific fluorescent probes. Furthermore, EPHB4 deficiency resulted in down-regulated expression of NRF1 and SOD2, which could be a significant contributor to mitochondrial oxidative stress. To validate this hypothesis, we conducted rescue experiments by restoring PGC-1 expression. The results showed a partial recovery of mitochondrial membrane potential and a reduction in cell senescence. These findings suggest that EPHB4 regulates mitochondrial functional integrity through the MAPK/PGC-1/TFAM signaling axis.

Keywords:  Aging; CM-AVM; EPHB4; MAPK; Vascular endothelial cell

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138536
Aging Dis. 2024 Nov 27.

Harnessing BDNF Signaling to Promote Resilience in Aging.

Jamshid Faraji, Gerlinde A S Metz.

As a key member of the neurotrophin family in the central nervous system, brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance and plasticity of the nervous system. Its innate neuroprotective advantage can also be shared with the brain when normal aging-dependent processes challenge neural circuits. The intricate relationship between BDNF and resilience during the aging process signifies the molecular mechanisms that underlie the maintenance and protection of brain function, such as cognition, movement and psychological well-being. As BDNF is crucial for neuronal growth and survival, it can also promote resilience against age-related functional decline and frailty, even if it fails to entirely prevent aging-related functional decline. In the present review, we discuss BDNF function from a neuroprotective perspective and how it may promote resilience in aging. We emphasize briefly the principal, well-known cellular hallmarks of brain aging and how BDNF may restrict such disabling molecular dynamics and enhance overall functional resilience in aging. Insight into the molecular pathways through which BDNF reduces age-related brain dysfunctions and/or improves resilience, provides a foundation for developing targeted interventions to promote mental well-being in an aging population.

DOI: https://doi.org/10.14336/AD.2024.0961
Brain Res. 2024 Dec 10. pii: S0006-8993(24)00653-X. [Epub ahead of print]1850 149398

Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.

Dandan Chen, Yuan Guo, Meng Zhang, Xingran Liu, Baowen Zhang, Xianjuan Kou.

  Notch signaling, a classical signaling pathway of neurogenesis, is downregulated during the aging and age-related neurodegenerative diseases. Exercise has been proposed as an effective lifestyle intervention for delaying cognitive decline. However, it remains unclear whether exercise intervention could alleviate cognitive decline by modulating neurogenesis in naturally aging rats. In this study, 21-month-old natural aging rats were used to study brain aging. The natural aging rats underwent different forms of exercise training (aerobic exercise or strength training or comprehensive exercise with aerobic exercise and strength training) for 12 consecutive weeks. The cognitive function of natural aging rats was determined by Morris Water Maze. Notch signaling, autophagy-related proteins and hippocampal neurogenesis were examined by immunofluorescence, qRT-PCR and Western blot. Results showed that natural aging rats exhibited cognitive decline, accumulation of AD pathological proteins (APP and Aβ), and decreased neurogenesis (decreased DCX, Ki67 and GFAP), compared with the young control rats. Moreover, a significant decline in Notch signaling and autophagy was found in the hippocampus of natural aging rats. However, different forms of exercise upregulated Notch signaling and its downstream target genes, as well as autophagy-related proteins, including LC3, Beclin1, and p62. In summary, our data suggest that different forms of exercise can mitigate brain aging by upregulating Notch signaling and autophagy, thereby increasing hippocampal neurogenesis and improves spatial learning and memory abilities.

Keywords:  Autophagy; Cognitive dysfunction; Exercise intervention; Notch signaling

DOI:  https://doi.org/10.1016/j.brainres.2024.149398
Transl Neurodegener. 2024 Dec 12. 13(1): 61

Cellular senescence as a key contributor to secondary neurodegeneration in traumatic brain injury and stroke.

Zhihai Huang, Peisheng Xu, David C Hess, Quanguang Zhang.

  Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. Herein, we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain. The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined. From a translational perspective, we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions.

Keywords:  Cellular senescence; Neurodegeneration; Senolytic therapy; Stroke; Traumatic brain injury

DOI:  https://doi.org/10.1186/s40035-024-00457-2
J Clin Invest. 2024 Dec 12. pii: e183561. [Epub ahead of print]

Senescence of endothelial cells increases susceptibility to Kaposi's sarcoma-associated herpesvirus infection via CD109-mediated viral entry.

Myung-Ju Lee, Jun-Hee Yeon, Jisu Lee, Yun Hee Kang, Beom Seok Park, Joo Hee Park, Sung-Ho Yun, Dagmar Wirth, Seung-Min Yoo, Changhoon Park, Shou-Jiang Gao, Myung-Shin Lee.

  The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovers a fascinating link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as novel host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR-Cas9-mediated knockout of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting an intriguing ability to inhibit infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide novel insights into the complex interplay between aging and viral pathogenesis.

Keywords:  Aging; Cellular senescence; Endothelial cells; Molecular biology; Virology

DOI:  https://doi.org/10.1172/JCI183561
J Nutr Health Aging. 2024 Dec 10. pii: S1279-7707(24)00515-3. [Epub ahead of print]29(2): 100427

Differential effects of short-term and long-term ketogenic diet on gene expression in the aging mouse brain.

Matthew S Stratton, José Alberto López-Domínguez, Alessandro Canella, Jon J Ramsey, Gino A Cortopassi.

   BACKGROUND: Aging is associated with multiple neurodegenerative conditions that severely limit quality of life and can shorten lifespan. Studies in rodents indicate that in addition to extending lifespan, the ketogenic diet (KD) improves cognitive function in aged animals, yet long term adherence to KD in Humans is poor.
OBJECTIVES: To broadly investigate what mechanisms might be activated in the brain in response to ketogenic diet.
METHODS: We conducted transcriptome wide analysis on whole brain samples from 13-month-old mice, 13-month-old mice fed a ketogenic diet for 1 month, 26-month-old mice, and 26-month-old mice fed a ketogenic diet for 14 months.
RESULTS: As expected, analysis of differently expressed genes between the old (26 month) vs younger mice (13 month) showed clear activation of inflammation and complement system pathways with aging. Analysis between the 26-month-old animals fed ketogenic diet for 14 months with 26-month-old animals fed control diet indicate that long-term KD resulted in activation of LRP, TCF7L2 (WNT pathway), and IGF1 signaling. There was also a significant increase in the expression of SOX2-dependent oligodendrocyte/myelination markers, though TCF7L2 and SOX2 dependent gene sets were largely overlapping. Remarkably, the effect of 1 month of ketogenic diet was minimal and there was no congruence between gene expression effects of short-term KD vs long-term KD.
CONCLUSIONS: This work informs target identification efforts for aging and neurodegenerative disorder therapeutics discovery while also establishing differential effects of short-term vs long-term KD on gene expression in the brain.

Keywords:  Brain aging; Ketogenic diet; Target discovery; Transcriptomics

DOI:  https://doi.org/10.1016/j.jnha.2024.100427
J Cosmet Dermatol. 2024 Dec 08. e16682

Autologous Cell-Free Fat Extract: A Novel Approach for Infraorbital Rejuvenation-A Pilot Study.

Yizuo Cai, Zhuoxuan Jia, Jiancheng Gu, Bijun Kang, Wei Li, Wenjie Zhang.

   BACKGROUND AND OBJECTIVE: CEFFE (Cell-free fat extract) treatment for periocular fine lines requires thorough clinical evaluation to determine its efficacy and safety in enhancing skin quality. The research enrolled 10 healthy female participants aged 31-58, focusing on skin texture, elasticity, and barrier function.
METHODS AND RESULTS: CEFFE treatment demonstrated significant benefits, with notable improvements observed as early as 3 months posttreatment, which continued throughout the 12-month follow-up period. Objective assessments revealed reductions in SEr% and SEw%, indicative of reduced skin roughness and wrinkles, particularly pronounced after the third month of treatment. Enhanced skin elasticity, as indicated by improvements in R2%, R5%, and R7%, was observed, with the most significant enhancements noted at the 6-month follow-up. Furthermore, TEWL decreased consistently, highlighting CEFFE's potential in maintaining the skin's barrier function and moisture retention. High patient satisfaction levels, with 70% expressing satisfaction ranging from satisfied to very satisfied, underscored CEFFE's clinical significance.
CONCLUSIONS: CEFFE demonstrates potential as an effective and safe intervention for addressing periocular fine lines, providing a solution for fine lines while ensuring skin health (ChiCTR1900024329).

Keywords:  aesthetic medicine; aging face; growth factors; rejuvenation; stem cells

DOI:  https://doi.org/10.1111/jocd.16682
Nat Aging. 2024 Dec 13.

The CALERIE Genomic Data Resource.

C P Ryan, D L Corcoran, N Banskota, C Eckstein Indik, A Floratos, R Friedman, M S Kobor, V B Kraus, W E Kraus, J L MacIsaac, M C Orenduff, C F Pieper, J P White, L Ferrucci, S Horvath, K M Huffman, D W Belsky.

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from the CALERIE randomized, controlled trial of long-term CR in healthy, nonobese humans broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n = 218 participants during the trial. These data constitute a genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome single-nucleotide polymorphism genotypes, and three-timepoint-longitudinal DNA methylation, mRNA and small RNA datasets generated from blood, skeletal muscle and adipose tissue samples (total sample n = 2,327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This multi-tissue, multi-omics, longitudinal data resource has great potential to advance translational geroscience. ClinicalTrials.gov registration: NCT00427193 .

DOI: https://doi.org/10.1038/s43587-024-00775-0