bims-caglex 2024-11-03 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–11–03
24 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

α-Terpineol Induces Shelterin Components TRF1 and TRF2 to Mitigate Senescence and Telomere Integrity Loss via A Telomerase-Independent Pathway.
Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.
Identification of lipid senolytics targeting senescent cells through ferroptosis induction.
Enhancing Cellular Homeostasis: Targeted Botanical Compounds Boost Cellular Health Functions in Normal and Premature Aging Fibroblasts.
Isotschimgine promotes lifespan, healthspan and neuroprotection of Caenorhabditis elegans via the activation of nuclear hormone receptors.
Topical Platelet Exosomes Reduce Senescence Signaling in Human Skin: An Exploratory Prospective Trial.
Accumulation of F-actin drives brain aging and limits healthspan in Drosophila.
Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.
Decoding the impact of ageing and environment stressors on skin cell communication.
The immunometabolic roots of aging.
Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?
The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.
Black goji berry anthocyanins extend lifespan and enhance the antioxidant defenses in Caenorhabditis elegans via the JNK-1 and DAF-16/FOXO pathways.
APE1 is a master regulator of the ATR-/ATM-mediated DNA damage response.
Five-factor theory of aging and death due to aging.
The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging.
Protective Effects of Sesame Glycoproteins on Ultraviolet-Induced Skin Aging: In Vitro and In Vivo Studies.
Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species.
Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice.
The PUF RNA-binding protein, FBF-2, maintains stem cells without binding to RNA.
Increased hydrogen sulfide turnover serves a cytoprotective role during the development of replicative senescence.
Protective Effect of Epigallocatechin-3-gallate against Hepatic Oxidative Stress Induced by tert-Butyl Hhydroperoxide in Yellow-Feathered Broilers.
Can salivary and skin microbiome become a biodetector for aging-associated diseases? Current insights and future perspectives.
When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.

Antioxidants (Basel). 2024 Oct 17. pii: 1258. [Epub ahead of print]13(10):

α-Terpineol Induces Shelterin Components TRF1 and TRF2 to Mitigate Senescence and Telomere Integrity Loss via A Telomerase-Independent Pathway.

Marianna Kapetanou, Sophia Athanasopoulou, Andreas Goutas, Dimitra Makatsori, Varvara Trachana, Efstathios Gonos.

  Cellular senescence is a hallmark of aging characterized by irreversible growth arrest and functional decline. Progressive telomeric DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. Therefore, protecting telomeres from DNA damage is essential in order to avoid entry into senescence and organismal aging. In several organisms, including mammals, telomeres are protected by a protein complex named shelterin that prevents DNA damage at the chromosome ends through the specific function of its subunits. Here, we reveal that the nuclear protein levels of shelterin components TRF1 and TRF2 decline in fibroblasts reaching senescence. Notably, we identify α-terpineol as an activator that effectively enhances TRF1 and TRF2 levels in a telomerase-independent manner, counteracting the senescence-associated decline in these crucial proteins. Moreover, α-terpineol ameliorates the cells' response to oxidative DNA damage, particularly at the telomeric regions, thus preserving telomere length and delaying senescence. More importantly, our findings reveal the significance of the PI3K/AKT pathway in the regulation of shelterin components responsible for preserving telomere integrity. In conclusion, this study deepens our understanding of the molecular pathways involved in senescence-associated telomere dysfunction and highlights the potential of shelterin components to serve as targets of therapeutic interventions, aimed at promoting healthy aging and combating age-related diseases.

Keywords:  PI3K/AKT pathway; aging; antioxidants; oxidative DNA damage; senescence; shelterin; telomeres

DOI:  https://doi.org/10.3390/antiox13101258
Res Sq. 2024 Oct 18. pii: rs.3.rs-5267673. [Epub ahead of print]

Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.

Federica Anastasi, Patricia Genius, Blanca Rodriguez-Fernandez, Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Felipe Hernández-Villamizar, Luigi Lorenzini, Marta Del Campo, Gonzalo Sanchez-Benavides, Carolina Minguillon, Arcadi Navarro, Carlos Cruchaga, Marc Suárez-Calvet, Natalia Vilor-Tejedor.

Background While numerous studies have identified blood proteins that modulate brain aging in mice, the direct translation of these findings to human health remains a substantial challenge. Bridging this gap is critical for developing interventions that can effectively target human brain aging and associated diseases. Methods We first identified 12 proteins with aging or rejuvenating properties in murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we developed polygenic scores to predict plasma protein levels, which we then validated in two independent human cohorts. We employed association models to explore the association between these genetically predicted protein levels and cognitive performance, focusing specifically on their interaction with key genetic markers such as sex, APOE -ε4 and Aβ42 status. Results Predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans, also when the models were stratified by sex, APOE -ε4, and Aβ42 status. Conclusions This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.

DOI: https://doi.org/10.21203/rs.3.rs-5267673/v1
bioRxiv. 2024 Oct 14. pii: 2024.10.14.618023. [Epub ahead of print]

Identification of lipid senolytics targeting senescent cells through ferroptosis induction.

Lei Justan Zhang, Rahagir Salekeen, Carolina Soto-Palma, Osama Elsallabi, Hongping Ye, Brian Hughes, Borui Zhang, Allancer Nunes, Kyooa Lee, Wandi Xu, Abdalla Mohamed, Ellie Piepgras, Sara J McGowan, Luise Angelini, Ryan O'Kelly, Xianlin Han, Laura J Niedernhofer, Paul D Robbins.

  Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs and ROS levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.

Keywords:  PUFA; aging; eleostearic acid; fatty acid; ferroptosis; healthspan; lipid; senescence; senolysis; senolytic; senotherapeutic

DOI:  https://doi.org/10.1101/2024.10.14.618023
Biomolecules. 2024 Oct 16. pii: 1310. [Epub ahead of print]14(10):

Enhancing Cellular Homeostasis: Targeted Botanical Compounds Boost Cellular Health Functions in Normal and Premature Aging Fibroblasts.

Ramona Hartinger, Khushboo Singh, Jesse Leverett, Karima Djabali.

  The human skin, the body's largest organ, undergoes continuous renewal but is significantly impacted by aging, which impairs its function and leads to visible changes. This study aimed to identify botanical compounds that mimic the anti-aging effects of baricitinib, a known JAK1/2 inhibitor. Through in silico screening of a botanical compound library, 14 potential candidates were identified, and 7 were further analyzed for their effects on cellular aging. The compounds were tested on both normal aged fibroblasts and premature aging fibroblasts derived from patients with Hutchinson-Gilford Progeria Syndrome (HGPS). Results showed that these botanical compounds effectively inhibited the JAK/STAT pathway, reduced the levels of phosphorylated STAT1 and STAT3, and ameliorated phenotypic changes associated with cellular aging. Treatments improved cell proliferation, reduced senescence markers, and enhanced autophagy without inducing cytotoxicity. Compounds, such as Resveratrol, Bisdemethoxycurcumin, Pinosylvin, Methyl P-Hydroxycinnamate, cis-Pterostilbene, and (+)-Gallocatechin, demonstrated significant improvements in both control and HGPS fibroblasts. These findings suggest that these botanical compounds have the potential to mitigate age-related cellular alterations, offering promising strategies for anti-aging therapies, particularly for skin health. Further in vivo studies are warranted to validate these results and explore their therapeutic applications.

Keywords:  HGPS; JAK/STAT pathway; autophagy; botanical compounds; cellular aging; fibroblasts; inflammation; premature aging; senescence; skin

DOI:  https://doi.org/10.3390/biom14101310
Biogerontology. 2024 Oct 29. 26(1): 2

Isotschimgine promotes lifespan, healthspan and neuroprotection of Caenorhabditis elegans via the activation of nuclear hormone receptors.

Hang Shi, Xiaoyan Gao, Jing Yu, Lijun Zhang, Bingbing Fan, Ying Liu, Xinyi Wang, Shengjie Fan, Cheng Huang.

  Isotschimgine (ITG) is a bornane-type monoterpenoid derivative naturally occurring in genus Ferula plants and propolis. Its effects on aging and the underlying mechanisms are not yet well understood. This study employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the potential of ITG in extending lifespan, enhancing healthspan, and promoting neuroprotection, while exploring the underlying mechanisms involved. The results showed that ITG extended the lifespan and healthspan of C. elegans, significantly enhanced stress resistance and detoxification functions. Studies on mutants and qPCR data indicated that ITG-mediated lifespan extension was modulated by the insulin/IGF-1 signaling pathway and nuclear hormone receptors. Furthermore, ITG markedly increased stress-responsive genes, including daf-16 and its downstream genes sod-3 and hsp-16.2, as well as NHR downstream detoxification-related genes cyp35a1, cyp35b3, cyp35c1, gst-4, pgp-3 and pgp-13. Additionally, ITG alleviated β-amyloid-induced paralysis and behavioral dysfunction in transgenic C. elegans strains. The neuroprotective efficacy of ITG was weakened by RNAi knockdown of nuclear hormone receptors daf-12 and nhr-8. Overall, our study identifies ITG as a potential compound for promoting longevity and neuroprotection, mediated through nuclear hormone receptors.

Keywords:   Caenorhabditis elegans ; Aging; Hormesis; IIS; Isotschimgine; Neuroprotection; Nuclear hormone receptor

DOI:  https://doi.org/10.1007/s10522-024-10142-6
Dermatol Surg. 2024 Nov 01. 50(11S): S160-S165

Topical Platelet Exosomes Reduce Senescence Signaling in Human Skin: An Exploratory Prospective Trial.

Saranya P Wyles, Grace T Yu, Michael Gold, Atta Behfar.

BACKGROUND: Cellular senescence, an irreversible cell cycle arrest with secretory phenotype, is a hallmark of skin aging. Regenerative exosome-based approaches, such as topical human platelet extract (HPE), are emerging to target age-related skin dysfunction.
OBJECTIVE: To evaluate the cellular and molecular effects of topical HPE for skin rejuvenation after 12 weeks of twice daily use.
METHODS: Skin biopsies were obtained for histological evaluation of senescence markers, p16INK4a and p21CIP1/WAF1. Telomere-associated foci, coassociation of telomeres, and DNA damage marker, γH2AX, were assessed. RNA sequencing evaluated senescence associated secretory phenotype (SASP) and extracellular matrix pathways.
RESULTS: p16INK4a and p21CIP1/WAF1 staining in senescent skin cells revealed low and high expression subgroups that did not correspond to chronological age. Topical HPE significantly reduced high p16INK4a cells in the dermis (p = .02). There was also a decrease in telomere damage after topical HPE (p = .03). In patients with high senescent cells at baseline, there was a 40% reduction in proinflammatory SASP. Extracellular matrix remodeling pathways, including collagen and elastic fibers, were up-regulated.
CONCLUSION: Topical HPE, applied on intact skin, reduced senescence signaling and senescence-associated telomere damage after 12 weeks of twice daily use, targeting a path for skin longevity or healthy skin aging.

DOI: https://doi.org/10.1097/DSS.0000000000004426
Nat Commun. 2024 Oct 25. 15(1): 9238

Accumulation of F-actin drives brain aging and limits healthspan in Drosophila.

Edward T Schmid, Joseph M Schinaman, Naomi Liu-Abramowicz, Kylie S Williams, David W Walker.

The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

DOI: https://doi.org/10.1038/s41467-024-53389-w
Elife. 2024 Nov 01. pii: RP89572. [Epub ahead of print]12

Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.

Priyanka Das, Alejandro Aballay, Jogender Singh.

  Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

Keywords:  C. elegans; Intestinal bloating; calorie restriction; cell biology; genetics; genomics; hlh-30; longevity; nhr-8; tax-6

DOI:  https://doi.org/10.7554/eLife.89572
Biogerontology. 2024 Oct 29. 26(1): 3

Decoding the impact of ageing and environment stressors on skin cell communication.

Alessandra V S Faria, Sheila Siqueira Andrade.

  The integumentary system serves as a crucial protective barrier and is subject to complex signaling pathways that regulate its physiological functions. As the body's first line of defense, the skin is continuously exposed to environmental stressors, necessitating a robust network of signaling molecules to maintain homeostasis. Considering the main cellular components to be keratinocytes, melanocytes, fibroblasts, and fibrous components, collagen of various types, this review explores the intricate signaling mechanisms that govern skin integrity, focusing on key pathways involved in impacts of ageing and environment factors on skin health. The role of growth factors, cytokines, hormones and other molecular mediators in these processes is examined. Specially for women, decrease of estrogen is determinant to alter signaling and to compromise skin structure, especially the dermis. Environmental factors, such as ultraviolet rays and pollution alongside the impact of ageing on signaling pathways, especially TGF-β and proteases (metalloproteinases and cathepsins). Furthermore, with advancing age, the skin's capacity to shelter microbiome challenges diminishes, leading to alterations in signal transduction and subsequent functional decline. Understanding these age-related changes is essential for developing targeted therapies aimed at enhancing skin health and resilience, but also offers a promising avenue for the treatment of skin disorders and the promotion of healthy ageing.

Keywords:  Ageing; Environmental effects; Menopause; Microbiome; Signaling; Skin health

DOI:  https://doi.org/10.1007/s10522-024-10145-3
Curr Opin Immunol. 2024 Oct 25. pii: S0952-7915(24)00088-8. [Epub ahead of print]91 102498

The immunometabolic roots of aging.

Pierpaolo Ginefra, Helen C Hope, Girieca Lorusso, Patrizia D'Amelio, Nicola Vannini.

Aging is one of the greatest risk factors for several chronic diseases and is accompanied by a progressive decline of cellular and organ function. Recent studies have highlighted the changes in metabolism as one of the main drivers of organism dysfunctions during aging and how that strongly deteriorate immune cell performance and function. Indeed, a dysfunctional immune system has been shown to have a pleiotropic impact on the organism, accelerating the overall aging process of an individual. Intrinsic and extrinsic factors are responsible for such metabolic alterations. Understanding the contribution, regulation, and connection of these different factors is fundamental to comprehend the process of aging and develop approaches to mitigate age-related immune decline. Here, we describe metabolic perturbations occurring at cellular and systemic levels. Particularly, we emphasize the interplay between metabolism and immunosenescence and describe novel interventions to protect immune function and promote health span.

DOI: https://doi.org/10.1016/j.coi.2024.102498
Int J Mol Sci. 2024 Oct 11. pii: 10932. [Epub ahead of print]25(20):

Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?

Thomas Gustafsson, Brun Ulfhake.

  As we age, we lose muscle strength and power, a condition commonly referred to as sarcopenia (ICD-10-CM code (M62.84)). The prevalence of sarcopenia is about 5-10% of the elderly population, resulting in varying degrees of disability. In this review we emphasise that sarcopenia does not occur suddenly. It is an aging-induced deterioration that occurs over time and is only recognised as a disease when it manifests clinically in the 6th-7th decade of life. Evidence from animal studies, elite athletes and longitudinal population studies all confirms that the underlying process has been ongoing for decades once sarcopenia has manifested. We present hypotheses about the mechanism(s) underlying this process and their supporting evidence. We briefly review various proposals to impede sarcopenia, including cell therapy, reducing senescent cells and their secretome, utilising targets revealed by the skeletal muscle secretome, and muscle innervation. We conclude that although there are potential candidates and ongoing preclinical and clinical trials with drug treatments, the only evidence-based intervention today for humans is exercise. We present different exercise programmes and discuss to what extent the interindividual susceptibility to developing sarcopenia is due to our genetic predisposition or lifestyle factors.

Keywords:  ageing; dynapenia; motor unit; muscle fibre atrophy; senescence

DOI:  https://doi.org/10.3390/ijms252010932
Front Aging. 2024 ;5 1490302

The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.

Marianna V Wrona, Rituparna Ghosh, Kaitlyn Coll, Connor Chun, Matthew J Yousefzadeh.

  As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals.

Keywords:  cellular senescence; immune resilience; immunosenescence; inflammaging; inflammation

DOI:  https://doi.org/10.3389/fragi.2024.1490302
J Sci Food Agric. 2024 Nov 01.

Black goji berry anthocyanins extend lifespan and enhance the antioxidant defenses in Caenorhabditis elegans via the JNK-1 and DAF-16/FOXO pathways.

Qiuxiong Xu, Bisheng Zheng, Tong Li, Rui Hai Liu.

   BACKGROUND: The black goji berry (Lycium ruthenicum Murr.) is known for its abundance of high-quality natural antioxidants, particularly anthocyanins. Black goji berry anthocyanins (BGA) are receiving increasing attention because of their high safety and beneficial biological activities. Studies have shown that oxidative stress is a key factor affecting aging, whereas antioxidants are critical preventive and delaying strategies.
RESULTS: In the present study, we investigated the potential anti-aging effects and mechanism of BGA using the Caenorhabditis elegans model. We found that BGA prolonged the mean lifespan of nematodes and improve their healthspan, including locomotion, pharyngeal pumping rate and stress resistance. Subsequently, we observed a significant decrease in reactive oxygen species and malondialdehyde levels in nematodes after administering BGA. Moreover, BGA enhanced the activities of the antioxidant enzymes superoxide dismutase and catalase, and elevated the glutathione disulfide/glutathione ratio. We confirmed that BGA exerted excellent antioxidative stress activity in nematodes, which may contribute substantially to its anti-aging effects. The health benefits of BGA in C. elegans might be closely related to petunidin-3-O-glucoside, the most abundant anthocyanin in BGA. Further mechanistic investigation revealed that the JNK-1 and DAF-16/FOXO pathways, rather than the calorie restriction pathway, were responsible for the antioxidant stress and life-prolonging effects of BGA in nematodes.
CONCLUSION: Our research provides a theoretical foundation for studying the anti-aging effect of BGA and a basis for developing black goji berry and its anthocyanins as functional foods with anti-aging and antioxidative stress benefits. © 2024 Society of Chemical Industry.

Keywords:  Caenorhabditis elegans; DAF‐16/FOXO; JNK‐1; anthocyanins; antioxidative stress; black goji berry

DOI:  https://doi.org/10.1002/jsfa.13998
DNA Repair (Amst). 2024 Oct 19. pii: S1568-7864(24)00152-6. [Epub ahead of print]144 103776

APE1 is a master regulator of the ATR-/ATM-mediated DNA damage response.

Haichao Zhao, Christine Richardson, Ian Marriott, In Hong Yang, Shan Yan.

  To maintain genomic integrity, cells have evolved several conserved DNA damage response (DDR) pathways in response to DNA damage and stress conditions. Apurinic/apyrimidinic endonuclease 1 (APE1) exhibits AP endonuclease, 3'-5' exonuclease, 3'-phosphodiesterase, and 3'-exoribonuclease activities and plays critical roles in the DNA repair and redox regulation of transcription. However, it remains unclear whether and how APE1 is involved in DDR pathways. In this perspective, we first updated our knowledge of APE1's functional domains and its nuclease activities and their specific associated substrates. We then summarized the newly discovered roles and mechanisms of action of APE1 in the global and nucleolar ATR-mediated DDR pathway. While the ATM-mediated DDR is well known to be activated by DNA double-strand breaks and oxidative stress, here we provided new perspectives as to how ATM DDR signaling is activated by indirect single-strand breaks (SSBs) resulting from genotoxic stress and defined SSB structures, and discuss how ATM kinase is directly activated and regulated by its activator, APE1. Together, accumulating body of new evidence supports the notion that APE1 is a master regulator protein of the ATR- and ATM-mediated DDR pathways. These new findings of APE1 in DDR signaling provide previously uncharacterized but critical functions and regulations of APE1 in genome integrity.

Keywords:  APE1; ATM; ATR; DNA damage response; DNA repair

DOI:  https://doi.org/10.1016/j.dnarep.2024.103776
Arch Gerontol Geriatr. 2024 Oct 19. pii: S0167-4943(24)00341-8. [Epub ahead of print]129 105665

Five-factor theory of aging and death due to aging.

Danko Obradovic.

  This new theory of aging explains that aging and death due to aging are due to five factors, and also explains how these factors are interconnected and jointly lead to aging and death of the organism, pointing to many facts that strongly support it. The first factor is the harmful changes that occur in cellular structures. The second factor is the cessation of cell division in adult organisms, which leads to the inability to restore cellular structures. The third factor is the feature that cells do not die due to the accumulation of harmful changes that occur in the cells during the life of the organism. The fourth factor is the inability of stem cells to regenerate tissue by replacing such cells with new ones, because somatic cells do not die and there are no signals that stimulate the proliferation of stem cells and their differentiation into new ones that would replace dead cells. The fifth factor is that all cells die suddenly, due to the cessation of one of the vital functions of the organism, and not gradually during life, due to a decrease in the functionality of cells caused by the introduction of harmful changes in cellular structures, which would allow stem cells to regenerate tissues and keep the body young. Also, to show that this aging theory is valid, the theory gives its view of the evolution of five factors, which according to this theory lead to aging, which gives strong support to this theory.

Keywords:  Ageing; Aging; Evolution; Immortality; Regeneration

DOI:  https://doi.org/10.1016/j.archger.2024.105665
Int J Mol Sci. 2024 Oct 11. pii: 10926. [Epub ahead of print]25(20):

The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging.

Zhi Su, Qianhua Hu, Xiang Li, Zirun Wang, Ying Xie.

  Circadian rhythms, the internal timekeeping systems governing physiological processes, significantly influence skin health, particularly in response to ultraviolet radiation (UVR). Disruptions in circadian rhythms can exacerbate UVR-induced skin damage and increase the risk of skin aging and cancer. This review explores how circadian rhythms affect various aspects of skin physiology and pathology, with a special focus on DNA repair. Circadian regulation ensures optimal DNA repair following UVR-induced damage, reducing mutation accumulation, and enhancing genomic stability. The circadian control over cell proliferation and apoptosis further contributes to skin regeneration and response to UVR. Oxidative stress management is another critical area where circadian rhythms exert influence. Key circadian genes like brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) modulate the activity of antioxidant enzymes and signaling pathways to protect cells from oxidative stress. Circadian rhythms also affect inflammatory and immune responses by modulating the inflammatory response and the activity of Langerhans cells and other immune cells in the skin. In summary, circadian rhythms form a complex defense network that manages UVR-induced damage through the precise regulation of DNA damage repair, cell proliferation, apoptosis, inflammatory response, oxidative stress, and hormonal signaling. Understanding these mechanisms provides insights into developing targeted skin protection and improving skin cancer prevention.

Keywords:  DNA damage repair; circadian rhythms; skin photoaging; ultraviolet radiation

DOI:  https://doi.org/10.3390/ijms252010926
Pharmaceuticals (Basel). 2024 Sep 30. pii: 1306. [Epub ahead of print]17(10):

Protective Effects of Sesame Glycoproteins on Ultraviolet-Induced Skin Aging: In Vitro and In Vivo Studies.

Kyung Kyu Baik, Woo-Yong Song, Dong Keun Song, Jaehyeok Yun, Ji Hwan Jang, Jae Young Oh, Mi-Jin Lee, Eunjandi Go, Kyong Jin Lee, Eunmiri Roh, Jong-Eun Kim.

   BACKGROUND/OBJECTIVES: Ultraviolet (UV) radiation is a primary factor in skin photoaging, leading to wrinkles, reduced elasticity, and pigmentation changes due to damage to cellular DNA, proteins, and lipids. Glycoproteins from sesame cake (SPE) have potential protective effects against UV-induced skin aging. This study investigated the anti-photoaging effects of SPE on UV-induced damage in human keratinocyte HaCaT cells and SKH-1 hairless mice.
METHODS: SPE was evaluated for its ability to mitigate UV-induced damage in HaCaT cells by assessing MMP-1 protein and mRNA expression levels, as well as the activity of transcription factors AP-1 and NF-κB. The phosphorylation of AKT and MAPK pathways was also analyzed. In vivo, SKH-1 hairless mice were exposed to UV radiation, and the effects of SPE on wrinkle formation and skin structure were assessed by measuring wrinkle length, area, and volume.
RESULTS: SPE significantly inhibited UV-induced MMP-1 protein and mRNA expression in HaCaT cells, indicating suppression of AP-1 and NF-κB transcription factors involved in MMP-1 production. Additionally, SPE reduced UV-induced phosphorylation of AKT and MAPK pathways. In SKH-1 hairless mice, SPE treatment led to significant reductions in wrinkle length, area, and volume, preserving skin structure in UV-exposed mice.
CONCLUSIONS: The findings demonstrate that SPE has protective effects against UV-induced photoaging by inhibiting key molecular pathways associated with skin aging. SPE shows promise as a natural anti-photoaging agent, providing a foundation for future skincare product development. Further studies are warranted to explore the molecular mechanisms in detail and to validate these effects through clinical trials.

Keywords:  aging; sesame glycoproteins; skin; ultraviolet

DOI:  https://doi.org/10.3390/ph17101306
Nat Commun. 2024 Oct 29. 15(1): 9330

Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species.

Tyler A U Hilsabeck, Vikram P Narayan, Kenneth A Wilson, Enrique M Carrera, Daniel Raftery, Daniel Promislow, Rachel B Brem, Judith Campisi, Pankaj Kapahi.

Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species-random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

DOI: https://doi.org/10.1038/s41467-024-52909-y
bioRxiv. 2024 Oct 20. pii: 2024.10.17.618893. [Epub ahead of print]

Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice.

Andrew M Pickering.

The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

DOI: https://doi.org/10.1101/2024.10.17.618893
bioRxiv. 2024 Oct 25. pii: 2024.10.25.620246. [Epub ahead of print]

The PUF RNA-binding protein, FBF-2, maintains stem cells without binding to RNA.

Brian H Carrick, Sarah L Crittenden, MaryGrace Linsley, Stephany J Costa Dos Santos, Marvin Wickens, Judith Kimble.

Like all canonical PUF proteins, C. elegans FBF-2 binds to specific RNAs via tripartite recognition motifs (TRMs). Here we report that an FBF-2 mutant protein that cannot bind to RNA, is nonetheless biologically active and maintains stem cells. This unexpected result challenges the conventional wisdom that RBPs must bind to RNAs to achieve biological activity. Also unexpectedly, FBF-2 interactions with partner proteins can compensate for loss of RNA-binding. FBF-2 only loses biological activity when its RNA-binding and partner interactions are both defective. These findings highlight the complementary contributions of RNA-binding and protein partner interactions to activity of an RNA-binding protein.

DOI: https://doi.org/10.1101/2024.10.25.620246
Biochem Pharmacol. 2024 Oct 23. pii: S0006-2952(24)00595-1. [Epub ahead of print]230(Pt 2): 116595

Increased hydrogen sulfide turnover serves a cytoprotective role during the development of replicative senescence.

Anna Kieronska-Rudek, Kelly Ascencao, Stefan Chlopicki, Csaba Szabo.

  The mammalian gasotransmitter hydrogen sulfide (H2S) is produced by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST). Prior studies suggest that H2S may have cytoprotective and anti-aging effects. This project explores the regulation and role of endogenous H2S in a murine model of replicative senescence. H2S and polysulfide levels in RAW 264.7 murine macrophages (control cells: passage 5-10; senescent cells: passage 30-40) were measured using fluorescent probes. The expression of H2S-related enzymes and the activity of senescence marker beta-galactosidase (SA-β-Gal) were also analyzed. CBS, CSE, and 3-MST were inhibited using selective pharmacological inhibitors. Senescence led to a moderate upregulation of CBS and in a significant increase in CSE and 3-MST. H2S degradation enzymes were also elevated in senescence. Inhibition of H2S-producing enzymes reduced H2S levels but increased polysulfides. Inhibition of H2S production during senescence suppressed cell proliferation, and elevated SA-β-Gal and p21 levels. Comparing young and old mice spleens revealed downregulation of CBS and ETHE1 and upregulation of rhodanese and SUOX in older mice. The results demonstrate that increased reactive sulfur turnover occurs in senescent macrophages and that reactive sulfur species support cell proliferation and regulate cellular senescence.

Keywords:  Aging; DNA damage; Gasotransmitters; H(2)S; Oxidative stress; Proliferation

DOI:  https://doi.org/10.1016/j.bcp.2024.116595
Antioxidants (Basel). 2024 Sep 24. pii: 1153. [Epub ahead of print]13(10):

Protective Effect of Epigallocatechin-3-gallate against Hepatic Oxidative Stress Induced by tert-Butyl Hhydroperoxide in Yellow-Feathered Broilers.

Xinyan Ma, Junli Ni, Wei Wang, Yongwen Zhu, Yuqing Zhang, Mingfei Sun.

  Recent studies have shown that epigallocatechin-3-gallate (EGCG), as an effective antioxidant, could attenuate the oxidative damage, inflammation and necrosis in the liver in response to oxidative stress. The present study investigated whether oral administration of EGCG could effectively alleviate the hepatic histopathological changes and oxidative damage in yellow-feathered broilers induced by tert-butyl hydroperoxide (t-BHP). Broilers were exposed to 600 μmol t-BHP/kg body weight (BW) to induce oxidative stress by intraperitoneal injection every five days, followed by oral administration of different doses of EGCG (0, 20, 40 and 60 mg/kg BW) and 20 mg vitamin E (VE)/kg BW every day during 5-21 days of age. The results showed that t-BHP injection decreased (p < 0.05) body weight and the relative weight of the spleen; the enzyme activities of total antioxidant capacity (T-AOC), catalase (CAT) and total superoxide dismutase (SOD); and gene mRNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), CAT, SOD1, SOD2 and acetyl-CoA carboxylase (ACACA); as well as increased (p < 0.05) necrosis formation, malondialdehyde (MDA) content, reactive oxygen species (ROS)accumulation, and peroxisome proliferator activates receptor-α (PPARα) mRNA expression in the liver of yellow-feathered female broilers at 21 days of age. Treatment with 60 mg EGCG/kg BW orally could enhance antioxidant enzyme activities and reverse the hepatic damage induced by t-BHP injection by reducing the accumulation of ROS and MDA in the liver and activating the Nrf2 and PPARα pathways related to the induction of antioxidant gene expression (p < 0.05). In conclusion, intraperitoneal injection of t-BHP impaired body growth and induced hepatic ROS accumulation, which destroyed the antioxidant system and led to oxidative damage in the liver of yellow-feathered broilers from 5 to 21 days of age. It is suggested that EGCG may play an antioxidant role through the Nrf2 and PPARα signaling pathways to effectively protect against t-BHP-induced hepatic oxidative damage in broilers, and the appropriate dose was 60 mg EGCG/kg BW by oral administration.

Keywords:  Nrf2; PPARα; antioxidant ability; epigallocatechin-3-gallate; oxidative damage; yellow-feathered broilers

DOI:  https://doi.org/10.3390/antiox13101153
Front Aging. 2024 ;5 1462569

Can salivary and skin microbiome become a biodetector for aging-associated diseases? Current insights and future perspectives.

Fahrul Nurkolis, Trianna Wahyu Utami, Aiman Idrus Alatas, Danar Wicaksono, Rudy Kurniawan, Satria Rafi Ratmandhika, Kartika Taufani Sukarno, Yehezkiel Gian Pradipta Pahu, Bonglee Kim, Trina Ekawati Tallei, Raymond Rubianto Tjandrawinata, Ananto Ali Alhasyimi, Reggie Surya, Helen Helen, Princella Halim, Adi Muradi Muhar, Rony Abdi Syahputra.

  Growth and aging are fundamental elements of human development. Aging is defined by a decrease in physiological activities and higher illness vulnerability. Affected by lifestyle, environmental, and hereditary elements, aging results in disorders including cardiovascular, musculoskeletal, and neurological diseases, which accounted for 16.1 million worldwide deaths in 2019. Stress-induced cellular senescence, caused by DNA damage, can reduce tissue regeneration and repair, promoting aging. The root cause of many age-related disorders is inflammation, encouraged by the senescence-associated secretory phenotype (SASP). Aging's metabolic changes and declining immune systems raise illness risk via promoting microbiome diversity. Stable, individual-specific skin and oral microbiomes are essential for both health and disease since dysbiosis is linked with periodontitis and eczema. Present from birth to death, the human microbiome, under the influence of diet and lifestyle, interacts symbiotically with the body. Poor dental health has been linked to Alzheimer's and Parkinson's diseases since oral microorganisms and systemic diseases have important interactions. Emphasizing the importance of microbiome health across the lifetime, this study reviews the understanding of the microbiome's role in aging-related diseases that can direct novel diagnosis and treatment approaches.

Keywords:  age-related disease; aging; biodetector; oral microbiome; skin microbiome

DOI:  https://doi.org/10.3389/fragi.2024.1462569
bioRxiv. 2024 Oct 25. pii: 2024.10.22.619720. [Epub ahead of print]

When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.

Daniel S Borrus, Raghav Sehgal, Jenel Fraij Armstrong, Jessica Kasamoto, John Gonzalez, Albert Higgins-Chen.

Recent human studies have suggested that aging interventions can reduce aging biomarkers related to morbidity and mortality risk. Such biomarkers may potentially serve as early, rapid indicators of effects on healthspan. An increasing number of studies are measuring intervention effects on epigenetic clocks, commonly used aging biomarkers based on DNA methylation profiles. However, with dozens of clocks to choose from, different clocks may not agree on the effect of an intervention. Furthermore, changes in some clocks may simply be the result of technical noise causing a false positive result. To address these issues, we measured the variability between 6 popular epigenetic clocks across a range of longitudinal datasets containing either an aging intervention or an age-accelerating event. We further compared them to the same clocks re-trained to have high test-retest reliability. We find the newer generation of clocks, trained on mortality or rate-of-aging, capture aging events more reliably than those clocks trained on chronological age, as these show consistent effects (or lack thereof) across multiple clocks including high-reliability versions, and including after multiple testing correction. In contrast, clocks trained on chronological age frequently show sporadic changes that are not replicable when using high-reliability versions of those same clocks, or when using newer generations of clocks and these results do not survive multiple-testing correction. These are likely false positive results, and we note that some of these clock changes were previously published, suggesting the literature should be re-examined. This work lays the foundation for future clinical trials that aim to measure aging interventions with epigenetic clocks, by establishing when to attribute a given change in biological age to a bona fide change in the aging process.

DOI: https://doi.org/10.1101/2024.10.22.619720