bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–07–21
24 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment.
  2. Targeting neuronal epigenomes for brain rejuvenation.
  3. Counteracting tissue aging through TERT activation.
  4. Macrophage iron dyshomeostasis promotes aging-related renal fibrosis.
  5. Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.
  6. Mitochondrial dysfunction and its association with age-related disorders.
  7. Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques.
  8. Immune surveillance of senescence: potential application to age-related diseases.
  9. Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system.
  10. Autophagy regulates age-related delayed jawbone regeneration and decreased osteoblast osteogenesis by degrading FABP3.
  11. Senomorphic activity of a combination of niacinamide and hyaluronic acid: correlation with clinical improvement of skin aging.
  12. qMAP enabled microanatomical mapping of human skin aging.
  13. Exploring the expression profiles of serum inflammatory proteins and potential anti-aging targets in Chinese long-living people.
  14. The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan.
  15. Network pharmacology-based approach to investigate the molecular targets and molecular mechanisms of Rosmarinus officinalis L. for treating aging-related disorders.
  16. Striking senescence with sodium transporter inhibition.
  17. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
  18. FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.
  19. Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Reversing Age-related Vision Decline.
  20. Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice.
  21. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
  22. Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
  23. The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.
  24. REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress.
  1. Aging Dis. 2024 Jun 25.
    Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment.
    Qiao Zheng, Jin Zhao, Jinguo Yuan, Yunlong Qin, Zhanxin Zhu, Jie Liu, Shiren Sun.
      Given the rapid aging of the population, age-related diseases have become an excessive burden on global health care. The kidney, a crucial metabolic organ, ages relatively quickly. While the aging process itself does not directly cause kidney damage, the physiological changes that accompany it can impair the kidney's capacity for self-repair. This makes aging kidneys more susceptible to diseases, including increased risks of chronic kidney disease and end-stage renal disease. Therefore, delaying the progression of renal aging and preserving the youthful vitality of the kidney are crucial for preventing kidney diseases. However, effective strategies against renal aging are still lacking due to the underlying mechanisms of renal aging, which have not been fully elucidated. Accumulating evidence suggests that metformin has beneficial effects in mitigating renal aging. Metformin has shown promising anti-aging results in animal models but has not been tested for this purpose yet in clinical trials. These findings indicate the potential of metformin as an anti-renal aging drug. In this review, we primarily discuss the characteristics and mechanisms of kidney aging and the potential effects of metformin against renal aging.
    DOI:  https://doi.org/10.14336/AD.2024.0168
  2. EMBO J. 2024 Jul 15.
    Targeting neuronal epigenomes for brain rejuvenation.
    Sara Zocher.
      Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain.
    Keywords:  Cognitive Decline; Epigenetic Rejuvenation; Epigenome Editing; Neuron Aging; Neuronal Epigenome
    DOI:  https://doi.org/10.1038/s44318-024-00148-8
  3. Nat Biotechnol. 2024 Jul;42(7): 1027
    Counteracting tissue aging through TERT activation.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-024-02327-8
  4. Aging Cell. 2024 Jul 17. e14275
    Macrophage iron dyshomeostasis promotes aging-related renal fibrosis.
    Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng.
      Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular cells during aging. Suppressing ferroptosis alleviates macrophage-mediated tubular partial epithelial-mesenchymal transition in vitro, thereby mitigating the expression of fibrosis-related genes. Using SCENIC analysis, we infer Stat1 as a key age-related transcription factor promoting iron dyshomeostasis and ferroptosis in macrophages by regulating the expression of Pcbp1, an iron chaperone protein that inhibits ferroptosis. Furthermore, through virtual screening and molecular docking from a library of anti-aging compounds, we construct a docking model targeting Pcbp1, which indicates that the natural small molecule compound Rutin can suppress macrophage senescence and ferroptosis by preserving Pcbp1. In summary, our study underscores the crucial role of macrophage iron dyshomeostasis and ferroptosis in renal aging. Our results also suggest Pcbp1 as an intervention target in aging-related renal fibrosis and highlight Rutin as a potential therapeutic agent in mitigating age-related renal chronic low-grade inflammation and fibrosis.
    Keywords:  aging‐related renal fibrosis; ferroptosis; iron dyshomeostasis; macrophage; pcbp1; rutin; single‐cell RNA sequencing data; stat1
    DOI:  https://doi.org/10.1111/acel.14275
  5. Biogerontology. 2024 Jul 13.
    Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.
    Virginia Boccardi, Luigi Cari, Patrizia Bastiani, Michela Scamosci, Roberta Cecchetti, Giuseppe Nocentini, Patrizia Mecocci.
      Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging.
    Keywords:  Healthy aging; Human aging; Telomere dysfunction; Telomeres
    DOI:  https://doi.org/10.1007/s10522-024-10120-y
  6. Front Physiol. 2024 ;15 1384966
    Mitochondrial dysfunction and its association with age-related disorders.
    Indumathi Somasundaram, Samatha M Jain, Marcel Blot-Chabaud, Surajit Pathak, Antara Banerjee, Sonali Rawat, Neeta Raj Sharma, Asim K Duttaroy.
      Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction.
    Keywords:  ROS production; chromosomal aberrations; mitochondrial DNA; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2024.1384966
  7. Aging Dis. 2024 Jul 08.
    Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques.
    Ruopeng Xiao, Sinan Hu, Xiaohui Du, Yiwen Wang, Ke Fang, Yibin Zhu, Nanbin Lou, Chunhui Yuan, Jing Yang.
      The accumulation of senescent cells is an important factor in the complex progression of aging, with significant implications for the development of numerous diseases. Thus, understanding the fundamental mechanisms of senescence is paramount for advancing preventive and therapeutic approaches to age-related conditions. Important to this pursuit is the precise identification and examination of senescent cells, contingent upon the recognition of specific biomarkers. Historically, detection methods relied on assessing molecular protein and mRNA levels and various staining techniques. While these conventional approaches have contributed substantially to the field, they possess limitations in capturing the dynamic evolution of cellular aging in real time. The emergence of novel technologies has led to a paradigm shift in senescence research. Gene-edited mouse models and the application of advanced probes have revolutionized our ability to detect senescent cells. These cutting-edge methodologies provide a more detailed and accurate means of dynamically monitoring, characterizing and potentially eliminating senescent cells, thus enhancing our understanding of the complex mechanisms of aging. This review comprehensively explores both traditional and innovative senescent cell detection methods, elucidating their advantages, limitations and implications for future investigations and could serve as a comprehensive guide and catalyst for further advancements in the understanding of aging and associated pathologies.
    DOI:  https://doi.org/10.14336/AD.202.0565
  8. Trends Cell Biol. 2024 Jul 17. pii: S0962-8924(24)00121-1. [Epub ahead of print]
    Immune surveillance of senescence: potential application to age-related diseases.
    Teh-Wei Wang, Makoto Nakanishi.
      Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.
    Keywords:  immune checkpoint blockade; immune clearance; senescence
    DOI:  https://doi.org/10.1016/j.tcb.2024.06.007
  9. Exp Gerontol. 2024 Jul 18. pii: S0531-5565(24)00165-7. [Epub ahead of print]194 112523
    Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system.
    Fenmiao Bao, Xiaoqin Zhao, Jiaqi You, Yiyao Liu, Zheng Xu, Yuqing Wu, Yufeng Wu, Zujie Xu, Liang Yu, Junping Li, Yan Wei.
      Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells.
    Keywords:  Aerobic exercise; Apoptosis; Sarcopenia; Skeletal muscle; TR; Trx
    DOI:  https://doi.org/10.1016/j.exger.2024.112523
  10. FASEB J. 2024 Jul 31. 38(14): e23824
    Autophagy regulates age-related delayed jawbone regeneration and decreased osteoblast osteogenesis by degrading FABP3.
    Yifan Xu, Bin Sun, Haicheng Wang, Yuyi Cai, Danna Chu, Rongkai Cao, Zuolin Wang.
      The regenerative ability of limb bones after injury decreases during aging, but whether a similar phenomenon occurs in jawbones and whether autophagy plays a role in this process remain unclear. Through retrospective analysis of clinical data and studies on a mouse model of jawbone defects, we confirmed the presence of delayed or impaired bone regeneration in the jawbones of old individuals and mice. Subsequently, osteoblasts (OBs) derived from mouse jawbones were isolated, showing reduced osteogenesis in senescent osteoblasts (S-OBs). We observed a reduction in autophagy within both aged jawbones and S-OBs. Additionally, pharmacological inhibition of autophagy in normal OBs (N-OBs) led to cell aging and decreased osteogenesis, while autophagic activation reversed the aging phenotype of S-OBs. The activator rapamycin (RAPA) increased the autophagy level and bone regeneration in aged jawbones. Finally, we found that fatty acid-binding protein 3 (FABP3) was degraded by autolysosomes through its interaction with sequestosome 1 (P62/SQSTM1). Autophagy inhibition within senescent jawbones and S-OBs led to the excessive accumulation of FABP3, and FABP3 knockdown partially rescued the decreased osteogenesis in S-OBs and alleviated age-related compromised jawbone regeneration. In summary, we confirmed that autophagy inhibition plays an important role in delaying bone regeneration in aging jawbones. Autophagic activation or FABP3 knockdown can partially rescue the osteogenesis of S-OBs and the regeneration of aging jawbones, providing insight into jawbone aging.
    Keywords:  aging; autophagy; bone regeneration; jaw; osteoblasts
    DOI:  https://doi.org/10.1096/fj.202400549RR
  11. Sci Rep. 2024 Jul 15. 14(1): 16321
    Senomorphic activity of a combination of niacinamide and hyaluronic acid: correlation with clinical improvement of skin aging.
    Patrick Bogdanowicz, Paul Bensadoun, Maïté Noizet, Benoît Béganton, Armony Philippe, Sandrine Alvarez-Georges, Gautier Doat, Amélie Tourette, Sandrine Bessou-Touya, Jean-Marc Lemaitre, Hélène Duplan.
      Intrinsic and extrinsic factors, including lifestyle and sun exposure, can contribute to cell senescence, which impairs skin homeostasis, that may in turn lead to skin aging. Senescent cells have a specific secretome, called the senescence-associated secretory phenotype (SASP) that includes MMPs, CXCLs and S100A8/9. Reducing the SASP with senotherapeutics is a promising strategy to reduce skin aging. Here we evaluated the effect of a formula containing niacinamide and hyaluronic acid, which are known to limit senescence and skin aging. We conducted three different studies. (1) Ex vivo explants treated with the formula had more collagen and glycosaminoglycan. (2) In a clinical trial with forty-four women, two months of treatment improved fine lines, wrinkles, luminosity, smoothness, homogeneity, and plumpness. (3) In a third study on thirty women, we treated one arm for two months and took skin biopsies to study gene expression. 101 mRNAs and 13 miRNAs were differentially expressed. We observed a likely senomorphic effect, as there was a decrease in many SASP genes including MMP12 and CXCL9 and a significant downregulation of autocrine signaling genes: S100A8 and S100A9. These pharmaco-clinical results are the first to demonstrate the senomorphic properties of an effective anti-aging formula in skin.
    DOI:  https://doi.org/10.1038/s41598-024-66624-7
  12. bioRxiv. 2024 Jul 06. pii: 2024.04.03.588011. [Epub ahead of print]
    qMAP enabled microanatomical mapping of human skin aging.
    Kyu Sang Han, Inbal B Sander, Jacqueline Kumer, Eric Resnick, Clare Booth, Guoqing Cheng, Yebin Im, Bartholomew Starich, Ashley L Kiemen, Jude M Phillip, Sashank Reddy, Corrine E Joshu, Joel C Sunshine, Jeremy D Walston, Denis Wirtz, Pei-Hsun Wu.
      Aging is a major driver of diseases in humans. Identifying features associated with aging is essential for designing robust intervention strategies and discovering novel biomarkers of aging. Extensive studies at both the molecular and organ/whole-body physiological scales have helped determined features associated with aging. However, the lack of meso-scale studies, particularly at the tissue level, limits the ability to translate findings made at molecular scale to impaired tissue functions associated with aging. In this work, we established a tissue image analysis workflow - quantitative micro-anatomical phenotyping (qMAP) - that leverages deep learning and machine vision to fully label tissue and cellular compartments in tissue sections. The fully mapped tissue images address the challenges of finding an interpretable feature set to quantitatively profile age-related microanatomic changes. We optimized qMAP for skin tissues and applied it to a cohort of 99 donors aged 14 to 92. We extracted 914 microanatomic features and found that a broad spectrum of these features, represented by 10 cores processes, are strongly associated with aging. Our analysis shows that microanatomical features of the skin can predict aging with a mean absolute error (MAE) of 7.7 years, comparable to state-of-the-art epigenetic clocks. Our study demonstrates that tissue-level architectural changes are strongly associated with aging and represent a novel category of aging biomarkers that complement molecular markers. Our results highlight the complex and underexplored multi-scale relationship between molecular and tissue microanatomic scales.
    DOI:  https://doi.org/10.1101/2024.04.03.588011
  13. Rejuvenation Res. 2024 Jul 14.
    Exploring the expression profiles of serum inflammatory proteins and potential anti-aging targets in Chinese long-living people.
    Jie Liu, Qifu Zhu, Dan Zhang, Qihui Yu, Xin Zheng, Shuihong Yao, Xinhua Wang.
      Chronic inflammation (inflammaging) is one of the important reasons for the development of age-related diseases and aging. Carrying out aging research and mining inflammatory markers can develop anti-aging intervention targets, thus promoting healthy aging. By comparing the levels of inflammatory proteome in the serum of Chinese long-living people over 90 years and elderly aged 60~79 which was detected by Olink platform, this study found that some pro-inflammatory or pro-aging proteins increased significantly in the long-living people, such as CXCL9, accompanied by a significant increase in the levels of several anti-inflammatory or anti-aging proteins, including FGF19 and FGF23, which confirmed that compared with elderly people, pro-inflammatory and anti-inflammatory (pro-aging and anti-aging) tend to be balanced in long-living people, thus reducing the risk of age-related diseases and prolonging the life span of the elderly. These differently expressed proteins could serve as therapeutic targets and monitoring indicators for anti-aging. At the same time, a few inflammatory protein markers, especially CXCL9 and OPG, could distinguish long-living and elderly correctly which could be used to predict lifespan combined with other anti-aging markers.
    DOI:  https://doi.org/10.1089/rej.2024.0038
  14. Acta Pharm Sin B. 2024 Jul;14(7): 3266-3280
    The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan.
    Wenfeng Li, Shuming Chen, Jing Lang, Jing Luo, Jiahui Chen, Liping Zhang, Zhijie Sun, Deli Dong.
      The drugs extending healthspan in clinic have always been searched. Nitazoxanide is an FDA-approved clinical antiprotozoal drug. Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo. Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK, oral nitazoxanide protects against experimental hyperlipidemia, hepatic steatosis, and atherosclerosis. Here, we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway. Additionally, both nitazoxanide and tizoxanide improve high glucose-induced shortening of C. elegans lifespan. Nitazoxanide has been a clinical drug with a good safety profile, we suggest that it is a novel anti-aging drug.
    Keywords:  AMPK; Akt; C. elegans; Healthspan; Lifespan; Mitochondrial uncoupling; Nitazoxanide; Tizoxanide
    DOI:  https://doi.org/10.1016/j.apsb.2024.03.031
  15. Biogerontology. 2024 Jul 17.
    Network pharmacology-based approach to investigate the molecular targets and molecular mechanisms of Rosmarinus officinalis L. for treating aging-related disorders.
    Amisha Bisht, Disha Tewari, Sanjay Kumar, Subhash Chandra.
      Aging, a natural biological process, presents challenges in maintaining physiological well-being and is associated with increased vulnerability to diseases. Addressing aging mechanisms is crucial for developing effective preventive and therapeutic strategies against age-related ailments. Rosmarinus officinalis L. is a medicinal herb widely used in traditional medicine, containing diverse bioactive compounds that have been studied for their antioxidant and anti-inflammatory properties, which are associated with potential health benefits. Using network pharmacology, this study investigates the anti-aging function and underlying mechanisms of R. officinalis. Through network pharmacology analysis, the top 10 hub genes were identified, including TNF, CTNNB1, JUN, MTOR, SIRT1, and others associated with the anti-aging effects. This analysis revealed a comprehensive network of interactions, providing a holistic perspective on the multi-target mechanism underlying Rosemary's anti-aging properties. GO and KEGG pathway enrichment analysis revealed the relevant biological processes, molecular functions, and cellular components involved in treating aging-related conditions. KEGG pathway analysis shows that anti-aging targets of R. officinalis involved endocrine resistance, pathways in cancer, and relaxin signaling pathways, among others, indicating multifaceted mechanisms. Genes like MAPK1, MMP9, and JUN emerged as significant players. These findings enhance our understanding of R. officinalis's potential in mitigating aging-related disorders through multi-target effects on various biological processes and pathways. Such approaches may reduce the risk of failure in single-target and symptom-based drug discovery and therapy.
    Keywords:   Rosmarinus officinalis L.; Anti-aging; Molecular targets; Network pharmacology; Pathways
    DOI:  https://doi.org/10.1007/s10522-024-10122-w
  16. Trends Mol Med. 2024 Jul 13. pii: S1471-4914(24)00188-6. [Epub ahead of print]
    Striking senescence with sodium transporter inhibition.
    Bettina Schock, Steven O'Reilly.
      Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty.
    Keywords:  AMPK; age-related diseases; immunosurveillance; senescence; senolysis
    DOI:  https://doi.org/10.1016/j.molmed.2024.07.002
  17. Nature. 2024 Jul 17.
    Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
    Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A Sims, Norbert Hübner, Enrico Petretto, Dominic J Withers, Lena Ho, Jesus Gil, David Carling, Stuart A Cook.
      For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
    DOI:  https://doi.org/10.1038/s41586-024-07701-9
  18. Exp Gerontol. 2024 Jul 16. pii: S0531-5565(24)00164-5. [Epub ahead of print] 112522
    FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.
    Yanqing Li, Chi Zhang, Haicheng Cheng, LinYan Lv, Xinning Zhu, Menghui Ma, Zhenhan Xu, Junxian He, Yun Xie, Xing Yang, Xiaoyan Liang, Chunhua Deng, Guihua Liu.
      Male ageing is always accompanied by decreased fertility. The forkhead O (FOXO) transcription factor FOXO4 is reported to be highly expressed in senescent cells. Upon activation, it binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ. Leydig cells play key roles in assisting spermatogenesis. Leydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis. In this study, we observed that FOXO4-DRI, a specific FOXO4- p53 binding blocker, induced apoptosis in senescent Leydig cells, reduced the secretion of certain Senescence-Associated Secretory Phenotype and improved the proliferation of cocultured GC-1 SPG cells. In naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality and improved spermatogenesis.
    Keywords:  FOXO4-DRI; Leydig cell; SASP (senescence-associated secretory phenotype); Senescence; Spermatogenesis
    DOI:  https://doi.org/10.1016/j.exger.2024.112522
  19. bioRxiv. 2024 Jul 02. pii: 2024.07.01.601592. [Epub ahead of print]
    Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Reversing Age-related Vision Decline.
    Fangyuan Gao, Emily Tom, Cezary Rydz, William Cho, Alexander V Kolesnikov, Yutong Sha, Anastasios Papadam, Samantha Jafari, Andrew Joseph, Ava Ahanchi, Nika Balalaei Someh Saraei, David Lyon, Andrzej Foik, Qing Nie, Felix Grassmann, Vladimir J Kefalov, Dorota Skowronska-Krawczyk.
      The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), which are primarily localized in cell membranes, where they govern membrane biophysical properties such as diffusion, permeability, domain formation, and curvature generation. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, and this decline is associated with normal age-related visual decline and pathological age-related macular degeneration (AMD). ELOVL2 (Elongation of very-long-chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs, and methylation level of its promoter is currently the best predictor of chronological age. Here, we show that mice lacking ELOVL2-specific enzymatic activity ( Elovl2 C234W ) have impaired contrast sensitivity and slower rod response recovery following bright light exposure. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals significantly improved visual function and reduced accumulation of ApoE, HTRA1 and complement proteins in sub-RPE deposits. At the molecular level, the gene expression pattern observed in retinas supplemented with 24:5n-3 exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature of younger retina. Finally, we present the first human genetic data showing significant association of several variants in the human ELOVL2 locus with the onset of intermediate AMD, underlying the translational significance of our findings. In sum, our study identifies novel therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss.
    DOI:  https://doi.org/10.1101/2024.07.01.601592
  20. Aging Dis. 2024 Jul 09.
    Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice.
    Chak Kwong Cheng, Jun Gao, Lijing Kang, Yu Huang.
      As a major risk factor for cardiometabolic diseases, aging refers to a gradual decline in physiological function, characterized with 12 conspicuous hallmarks, like telomere attrition, chronic inflammation, and dysbiosis. Common vascular aging hallmarks include endothelial dysfunction, telomere dysfunction, and vascular inflammation. In this study, we sought to test the hypothesis that young-derived gut microbiota retards vascular aging hallmarks and metabolic impairments in aged hosts. We also aimed to study the therapeutic efficacy of young microbiota in hosts of different ages. Fecal microbiota transplantation (FMT) from young to aged or middle-aged C57BL/6 mice was conducted for 6 consecutive weeks after antibiotic pretreatment. Endothelium-dependent relaxations (EDRs) in mouse arteries were determined by wire myography. Inflammation and AMPK/SIRT1 signaling in mouse aortas and intestines were studied by biochemical assays. The telomere function of aortas and intestines, in terms of telomerase reverse transcriptase expression, telomerase activity, and relative telomere length, were also studied. FMT significantly reverted vascular dysfunction and metabolic impairments in middle-aged mice than in aged mice. Besides, FMT significantly reverted inflammation and telomere dysfunction in aortas and intestines of middle-aged mice. Improved intestinal barrier function and activated AMPK/SIRT1 signaling potentially underlie benefits of FMT. The findings imply gut-vascular connection as potential target against age-associated cardiometabolic disorders, highlight crosstalk among aging hallmarks, and suggest a critical timepoint for efficacy of anti-aging interventions.
    DOI:  https://doi.org/10.14336/AD.2024.0384
  21. Nat Commun. 2024 Jul 16. 15(1): 5956
    PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
    Mahdi Moqri, Andrea Cipriano, Daniel J Simpson, Sajede Rasouli, Tara Murty, Tineke Anna de Jong, Daniel Nachun, Guilherme de Sena Brandine, Kejun Ying, Andrei Tarkhov, Karolina A Aberg, Edwin van den Oord, Wanding Zhou, Andrew Smith, Crystal Mackall, Vadim N Gladyshev, Steve Horvath, Michael P Snyder, Vittorio Sebastiano.
      DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.
    DOI:  https://doi.org/10.1038/s41467-024-50098-2
  22. Geroscience. 2024 Jul 19.
    Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
    Annika Traa, Aura A Tamez González, Jeremy M Van Raamsdonk.
      The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell's ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.
    Keywords:   C. elegans ; Aging; Biological resilience; DRP1; Insulin/IGF-1 signaling; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11357-024-01276-z
  23. Aging Cell. 2024 Jul 16. e14258
    The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.
    Florencia Herbstein, Melanie Sapochnik, Alejandra Attorresi, Cora Pollak, Sergio Senin, David Gonilski-Pacin, Nicolas Ciancio Del Giudice, Manuel Fiz, Belén Elguero, Mariana Fuertes, Lara Müller, Marily Theodoropoulou, Lucas B Pontel, Eduardo Arzt.
      Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.
    Keywords:  interleukin‐6; intracellular; pituitary; senescence; signaling; therapy‐induced senescence; tumors
    DOI:  https://doi.org/10.1111/acel.14258
  24. Mech Ageing Dev. 2024 Jul 14. pii: S0047-6374(24)00062-9. [Epub ahead of print]221 111962
    REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress.
    Qingqiu Chen, Rong Hu, Hongmei Qiu, Shan Li, Peng Xiang, Yining Lu, Xianmin Wang, Tongchuan Wang, Lan Zhou, Wanping Zhang, E Wen, Limei Ma, Chao Yu.
      Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.
    Keywords:  Atherosclerosis; Endothelial cell senescence; Oxidative stress; REDD1; TXNIP
    DOI:  https://doi.org/10.1016/j.mad.2024.111962
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒09 at 18:19.