bims-longev Biomed News
on Longevity
Issue of 2023‒04‒02
twenty papers selected by
Andreea Nitescu
  1. Ageing as a software design flaw.
  2. Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence.
  3. Mulberry leaves attenuate D-galactose-induced aging in vivo and in vitro.
  4. Potential Active Marine Peptides as Anti-Aging Drugs or Drug Candidates.
  5. A Systematic Review of In Vivo Studies of the Efficacy of Herbal Medicines for Anti-Aging in the Last Five Years.
  6. Klotho protects against aged myocardial cells by attenuating ferroptosis.
  7. Repurposing Canagliflozin to target brain aging.
  8. Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice.
  9. Mosaic chromosomal alterations and human longevity.
  10. Genetic Networks of Alzheimer's Disease, Aging, and Longevity in Humans.
  11. The loss of epigenetic information: not only consequences but a cause of mammalian aging.
  12. Editorial: Sarcopenia and Pain as Determinants of Successful Ageing.
  13. Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue.
  14. VEGFA Promotes Skeletal Muscle Regeneration in Aging.
  15. Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.
  16. Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.
  17. Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.
  18. Epigenetic clocks suggest accelerated aging in patients with isolated REM Sleep Behavior Disorder.
  19. Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.
  20. Model organism life extending therapeutics modulate diverse nodes in the drug-gene-microbe tripartite human longevity interactome.
  1. Genome Biol. 2023 Mar 28. 24(1): 51
    Ageing as a software design flaw.
    João Pedro de Magalhães.
      Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.
    Keywords:  Antagonistic pleiotropy; Genome; Information theory; Longevity; Programmed ageing
    DOI:  https://doi.org/10.1186/s13059-023-02888-y
  2. Brain Sci. 2023 Mar 16. pii: 500. [Epub ahead of print]13(3):
    Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence.
    Samuel T Vielee, John P Wise.
      Advancements in modern medicine have improved the quality of life across the globe and increased the average lifespan of our population by multiple decades. Current estimates predict by 2030, 12% of the global population will reach a geriatric age and live another 3-4 decades. This swelling geriatric population will place critical stress on healthcare infrastructures due to accompanying increases in age-related diseases and comorbidities. While much research focused on long-lived individuals seeks to answer questions regarding how to age healthier, there is a deficit in research investigating what aspects of our lives accelerate or exacerbate aging. In particular, heavy metals are recognized as a significant threat to human health with links to a plethora of age-related diseases, and have widespread human exposures from occupational, medical, or environmental settings. We believe heavy metals ought to be classified as a class of gerontogens (i.e., chemicals that accelerate biological aging in cells and tissues). Gerontogens may be best studied through their effects on the "Hallmarks of Aging", nine physiological hallmarks demonstrated to occur in aged cells, tissues, and bodies. Evidence suggests that cellular senescence-a permanent growth arrest in cells-is one of the most pertinent hallmarks of aging and is a useful indicator of aging in tissues. Here, we discuss the roles of heavy metals in brain aging. We briefly discuss brain aging in general, then expand upon observations for heavy metals contributing to age-related neurodegenerative disorders. We particularly emphasize the roles and observations of cellular senescence in neurodegenerative diseases. Finally, we discuss the observations for heavy metals inducing cellular senescence. The glaring lack of knowledge about gerontogens and gerontogenic mechanisms necessitates greater research in the field, especially in the context of the global aging crisis.
    Keywords:  aging; cellular senescence; gerontogens; heavy metals; neurodegeneration
    DOI:  https://doi.org/10.3390/brainsci13030500
  3. J Ethnopharmacol. 2023 Mar 23. pii: S0378-8741(23)00154-X. [Epub ahead of print] 116286
    Mulberry leaves attenuate D-galactose-induced aging in vivo and in vitro.
    Yan Zhu, Yaping Han, Wuyang Wang, Guangming Liang, Jin Qi.
      ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaves contain many bioactive compounds and have been widely used in traditional medicines and functional foods for prevention and treatment of age-related diseases, such as diabetes, cognitive impairment and obesity-mediated liver cancer. Aging has an irreversible negative impact on human health for many years, even decades, before death, which is a social and economic burden on society.AIM OF THE STUDY: The objective of this study was to investigate the antioxidant and anti-aging effects of mulberry leaf extract (MLE) in vivo and in vitro.
    MATERIALS AND METHODS: The Caenorhabditis elegans (C. elegans) was used as a model organism to observe the effects of different concentrations of MLE (1, 2, 4, 8 mg/mL) on nematodes' healthy lifespan, reproductive capacity, locomotion, stress resistance, and antioxidation. In addition, D-galactose (D-gal) induced liver aging in mice and L-02 cells were established. The antioxidant and anti-aging effects of MLE were evaluated by body weight, organ indexes, malondialdehyde (MDA), total superoxide dismutase (T-SOD), total antioxidant capacity (T-AOC), aspartate and alanine aminotransferases (AST and ALT), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), hematoxylin and eosin (H&E), senescence-associated β-galactosidase (SA-β-Gal). Besides, the expressions of AMPK/SIRT1/PGC-1α and Nrf2-Keap1 were detected by Western blotting.
    RESULTS: MLE could significantly prolonged nematodes' average life span and improved most physiological indicators related to aging of C. elegans. Moreover, Treatment with MLE ameliorated the decreased body weight and organ index (weight of organ/body weight) in model mice, and protected against oxidative stress in mice and liver cells, in a dose-dependent manner, up-regulating T-SOD and T-AOC, while reducing ROS and MDA levels. MLE decreased both liver and cell levels of AST and ALT, and enhanced the mitochondrial membrane potential. MLE activated the AMPK/SIRT1/PGC-1α pathways, participated in mitochondrial biosynthesis and oxidative metabolism and delayed D-gal-induced aging. MLE promoted the accumulation of Nrf2 in the nucleus, indicating that the improved oxidative stress response was mediated by the Nrf2-Keap1 pathway in vivo and in vitro.
    CONCLUSION: MLE appeared to have great potential for stimulating the oxidative stress response and attenuating the aging process of in vivo and in vitro, and provide a novel health-promoting resource against aging and aging-related diseases.
    Keywords:  Aging; Antioxidant; In vitro; In vivo; Mulberry leaf extract
    DOI:  https://doi.org/10.1016/j.jep.2023.116286
  4. Mar Drugs. 2023 Feb 23. pii: 144. [Epub ahead of print]21(3):
    Potential Active Marine Peptides as Anti-Aging Drugs or Drug Candidates.
    Hui Yang, Qiting Zhang, Bin Zhang, Yufen Zhao, Ning Wang.
      Aging is an irreversible physiological process in the human body, and the aging characteristics of the body that accompany this process also lead to many other chronic diseases, such as neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease, cardiovascular diseases, hypertension, obesity, cancer, and so on. The marine environment is highly biodiverse, the natural active products of these organisms constitute a vast treasure trove of marine drugs or drug candidates that play an essential role in disease prevention and treatment, and the active peptide products among them have received special attention because of their unique chemical properties. Therefore, the development of marine peptide compounds as anti-aging drugs is emerging as an important research area. This review highlights the currently available data on marine bioactive peptides with anti-aging potential from 2000 to 2022 by analyzing the prevalent aging mechanisms, critical aging metabolic pathways and well-established multi-omics aging characteristics, as well as grouping different bioactive and biological species lines of peptides from marine organisms and discussing their research modalities and functional characteristics. Active marine peptides is a promising topic to explore and to develop their potential as anti-aging drugs or drug candidates. We expect this review to be instructive for future marine drug development and to reveal new directions for future biopharmaceuticals.
    Keywords:  active peptides; aging mechanisms; anti-aging drugs; marine organisms; multi-omics aging characteristics
    DOI:  https://doi.org/10.3390/md21030144
  5. Pharmaceuticals (Basel). 2023 Mar 16. pii: 448. [Epub ahead of print]16(3):
    A Systematic Review of In Vivo Studies of the Efficacy of Herbal Medicines for Anti-Aging in the Last Five Years.
    Seung-Yeon Cho, Han-Gyul Lee, Seungwon Kwon, Seong-Uk Park, Woo-Sang Jung, Sang-Kwan Moon, Jung-Mi Park, Chang-Nam Ko.
      BACKGROUND: The world's population is rapidly aging, and attention to and research on the increase in life expectancy and age-related diseases are needed. This study aimed to review the in vivo studies on the anti-aging effects of herbal medicines.METHODS: In vivo studies of single or complex herbal medicines for anti-aging that were published in the last five years were included in this review. The following databases were used: PubMed, Scopus, ScienceDirect, Web of Science and EMBASE.
    RESULTS: A total of 41 studies were considered eligible for the review. The articles were classified into body organs and functions, experimental country, herbal medicine, extraction method, administration route, dosage, duration, animal model, aging-induced method, sex, number of animals per group, and outcomes and mechanisms A single herbal extract was used in a total of 21 studies including Alpinia oxyphylla Miq., Acanthopanax senticosus and Lyceum barbarum, and a multi-compound herbal prescription was used in a total of 20 studies, including Modified Qiongyu paste, Wuzi Yanzong recipe, etc. Each herbal medicine had anti-aging effects on learning and memory, cognition, emotion, internal organs, gastrointestinal tracts, sexual functions, musculoskeletal function and so on. The common mechanisms of action were antioxidant and anti-inflammatory, and various effects and mechanisms for each organ and function were identified.
    CONCLUSIONS: Herbal medicine exhibited beneficial effects on anti-aging in various parts of the body and its function. Further investigation of the appropriate herbal medicine prescriptions and their components is recommended.
    Keywords:  aging; anti-aging; herbal medicine; in vivo studies; mechanisms of action; review; senescence
    DOI:  https://doi.org/10.3390/ph16030448
  6. Exp Gerontol. 2023 Mar 28. pii: S0531-5565(23)00078-5. [Epub ahead of print]175 112157
    Klotho protects against aged myocardial cells by attenuating ferroptosis.
    Xicheng Xiong, Gang Wang, Yiping Wang, Tian Zhang, Yali Bao, Kun Wang, Dina Ainiwaer, Zhan Sun.
      Klotho (KL) is a renal protein with aging-suppression properties that mediates its regulatory effect during cardiac fibroblast aging. However, to determine whether KL can protect aged myocardial cells by attenuating ferroptosis, this study aimed to investigate the protective effect of KL on aged cells and to explore its potential mechanism. Cell injury of H9C2 cells was induced with D-galactose (D-gal) and treated with KL in vitro. This study demonstrated that D-gal induces aging in H9C2 cells. D-gal treatment increased β-GAL(β-galactosidase) activity, decreased cell viability, enhanced oxidative stress, reduced mitochondrial cristae, and decreased the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase-4 (GPx4), and P53, which are primary regulators of ferroptosis. The results showed that KL can eliminate D-gal-induced aging in H9C2 cells, likely due to its ability to increase the expression of the ferroptosis-associated proteins SLC7A11 and GPx4. Moreover, pifithrin-α, a P53-specific inhibitor, enhanced the expression of SLC7A11 and GPx4. These results suggest that KL may be involved in D-gal-induced H9C2 cellular aging during ferroptosis, mainly through the P53/SLC7A11/GPx4 signaling pathway.
    Keywords:  Cell aging; Ferroptosis; Klotho; Myocardial cells; P53
    DOI:  https://doi.org/10.1016/j.exger.2023.112157
  7. Aging (Albany NY). 2023 Mar 24. 15
    Repurposing Canagliflozin to target brain aging.
    Hashan Jayarathne, Wanqing Liu, Marianna Sadagurski.
      
    Keywords:  Canagliflozin; aging; brain; metabolism; sex
    DOI:  https://doi.org/10.18632/aging.204624
  8. Aging Cell. 2023 Mar 26. e13806
    Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice.
    Niraj Shrestha, Pallavi Chaturvedi, Xiaoyun Zhu, Michael J Dee, Varghese George, Christopher Janney, Jack O Egan, Bai Liu, Mark Foster, Lynne Marsala, Pamela Wong, Celia C Cubitt, Jennifer A Foltz, Jennifer Tran, Timothy Schappe, Karin Hsiao, Gilles M Leclerc, Lijing You, Christian Echeverri, Catherine Spanoudis, Ana Carvalho, Leah Kanakaraj, Crystal Gilkes, Nicole Encalada, Lin Kong, Meng Wang, Byron Fang, Zheng Wang, Jin-An Jiao, Gabriela J Muniz, Emily K Jeng, Nicole Valdivieso, Liying Li, Richard Deth, Melissa M Berrien-Elliott, Todd A Fehniger, Peter R Rhode, Hing C Wong.
      Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro-inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single-nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell-cycle, and senescence-associated pathways in naturally aged mice. Long-term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.
    Keywords:  aging; cellular immunology; circadian genes; immunotherapy; inflammation; physical performance; senescence; senescent cell reduction; senomorphic; type 2 diabetes
    DOI:  https://doi.org/10.1111/acel.13806
  9. J Gerontol A Biol Sci Med Sci. 2023 Mar 29. pii: glad095. [Epub ahead of print]
    Mosaic chromosomal alterations and human longevity.
    Anastasia Leshchyk, Qingyan Xiang, Stacy L Andersen, Anastasia Gurinovich, Zeyuan Song, Joseph H Lee, Kaare Christensen, Anatoliy Yashin, Mary Wojczynski, Karen Schwander, Thomas T Perls, Stefano Monti, Paola Sebastiani.
      Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared to controls (relative risk 0.637, p=0.0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p=0.002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p=5.15e-05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p=0.0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages > 102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.
    Keywords:  Clonal hematopoiesis; aging; mosaicism
    DOI:  https://doi.org/10.1093/gerona/glad095
  10. Int J Mol Sci. 2023 Mar 08. pii: 5178. [Epub ahead of print]24(6):
    Genetic Networks of Alzheimer's Disease, Aging, and Longevity in Humans.
    Timothy Balmorez, Amy Sakazaki, Shin Murakami.
      Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer's disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10-5 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10-5, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10-11) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10-10); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10-7); ERBB4 signal transduction (p = 2.69 × 10-6); the immune system, including IL-3 and IL-13 (p = 3.83 × 10-6); programmed cell death (p = 4.36 × 10-6); and platelet degranulation (p = 8.16 × 10-6), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10-8), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10-6), and the metabolism of fat-soluble vitamins (p = 1.96 × 10-5). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.
    Keywords:  age-related comorbidity; centenarian; dementia; epigenetics; hallmark of aging; life extension; longevity
    DOI:  https://doi.org/10.3390/ijms24065178
  11. Signal Transduct Target Ther. 2023 Mar 27. 8(1): 140
    The loss of epigenetic information: not only consequences but a cause of mammalian aging.
    Chen Pan, Fangfang Zhou, Long Zhang.
      
    DOI:  https://doi.org/10.1038/s41392-023-01412-9
  12. J Nutr Health Aging. 2023 ;27(3): 192-193
    Editorial: Sarcopenia and Pain as Determinants of Successful Ageing.
    J L Sánchez-Sánchez, L He.
      
    DOI:  https://doi.org/10.1007/s12603-023-1097-1
  13. Antioxidants (Basel). 2023 Mar 11. pii: 695. [Epub ahead of print]12(3):
    Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue.
    Russel J Reiter, Ramaswamy Sharma, Alejandro Romero, Walter Manucha, Dun-Xian Tan, Debora Aparecida Pires de Campos Zuccari, Luiz Gustavo de Almeida Chuffa.
      Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.
    Keywords:  extrapineal melatonin; granulosa cells; in vitro fertilization–embryo transfer; inflammation; mitochondrial physiology; oocyte; oxidative stress; reproductive life span; sirtuins
    DOI:  https://doi.org/10.3390/antiox12030695
  14. Adv Biol (Weinh). 2023 Mar 29. e2200320
    VEGFA Promotes Skeletal Muscle Regeneration in Aging.
    Yori Endo, Charles D Hwang, Yuteng Zhang, Shayan Olumi, Daniel J Koh, Christina Zhu, Ronald L Neppl, Shailesh Agarwal, Indranil Sinha.
      Aging is associated with loss of skeletal muscle regeneration. Differentially regulated vascular endothelial growth factor (VEGF)A with aging may partially underlies this loss of regenerative capacity. To assess the role of VEGFA in muscle regeneration, young (12-14 weeks old) and old C57BL/6 mice (24,25 months old) are subjected to cryoinjury in the tibialis anterior (TA) muscle to induce muscle regeneration. The average cross-sectional area (CSA) of regenerating myofibers is 33% smaller in old as compared to young (p < 0.01) mice, which correlates with a two-fold loss of muscle VEGFA protein levels (p = 0.02). The capillary density in the TA is similar between the two groups. Young VEGFlo mice, with a 50% decrease in systemic VEGFA activity, exhibit a two-fold reduction in the average regenerating fiber CSA following cryoinjury (p < 0.01) in comparison to littermate controls. ML228, a hypoxia signaling activator known to increase VEGFA levels, augments muscle VEGFA levels and increases average CSA of regenerating fibers in both old mice (25% increase, p < 0.01) and VEGFlo (20% increase, p < 0.01) mice, but not in young or littermate controls. These results suggest that VEGFA may be a therapeutic target in age-related muscle loss.
    Keywords:  aging; hypoxia signaling; muscle regeneration; sarcopenia
    DOI:  https://doi.org/10.1002/adbi.202200320
  15. bioRxiv. 2023 Mar 23. pii: 2023.03.20.533514. [Epub ahead of print]
    Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.
    Corey D Holman, Alexander P Sakers, Ryan P Calhoun, Lan Cheng, Ethan C Fein, Christopher Jacobs, Linus Tsai, Evan D Rosen, Patrick Seale.
      The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression of Cd9 and other fibrogenic genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro , suggesting that environmental factors suppress adipogenesis in vivo . Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with age and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified natriuretic peptide clearance receptor Npr3 , a beige fat repressor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a unique resource for identifying cold and/or aging-regulated pathways in adipose tissue.
    DOI:  https://doi.org/10.1101/2023.03.20.533514
  16. Int J Mol Sci. 2023 Mar 20. pii: 5896. [Epub ahead of print]24(6):
    Berberine Rescues D-Ribose-Induced Alzheimer's Pathology via Promoting Mitophagy.
    Chuanling Wang, Qian Zou, Yinshuang Pu, Zhiyou Cai, Yong Tang.
      Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1-Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.
    Keywords:  Alzheimer’s disease; BBR; D-ribose; cognition; mitophagy
    DOI:  https://doi.org/10.3390/ijms24065896
  17. Front Cell Dev Biol. 2023 ;11 1146564
    Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.
    Yuvraj Anandrao Jagtap, Prashant Kumar, Sumit Kinger, Ankur Rakesh Dubey, Akash Choudhary, Ravi Kumar Gutti, Sarika Singh, Hem Chandra Jha, Krishna Mohan Poluri, Amit Mishra.
      The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson's disease, Amyotrophic Lateral Sclerosis, and Alzheimer's disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.
    Keywords:  autophagy; mitochondria; mitostasis; neurodegeneration; oxidative stress; proteasome
    DOI:  https://doi.org/10.3389/fcell.2023.1146564
  18. NPJ Parkinsons Dis. 2023 Mar 30. 9(1): 48
    Epigenetic clocks suggest accelerated aging in patients with isolated REM Sleep Behavior Disorder.
    Luca Baldelli, Chiara Pirazzini, Luisa Sambati, Francesco Ravaioli, Davide Gentilini, Giovanna Calandra-Buonaura, Pietro Guaraldi, Claudio Franceschi, Pietro Cortelli, Paolo Garagnani, Maria Giulia Bacalini, Federica Provini.
      Isolated REM Sleep Behavior Disorder (iRBD) is the strongest prodromal marker for α-synucleinopathies. Overt α-synucleinopathies and aging share several mechanisms, but this relationship has been poorly investigated in prodromal phases. Using DNA methylation-based epigenetic clocks, we measured biological aging in videopolysomnography confirmed iRBD patients, videopolysomnography-negative and population-based controls. We found that iRBDs tended to be epigenetically older than controls, suggesting that accelerated aging characterizes prodromal neurodegeneration.
    DOI:  https://doi.org/10.1038/s41531-023-00492-2
  19. Cells. 2023 Mar 16. pii: 915. [Epub ahead of print]12(6):
    Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies.
    Roula Khalil, Mona Diab-Assaf, Jean-Marc Lemaitre.
      Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.
    Keywords:  SASP; age-related disorders; cellular senescence; immune surveillance; senolytic drugs
    DOI:  https://doi.org/10.3390/cells12060915
  20. J Biomol Struct Dyn. 2023 Mar 27. 1-19
    Model organism life extending therapeutics modulate diverse nodes in the drug-gene-microbe tripartite human longevity interactome.
    Rahagir Salekeen, Michael S Lustgarten, Kazi Mohammed Didarul Islam.
      Advances in antiaging drug/lead discovery in animal models constitute a large body of literature on novel senotherapeutics and geroprotectives. However, with little direct evidence or mechanism of action in humans-these drugs are utilized as nutraceuticals or repurposed supplements without proper testing directions, appropriate biomarkers, or consistent in-vivo models. In this study, we take previously identified drug candidates that have significant evidence of prolonging lifespan and promoting healthy aging in model organisms, and simulate them in human metabolic interactome networks. Screening for drug-likeness, toxicity, and KEGG network correlation scores, we generated a library of 285 safe and bioavailable compounds. We interrogated this library to present computational modeling-derived estimations of a tripartite interaction map of animal geroprotective compounds in the human molecular interactome extracted from longevity, senescence, and dietary restriction-associated genes. Our findings reflect previous studies in aging-associated metabolic disorders, and predict 25 best-connected drug interactors including Resveratrol, EGCG, Metformin, Trichostatin A, Caffeic Acid and Quercetin as direct modulators of lifespan and healthspan-associated pathways. We further clustered these compounds and the functionally enriched subnetworks therewith to identify longevity-exclusive, senescence-exclusive, pseudo-omniregulators and omniregulators within the set of interactome hub genes. Additionally, serum markers for drug-interactions, and interactions with potentially geroprotective gut microbial species distinguish the current study and present a holistic depiction of optimum gut microbial alteration by candidate drugs. These findings provide a systems level model of animal life-extending therapeutics in human systems, and act as precursors for expediting the ongoing global effort to find effective antiaging pharmacological interventions.Communicated by Ramaswamy H. Sarma.
    Keywords:  Antiaging; dietary restriction; gut microbiome; network modeling; senescence; senolytics
    DOI:  https://doi.org/10.1080/07391102.2023.2192823
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