bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–01–15
nine papers selected by
Ayesh Seneviratne, Western University
  1. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation.
  2. Genetics of clonal hematopoiesis.
  3. The aging of the immune system and its implications for transplantation.
  4. NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease.
  5. Azacitidine Maintenance Therapy Post-Allogeneic Stem Cell Transplantation in Poor-Risk Acute Myeloid Leukemia.
  6. Epigenetic aging in adult neurogenesis.
  7. Anti-ageing effects of FDA-approved medicines: a focused review.
  8. Lipid metabolism alterations and ferroptosis in cancer: Paving the way for solving cancer resistance.
  9. Nano-ayurvedic medicine and its potential in cancer treatment.
  1. Blood. 2023 Jan 13. pii: blood.2022017514. [Epub ahead of print]
    Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation.
    Xiangjun Zeng, Xiaoqing Li, Xia Li, Cong Wei, Ce Shi, Kejia Hu, Delin Kong, Qian Luo, Yulin Xu, Wei Shan, Meng Zhang, Jimin Shi, Jingjing Feng, Yingli Han, He Huang, Pengxu Qian.
      Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has been recently reported to impact hematopoiesis. However, there is currently limited empirical evidence elucidating the direct impact of gut microbiome on aging hematopoiesis. In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Further, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated FoxO signaling pathway and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota construction and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.
    DOI:  https://doi.org/10.1182/blood.2022017514
  2. Nat Genet. 2023 Jan;55(1): 1
    Genetics of clonal hematopoiesis.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-022-01290-x
  3. Geroscience. 2023 Jan 10.
    The aging of the immune system and its implications for transplantation.
    Kathryn E McGovern, Sandip A Sonar, Makiko Watanabe, Christopher P Coplen, Christine M Bradshaw, Janko Ž Nikolich.
      By the last third of life, most mammals, including humans, exhibit a decline in immune cell numbers, immune organ structure, and immune defense of the organism, commonly known as immunosenescence. This decline leads to clinical manifestations of increased susceptibility to infections, particularly those caused by emerging and reemerging microorganisms, which can reach staggering levels-infection with SARS-CoV-2 has been 270-fold more lethal to older adults over 80 years of age, compared to their 18-39-year-old counterparts. However, while this would be expected to be beneficial to situations where hyporeactivity of the immune system may be desirable, this is not always the case. Here, we discuss the cellular and molecular underpinnings of immunosenescence as they pertain to outcomes of solid organ and hematopoietic transplantation.
    Keywords:  Aging; Immune response; Immunosenescence; Transplantation
    DOI:  https://doi.org/10.1007/s11357-022-00720-2
  4. Cells. 2022 Dec 21. pii: 21. [Epub ahead of print]12(1):
    NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease.
    Lucie Chanvillard, Alessandra Tammaro, Vincenzo Sorrentino.
      Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD+ homeostasis, crucial for PTECs' oxidative metabolism, is impaired in CKD, and administration of dietary NAD+ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD+ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD+ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD+ levels in premature renal aging and CKD.
    Keywords:  NAD+; NAD+ precursors; age-related diseases; chronic kidney disease; clinical trials; kidney; mouse models; premature renal aging; tubular epithelial cells metabolism
    DOI:  https://doi.org/10.3390/cells12010021
  5. Hematol Oncol Stem Cell Ther. 2023 Jan 12. 16(1): 52-60
    Azacitidine Maintenance Therapy Post-Allogeneic Stem Cell Transplantation in Poor-Risk Acute Myeloid Leukemia.
    Amany R Keruakous, Jennifer Holter-Chakrabarty, Sarah A Schmidt, Mohamad O Khawandanah, George Selby, Carrie Yuen.
       OBJECTIVE/BACKGROUND: Allogeneic hematopoietic stem cell transplant (HSCT) is the potential curative modality for poor-risk acute myeloid leukemia (AML), relapse remains the main reason for transplant failure. Early-phase studies showed azacitidine is safe for post-transplant maintenance therapy in AML.
    METHODS: We performed a single institutional prospective cohort study to evaluate the benefit of azacitidine maintenance therapy following allogeneic HSCT in poor-risk AML. The main objective of this study is to generate a hypothesis aiming to optimize post-transplantation outcomes in poor-risk AML. Forty-nine adults with poor-risk AML who underwent allogeneic HSCT were evaluated in a nonrandomized prospective cohort fashion. Thirty-one participants received post-transplant azacitidine (32 mg/m2) on Days 1-5 for a 28-day treatment cycle beginning approximately 40 days after transplantation. The study was controlled using 18 matched individuals who were on a noninterventional surveillance protocol.
    RESULTS: The relapse rate was significantly higher in the control cohort (66.67%) versus (25.81%) in the azacitidine maintenance cohort ( p < .005). Time to relapse was significantly prolonged by azacitidine maintenance, not reached versus 4.1 months in the control arm ( p < .0001). In addition, median overall survival was lower in the control cohort at 7.6 versus 27.4 months in the interventional cohort ( p < .0001). At a median follow-up of 24 months, incidence of graft-versus-host disease (GVHD) did not differ between study groups ( p = .325). In both cohorts, minimal residual disease was correlated with higher hazard of relapse (95% confidence interval, 2.31-13.74; p < .001).
    CONCLUSION: We conclude that low dose azacitidine maintenance following allogeneic HSCT in poor-risk AML, decreased relapse rate, and increased both the time to relapse and overall survival without increased risk of GVHD.
    DOI:  https://doi.org/10.1016/j.hemonc.2021.03.001
  6. Hippocampus. 2023 Jan 09.
    Epigenetic aging in adult neurogenesis.
    Sara Zocher, Tomohisa Toda.
      Neural stem cells (NSCs) in the hippocampus generate new neurons throughout life, which functionally contribute to cognitive flexibility and mood regulation. Yet adult hippocampal neurogenesis substantially declines with age and age-related impairments in NSC activity underlie this reduction. Particularly, increased NSC quiescence and consequently reduced NSC proliferation are considered to be major drivers of the low neurogenesis levels in the aged brain. Epigenetic regulators control the gene expression programs underlying NSC quiescence, proliferation and differentiation and are hence critical to the regulation of adult neurogenesis. Epigenetic alterations have also emerged as central hallmarks of aging, and recent studies suggest the deterioration of the NSC-specific epigenetic landscape as a driver of the age-dependent decline in adult neurogenesis. In this review, we summarize the recently accumulating evidence for a role of epigenetic dysregulation in NSC aging and propose perspectives for future research directions.
    Keywords:  DNA methylation; Lamin B1; aging; chromatin; epigenetic; hippocampus; histone; neural stem cells; neurogenesis
    DOI:  https://doi.org/10.1002/hipo.23494
  7. J Basic Clin Physiol Pharmacol. 2023 Jan 13.
    Anti-ageing effects of FDA-approved medicines: a focused review.
    Koranit Thanapairoje, Supanut Junsiritrakhoon, Surasak Wichaiyo, Mohd Azuraidi Osman, Wasu Supharattanasitthi.
      Ageing is the process generated by senescent cells, free radicals, inflammation and other relevant factors. Ageing contributes to age-related diseases that affect the quality of life. People are interested in anti-ageing intervention and many scientists attempt to search for anti-ageing medicines. This review focused on describing in vivo anti-ageing activity of US-FDA-approved drugs and found that alogliptin, canagliflozin and metformin might produce anti-ageing activity via AMPK activation. Rapamycin and canagliflozin are capable to inhibit mTOR to promote lifespan. Atracurium, carnitine and statins act as DAF-16 activators, which potentially contribute to anti-ageing activity. Hydralazine, lisinopril, rosiglitazone and zidovudine may help stabilize genomic integrity to prolong life expectancy. Other indirect mechanisms, including insulin-lowering effect by acarbose and calcium channel blocking activity by verapamil may also promote longevity. Interestingly, some drugs (i.e., canagliflozin, metformin, rapamycin and acarbose) are likely to demonstrate a lifespan-promoting effect predominantly in male animals. These pre-clinical data might provide mechanistic and phenotypic perspectives to better understand the targets of anti-ageing interventions.
    Keywords:  FDA-approved; ageing; anti-ageing; drug; lifespan
    DOI:  https://doi.org/10.1515/jbcpp-2022-0242
  8. Eur J Pharmacol. 2023 Jan 06. pii: S0014-2999(23)00008-0. [Epub ahead of print]941 175497
    Lipid metabolism alterations and ferroptosis in cancer: Paving the way for solving cancer resistance.
    Jaewang Lee, Daiha Shin, Jong-Lyel Roh.
      Cancer often perturbs lipid metabolism, which leads to the alteration of metabolism intermediates, contributing to their deregulated growth and metastasis. Alteration of lipid metabolism shifting to contain more polyunsaturated fatty acids (PUFAs) in membrane phospholipids (PLs) also leads to cancer therapy resistance. High amounts of PL-PUFAs render cancer cells more vulnerable to lipid peroxidation (LPO), predisposing them towards ferroptosis, a new form of iron-dependent oxidative regulated cell death. The commitment of cancer undergoing ferroptotic cell death depends on the adaptive lipidome remodeling, LPO patterns, and LPO scavenging ability in heterogeneous cancer cells. Ferroptosis is receiving attention in cancer research as treating cancers, altering membrane lipid homeostasis, and refractory from conventional therapies. Therefore, a better understanding of the molecular underpinning of lipid metabolism alterations may provide new opportunities for solving cancer resistance. This review intends to understand altered lipid metabolism in cancers and discuss lipid composition and metabolic processes associated with ferroptosis induction in cancers.
    Keywords:  Cancer; Ferroptosis; Lipid metabolism; Lipid peroxidation; Polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175497
  9. J Integr Med. 2022 Dec 24. pii: S2095-4964(22)00125-X. [Epub ahead of print]
    Nano-ayurvedic medicine and its potential in cancer treatment.
    Manu Lopus.
      Nano-ayurvedic medicine is an emerging field in which nanoparticles are functionalized with active principles of potent ayurvedic herbs to enhance their efficacy and target-specific delivery. Scientific advances in the past couple of decades have revealed the molecular mechanisms behind the anticancer potential of several ayurvedic herbs, attributed chiefly to their secondary metabolites including polyphenols and other active substances. With the advancement of nanotechnology, it has been established that size-, shape-, and surface-chemistry-optimized nanoparticles can be utilized as synergizing carriers for these phytochemicals. Nano-ayurvedic medicine utilizes herbs that are commonly used in Ayurveda to functionalize different nanoparticles and thereby enhance their potency and target specificity. Studies have shown that the active phytochemicals of such herbs can be coated onto the nanoparticles of different metals, such as gold, and that they work more efficiently than the free herbal extract, for example, in inhibiting cancer cell proliferation. Recently, an Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homeopathy (AYUSH)-based clinical trial in humans indicated the anticancer potential of such formulations. Nano-ayurvedic medicine is emerging as a potential treatment option for hyperproliferative diseases.
    Keywords:  Apoptosis; Cancer; Cell cycle; Nano-ayurvedic medicine; Nanomedicine
    DOI:  https://doi.org/10.1016/j.joim.2022.12.001
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