bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2024–07–21
twenty papers selected by
Ayesh Seneviratne, Western University
  1. Mice live longer when inflammation-boosting protein is blocked.
  2. Healthspan Can Matter More Than Life Span: The biology of aging holds clues to extending your healthy years.
  3. Targeting neuronal epigenomes for brain rejuvenation.
  4. A clinical perspective on the revised criteria for diagnosis and staging of Alzheimer's disease.
  5. Pathological mechanisms of kidney disease in ageing.
  6. Editorial: Inflammation and chronic disease.
  7. Recalibrate concepts of epigenetic aging clocks in human health.
  8. Exploring the expression profiles of serum inflammatory proteins and potential anti-aging targets in Chinese long-living people.
  9. Counteracting tissue aging through TERT activation.
  10. Advances in clinical application of lipidomics in healthy ageing and healthy longevity medicine.
  11. Editorial: Epidemiological studies on Japanese diets, health, and nutritional outcomes.
  12. Time's up: Epigenetic clocks in plants.
  13. Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.
  14. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
  15. Erratum: Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
  16. Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment.
  17. Daily briefing: Blocking an inflammation protein lets mice live longer.
  18. Frailty and its association with long-term mortality among community-dwelling older adults aged 75 years and over.
  19. Systemic inflammatory markers in ageing, Alzheimer's disease and other dementias.
  20. Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
  1. Nature. 2024 Jul 17.
    Mice live longer when inflammation-boosting protein is blocked.
    Heidi Ledford.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02298-5
  2. Sci Am. 2023 Nov 01. 329(4): 83
    Healthspan Can Matter More Than Life Span: The biology of aging holds clues to extending your healthy years.
    Lydia Denworth.
      
    DOI:  https://doi.org/10.1038/scientificamerican1123-83
  3. 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
  4. Nat Aging. 2024 Jul 15.
    A clinical perspective on the revised criteria for diagnosis and staging of Alzheimer's disease.
    Oskar Hansson, Clifford R Jack.
      
    DOI:  https://doi.org/10.1038/s43587-024-00675-3
  5. Nat Rev Nephrol. 2024 Jul 18.
    Pathological mechanisms of kidney disease in ageing.
    Takeshi Yamamoto, Yoshitaka Isaka.
      The kidney is a metabolically active organ that requires energy to drive processes such as tubular reabsorption and secretion, and shows a decline in function with advancing age. Various molecular mechanisms, including genomic instability, telomere attrition, inflammation, autophagy, mitochondrial function, and changes to the sirtuin and Klotho signalling pathways, are recognized regulators of individual lifespan and pivotal factors that govern kidney ageing. Thus, mechanisms that contribute to ageing not only dictate renal outcomes but also exert a substantial influence over life expectancy. Conversely, kidney dysfunction, in the context of chronic kidney disease (CKD), precipitates an expedited ageing trajectory in individuals, leading to premature ageing and a disconnect between biological and chronological age. As CKD advances, age-related manifestations such as frailty become increasingly conspicuous. Hence, the pursuit of healthy ageing necessitates not only the management of age-related complications but also a comprehensive understanding of the processes and markers that underlie systemic ageing. Here, we examine the hallmarks of ageing, focusing on the mechanisms by which they affect kidney health and contribute to premature organ ageing. We also review diagnostic methodologies and interventions for premature ageing, with special consideration given to the potential of emerging therapeutic avenues to target age-related kidney diseases.
    DOI:  https://doi.org/10.1038/s41581-024-00868-4
  6. Front Med (Lausanne). 2024 ;11 1434533
    Editorial: Inflammation and chronic disease.
    Frank A Orlando, Arch G Mainous.
      
    Keywords:  CRP; cancer; cardiometabolic; cardiovascular; chronic disease; clonal hematopoiesis; inflammation; social determinants of health
    DOI:  https://doi.org/10.3389/fmed.2024.1434533
  7. Aging (Albany NY). 2024 Jul 17. 16
    Recalibrate concepts of epigenetic aging clocks in human health.
    Ze Zhang, Brock C Christensen, Lucas A Salas.
      
    Keywords:  DNA methylation; epigenetic age acceleration; epigenetic clock; epigenetics; methylation cytometry
    DOI:  https://doi.org/10.18632/aging.206027
  8. 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
  9. 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
  10. Ageing Res Rev. 2024 Jul 17. pii: S1568-1637(24)00250-2. [Epub ahead of print] 102432
    Advances in clinical application of lipidomics in healthy ageing and healthy longevity medicine.
    Opeyemi Stella Ademowo, Markus R Wenk, Andrea B Maier.
      It is imperative to optimise health and healthspan across the lifespan. The accumulation of reactive oxygen species (ROS) has been implicated in the hallmarks of ageing and inhibiting ROS production can potentially delay ageing whilst increasing healthy longevity. Lipids and lipid mediators (derivatives of lipids) are becoming increasingly recognized as central molecule in tissue and cellular function and are susceptible to peroxidation; hence linked with ageing. Lipid classes implicated in the ageing process include sterols, glycerophospholipids, sphingolipids and the oxidation products of polyunsaturated fatty acids but these are not yet translated into the clinic. Further mechanistic studies are required for the understanding of lipid classes in the ageing process. Lipidomics, the system level characterisation of lipid species with respect to metabolism and function, might provide a significant and useful biological age profiling tool through longitudinal studies. Lipid profiles in different ages among healthy individuals could be harnessed as lipid biomarkers of healthy ageing with potential integration for the development of lipid-based ageing clock (lipid clock). The potential of a lipid clock includes the prediction of future morbidity or mortality, which will promote precision and healthy longevity medicine.
    Keywords:  Lipids; biomarkers; healthy ageing; lipidomics; longevity; peroxidation
    DOI:  https://doi.org/10.1016/j.arr.2024.102432
  11. Front Nutr. 2024 ;11 1448258
    Editorial: Epidemiological studies on Japanese diets, health, and nutritional outcomes.
    Akio Shimizu, Yasutake Tomata.
      
    Keywords:  diet; healthy aging; life expectancy; mortality; nutrients
    DOI:  https://doi.org/10.3389/fnut.2024.1448258
  12. Curr Opin Plant Biol. 2024 Jul 17. pii: S1369-5266(24)00093-1. [Epub ahead of print]81 102602
    Time's up: Epigenetic clocks in plants.
    Binh Thanh Vo, Paloma Mas, Frank Johannes.
      For over a decade, the animal field has led the way in using DNA methylation measurements to construct epigenetic clocks of aging. These clocks can predict organismal age with a level of accuracy that surpasses any other molecular proxy known to date. Evidence is finally emerging that epigenetic clocks also exist in plants. However, these clocks appear to differ from those in animals in some key aspects, including in their ability to measure time beyond the life span of an individual. Clock-like epigenetic changes can be found in plant circadian rhythms (scale: 24 h), during plant aging (scale: weeks/centuries), and across plant lineage evolution (scale: decades/millennia). Here, we provide a first classification of these different types of epigenetic clocks, highlight their main features, and discuss their biological basis.
    DOI:  https://doi.org/10.1016/j.pbi.2024.102602
  13. Leukemia. 2024 Jul 18.
    Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.
    Jiachen Wang, Yu Zhang, Lei Li, Liujiao Wang, Shuainan Sun, Bowu Wang, Yanwen Ge, Zhonghui Zhang.
      NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.
    DOI:  https://doi.org/10.1038/s41375-024-02352-1
  14. 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
  15. iScience. 2024 Jul 19. 27(7): 110313
    Erratum: Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
    Jaime M Reyes, Ayala Tovy, Linda Zhang, Angelina S Bortoletto, Carina Rosas, Chun-Wei Chen, Sarah M Waldvogel, Anna G Guzman, Rogelio Aguilar, Sinjini Gupta, Ling Liu, Matthew T Buckley, Kalyani R Patel, Andrea N Marcogliese, Yumei Li, Choladda V Curry, Thomas A Rando, Anne Brunet, Ronald J Parchem, Rachel E Rau, Margaret A Goodell.
      [This corrects the article DOI: 10.1016/j.isci.2024.109122.].
    DOI:  https://doi.org/10.1016/j.isci.2024.110313
  16. 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
  17. Nature. 2024 Jul 18.
    Daily briefing: Blocking an inflammation protein lets mice live longer.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02367-9
  18. Isr J Health Policy Res. 2024 Jul 16. 13(1): 26
    Frailty and its association with long-term mortality among community-dwelling older adults aged 75 years and over.
    Maor Lewis, Anthony Heymann, Galia Zacay, Dan Justo.
       BACKGROUND: Frailty, a significant risk factor for adverse outcomes and mortality, poses an emerging challenge with profound implications for public health and clinical practice. The measurement of frailty offers potential enhancements in healthcare services for older adults. The prevalence of frailty and its association with long-term mortality in a nationwide, unselected population of community-dwelling older adults, particularly those aged 75 and over, has not been previously studied on a large scale in Israel.
    METHODS: A retrospective cohort study was conducted at Meuhedet Health Maintenance Organization, Israel's third largest healthcare service provider, serving 1,276,000 people (13.8% of Israelis). The prevalence of frailty and its association with all-cause mortality were studied among older adults aged 75 years and over who were followed for 2-8 years. Frailty, defined by the cumulative deficit method, utilized clinical data from the preceding 10-year period, comprising 28 chronic diseases and age-related health deficits.
    RESULTS: The cohort included 43,737 older adults, with a median age of 77 years (IQR 75-82 years); among them, 19,300 (44.1%) were males. Overall, 19,396 (44.3%) older adults were frail: 12,260 (28.0%) mildly frail, 5,533 (12.7%) moderately frail and 1,603 (3.7%) severely frail. During the follow-up period 15,064 (34.4%) older adults died: 4,782 (39.0%) mildly frail, 3,016 (54.5%) moderately frail and 1,080 (67.4%) severely frail. Cox regression analysis demonstrated that mortality was associated with severe frailty (HR 2.63, 95%CI 2.45-2.80), moderate frailty (HR 2.05, 95%CI 1.96-2.14), and mild frailty (HR 1.45, 95%CI 1.39-1.51), independent of age, gender, and population sector. Among patients aged 90 years and over, no significant differences in cumulative survival were found between those with moderate and severe frailty (p = 0.408).
    CONCLUSIONS: Frailty is prevalent among community-dwelling Israeli older adults aged 75 years and over, and it is associated with long-term mortality. Considering its association with long-term mortality across frailty levels until the age of 90, early identification and intervention for frailty are recommended within this population. Policymakers should consider the use of the cumulative deficit method for evaluating frailty at both the population health and clinical levels.
    Keywords:  Aging; Community-dwelling; Cumulative deficit method; Frailty; Mortality; Older adults
    DOI:  https://doi.org/10.1186/s13584-024-00614-y
  19. Brain. 2024 Jul 15. pii: awae230. [Epub ahead of print]
    Systemic inflammatory markers in ageing, Alzheimer's disease and other dementias.
    Huimin Cai, Tan Zhao, Yana Pang, Xiaofeng Fu, Ziye Ren, Shuiyue Quan, Longfei Jia.
      Systemic inflammation with alterations in inflammatory markers is involved in aging and Alzheimer's disease. However, few studies have investigated the longitudinal trajectories of systemic inflammatory markers during aging and Alzheimer's disease, and specific markers contributing to Alzheimer's disease remain undetermined. In this study, a longitudinal cohort (cohort 1: n = 290; controls, 136; preclinical Alzheimer's disease, 154) and a cross-sectional cohort (cohort 2: n = 351; controls, 62; Alzheimer's disease, 63; vascular dementia, 58; Parkinson's disease dementia, 56; behavioural variant frontotemporal dementia, 57; dementia with Lewy bodies, 55) were included. Plasma levels of inflammatory markers were measured every 2 years during a 10-year follow-up in the longitudinal cohort and once in the cross-sectional cohort. The study demonstrated that the inflammatory markers significantly altered during both aging and the development of Alzheimer's disease. However, only complement C3, interleukin-1β, and interleukin-6 exhibited significant changes in participants with preclinical Alzheimer's disease, and their longitudinal changes were significantly associated with the development of Alzheimer's disease compared to controls over the 10-year follow-up. In the cross-sectional cohort, complement C3 demonstrates specificity to Alzheimer's disease, while interleukin-1β and interleukin-6 were also altered in other dementias. The study provides a new perspective on the involvement of inflammatory markers in the aging process and the development of Alzheimer's disease, implying that regulating inflammation may have a pivotal role in promoting successful aging and in the prevention and treatment of Alzheimer's disease.
    Keywords:  Alzheimer’s disease; aging; complement; interleukin; longitudinal; systemic inflammation
    DOI:  https://doi.org/10.1093/brain/awae230
  20. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516
    Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
    Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.
      Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.
    Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network
    DOI:  https://doi.org/10.1016/j.celrep.2024.114516
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