bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–07–09
twenty-one papers selected by
Ayesh Seneviratne, Western University
  1. Senolytics combat COVID-19 in aging.
  2. Taurine levels modulate aging.
  3. Senescent macrophages drive lung cancer and accumulate in aging.
  4. Spatial mapping of cellular senescence: emerging challenges and opportunities.
  5. Clonal hematopoiesis, aging and Alzheimer's disease.
  6. When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging.
  7. Anti-ageing protein injection boosts monkeys' memories.
  8. Biomolecular Markers of Brain Aging.
  9. TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα.
  10. Daily briefing: Longevity protein boosts ageing monkeys' memories.
  11. Mammalian aging driven by transcription going awry.
  12. Diet, nutrient supply, and tumor immune responses.
  13. Global and tissue-specific aging effects on murine proteomes.
  14. Senolysis through thrombomodulation.
  15. The contradictory role of branched-chain amino acids in lifespan and insulin resistance.
  16. Metabolomics in aging research: aging markers from organs.
  17. Plant bioactive compounds from Mediterranean diet improve risk factors for metabolic syndrome.
  18. Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice.
  19. Fasting No Better Than Calorie Counting for Weight Loss.
  20. Translational longevity medicine: a Swiss perspective in an ageing country.
  21. Using the Hospital Frailty Risk Score to assess mortality risk in older medical patients admitted to the intensive care unit.
  1. Nat Aging. 2023 Jul 06.
    Senolytics combat COVID-19 in aging.
    Xu Zhang, Masayoshi Suda, Yi Zhu.
      
    DOI:  https://doi.org/10.1038/s43587-023-00450-w
  2. Nat Aging. 2023 Jul 06.
    Taurine levels modulate aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00465-3
  3. Nat Aging. 2023 Jul 06.
    Senescent macrophages drive lung cancer and accumulate in aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00459-1
  4. Nat Aging. 2023 Jul 03.
    Spatial mapping of cellular senescence: emerging challenges and opportunities.
    Aditi U Gurkar, Akos A Gerencser, Ana L Mora, Andrew C Nelson, Anru R Zhang, Anthony B Lagnado, Archibald Enninful, Christopher Benz, David Furman, Delphine Beaulieu, Diana Jurk, Elizabeth L Thompson, Fei Wu, Fernanda Rodriguez, Grant Barthel, Hao Chen, Hemali Phatnani, Indra Heckenbach, Jeffrey H Chuang, Jeremy Horrell, Joana Petrescu, Jonathan K Alder, Jun Hee Lee, Laura J Niedernhofer, Manoj Kumar, Melanie Königshoff, Marta Bueno, Miiko Sokka, Morten Scheibye-Knudsen, Nicola Neretti, Oliver Eickelberg, Peter D Adams, Qianjiang Hu, Quan Zhu, Rebecca A Porritt, Runze Dong, Samuel Peters, Stella Victorelli, Thomas Pengo, Timur Khaliullin, Vidyani Suryadevara, Xiaonan Fu, Ziv Bar-Joseph, Zhicheng Ji, João F Passos.
      Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-023-00446-6
  5. Nat Med. 2023 Jul 04.
    Clonal hematopoiesis, aging and Alzheimer's disease.
    Pablo Sánchez Vela, Jennifer J Trowbridge, Ross L Levine.
      
    DOI:  https://doi.org/10.1038/s41591-023-02406-4
  6. Cell Metab. 2023 Jun 25. pii: S1550-4131(23)00218-8. [Epub ahead of print]
    When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging.
    Maria M Mihaylova, Amandine Chaix, Mirela Delibegovic, Jon J Ramsey, Joseph Bass, Girish Melkani, Rajat Singh, Zheng Chen, William W Ja, Michele Shirasu-Hiza, Mary N Latimer, Julie A Mattison, Anna E Thalacker-Mercer, Vishwa Deep Dixit, Satchidananda Panda, Dudley W Lamming.
      An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel. Here, we summarize discussions conducted at a recent NIH workshop that brought together experts in calorie restriction, macronutrient composition, and time-restricted feeding to discuss how dietary composition and feeding schedule impact whole-body metabolism, longevity, and healthspan. These discussions may provide insights into the long-sought molecular mechanisms engaged by calorie restriction to extend lifespan, lead to novel therapies, and potentially inform the development of a personalized food-as-medicine approach to healthy aging.
    Keywords:  calorie restriction; fasting; isoleucine; ketogenesis; methionine; protein restriction; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.008
  7. Nature. 2023 Jul 04.
    Anti-ageing protein injection boosts monkeys' memories.
    Lilly Tozer.
      
    Keywords:  Ageing; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02214-3
  8. Adv Exp Med Biol. 2023 ;1419 111-126
    Biomolecular Markers of Brain Aging.
    Min Li, Haiting An, Wenxiao Wang, Dongfeng Wei.
      Characterized by the gradual loss of physiological integrity, impaired function, and increased susceptibility to death, aging is considered the primary risk factor for major human diseases, such as cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. The time-dependent accumulation of cellular damage is widely considered the general cause of aging. While the mechanism of normal aging is still unresolved, researchers have identified different markers of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Theories of aging can be divided into two categories: (1) aging is a genetically programmed process, and (2) aging is a random process caused by gradual damage to the organism over time as a result of its vital activities. Aging affects the entire human body, and aging of the brain is undoubtedly different from all other organs, as neurons are highly differentiated postmitotic cells, and the lifespan of most neurons in the postnatal period is equal to the lifespan of the brain. In this chapter, we discuss the conserved mechanisms of aging that may underlie the changes observed in the aging brain, with a focus on mitochondrial function and oxidative stress, autophagy and protein turnover, insulin/IGF signaling, target of rapamycin (TOR) signaling, and sirtuin function.
    Keywords:  Calcium homeostasis; Genomic instability; Mitochondrial dysfunction; Neural regulators; Proteostasis
    DOI:  https://doi.org/10.1007/978-981-99-1627-6_9
  9. Immun Ageing. 2023 Jul 03. 20(1): 31
    TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα.
    Alexandre Poirier, Chenyue Wu, Ana Maria Hincapie, Zuzet Martinez-Cordova, Belma Melda Abidin, Michel L Tremblay.
       BACKGROUND: Human aging is characterized by a state of chronic inflammation, termed inflammaging, for which the causes are incompletely understood. It is known, however, that macrophages play a driving role in establishing inflammaging by promoting pro-inflammatory rather than anti-inflammatory responses. Numerous genetic and environmental risk factors have been implicated with inflammaging, most of which are directly linked to pro-inflammatory mediators IL-6, IL1Ra, and TNFα. Genes involved in the signaling and production of those molecules have also been highlighted as essential contributors. TAOK3 is a serine/threonine kinase of the STE-20 kinase family that has been associated with an increased risk of developing auto-immune conditions in several genome-wide association studies (GWAS). Yet, the functional role of TAOK3 in inflammation has remained unexplored.
    RESULTS: We found that mice deficient in the serine/Threonine kinase Taok3 developed severe inflammatory disorders with age, which was more pronounced in female animals. Further analyses revealed a drastic shift from lymphoid to myeloid cells in the spleens of those aged mice. This shift was accompanied by hematopoietic progenitor cells skewing in Taok3-/- mice that favored myeloid lineage commitment. Finally, we identified that the kinase activity of the enzyme plays a vital role in limiting the establishment of proinflammatory responses in macrophages.
    CONCLUSIONS: Essentially, Taok3 deficiency promotes the accumulation of monocytes in the periphery and their adoption of a pro-inflammatory phenotype. These findings illustrate the role of Taok3 in age-related inflammation and highlight the importance of genetic risk factors in this condition.
    Keywords:  Chemotaxis; Inflammaging; Macrophages; Pro-inflammatory cytokines; TAOK3
    DOI:  https://doi.org/10.1186/s12979-023-00350-y
  10. Nature. 2023 Jul 04.
    Daily briefing: Longevity protein boosts ageing monkeys' memories.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-023-02224-1
  11. Trends Genet. 2023 Jul 05. pii: S0168-9525(23)00137-3. [Epub ahead of print]
    Mammalian aging driven by transcription going awry.
    Brenna S McCauley, Weiwei Dang.
      The mechanisms that underlie increased cryptic transcription during senescence and aging have been poorly understood. Sen et al. recently identified cryptic transcription start sites (cTSSs) and chromatin state changes that may contribute to cTSS activation in mammals. Their results indicate that enhancer-promoter conversion may drive cryptic transcription in senescence.
    Keywords:  Cryptic transcription; aging; chromatin
    DOI:  https://doi.org/10.1016/j.tig.2023.06.006
  12. Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00104-8. [Epub ahead of print]
    Diet, nutrient supply, and tumor immune responses.
    Claire L McIntyre, Ayantu Temesgen, Lydia Lynch.
      Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies.
    Keywords:  T cells; cancer; diet; immune cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.trecan.2023.06.003
  13. Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00726-X. [Epub ahead of print]42(7): 112715
    Global and tissue-specific aging effects on murine proteomes.
    Gregory R Keele, Ji-Gang Zhang, John Szpyt, Ron Korstanje, Steven P Gygi, Gary A Churchill, Devin K Schweppe.
      Maintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional aging changes. To define the effects of age directly at the protein level, we perform discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes at adult and late midlife ages (8 and 18 months). Consistent with previous studies, age-related changes in protein abundance often have no corresponding transcriptional change. Aging results in increases in immune proteins across all tissues, consistent with a global pattern of immune infiltration with age. Our protein-centric data reveal tissue-specific aging changes with functional consequences, including altered endoplasmic reticulum and protein trafficking in the spleen. We further observe changes in the stoichiometry of protein complexes with important roles in protein homeostasis, including the CCT/TriC complex and large ribosomal subunit. These data provide a foundation for understanding how proteins contribute to systemic aging across tissues.
    Keywords:  B6; C57BL/6J; CP: Genomics; CP: Metabolism; TMT; multitissue; organismal aging; protein complex; protein homeostasis; proteomics; proteostasis; tandem mass tag
    DOI:  https://doi.org/10.1016/j.celrep.2023.112715
  14. Cell Res. 2023 Jul 04.
    Senolysis through thrombomodulation.
    Corey M Webster, Jan M van Deursen.
      
    DOI:  https://doi.org/10.1038/s41422-023-00842-y
  15. Front Nutr. 2023 ;10 1189982
    The contradictory role of branched-chain amino acids in lifespan and insulin resistance.
    He Yao, Kai Li, Jie Wei, Yajun Lin, Yinghua Liu.
      Branched-chain amino acids (BCAAs; a mixture of leucine, valine and isoleucine) have important regulatory effects on glucose and lipid metabolism, protein synthesis and longevity. Many studies have reported that circulating BCAA levels or dietary intake of BCAAs is associated with longevity, sarcopenia, obesity, and diabetes. Among them, the influence of BCAAs on aging and insulin resistance often present different benefits or harmful effects in the elderly and in animals. Considering the nonobvious correlation between circulating BCAA levels and BCAA uptake, as well as the influence of diseases, diet and aging on the body, some of the contradictory conclusions have been drawn. The regulatory mechanism of the remaining contradictory role may be related to endogenous branched-chain amino acid levels, branched-chain amino acid metabolism and mTOR-related autophagy. Furthermore, the recent discovery that insulin resistance may be independent of longevity has expanded the research thinking related to the regulatory mechanism among the three. However, the negative effects of BCAAs on longevity and insulin resistance were mostly observed in high-fat diet-fed subjects or obese individuals, while the effects in other diseases still need to be studied further. In conclusion, there is still no definite conclusion on the specific conditions under which BCAAs and insulin resistance extend life, shorten life, or do not change lifespan, and there is still no credible and comprehensive explanation for the different effects of BCAAs and insulin resistance on lifespan.
    Keywords:  aging; branched-chain amino acids; insulin resistance; lifespan; longevity
    DOI:  https://doi.org/10.3389/fnut.2023.1189982
  16. Front Cell Dev Biol. 2023 ;11 1198794
    Metabolomics in aging research: aging markers from organs.
    Weicheng Fang, Shuxin Chen, Xuejiao Jin, Shenkui Liu, Xiuling Cao, Beidong Liu.
      Metabolism plays an important role in regulating aging at several levels, and metabolic reprogramming is the main driving force of aging. Due to the different metabolic needs of different tissues, the change trend of metabolites during aging in different organs and the influence of different levels of metabolites on organ function are also different, which makes the relationship between the change of metabolite level and aging more complex. However, not all of these changes lead to aging. The development of metabonomics research has opened a door for people to understand the overall changes in the metabolic level in the aging process of organisms. The omics-based "aging clock" of organisms has been established at the level of gene, protein and epigenetic modifications, but there is still no systematic summary at the level of metabolism. Here, we reviewed the relevant research published in the last decade on aging and organ metabolomic changes, discussed several metabolites with high repetition rate, and explained their role in vivo, hoping to find a group of metabolites that can be used as metabolic markers of aging. This information should provide valuable information for future diagnosis or clinical intervention of aging and age-related diseases.
    Keywords:  aging; aging clock; biomarker; metabolite; metabolomics
    DOI:  https://doi.org/10.3389/fcell.2023.1198794
  17. Int J Food Sci Nutr. 2023 Jul 06. 1-21
    Plant bioactive compounds from Mediterranean diet improve risk factors for metabolic syndrome.
    Renalison Farias-Pereira, Joshua B Zuk, Hannah Khavaran.
      Mediterranean (Med) dietary pattern consists of moderate or high consumption of foods that are linked to reduced risk factors for metabolic syndrome (MetS). This comprehensive review evaluates studies on Med diet-representative foods and beverages, such as red wine and olive oil, to understand the inverse associations of Med diet and MetS. The intake of dietary fibre, unsaturated fatty acids, vitamins, and polyphenols - including flavonoids and stilbenes - help to explain the benefits of Med diet on abdominal adiposity, glucose intolerance, hyperlipidaemia, and high blood pressure to some extent. Antioxidant and anti-inflammatory properties of polyphenols as well as the effects of unsaturated fatty acids on lipid metabolism are part of the underlying mechanisms. Overall, this review shows that dietary interventions using Med diet components improve MetS health markers in humans and/or rodents.
    Keywords:  Diabetes; hypertension; obesity; olive; polyphenols; wine
    DOI:  https://doi.org/10.1080/09637486.2023.2232949
  18. Aging Cell. 2023 Jul 03.
    Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice.
    Mustafa N Okur, Burcin Duan Sahbaz, Risako Kimura, Uri Manor, Jaimin Patel, Jae-Hyeon Park, Leo Andrade, Chandrakala Puligilla, Deborah L Croteau, Vilhelm A Bohr.
      Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.
    Keywords:  NAD+; age-related hearing loss; nicotinamide riboside
    DOI:  https://doi.org/10.1111/acel.13909
  19. JAMA. 2023 Jul 05.
    Fasting No Better Than Calorie Counting for Weight Loss.
    Emily Harris.
      
    DOI:  https://doi.org/10.1001/jama.2023.12054
  20. Swiss Med Wkly. 2023 Jun 30. 153 40088
    Translational longevity medicine: a Swiss perspective in an ageing country.
    Marco M Ruckstuhl, Evelyne Bischof, Dana Blatch, Aliki Buhayer, Jörg Goldhahn, Edouard Battegay, Andre Tichelli, Collin Y Ewald.
      Breakthroughs in medical research in the last century have led to a significant extension of the human lifespan, resulting in a shift towards an elderly population worldwide. Due to the ongoing progress of global development towards elevated standards of living, this study specifically examines Switzerland as a representative nation to explore the socioeconomic and healthcare ramifications associated with an ageing population, thereby highlighting the tangible impact experienced in this context. Beyond the exhaustion of pension funds and medical budgets, by reviewing the literature and analysing publicly available data, we observe a "Swiss Japanification". Old age is associated with late-life comorbidities and an increasing proportion of time spent in poor health. To address these problems, a paradigm shift in medical practice is needed to improve health rather than respond to existing diseases. Basic ageing research is gaining momentum to be translated into therapeutic interventions and provides machine learning tools driving longevity medicine. We propose that research focus on closing the translational gap between the molecular mechanisms of ageing and a more prevention-based medicine, which would help people age better and prevent late-life chronic diseases.
    DOI:  https://doi.org/10.57187/smw.2023.40088
  21. CMAJ Open. 2023 Jul-Aug;11(4):11(4): E607-E614
    Using the Hospital Frailty Risk Score to assess mortality risk in older medical patients admitted to the intensive care unit.
    Michael E Detsky, Saeha Shin, Michael Fralick, Laveena Munshi, Jacqueline M Kruser, Katherine R Courtright, Lauren Lapointe-Shaw, Terence Tang, Shail Rawal, Janice L Kwan, Adina Weinerman, Fahad Razak, Amol A Verma.
       BACKGROUND: Prognostic information at the time of hospital discharge can help guide goals-of-care discussions for future care. We sought to assess the association between the Hospital Frailty Risk Score (HFRS), which may highlight patients' risk of adverse outcomes at the time of hospital discharge, and in-hospital death among patients admitted to the intensive care unit (ICU) within 12 months of a previous hospital discharge.
    METHODS: We conducted a multicentre retrospective cohort study that included patients aged 75 years or older admitted at least twice over a 12-month period to the general medicine service at 7 academic centres and large community-based teaching hospitals in Toronto and Mississauga, Ontario, Canada, from Apr. 1, 2010, to Dec. 31, 2019. The HFRS (categorized as low, moderate or high frailty risk) was calculated at the time of discharge from the first hospital admission. Outcomes included ICU admission and death during the second hospital admission.
    RESULTS: The cohort included 22 178 patients, of whom 1767 (8.0%) were categorized as having high frailty risk, 9464 (42.7%) as having moderate frailty risk, and 10 947 (49.4%) as having low frailty risk. One hundred patients (5.7%) with high frailty risk were admitted to the ICU, compared to 566 (6.0%) of those with moderate risk and 790 (7.2%) of those with low risk. After adjustment for age, sex, hospital, day of admission, time of admission and Laboratory-based Acute Physiology Score, the odds of ICU admission were not significantly different for patients with high (adjusted odds ratio [OR] 0.99, 95% confidence interval [CI] 0.78 to 1.23) or moderate (adjusted OR 0.97, 95% CI 0.86 to 1.09) frailty risk compared to those with low frailty risk. Among patients admitted to the ICU, 75 (75.0%) of those with high frailty risk died, compared to 317 (56.0%) of those with moderate risk and 416 (52.7%) of those with low risk. After multivariable adjustment, the risk of death after ICU admission was higher for patients with high frailty risk than for those with low frailty risk (adjusted OR 2.86, 95% CI 1.77 to 4.77).
    INTERPRETATION: Among patients readmitted to hospital within 12 months, patients with high frailty risk were similarly likely as those with lower frailty risk to be admitted to the ICU but were more likely to die if admitted to ICU. The HFRS at hospital discharge can inform prognosis, which can help guide discussions for preferences for ICU care during future hospital stays.
    DOI:  https://doi.org/10.9778/cmajo.20220094
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