bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–11–24
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis.
  2. The effects of WWP1 overexpression on the golgi apparatus stress response and proteoglycan production in adipocytes.
  3. Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway.
  4. Adipose tissue retains an epigenetic memory of obesity after weight loss.
  5. Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
  6. Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise-dependent manner.
  7. PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis.
  8. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  9. Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
  10. New Epigenome Players in the Regulation of PCSK9 - H3K4me3 and H3K9ac Alteration by Statins in hypercholesterolemia.
  11. A framework for conducting GWAS using repeated measures data with an application to childhood BMI.
  12. Ucp1 Ablation Improves Skeletal Muscle Glycolytic Function in Aging Mice.
  13. The Multi-State Epigenetic Pacemaker enables the identification of combinations of factors that influence DNA methylation.
  1. Nat Commun. 2024 Nov 19. 15(1): 9996
    G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis.
    Srinivas Pittala, Dhanush Haspula, Yinghong Cui, Won-Mo Yang, Young-Bum Kim, Roger J Davis, Allison Wing, Yaron Rotman, Owen P McGuinness, Asuka Inoue, Jürgen Wess.
      Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling.
    DOI:  https://doi.org/10.1038/s41467-024-54299-7
  2. Sci Rep. 2024 Nov 22. 14(1): 29004
    The effects of WWP1 overexpression on the golgi apparatus stress response and proteoglycan production in adipocytes.
    Yuka Nozaki, Fumika Suwa, Kazuhiro Furuya, Masahiro Komeno, Shunsuke Hoshino, Yuhei Mizunoe, Kyohei Higashi, Masaki Kobayashi, Yoshikazu Higami.
      White adipocytes are a major component of white adipose tissue (WAT) and help to maintain systemic metabolic homeostasis by storing energy and secreting adipokines. In mice deficient in the protein WWP1 (WW domain-containing E3 ubiquitin protein ligase 1), oxidative stress in adipocytes increases but insulin resistance induced by obesity improves. However, the specific roles of WWP1 in adipocytes remain unclear. Here, we show that in 3T3L1 adipocytes, WWP1 localized in the Golgi apparatus via its C2 domain, where it protected the Golgi apparatus from monensin-induced disruption. By contrast, WWP1 knockdown by short hairpin RNA failed to protect the Golgi apparatus and enhanced Golgi apparatus disruption by monensin. The Golgi apparatus acts as a central organelle to establish accurate protein glycosylation of proteoglycans containing glycosaminoglycans, including chondroitin sulfate and heparan sulfate (HS). WWP1 overexpression increased chondroitin sulfate and HS levels, whereas WWP1 knockdown decreased them. Furthermore, obesity-related increases in HS were prevented by WWP1 knockout in adipose tissue. In summary, our results demonstrate a novel role for WWP1 in maintaining Golgi apparatus morphology and proteoglycan synthesis in adipocytes.
    Keywords:  Adipose tissue; Glycosaminoglycan; Golgi apparatus; WWP1
    DOI:  https://doi.org/10.1038/s41598-024-79114-7
  3. EMBO J. 2024 Nov 19.
    Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway.
    Shan Geng, Shan Yang, Xuejiao Tang, Shiyao Xue, Ke Li, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Yuanqiang Wang, Gangyi Yang, Ling Li, Mengliu Yang.
      Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system.
    Keywords:  Gut Hormones; Gut-Brain-Liver Neural Circuit; Hepatic Glucose Production (HGP); Melanocortin 4 Receptor (MC4R); NUCB2/nesfatin-1
    DOI:  https://doi.org/10.1038/s44318-024-00300-4
  4. Nature. 2024 Nov 18.
    Adipose tissue retains an epigenetic memory of obesity after weight loss.
    Laura C Hinte, Daniel Castellano-Castillo, Adhideb Ghosh, Kate Melrose, Emanuel Gasser, Falko Noé, Lucas Massier, Hua Dong, Wenfei Sun, Anne Hoffmann, Christian Wolfrum, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Ferdinand von Meyenn.
      Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-08165-7
  5. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00414-5. [Epub ahead of print]
    Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
    Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P Blondin, Pierre-Damien Denechaud, André C Carpentier, Dominique Langin.
      Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [11C]-acetate and [11C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.
    Keywords:  PET/CT; adipose triglyceride lipase; body temperature; brown adipose tissue; hormone-sensitive lipase; lipid droplet; lipolysis; mouse models; obesity; oxidative metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.018
  6. Aging Cell. 2024 Nov 18. e14413
    Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise-dependent manner.
    Casper Soendenbroe, Peter Schjerling, Cecilie J L Bechshøft, Rene B Svensson, Laurent Schaeffer, Michael Kjaer, Bénédicte Chazaud, Arnaud Jacquier, Abigail L Mackey.
      Exercise preserves neuromuscular function in aging through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant in skeletal muscle and reside close to neuromuscular junctions, but their relative roles in motor neuron maintenance remain undescribed. Using direct cocultures of embryonic rat motor neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation of the motor neuron transcriptome, with FIB generally favoring neuron growth and cell migration and MuSC favoring production of ribosomes and translational machinery. Conditioned medium from FIB was superior to MuSC in preserving motor neurons and increasing their maturity. Lastly, we established the importance of donor age and exercise status and found an age-related distortion of motor neuron and muscle cell interaction that was fully mitigated by lifelong physical activity. In conclusion, we show that human muscle FIB and MuSC synergistically stimulate the growth and viability of motor neurons, which is further amplified by regular exercise.
    Keywords:  aging; neural plasticity; neurodegeneration; sarcopenia; satellite stem cell; skeletal muscle; training
    DOI:  https://doi.org/10.1111/acel.14413
  7. J Hepatol. 2024 Nov 14. pii: S0168-8278(24)02707-7. [Epub ahead of print]
    PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis.
    Yang Wang, Sen Hong, Hannah Hudson, Nora Kory, Lisa N Kinch, Julia Kozlitina, Jonathan C Cohen, Helen H Hobbs.
       BACKGROUND & AIMS: PNPLA3(148M) (patatin-like phospholipase domain-containing protein 3) is the most impactful genetic risk factor for steatotic liver disease (SLD). A key unresolved issue is whether PNPLA3(148M) confers a loss- or gain-of-function. Here we test the hypothesis that PNPLA3 causes steatosis by sequestering ABHD5 (α/β hydrolase domain containing protein 5), the cofactor of ATGL (adipose TG lipase), thus limiting mobilization of hepatic triglyceride (TG).
    METHODS: We quantified and compared the physical interactions between ABHD5 and PNPLA3/ATGL in cultured hepatocytes using NanoBiT complementation assays and immunocytochemistry. Recombinant proteins purified from human cells were used to compare TG hydrolytic activities of PNPLA3 and ATGL in the presence or absence of ABHD5. Adenoviruses and adeno-associated viruses were used to express PNPLA3 in liver-specific Atgl-/- mice and to express ABHD5 in livers of Pnpla3M/M mice, respectively.
    RESULTS: ABHD5 interacted preferentially with PNPLA3 relative to ATGL in cultured hepatocytes. No differences were seen in the strength of the interactions between ABHD5 with PNPLA3(WT) and PNPLA3(148M). In contrast to prior findings, we found that PNPLA3, like ATGL, is activated by ABHD5 in in vitro assays using purified proteins. PNPLA3(148M)-associated inhibition of TG hydrolysis required that ATGL be expressed and that PNPLA3 be located on LDs. Finally, overexpression of ABHD5 reversed the hepatic steatosis in Pnpla3M/M mice.
    CONCLUSIONS: These findings support the premise that PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by accumulating on LDs and inhibiting ATGL-mediated lipolysis in an ABHD5-dependent manner. Our results predict that reducing, rather that increasing, PNPLA3 expression will be the best strategy to treat PNPLA3(148M)-associated SLD.
    IMPACT AND IMPLICATIONS: Steatotic liver disease (SLD) is a common complex disorder associated with both environmental and genetic risk factors. PNPLA3(148M) is the most impactful genetic risk factor for SLD and yet its pathogenic mechanism remains controversial. Here we provide evidence that PNPLA3(148M) promotes triglyceride (TG) accumulation by sequestering ABHD5, thus limiting its availability to activate ATGL. Although the substitution of methionine for isoleucine reduces the TG hydrolase activity of PNPLA3, the loss of enzymatic function is not directly related to the steatotic effect of the variant. It is the resulting accumulation of PNPLA3 on LDs that confers a gain-of-function by interfering with ATGL-mediated TG hydrolysis. These findings have implications for the design of potential PNPLA3(148M)-based therapies. Reducing, rather than increasing, PNPLA3 levels is predicted to reverse steatosis in susceptible individuals.
    Keywords:  Steatotic liver disease; lipid droplets; lipolysis; triglyceride hydrolase
    DOI:  https://doi.org/10.1016/j.jhep.2024.10.048
  8. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  9. Cell Metab. 2024 Nov 14. pii: S1550-4131(24)00403-0. [Epub ahead of print]
    Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
    Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J Rader, Liming Pei, Joseph A Baur, Megan L Matthews, Garret A FitzGerald, Melanie R McReynolds, Katalin Susztak.
      The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.
    Keywords:  GWAS; cardiovascular-kidney-metabolic syndrome; ferroptosis; genetics; kidney disease; mitochondria; phospholipase; phospholipid; serine protease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.007
  10. J Lipid Res. 2024 Nov 18. pii: S0022-2275(24)00204-9. [Epub ahead of print] 100699
    New Epigenome Players in the Regulation of PCSK9 - H3K4me3 and H3K9ac Alteration by Statins in hypercholesterolemia.
    Sushmitha Duddu, Yash T Katakia, Rituparna Chakrabarti, Pooja Sharma, Praphulla Chandra Shukla.
      Statins are the most effective drugs used worldwide to lower the serum LDL-c by inhibiting the rate-limiting step, HMG-CoA reductase, in cholesterol biosynthesis. Despite its prevalent use, statins are known to increase PCSK9 expression, hindering its efficiency. However, the underlying mechanisms remain elusive. In this study, we have unraveled the pleiotropic effects of statins on hypercholesterolemia via epigenetic regulation of PCSK9. We observed that atorvastatin increases the fold enrichment of H3K4me3 at the promoter of PCSK9 by elevating the expression of the SET1/COMPASS family of proteins like SET1b and MLL1 in HepG2. Additionally, atorvastatin also acetylates H3K9 by increasing the expression of acetyltransferases like CBP and PCAF. Similarly, in mice fed a high-fat diet, atorvastatin showed increased levels of H3K4me3 and H3K9ac in the liver. Furthermore, a pharmacological intervention that inhibits the H3K4me3 and H3K9ac enrichment resulted in the reversal of statin-induced upregulation of PCSK9. Combining statin and OICR-9429 or resveratrol improved the overall uptake of LDL by hepatocytes. Together, these findings suggest that statin induces the colocalization of H3K4me3 and H3K9ac to transcribe PCSK9 actively and that inhibiting these marks reduces PCSK9 expression and ultimately increases hepatocyte LDL uptake. Our study unveils a previously unknown epigenetic mechanism of PCSK9 regulation that may lead to statin resistance or futility in patients and provide a potential therapeutic solution.
    Keywords:  Atorvastatin; Cholesterol Metabolism; Epigenetics; Histone modification; Hypercholesterolemia
    DOI:  https://doi.org/10.1016/j.jlr.2024.100699
  11. Nat Commun. 2024 Nov 20. 15(1): 10067
    A framework for conducting GWAS using repeated measures data with an application to childhood BMI.
    Kimberley Burrows, Anni Heiskala, Jonathan P Bradfield, Zhanna Balkhiyarova, Lijiao Ning, Mathilde Boissel, Yee-Ming Chan, Philippe Froguel, Amelie Bonnefond, Hakon Hakonarson, Alexessander Couto Alves, Deborah A Lawlor, Marika Kaakinen, Marjo-Riitta Järvelin, Struan F A Grant, Kate Tilling, Inga Prokopenko, Sylvain Sebert, Mickaël Canouil, Nicole M Warrington.
      Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS of the 12 estimated phenotypes identified 28 genome-wide significant variants at 13 loci, one of which (in DAOA) has not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover unique biological mechanisms influencing quantitative traits.
    DOI:  https://doi.org/10.1038/s41467-024-53687-3
  12. Adv Sci (Weinh). 2024 Nov 21. e2411015
    Ucp1 Ablation Improves Skeletal Muscle Glycolytic Function in Aging Mice.
    Jin Qiu, Yuhan Guo, Xiaozhen Guo, Ziqi Liu, Zixuan Li, Jun Zhang, Yutang Cao, Jiaqi Li, Shuwu Yu, Sainan Xu, Juntong Chen, Dongmei Wang, Jian Yu, Mingwei Guo, Wenhao Zhou, Sainan Wang, Yiwen Wang, Xinran Ma, Cen Xie, Lingyan Xu.
      Muscular atrophy is among the systematic decline in organ functions in aging, while defective thermogenic fat functionality precedes these anomalies. The potential crosstalk between adipose tissue and muscle during aging is poorly understood. In this study, it is showed that UCP1 knockout (KO) mice characterized deteriorated brown adipose tissue (BAT) function in aging, yet their glucose homeostasis is sustained and energy expenditure is increased, possibly compensated by improved inguinal adipose tissue (iWAT) and muscle functionality compared to age-matched WT mice. To understand the potential crosstalk, RNA-seq and metabolomic analysis were performed on adipose tissue and muscle in aging mice and revealed that creatine levels are increased both in iWAT and muscle of UCP1 KO mice. Interestingly, molecular analysis and metabolite tracing revealed that creatine biosynthesis is increased in iWAT while creatine uptake is increased in muscle in UCP1 KO mice, suggesting creatine transportation from iWAT to muscle. Importantly, creatine analog β-GPA abolished the differences in muscle functions between aging WT and UCP1 KO mice, while UCP1 inhibitor α-CD improved muscle glycolytic function and glucose metabolism in aging mice. Overall, these results suggested that iWAT and skeletal muscle compensate for declined BAT function during aging via creatine metabolism to sustain metabolic homeostasis.
    Keywords:  aging; creatine; glycolytic function; skeletal muscle; thermogenic adipose tissue
    DOI:  https://doi.org/10.1002/advs.202411015
  13. Geroscience. 2024 Nov 16.
    The Multi-State Epigenetic Pacemaker enables the identification of combinations of factors that influence DNA methylation.
    Colin Farrell, Keshiv Tandon, Roberto Ferrari, Kalsuda Lapborisuth, Rahil Modi, Sagi Snir, Matteo Pellegrini.
      Epigenetic clocks, DNA methylation-based predictive models of chronological age, are often utilized to study aging associated biology. Despite their widespread use, these methods do not account for other factors that also contribute to the variability of DNA methylation data. For example, many CpG sites show strong sex-specific or cell-type-specific patterns that likely impact the predictions of epigenetic age. To overcome these limitations, we developed a multidimensional extension of the Epigenetic Pacemaker, the Multi-state Epigenetic Pacemaker (MSEPM). We show that the MSEPM is capable of accurately modeling multiple methylation-associated factors simultaneously, while also providing site-specific models that describe the per site relationship between methylation and these factors. We utilized the MSEPM with a large aggregate cohort of blood methylation data to construct models of the effects of age-, sex-, and cell-type heterogeneity on DNA methylation. We found that these models capture a large faction of the variability at thousands of DNA methylation sites. Moreover, this approach allows us to identify sites that are primarily affected by aging and no other factors. An analysis of these sites reveals that those that lose methylation over time are enriched for CTCF transcription factor chip peaks, while those that gain methylation over time are associated with bivalent promoters of genes that are not expressed in blood. These observations suggest mechanisms that underlie age-associated methylation changes and suggest that age-associated increases in methylation may not have strong functional consequences on cell states. In conclusion, the MSEPM is capable of accurately modeling multiple methylation-associated factors, and the models produced can illuminate site-specific combinations of factors that affect methylation dynamics.
    DOI:  https://doi.org/10.1007/s11357-024-01414-7
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