bims-caglex 2023-12-31 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2023–12–31
27 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Telomeres, cellular senescence, and aging: past and future.
[Pathophysiological implications of cellular senescence and prospects for novel anti-aging drugs].
Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts.
From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.
cGAS Mediates the Inflammatory Responses of Human Microglial Cells to Genotoxic DNA Damage.
Phosphodiesterase inhibitor ameliorates senescent changes of renal interstitial pericytes in aging kidney.
Betaine attenuates age-related suppression in autophagy via Mettl21c/p97/VCP axis to delay muscle loss.
The peptide Acein promotes dopamine secretion through clec-126 to extend the lifespan of elderly C. elegans.
Mitophagy Decreases in the Peripheral Vestibular System of Aged C57BL/6J Mice.
Chronological age enhances aging phenomena and protein nitration in oocyte.
A versatile method for the identification of senolytic compounds.
Resistance and Resilience to Alzheimer's Disease.
Lipoprotein (a) as a Biomarker for Cardiovascular Diseases and Potential New Therapies to Mitigate Risk.
Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.
Melatonin facts: Lack of evidence that melatonin is a radical scavenger in living systems.
Small airway fibroblasts from Chronic Obstructive Pulmonary Disease patients exhibit cellular senescence.
[Traditional Chinese medicine used as anti-aging agent by targeting nuclear factor erythroid 2-related factor 2 signaling pathway].
NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.
Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.
Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell-type deconvolution applied to human blood epigenetic clocks.
Age-related changes in hematological biomarkers in common marmosets.
Temperature-Dependent Relationship of Autophagy and Apoptotic Signaling During Cold-Water Immersion in Young and Older Males.
Automated calibration for stability selection in penalised regression and graphical models.
Recent strategies for evoking immunogenic Pyroptosis in antitumor immunotherapy.
The Correlation Between Leg Muscle Mass Index and Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.
Androgen receptor contributes to repairing DNA damage induced by inflammation and oxidative stress in prostate cancer.
The regulatory effect of growth differentiation factor 11 on different cells.

Biogerontology. 2023 Dec 27.

Telomeres, cellular senescence, and aging: past and future.

Madeline Eppard, João F Passos, Stella Victorelli.

  Over half a century has passed since Alexey Olovnikov's groundbreaking proposal of the end-replication problem in 1971, laying the foundation for our understanding of telomeres and their pivotal role in cellular senescence. This review paper delves into the intricate and multifaceted relationship between cellular senescence, the influence of telomeres in this process, and the far-reaching consequences of telomeres in the context of aging and age-related diseases. Additionally, the paper investigates the various factors that can influence telomere shortening beyond the confines of the end-replication problem and how telomeres can exert their impact on aging, even in the absence of significant shortening. Ultimately, this paper stands as a tribute to the pioneering work of Olovnikov, whose seminal contributions established the solid foundation upon which our ongoing explorations of telomeres and the aging process are based.

Keywords:  Aging; Olovnikov; Senescence; Telomeres

DOI:  https://doi.org/10.1007/s10522-023-10085-4
Sheng Li Xue Bao. 2023 Dec 25. 75(6): 847-863

[Pathophysiological implications of cellular senescence and prospects for novel anti-aging drugs].

Yu Sun.

Chronological aging is the leading risk factor for human diseases, while aging at the cellular level, namely cellular senescence, is the fundamental driving force of organismal aging. The impact of cellular senescence on various life processes, including normal physiology, organismal aging and the progress of various age-related pathologies, has been largely ignored for a long time. However, with recent advancement in relevant fields, cellular senescence has become the core of aging biology and geriatric medicine. Although senescent cells play important roles in physiological processes including tissue repair, wound healing, and embryonic development, they can also contribute to tissue dysfunction, organ degeneration and various pathological conditions during adulthood. Senescent cells exert paracrine effects on neighboring cells in tissue microenvironments by developing a senescence-associated secretory phenotype, thus maintaining long-term and active intercellular communications that ultimately results in multiple pathophysiological effects. This is regarded as one of the most important discoveries in life science of this century. Notably, selective elimination of senescent cells through inducing their apoptosis or specifically inhibiting the senescence-associated secretory phenotype has shown remarkable potential in preclinical and clinical interventions of aging and age-related diseases. This reinforces the belief that senescent cells are the key drug target to alleviate various aging syndromes. However, senescent cells exhibit heterogeneity in terms of form, function and tissue distribution, and even differ among species, which presents a challenge for the translation of significant research achievements to clinical practice in future. This article reviews and discusses the characteristics of senescent cells, current targeting strategies and future trends, providing useful and valuable references for the rapidly blooming aging biology and geriatric medicine.
Front Cell Dev Biol. 2023 ;11 1274807

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts.

Valentina Woronzow, Jonas Möhner, Daniel Remane, Hans Zischler.

  Cellular senescence is characterized by replication arrest in response to stress stimuli. Senescent cells accumulate in aging tissues and can trigger organ-specific and possibly systemic dysfunction. Although senescent cell populations are heterogeneous, a key feature is that they exhibit epigenetic changes. Epigenetic changes such as loss of repressive constitutive heterochromatin could lead to subsequent LINE-1 derepression, a phenomenon often described in the context of senescence or somatic evolution. LINE-1 elements decode the retroposition machinery and reverse transcription generates cDNA from autonomous and non-autonomous TEs that can potentially reintegrate into genomes and cause structural variants. Another feature of cellular senescence is mitochondrial dysfunction caused by mitochondrial damage. In combination with impaired mitophagy, which is characteristic of senescent cells, this could lead to cytosolic mtDNA accumulation and, as a genomic consequence, integrations of mtDNA into nuclear DNA (nDNA), resulting in mitochondrial pseudogenes called numts. Thus, both phenomena could cause structural variants in aging genomes that go beyond epigenetic changes. We therefore compared proliferating and senescent IMR-90 cells in terms of somatic de novo numts and integrations of a non-autonomous composite retrotransposons - the so-called SVA elements-that hijack the retropositional machinery of LINE-1. We applied a subtractive and kinetic enrichment technique using proliferating cell DNA as a driver and senescent genomes as a tester for the detection of nuclear flanks of de novo SVA integrations. Coupled with deep sequencing we obtained a genomic readout for SVA retrotransposition possibly linked to cellular senescence in the IMR-90 model. Furthermore, we compared the genomes of proliferative and senescent IMR-90 cells by deep sequencing or after enrichment of nuclear DNA using AluScan technology. A total of 1,695 de novo SVA integrations were detected in senescent IMR-90 cells, of which 333 were unique. Moreover, we identified a total of 81 de novo numts with perfect identity to both mtDNA and nuclear hg38 flanks. In summary, we present evidence for possible age-dependent structural genomic changes by paralogization that go beyond epigenetic modifications. We hypothesize, that the structural variants we observe potentially impact processes associated with replicative aging of IMR-90 cells.

Keywords:  RDA; SVA; cellular senescence; mtDNA; numts; retrotransposition; somatic mosaicism

DOI:  https://doi.org/10.3389/fcell.2023.1274807
Ageing Res Rev. 2023 Dec 23. pii: S1568-1637(23)00334-3. [Epub ahead of print]93 102175

From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.

Xiaxia Li, Lina Ma.

  Intrinsic capacity is the sum of an individual's physical and mental capacities, which helps determine functional ability. Intrinsic capacity decline is an important predictor of adverse health outcomes and can identify individuals at higher risk of functional decline. Aging is characterized by a decrease in physiological reserves and functional abilities. Chronic inflammation, a mechanism of aging, is associated with decreased intrinsic capacity, which may mirror the broader relationship between aging and functional ability. Therefore, it is crucial for maintaining functional ability and promoting healthy aging to study the mechanisms of intrinsic capacity decline, identify easily available markers, and make targets for intervention from the perspective of chronic inflammation. We reviewed the current research on chronic inflammation, inflammation-related markers, and intrinsic capacity. To date, there is still no inflammatory markers with high specificity and sensitivity to monitor intrinsic capacity decline. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha may potentially indicate changes in intrinsic capacity, but their results with intrinsic capacity or each intrinsic capacity domain are inconsistent. Considering the variations in individual responses to changes in inflammatory markers, it may be beneficial to explore the use of multiple analytes instead of relying on a single marker. This approach could be valuable in monitoring the decline of intrinsic capacity in the future.

Keywords:  Chronic inflammation; Functional ability; Healthy aging; Inflammatory markers; Intrinsic capacity; Older adults

DOI:  https://doi.org/10.1016/j.arr.2023.102175
Inflammation. 2023 Dec 26.

cGAS Mediates the Inflammatory Responses of Human Microglial Cells to Genotoxic DNA Damage.

Alexander J Suptela, Yasmine Radwan, Christine Richardson, Shan Yan, Kirill A Afonin, Ian Marriott.

  Genomic instability is a key driving force for the development and progression of many age-related neurodegenerative diseases and central nervous system (CNS) cancers. Recently, the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), has been shown to detect and respond to self-DNA accumulation resulting from DNA damaging insults in peripheral cell types. cGAS has been shown to be important in the responses of microglia to DNA viruses and amyloid beta, and we have reported that it underlies the responses of human microglia to exogenous DNA. However, the role of this cytosolic sensor in the detection of self-DNA by glia is poorly understood and its ability to mediate the cellular responses of human microglia to genotoxic DNA damage has not been established. Here, we describe the ability of ionizing radiation and oxidative stress to elicit genomic DNA damage in human microglial cells and to stimulate the production of key inflammatory mediators by these cells in an NF-kB dependent manner. Importantly, we have utilized CRISPR/Cas9 and siRNA-mediated knockdown approaches and a pharmacological inhibitor of the cGAS adaptor protein stimulator of interferon genes (STING) to demonstrate that the cGAS-STING pathway plays a critical role in the generation of these microglial immune responses to such genotoxic insults. Together, these studies support the notion that cGAS mediates the detection of cytosolic self-DNA by microglia, providing a potential mechanism linking genomic instability to the development of CNS cancers and neurodegenerative disorders.

Keywords:  DNA damage; cGAS; genomic instability; inflammation.; microglia

DOI:  https://doi.org/10.1007/s10753-023-01946-8
Aging Cell. 2023 Dec 28. e14075

Phosphodiesterase inhibitor ameliorates senescent changes of renal interstitial pericytes in aging kidney.

Hyung Duk Kim, Eun Nim Kim, Ji Hee Lim, Yaeni Kim, Tae Hyun Ban, Hajeong Lee, Yon Su Kim, Cheol Whee Park, Bum Soon Choi.

  Pericytes are mesenchymal cells that surround endothelial cells, playing a crucial role in angiogenesis and vessel maturation. Additionally, they are associated with interstitial fibrosis as a major contributor to renal myofibroblasts. In this study, we aim to investigate whether the phosphodiesterase inhibitor, pentoxifylline (PTX), can ameliorate aging-related functional and histological deterioration in the kidney. We subjected aging C57BL/6 mice, dividing into young, aging, and PTX-treated aging groups. Renal function, albuminuria, and histological changes were assessed. Interstitial pericytes were assessed by immunohistochemistry analysis. We examined changes in pericytes in elderly patients using human kidney tissue obtained from healthy kidney donors for kidney transplantation. In vitro experiments with human pericytes and endothelial cells were performed. Aging mice exhibited declined renal function, increased albuminuria, and aging-related histological changes including mesangial expansion and tubulointerstitial fibrosis. Notably, number of pericytes declined in aging kidneys, and myofibroblasts increased. PTX treatment ameliorated albuminuria, histological alterations, and microvascular rarefaction, as well as modulated angiopoietin expression. In vitro experiments showed PTX reduced cellular senescence and inflammation. Human kidney analysis confirmed similar pericyte changes in aging kidneys. The phosphodiesterase inhibitor, PTX preserved microvascular density and improved renal interstitial fibrosis and inflammation in aging mice kidneys. These protective effects were suggested to be associated with the amelioration of pericytes reduction and the transition to myofibroblasts. Additionally, the upregulation of angiopoietin-1 expression may exert potential impacts. To the best of our knowledge, this is the first report on the changes in renal interstitial pericytes in aging human kidneys.

Keywords:  aging; microvascular rarefaction; pentoxifylline; pericytes; phosphodiesterase inhibitors

DOI:  https://doi.org/10.1111/acel.14075
J Nutr Biochem. 2023 Dec 24. pii: S0955-2863(23)00288-7. [Epub ahead of print] 109555

Betaine attenuates age-related suppression in autophagy via Mettl21c/p97/VCP axis to delay muscle loss.

Si Chen, Jiedong Chen, Chen Wang, Tongtong He, Zhijun Yang, Wenge Huang, Xiaolin Luo, Huilian Zhu.

  Age-related impairment of autophagy accelerates muscle loss and lead to sarcopenia. Betaine can delay muscle loss as a dietary methyl donor via increasing S-adenosyl-L-methionine (SAM, a crucial metabolite for autophagy regulation) in methionion cycle. However, whether betaine can regulate autophagy level to attenuate degeneration in aging muscle remains unclear. Herein, male C57BL/6J young mice (YOU, 2-month-old), old mice (OLD, 15-month-old), and 2%-betaine-treated old mice (BET, 15-month-old) were employed and raised for 12 weeks. All mice underwent body composition examination and grip strength test before being sacrificed. Betaine alleviated age-related decline in muscle mass and strength. Meanwhile, betaine preserved the expression autophagy markers (Atg5, Atg7, LC3-II, and Beclin1) both at transcriptional and translational level during the aging process. RNA-sequencing results generated from mice gastrocnemius muscle found Mettl21c, a SAM-dependent autophagy-regulating methyltransferase, was significantly higher expressed in BET and YOU group. Results were further validated by qPCR and Western bloting. In vitro, C2C12 cells with or without Mettl21c RNA interference were treated different concentration of betaine (0mM, 10mM) under methionine-starved condition. Compared with control group, betaine upregulated autophagy markers expression and autophagy flux. By increasing the SAM level, betaine facilitated trimethylation of p97 (Mettl21c downstream effector) into valosin-containing protein (VCP). Increased VCP promoted autophagic turnover of cellular components, ATP production, and cell differentiation. Knock-down of Metthl21c dismissed improvements mentioned above. Collectively, betaine could enhance aged skeletal muscle autophagy level via Mettl21c/p97/VCP axis to delay muscle loss.

Keywords:  Mettl21c; age-related muscle loss; autophagy; betaine

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109555
Aging (Albany NY). 2023 Dec 27. 15

The peptide Acein promotes dopamine secretion through clec-126 to extend the lifespan of elderly C. elegans.

Jiaqi Wang, Dong Wang, Sarra Setrerrahmane, Jean Martinez, Han-Mei Xu.

  Dopamine plays a crucial role in regulating brain activity and movement and modulating human behavior, cognition and mood. Regulating dopamine signaling may improve cognitive abilities and physical functions during aging. Acein, a nonapeptide of sequence H-Pro-Pro-Thr-Thr-Thr-Lys-Phe-Ala-Ala-OH is able to stimulate dopamine secretion in the brain. By using genetic editing and lifespan investigation in C. elegans, we showed that the lack of the C-type lectin domain-containing protein clec-126 significantly suppressed the aging phenotype and prolonged lifespan, while overexpression of clec-126 promoted aging-related phenotypes and accelerated the aging process. We examined the aging phenotype of C. elegans and showed that Acein could induce a decrease in clec-126 expression, prolonging the lifespan of aged C. elegans. The mechanism proceeds through the Acein-induced stimulation of dopamine secretion that ameliorates motor function decline and extends the healthy lifespan of aged C. elegans. In addition, we also observed an increase in brood number. Our study has shown that Acein regulates dopamine secretion and has good antiaging activity by decreasing clec-126 expression.

Keywords:  Acein; Caenorhabditis elegans; aging; clec-126; dopamine

DOI:  https://doi.org/10.18632/aging.205150
In Vivo. 2024 Jan-Feb;38(1):38(1): 196-204

Mitophagy Decreases in the Peripheral Vestibular System of Aged C57BL/6J Mice.

Sung Il Cho, Eu-Ri Jo, Suhyun Lee.

   BACKGROUND/AIM: Mitophagy is a cardinal process for maintaining healthy and functional mitochondria. A decline in mitophagy has been associated with age-related pathologies. We aimed to investigate mitophagy changes in age-related balance problems using an animal model.
MATERIALS AND METHODS: C57BL/6J mice were divided into young (1 month old) and aged (12 months old) groups. Balance performance, mitochondrial DNA integrity, ATP content, mitophagic process, and mitophagy-related genes and proteins were investigated in both groups.
RESULTS: Balance and motor performance were reduced in the aged group. Mitochondrial DNA integrity and ATP content, and mRNA levels of PINK1, Parkin, BNIP3, AMBRA1, MUL1, NIX, Bcl2-L-13, Atg3, Atg5, Atg12, and Atg13 in the vestibule were significantly lower in aged mice compared with those in young mice. The protein levels of PINK1, Parkin, BNIP3, LC3B, and OXPHOS subunits were significantly decreased in the aged vestibule. Mitophagosome and mitophagolysosome counts and the immunohistochemical expression of Parkin and BNIP3 were also decreased in the saccule, utricle, and crista ampullaris in the aged group.
CONCLUSION: A general decrease in mitophagy with aging might be attributed to a decrease in cellular function in the aged vestibule during the development of age-related balance problems.

Keywords:  Mitophagy; aging; mice; vestibular system

DOI:  https://doi.org/10.21873/invivo.13426
Front Endocrinol (Lausanne). 2023 ;14 1251102

Chronological age enhances aging phenomena and protein nitration in oocyte.

Pravin T Goud, Anuradha P Goud, Olivia G Camp, David Bai, Bernard Gonik, Michael P Diamond, Husam M Abu-Soud.

   Background: The average age of childbearing has increased over the years contributing to infertility, miscarriages, and chromosomal abnormalities largely invoked by an age-related decline in oocyte quality. In this study, we investigate the role of nitric oxide (NO) insufficiency and protein nitration in oocyte chronological aging.
Methods: Mouse oocytes were retrieved from young breeders (YB, 8-14 weeks [w]), retired breeders (RB, 48-52w) and old animals (OA, 80-84w) at 13.5 and 17 hours after ovulation trigger. They were assessed for zona pellucida dissolution time (ZPDT); ooplasmic microtubule dynamics (OMD); cortical granule (CG) status and spindle morphology (SM), as markers of oocyte quality. Sibling oocytes from RB were exposed to NO supplementation and assessed for aging phenomena (AP). All oocyte cumulus complexes were subjected to fluorescence nitrotyrosine (NT) immunocytochemistry and confocal microscopy to assess morphology and protein nitration.
Results: At 13.5 h from hCG trigger, oocytes from RB compared to YB had significantly increased ZPDT (37.8 ± 11.9 vs 22.1 ± 4.1 seconds [s]), OMD (46.9 vs 0%), CG loss (39.4 vs 0%), and decreased normal SM (30.3 vs 81.3%), indicating premature AP that worsened among oocytes from RB at 17 hours post-hCG trigger. When exposed to SNAP, RB AP significantly decreased (ZPDT: 35.1 ± 5.5 vs 46.3 ± 8.9s, OMD: 13.3 vs 75.0% and CG loss: 50.0 vs 93.3%) and SM improved (80.0 vs 14.3%). The incidence of NT positivity was significantly higher in cumulus cells (13.5 h, 46.7 ± 4.5 vs 3.4 ± 0.7%; 17 h, 82.2 ± 2.9 vs 23.3 ± 3.6%) and oocytes (13.5 h, 57.1 vs 0%; 17 h, 100.0 vs 55.5%) from RB compared to YB. Oocytes retrieved decreased with advancing age (29.8 ± 4.1 per animal in the YB group compared to 10.2 ± 2.1 in RB and 4.0 ± 1.6 in OA). Oocytes from OA displayed increased ZPDT, major CG loss, increased OMD and spindle abnormalities, as well as pronuclear formation, confirming spontaneous meiosis to interphase transition.
Conclusions: Oocytes undergo zona pellucida hardening, altered spindle and ooplasmic microtubules, and premature cortical granule release, indicative of spontaneous meiosis-interphase transition, as a function of chronological aging. These changes are also associated with NO insufficiency and protein nitration and may be alleviated through supplementation with an NO-donor.

Keywords:  advanced reproductive age; nitric oxide; oocyte aging; oocyte quality; oocyte temporal window

DOI:  https://doi.org/10.3389/fendo.2023.1251102
Cell Stress. 2023 Dec;7(12): 105-111

A versatile method for the identification of senolytic compounds.

Chiara Annunziata, Francesca Castoldi, Schlegel Jan, Hazel X Ang, Mina Ristovska, Stefania Melini, Robert Welch, Christian G Riedel, Federico Pietrocola.

  The increased burden of senescent cells is as a well-established hallmark of aging and age-related diseases. This finding sparked significant interest in the identification of molecules capable of selectively eliminating senescent cells, so-called senolytics. Here, we fine-tuned a method for the identification of senolytics that is compatible with high-content fluorescence microscopy. We used spectral detector imaging to measure the emission spectrum of unlabeled control or senescent cells. We observed that senescent cells exhibited higher levels of autofluorescence than their non-senescent counterparts, particularly in the cytoplasmic region. Building on this result, we devised a senolytic assay based on co-culturing quiescent and senescent cells, fluorescently tagged in the nuclear region through the overexpression of H2B-GFP and H2B-RFP, respectively. We validated this approach by showing that first generation senolytics were effective in reducing the number of RFP+ nuclei leaving the count of GFP+ nuclei unaffected. The result was confirmed by flow cytometry analysis of nuclei isolated from these quiescent-senescent cell co-cultures. We found that this system enables to capture cell type-specific effects of senolytics as in the case of fisetin, which kills senescent Mouse Embryonic Fibroblasts but not senescent human melanoma SK-MEL-103 cells. This approach is amenable to genetic and chemical screening for the discovery of senolytic compounds in that it overcomes the limitations of current methods, which rely upon costly chemical reagents or fluorescence microscopy using cells labeled with fluorescent cytoplasmic probes that overlap with the autofluorescence signal emitted by senescent cells.

Keywords:  cell death; fluorescence microscopy; navitoclax; nucleus; senescence

DOI:  https://doi.org/10.15698/cst2023.12.292
Cold Spring Harb Perspect Med. 2023 Dec 27. pii: a041201. [Epub ahead of print]

Resistance and Resilience to Alzheimer's Disease.

Caitlin S Latimer, Katherine E Prater, Nadia Postupna, C Dirk Keene.

Dementia is a significant public health crisis; the most common underlying cause of age-related cognitive decline and dementia is Alzheimer's disease neuropathologic change (ADNC). As such, there is an urgent need to identify novel therapeutic targets for the treatment and prevention of the underlying pathologic processes that contribute to the development of AD dementia. Although age is the top risk factor for dementia in general and AD specifically, these are not inevitable consequences of advanced age. Some individuals are able to live to advanced age without accumulating significant pathology (resistance to ADNC), whereas others are able to maintain cognitive function despite the presence of significant pathology (resilience to ADNC). Understanding mechanisms of resistance and resilience will inform therapeutic strategies to promote these processes to prevent or delay AD dementia. This article will highlight what is currently known about resistance and resilience to AD, including our current understanding of possible underlying mechanisms that may lead to candidate preventive and treatment interventions for this devastating neurodegenerative disease.

DOI: https://doi.org/10.1101/cshperspect.a041201
Curr Vasc Pharmacol. 2023 Dec 20.

Lipoprotein (a) as a Biomarker for Cardiovascular Diseases and Potential New Therapies to Mitigate Risk.

Debabrata Mukherjee, Steven E Nissen.

   BACKGROUND: Lipoprotein (a) [Lp(a)] is a molecule that induces inflammation of the blood vessels, atherogenesis, valvular calcification, and thrombosis.
METHODS: We review the available evidence that suggests that high Lp(a) levels are associated with a persisting risk for atherosclerotic cardiovascular diseases despite optimization of established risk factors, including low-density lipoprotein cholesterol (LDL-C) levels.
OBSERVATIONS: Approximately a quarter of the world population have Lp(a) levels of >50 mg/dL (125 nmol/L), a level associated with elevated cardiovascular risk. Lifestyle modification, statins, and ezetimibe do not effectively lower Lp(a) levels, while proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors and niacin only lower Lp(a) levels modestly. We describe clinical studies suggesting that gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting Lp(a), offer a targeted approach with the potential for safe and robust Lp(a)- lowering with only a few doses (3-4) per year. Prospective randomized phase 3 studies are ongoing to validate safety, effectiveness in improving hard clinical outcomes, and tolerability to assess these therapies.
CONCLUSION: Several emerging treatments with robust Lp(a)-lowering effects may significantly lower atherosclerotic cardiovascular risk.

Keywords:  Lipoprotein (a); antisense oligonucleotide; atherosclerosis; coronary artery disease; low-density lipoprotein; small interfering RNA.

DOI:  https://doi.org/10.2174/0115701611267835231210054909
J Am Geriatr Soc. 2023 Dec 27.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

Harlyn G Skinner, Helena Palma-Gudiel, James D Stewart, Shelly-Ann Love, Parveen Bhatti, Aladdin H Shadyab, Robert B Wallace, Elena Salmoirago-Blotcher, JoAnn E Manson, Candyce H Kroenke, Daniel W Belsky, Yun Li, Eric A Whitsel, Anthony S Zannas.

   BACKGROUND: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging-related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk.
METHODS: We leveraged the Women's Health Initiative, a large muti-ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self-report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm-based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL).
RESULTS: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (β: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (β: -0.016, 95% CI: -0.028, -0.004). Exploratory analyses showed that SLEs-GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs-DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups.
CONCLUSIONS: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self-reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging-related outcomes and have important implications for disease prevention and treatment in aging women.

Keywords:  aging; epigenetics; health disparities; psychosocial stress; social support

DOI:  https://doi.org/10.1111/jgs.18726
J Pineal Res. 2023 Dec 26. e12926

Melatonin facts: Lack of evidence that melatonin is a radical scavenger in living systems.

Jean A Boutin, Maxime Liberelle, Saïd Yous, Gilles Ferry, Françoise Nepveu.

  Melatonin is a small natural compound, so called a neuro-hormone that is synthesized mainly in pineal gland in animals. Its main role is to master the clock of the body, under the surveillance of light. In other words, it transfers the information concerning night and day to the peripheral organs which, without it, could not "know" which part of the circadian rhythm the body is in. Besides its main circadian and circannual rhythms mastering, melatonin is reported to be a radical scavenger and/or an antioxidant. Because radical scavengers are chemical species able to neutralize highly reactive and toxic species such as reactive oxygen species, one would like to transfer this property to living system, despite impossibilities already largely reported in the literature. In the present commentary, we refresh the memory of the readers with this notion of radical scavenger, and review the possible evidence that melatonin could be an in vivo radical scavenger, while we only marginally discuss here the fact that melatonin is a molecular antioxidant, a feature that merits a review on its own. We conclude four things: (i) the evidence that melatonin is a scavenger in acellular systems is overwhelming and could not be doubted; (ii) the transposition of this property in living (animal) systems is (a) theoretically impossible and (b) not proven in any system reported in the literature where most of the time, the delay of the action of melatonin is over several hours, thus signing a probable induction of cellular enzymatic antioxidant defenses; (iii) this last fact needs a confirmation through the discovery of a nuclear factor-a key relay in induction processes-that binds melatonin and is activated by it and (iv) we also gather the very important description of the radical scavenging capacity of melatonin in acellular systems that is now proven and shared by many other double bond-bearing molecules. We finally discussed briefly on the reason-scientific or else-that led this description, and the consequences of this claim, in research, in physiology, in pathology, but most disturbingly in therapeutics where a vast amount of money, hope, and patient bien-être are at stake.

Keywords:  antioxidant; melatonin; review

DOI:  https://doi.org/10.1111/jpi.12926
Am J Physiol Lung Cell Mol Physiol. 2023 Dec 27.

Small airway fibroblasts from Chronic Obstructive Pulmonary Disease patients exhibit cellular senescence.

Catherine L Wrench, Jonathan R Baker, Sue Monkley, Peter S Fenwick, Lynne Murray, Louise E Donnelly, Peter J Barnes.

   RATIONALE: Small airways disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodelling. Parenchymal derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAF) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD.
OBJECTIVES: To investigate the senescent and fibrotic phenotype of SAF in COPD.
METHODS: SAF were isolated from non-smoker, smoker and COPD lung resection tissue (n=9-17). Senescence and fibrotic marker expression were determined using iCELLigence (proliferation), qPCR, Seahorse assay and ELISAs. COPD SAF were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent v 10% smallest/non-autofluorescent). The phenotype of the senescence-enriched population was investigated using RNA-sequencing and pathway analysis.
MAIN RESULTS: Markers of senescence were observed in COPD SAF, including senescence-associated β-galactosidase, SASP release and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell-sorting to enrich for senescent COPD SAF. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA-sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis and mitochondrial dysfunction pathways.
CONCLUSIONS: These data suggest COPD SAF are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding cellular senescence in SAF may lead to potential therapies to limit SAD progression.

Keywords:  COPD; Fibroblast; Senescence; Small airways disease

DOI:  https://doi.org/10.1152/ajplung.00419.2022
Sheng Li Xue Bao. 2023 Dec 25. 75(6): 877-886

[Traditional Chinese medicine used as anti-aging agent by targeting nuclear factor erythroid 2-related factor 2 signaling pathway].

Jia-Yi Xu, Liang-Wen Yan, Shen-Kang Tang, Peng-Fei Liu.

The imbalance of redox homeostasis is a major characteristic of aging and contributes to the pathogenesis of various aging-related diseases. As a regulatory hub of redox homeostasis, nuclear factor erythroid 2-related factor 2 (NRF2) can attenuate oxidative stress by activating the transcription of many antioxidant enzymes. China is the birthplace of traditional Chinese medicine (TCM) which has been wildly used as medicine for thousands of years. Recently, TCM as anti-aging medicine has attracted enormous attention. Focusing on the NRF2 signaling pathway, this paper summarizes the correlation between various anti-aging TCM and the NRF2 signaling, and discusses the common key mechanisms by which TCM slows the aging process by targeting the NRF2 signaling network.
Redox Biol. 2023 Dec 18. pii: S2213-2317(23)00404-4. [Epub ahead of print]69 103003

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.

Kamila Łuczyńska, Zhengwen Zhang, Tadeusz Pietras, Yiguo Zhang, Hiroaki Taniguchi.

  The failure of the proper protein turnover in the nervous system is mainly linked to a variety of neurodegenerative disorders. Therefore, a better understanding of key protein degradation through the ubiquitin-proteasome system is critical for effective prevention and treatment of those disorders. The proteasome expression is tightly regulated by a CNC (cap'n'collar) family of transcription factors, amongst which the nuclear factor-erythroid 2-like bZIP factor 1 (NFE2L1, also known as Nrf1, with its long isoform TCF11 and short isoform LCR-F1) has been identified as an indispensable regulator of the transcriptional expression of the ubiquitin-proteasome system. However, much less is known about how the pivotal role of NFE2L1/Nrf1, as compared to its homologous NFE2L2 (also called Nrf2), is translated to its physiological and pathophysiological functions in the nervous system insomuch as to yield its proper cytoprotective effects against neurodegenerative diseases. The potential of NFE2L1 to fulfill its unique neuronal function to serve as a novel therapeutic target for neurodegenerative diseases is explored by evaluating the hitherto established preclinical and clinical studies of Alzheimer's and Parkinson's diseases. In this review, we have also showcased a group of currently available activators of NFE2L1, along with an additional putative requirement of this CNC-bZIP factor for healthy longevity based on the experimental evidence obtained from its orthologous SKN1-A in Caenorhabditis elegans.

Keywords:  CNC; NFE2L1(Nrf1); NFE2L2(Nrf2); Neuroprotection; SKN-1; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.redox.2023.103003
Curr Atheroscler Rep. 2023 Dec 27.

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.

Jingjing Zhu, John P H Wilding.

   PURPOSE OF REVIEW: To highlight that body fat depletion (the Yin paradigm) with glucose-lowering treatments (the Yang paradigm) are associated with metabolic benefits for patients with type 2 diabetes mellitus (T2DM).
RECENT FINDINGS: The sodium-glucose cotransporter-2 inhibitor-mediated sodium/glucose deprivation can directly improve glycemic control and kidney outcome in patients with T2DM. The glucose deprivation might also promote systemic fatty acid β-oxidation to deplete ectopic/visceral fat and thereby contribute to the prevention of cardiovascular diseases. As with metabolic surgery, bioengineered incretin-based medications with potent anorexigenic and insulinotropic efficacy can significantly reduce blood glucose as well as body weight (especially in the ectopic/visceral fat depots). The latter effects could be a key contributor to their cardiovascular-renal protective effects. In addition to a healthy diet, the newer glucose-lowering medications, with body fat reduction effects, should be prioritized when treating patients with T2DM, especially for those with established cardiovascular/renal risks or diseases.

Keywords:  Body fat; Incretin; Metabolic benefit; Sodium-glucose cotransporter-2 inhibitor; Type 2 diabetes

DOI:  https://doi.org/10.1007/s11883-023-01181-4
Aging Cell. 2023 Dec 25. e14071

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell-type deconvolution applied to human blood epigenetic clocks.

Ze Zhang, Samuel R Reynolds, Hannah G Stolrow, Ji-Qing Chen, Brock C Christensen, Lucas A Salas.

  Aging is a significant risk factor for various human disorders, and DNA methylation clocks have emerged as powerful tools for estimating biological age and predicting health-related outcomes. Methylation data from blood DNA has been a focus of more recently developed DNA methylation clocks. However, the impact of immune cell composition on epigenetic age acceleration (EAA) remains unclear as only some clocks incorporate partial cell type composition information when analyzing EAA. We investigated associations of 12 immune cell types measured by cell-type deconvolution with EAA predicted by six widely-used DNA methylation clocks in data from >10,000 blood samples. We observed significant associations of immune cell composition with EAA for all six clocks tested. Across the clocks, nine or more of the 12 cell types tested exhibited significant associations with EAA. Higher memory lymphocyte subtype proportions were associated with increased EAA, and naïve lymphocyte subtypes were associated with decreased EAA. To demonstrate the potential confounding of EAA by immune cell composition, we applied EAA in rheumatoid arthritis. Our research maps immune cell type contributions to EAA in human blood and offers opportunities to adjust for immune cell composition in EAA studies to a significantly more granular level. Understanding associations of EAA with immune profiles has implications for the interpretation of epigenetic age and its relevance in aging and disease research. Our detailed map of immune cell type contributions serves as a resource for studies utilizing epigenetic clocks across diverse research fields, including aging-related diseases, precision medicine, and therapeutic interventions.

Keywords:  DNA methylation; biological aging; cell deconvolution; epigenetic aging; epigenetic clock; epigenetics; immune cell

DOI:  https://doi.org/10.1111/acel.14071
Am J Primatol. 2023 Dec 25. e23589

Age-related changes in hematological biomarkers in common marmosets.

Alexana J Hickmott, Lidia Cervantes, Juan Pablo Arroyo, Kathy Brasky, Michael Bene, Adam B Salmon, Kimberley A Phillips, Corinna N Ross.

  Researchers and veterinarians often use hematology and clinical chemistry to evaluate animal health. These biomarkers are relatively easy to obtain, and understanding how they change across healthy aging is critical to clinical care and diagnostics for these animals. We aimed to evaluate how clinical biomarkers from a chemistry profile and complete blood count (CBC) change with age in common marmosets (Callithrix jacchus). We assessed blood samples collected during routine physical exams at the Southwest National Primate Research Center and the University of Texas Health San Antonio marmoset colonies from November 2020-November 2021. We found that chemistry and CBC profiles varied based on facility, sex, and age. Significant changes in albumin, phosphorus/creatinine ratio, albumin/globulin ratio, amylase, creatinine, lymphocyte percent, hematocrit, granulocytes percent, lymphocytes, hemoglobin, red cell distribution width, and platelet distribution width were all reported with advancing age. Aged individuals also demonstrated evidence for changes in liver, kidney, and immune system function compared with younger individuals. Our results suggest there may be regular changes associated with healthy aging in marmosets that are outside of the range typically considered as normal values for healthy young individuals, indicating the potential need for redefined healthy ranges for clinical biomarkers in aged animals. Identifying animals that exhibit values outside of this defined healthy aging reference will allow more accurate diagnostics and treatments for aging colonies.

Keywords:  aging; complete blood counts; marmoset; reference ranges; serum chemistry

DOI:  https://doi.org/10.1002/ajp.23589
Adv Biol (Weinh). 2023 Dec 27. e2300560

Temperature-Dependent Relationship of Autophagy and Apoptotic Signaling During Cold-Water Immersion in Young and Older Males.

Kelli E King, James J McCormick, Glen P Kenny.

  Autophagy is a crucial cytoprotective mechanism preventing the accumulation of cellular damage, especially during external stimuli such as cold exposure. Older adults poorly tolerate cold exposure and age-related impairments in autophagy may contribute to the associated reductions in cold tolerance. The purpose of this investigation is to evaluate the effect of different intensities of in vivo cold-water immersion and in vitro cold exposure on autophagic and apoptotic signaling in young and older males. Peripheral blood mononuclear cells (PBMCs) are isolated at baseline, end-cold exposure, and after 3 h of thermoneutral recovery. Additionally, PBMCs are treated with rapamycin and bafilomycin prior to in vitro cold exposure equivalent to in vivo core temperatures (35-37 °C). Proteins associated with autophagy, apoptosis, the heat shock response, and inflammation are analyzed via Western blotting. Moderate cold stress (0.5 °C decrease in core temperature) increased autophagic and heat shock protein activity while high cold stress (1.0 °C decrease in core temperature) augmented apoptosis in young males. In older males, minimal autophagic activation during both cold-water exposures are associated with increased apoptotic and inflammatory proteins. Although in vitro cold exposure confirmed age-related dysfunction in autophagy, rapamycin-induced stimulation of autophagic proteins underlie the potential to reverse age-related vulnerability to cold exposure.

Keywords:  aging; apoptosis; cold; heat shock proteins; macroautophagy

DOI:  https://doi.org/10.1002/adbi.202300560
J R Stat Soc Ser C Appl Stat. 2023 Nov;72(5): 1375-1393

Automated calibration for stability selection in penalised regression and graphical models.

Barbara Bodinier, Sarah Filippi, Therese Haugdahl Nøst, Julien Chiquet, Marc Chadeau-Hyam.

  Stability selection represents an attractive approach to identify sparse sets of features jointly associated with an outcome in high-dimensional contexts. We introduce an automated calibration procedure via maximisation of an in-house stability score and accommodating a priori-known block structure (e.g. multi-OMIC) data. It applies to [Least Absolute Shrinkage Selection Operator (LASSO)] penalised regression and graphical models. Simulations show our approach outperforms non-stability-based and stability selection approaches using the original calibration. Application to multi-block graphical LASSO on real (epigenetic and transcriptomic) data from the Norwegian Women and Cancer study reveals a central/credible and novel cross-OMIC role of LRRN3 in the biological response to smoking. Proposed approaches were implemented in the R package sharp.

Keywords:  OMICs integration; calibration; graphical model; penalised model; stability selection

DOI:  https://doi.org/10.1093/jrsssc/qlad058
J Control Release. 2023 Dec 22. pii: S0168-3659(23)00807-6. [Epub ahead of print]

Recent strategies for evoking immunogenic Pyroptosis in antitumor immunotherapy.

Zhangxin He, Dexiang Feng, Chaoji Zhang, Zhiqian Chen, He Wang, Jianquan Hou, Shengliang Li, Xuedong Wei.

  Pyroptosis is a specific type of programmed cell death (PCD) characterized by distinct morphological changes, including cell swelling, membrane blebbing, DNA fragmentation, and eventual cell lysis. Pyroptosis is closely associated with human-related diseases, such as inflammation and malignancies. Since the initial observation of pyroptosis in Shigella flexneri-infected macrophages more than 20 years ago, various pyroptosis-inducing agents, including ions, small molecules, and biological nanomaterials, have been developed for tumor treatment. Given that pyroptosis can activate the body's robust immune response against tumor and promote the formation of the body's long-term immune memory in tumor treatment, its status as a type of immunogenic cell death is self-evident. Therefore, pyroptosis should be used as a powerful anti-tumor strategy. However, there still is a lack of a comprehensive summary of the most recent advances in pyroptosis-based cancer therapy. Therefore, it is vital to fill this gap and inspire future drug design to better induce tumor cells to undergo pyroptosis to achieve advanced anti-tumor effects. In this review, we summarize in detail the most recent advances in triggering tumor cell immunogenic pyroptosis for adequate tumor clearance based on various treatment modalities, and highlight material design and therapeutic advantages. Besides, we also provide an outlook on the prospects of this emerging field in the next development.

Keywords:  Immunogenic cell death; Pyroptosis; Reactive oxygen species; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.jconrel.2023.12.023
Diabetes Metab Syndr Obes. 2023 ;16 4169-4177

The Correlation Between Leg Muscle Mass Index and Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.

Menggege Liu, Qing Zhang, Juan Liu, Huiling Bai, Ping Yang, Xinhua Ye, Xiaoqing Yuan.

   Objective: To analyze the relationship between leg skeletal muscle mass index (LSMI) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) and the ability of LSMI to predict NAFLD.
Methods: Two hundred patients with T2DM and NAFLD treated at Changzhou Second People's Hospital Affiliated with Nanjing Medical University and the National Metabolic Management Center from June 2022 to June 2023 were divided into four LSMI quartiles. The clinical information from the four patient groups was compared, and the relationship between type 2 diabetes and LSMI and NAFLD was examined. We used receiver operating characteristic curves to determine how well the LSMI predicts NAFLD in T2DM.
Results: The lowest quartile (Q1) had a higher prevalence of NAFLD than group Q4 (P < 0.05). LSMI was negatively associated with body mass index, LS, CAP, and other markers (P < 0.05). Receiver operating characteristic curve analysis LSMI predicted NAFLD with an ideal critical value of 0.64 and an area under the curve of 70.9%. The combined predictive value of the LSMI and the appendicular skeletal muscle mass index was more significant.
Conclusion: Reduced LSMI is associated with NAFLD.

Keywords:  ASMI; LSMI; non-alcoholic fatty liver disease; type 2 diabetes mellitus

DOI:  https://doi.org/10.2147/DMSO.S443329
Turk J Biol. 2023 ;47(5): 325-335

Androgen receptor contributes to repairing DNA damage induced by inflammation and oxidative stress in prostate cancer.

Bilge Debeleç Bütüner, Nurşah Ertunç Hasbal, Elif Işel, Dirk Roggenbuck, Kemal Sami Korkmaz.

   Background: Androgen deprivation therapy remains the first-line therapy option for prostate cancer, mostly resulting in the transition of the disease to a castration-resistant state. The lack of androgen signaling during therapy affects various cellular processes, which sometimes paradoxically contributes to cancer progression. As androgen receptor (AR) signaling is known to contribute to oxidative stress regulation, loss of AR may also affect DNA damage level and the response mechanism in oxidant and inflammatory conditions of the prostate tumor microenvironment. Therefore, this study aimed to investigate the role of AR and AR-regulated tumor suppressor NKX3.1 upon oxidative stress-induced DNA damage response (DDR) in the inflammatory tumor microenvironment of the prostate.
Materials and methods: Intracellular reactive oxygen species (ROS) level was induced by either inflammatory conditioned media obtained from lipopolysaccharide-induced macrophages or oxidants and measured by dichlorodihydrofluorescein diacetate. In addition to this, DNA damage was subsequently quantified by counting gH2AX foci using an immunofluorescence-based Aklides platform. Altered expression of proteins function in DDR detected by western blotting.
Results: Cellular levels of ROS and ROS-induced DNA double-strand break damage were analyzed in the absence and presence of AR signaling upon treatment of prostate cancer cells by either oxidants or inflammatory microenvironment exposure. The results showed that AR suppresses intracellular ROS and contributes to DNA damage recognition under oxidant conditions. Besides, increased DNA damage due to loss of NKX3.1 under inflammatory conditions was alleviated by its overexpression. Moreover, the activation of the DDR mediators caused by AR and NKX3.1 activation in androgen-responsive and castration-resistant prostate cancer cells indicated that the androgen receptor function is essential both in controlling oxidative stress and in activating the ROS-induced DDR.
Conclusion: Taken together, it is concluded that the regulatory function of androgen receptor signaling has a vital function in the balance between antioxidant response and DDR activation.

Keywords:  NKX3.1; Prostate cancer; androgen receptor; inflammation-induced carcinogenesis; reactive oxygen species; γH2AX

DOI:  https://doi.org/10.55730/1300-0152.2667
Front Immunol. 2023 ;14 1323670

The regulatory effect of growth differentiation factor 11 on different cells.

Yingchun Shao, Ting Liu, Xiaobo Wen, Renshuai Zhang, Xinlin Liu, Dongming Xing.

  Growth differentiation factor 11 (GDF11) is one of the important factors in the pathophysiological process of animals. It is widely expressed in many tissues and organs of animals, showing its wide biological activity and potential application value. Previous research has demonstrated that GDF11 has a therapeutic effect on various diseases, such as anti-myocardial aging and anti-tumor. This has not only sparked intense interest and enthusiasm among academics but also spurred some for-profit businesses to attempt to develop GDF11 as a medication for regenerative medicine or anti-aging application. Currently, Sotatercept, a GDF11 antibody drug, is in the marketing application stage, and HS-235 and rGDF11 are in the preclinical research stage. Therefore, we believe that figuring out which cells GDF11 acts on and its current problems should be an important issue in the scientific and commercial communities. Only through extensive, comprehensive research and discussion can we better understand the role and potential of GDF11, while avoiding unnecessary risks and misinformation. In this review, we aimed to summarize the role of GDF11 in different cells and its current controversies and challenges, providing an important reference for us to deeply understand the function of GDF11 and formulate more effective treatment strategies in the future.

Keywords:  GDF11; cells; diseases; function; growth differentiation factor 11

DOI:  https://doi.org/10.3389/fimmu.2023.1323670