bims-caglex 2024-04-21 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–04–21
fiveteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo.
Targeting aging and age-related diseases with vaccines.
Air Pollution Drives Macrophage Senescence through a Phagolysosome-15-Lipoxygenase Pathway.
[Senolytic effects on dental pulp stem cell's proliferation and differentiation during long-term expansion].
Techniques for assessing telomere length: A methodological review.
[Genetics, epigenetics, and environmental factors in life expectancy-What role does nature-versus-nurture play in aging?]
Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.
Aging as a loss of morphostatic information: a developmental bioelectricity perspective.
Chk2 Modulates Bmi1-Deficiency-Induced Renal Aging and Fibrosis via Oxidative Stress, DNA Damage, and p53/TGFβ1-Induced Epithelial-Mesenchymal Transition.
Plant-derived nanovesicles offer a promising avenue for anti-aging interventions.
Long-lived proteins and DNA as candidate predictive biomarkers for tissue associated diseases.
Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight.
The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.
LKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes.
Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

Biogerontology. 2024 Apr 15.

Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo.

Kento Takaya, Kazuo Kishi.

  The skin's protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and sagging, a consequence of the senescence-associated secretory phenotype (SASP) that involves the accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling. Although therapeutic approaches for eliminating senescent cells from the skin are available, their efficacy remains unclear. Accordingly, we aimed to examine the effects of dasatinib in combination with quercetin (D + Q) on senescent human skin fibroblasts and aging human skin. Senescence was induced in human dermal fibroblasts (HDFs) using approaches such as long-term passaging, ionizing radiation, and doxorubicin treatment. The generated senescent cells were treated with D + Q or vehicle. Additionally, a mouse-human chimera model was generated by subcutaneously transplanting whole-skin grafts of aged individuals onto nude mice. Mouse models were administered D + Q or vehicle by oral gavage for 30 days. Subsequently, skin samples were harvested and stained for senescence-associated beta-galactosidase. Senescence-associated markers were assessed by western blotting, reverse transcription-quantitative PCR and histological analyses. Herein, D + Q selectively eliminated senescent HDFs in all cellular models of induced senescence. Additionally, D + Q-treated aged human skin grafts exhibited increased collagen density and suppression of the SASP compared with control grafts. No adverse events were observed during the study period. Collectively, D + Q could ameliorate skin aging through selective elimination of senescent dermal fibroblasts and suppression of the SASP. Our findings suggest that D + Q could be developed as an effective therapeutic approach for combating skin aging.

Keywords:  Chimeric model; Dasatinib; Quercetin; Senolytics; Skin rejuvenation

DOI:  https://doi.org/10.1007/s10522-024-10103-z
Nat Aging. 2024 Apr;4(4): 464-482

Targeting aging and age-related diseases with vaccines.

Ruochen Wu, Fei Sun, Weiqi Zhang, Jie Ren, Guang-Hui Liu.

Aging is a major risk factor for numerous chronic diseases. Vaccination offers a promising strategy to combat these age-related diseases by targeting specific antigens and inducing immune responses. Here, we provide a comprehensive overview of recent advances in vaccine-based interventions targeting these diseases, including Alzheimer's disease, type II diabetes, hypertension, abdominal aortic aneurysm, atherosclerosis, osteoarthritis, fibrosis and cancer, summarizing current approaches for identifying disease-associated antigens and inducing immune responses against these targets. Further, we reflect on the recent development of vaccines targeting senescent cells, as a strategy for more broadly targeting underlying causes of aging and associated pathologies. In addition to highlighting recent progress in these areas, we discuss important next steps to advance the therapeutic potential of these vaccines, including improving and robustly demonstrating efficacy in human clinical trials, as well as rigorously evaluating the safety and long-term effects of these vaccine strategies.

DOI: https://doi.org/10.1038/s43587-024-00597-0
Immunohorizons. 2024 Apr 01. 8(4): 307-316

Air Pollution Drives Macrophage Senescence through a Phagolysosome-15-Lipoxygenase Pathway.

Sarah A Thomas, Hwan Mee Yong, Ana M Rule, Naina Gour, Stephane Lajoie.

Urban particulate matter (PM; uPM) poses significant health risks, particularly to the respiratory system. Fine particles, such as PM2.5, can penetrate deep into the lungs and exacerbate a range of health problems, including emphysema, asthma, and lung cancer. PM exposure is also linked to extrapulmonary disorders such as heart and neurodegenerative diseases. Moreover, prolonged exposure to elevated PM levels can reduce overall life expectancy. Senescence is a dysfunctional cell state typically associated with age but can also be precipitated by environmental stressors. This study aimed to determine whether uPM could drive senescence in macrophages, an essential cell type involved in particulate phagocytosis-mediated clearance. Although it is known that uPM exposure impairs immune function, this deficit is multifaceted and incompletely understood, partly because of the use of particulates such as diesel exhaust particles as a surrogate for true uPM. uPM was collected from several locations in the United States, including Baltimore, Houston, and Phoenix. Bone marrow-derived macrophages were stimulated with uPM or reference particulates (e.g., diesel exhaust particles) to assess senescence-related parameters. We report that uPM-exposed bone marrow-derived macrophages adopt a senescent phenotype characterized by increased IL-1α secretion, senescence-associated β-galactosidase activity, and diminished proliferation. Exposure to allergens failed to elicit such a response, supporting a distinction between different types of environmental exposure. uPM-induced senescence was independent of key macrophage activation pathways, specifically inflammasome and scavenger receptors. However, inhibition of the phagolysosome pathway abrogated senescence markers, supporting this phenotype's attribution to uPM phagocytosis. These data suggest that uPM exposure leads to macrophage senescence, which may contribute to immunopathology.

DOI: https://doi.org/10.4049/immunohorizons.2300096
Zhonghua Kou Qiang Yi Xue Za Zhi. 2024 Apr 18. 59(5): 444-453

[Senolytic effects on dental pulp stem cell's proliferation and differentiation during long-term expansion].

G Y Wang, L Liao, W D Tian.

Objective: To investigate the impact of intermittent senescent cell clearance on the proliferation and differentiation of dental pulp stem cells (DPSC) in long-term, large-scale expansion, and to explore strategies for maintaining the youthful state of DPSC in vitro. Methods: Human-derived dental pulp stem cells were isolated from healthy permanent teeth extracted for orthodontic or impeding eruption reasons, provided by the Department of Oral and Maxillofacial Surgery at West China Hospital of Stomatology, Sichuan University. Long-term, large-scale in vitro expansion of DPSC was conducted. The study compared young DPSC (passage 5) with aged DPSC (passage 25) using cellular senescence-associated β-galactosidase staining, colony formation assay, and Alizarin Red S staining for osteogenic differentiation induction. To assess the differences between the two cell populations in terms of senescence and amplification and differentiation ability. Medicine screening for the most effective senolytic was compared among 5 common senolytics [Navitoclax (ABT-263), curcumin, dasatinib, fisetin, and quercetin]. The clearance efficacy was compared using cellular senescence-associated β-galactosidase staining to reflect the changes in senescent cell ratio. The senolytic with the highest efficacy was chosen for further experiments. The passage at which the proportion of senescent cells significantly increased was identified, and the selected senolytic was administered three times at three-generation intervals from that passage to remove senescent cells. Both the control and senolytic-treated groups were estimated by fluorescence cellular senescence-associated β-galactosidase staining, real-time flurogenic quantitative PCR (qPCR), colony formation assay, wound healing assay, and Alizarin Red S staining for osteogenic differentiation induction. Subcutaneous heterotopic osteogenesis was performed in nude mice and the grafts were analyzed by HE staining and alkaline phosphatase (ALP) immunohistochemical staining. Results: The proportion of senescent cells increased as the expansion extended, leading to decreased proliferation and osteogenic differentiation ability of senescent DPSC compared to young DPSC (P<0.05). Senescent DPSC exhibited altered mRNA expression levels of senescence-related genes, including p21, p16INK4a, IL-6, and Ki67 (P<0.001). Among the five senolytics, ABT-263 demonstrated higher clearance efficiency (P<0.05). After intermittent ABT-263 treatment during expansion, the proportion of senescent cells in the senolytic-treated group [(6.72±2.34)%] was significantly lower than that in the control group [(31.82±0.57)%] (P<0.001). qPCR confirmed that compared with the control group, mRNA expressions of p21, p16INK4a, and IL-6 in the senolytic-treated group were significantly decreased (P<0.05), while mRNA expressions of Ki67 were significantly increased (P<0.01). Furthermore, the cell healing ability and osteogenic differentiation ability of the senolytic-treated group were higher than those of the control group (P<0.05). In vivo experimental results indicated that the relative new bone area [(2.36±0.48)%] after DPSC transplantation in the senolytic-treated group was greater than that in the control group [(1.00±0.46)%] (P<0.05), and the expression of ALP was higher than that in the control group (P<0.01). Conclusions: ABT-263 can effectively eliminate senescent cells in long-term large-scale DPSC expansion. Continuous: treatment with ABT-263 during cultivation can maintain the proliferation and differentiation ability of DPSC both in vivo and in vitro.

DOI: https://doi.org/10.3760/cma.j.cn112144-20240119-00030
Comput Struct Biotechnol J. 2024 Dec;23 1489-1498

Techniques for assessing telomere length: A methodological review.

Hyeon Jong Yu, Yoon Hwan Byun, Chul-Kee Park.

  Telomeres are located at the ends of chromosomes and have specific sequences with a distinctive structure that safeguards genes. They possess capping structures that protect chromosome ends from fusion events and ensure chromosome stability. Telomeres shorten in length during each cycle of cell division. When this length reaches a certain threshold, it can lead to genomic instability, thus being implicated in various diseases, including cancer and neurodegenerative disorders. The possibility of telomeres serving as a biomarker for aging and age-related disease is being explored, and their significance is still under study. This is because post-mitotic cells, which are mature cells that do not undergo mitosis, do not experience telomere shortening due to age. Instead, other causes, for example, exposure to oxidative stress, can directly damage the telomeres, causing genomic instability. Nonetheless, a general agreement has been established that measuring telomere length offers valuable insights and forms a crucial foundation for analyzing gene expression and epigenetic data. Numerous approaches have been developed to accurately measure telomere lengths. In this review, we summarize various methods and their advantages and limitations for assessing telomere length.

Keywords:  Genetic Techniques; Sequence Analysis; Southern Blotting; Telomere Lengths

DOI:  https://doi.org/10.1016/j.csbj.2024.04.011
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2024 Apr 18.

[Genetics, epigenetics, and environmental factors in life expectancy-What role does nature-versus-nurture play in aging?]

Holger Bierhoff.

  In Germany and worldwide, the average age of the population is continuously rising. With this general increase in chronological age, the focus on biological age, meaning the actual health and fitness status, is becoming more and more important. The key question is to what extent the age-related decline in fitness is genetically predetermined or malleable by environmental factors and lifestyle.Many epigenetic studies in aging research have provided interesting insights in this nature-versus-nurture debate. In most model organisms, aging is associated with specific epigenetic changes, which can be countered by certain interventions like moderate caloric restriction or increased physical activity. Since these interventions also have positive effects on lifespan and health, epigenetics appears to be the interface between environmental factors and the aging process. This notion is supported by the fact that an epigenetic drift occurs through the life course of identical twins, which is related to the different manifestations of aging symptoms. Furthermore, biological age can be determined with high precision based on DNA methylation patterns, further emphasizing the importance of epigenetics in aging.This article provides an overview of the importance of genetic and epigenetic parameters for life expectancy. A major focus will be on the possibilities of maintaining a young epigenome through lifestyle and environmental factors, thereby slowing down biological aging.

Keywords:  Aging research; Chronological and biological age; Epigenetic markers of aging; Epigenetics; Geroprotection

DOI:  https://doi.org/10.1007/s00103-024-03873-x
Biochemistry (Mosc). 2024 Feb;89(2): 356-366

Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.

Josh Mitteldorf.

  Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

Keywords:  aging clocks; epigenetic clocks; methylation clocks; phenoptosis; programmed aging

DOI:  https://doi.org/10.1134/S0006297924020135
Ageing Res Rev. 2024 Apr 16. pii: S1568-1637(24)00128-4. [Epub ahead of print] 102310

Aging as a loss of morphostatic information: a developmental bioelectricity perspective.

Léo Pio-Lopez, Michael Levin.

  Maintaining order at the tissue level is crucial throughout the lifespan, as failure can lead to cancer and an accumulation of molecular and cellular disorders. Perhaps, the most consistent and pervasive result of these failures is aging, which is characterized by the progressive loss of function and decline in the ability to maintain anatomical homeostasis and reproduce. This leads to organ malfunction, diseases, and ultimately death. The traditional understanding of aging is that it is caused by the accumulation of molecular and cellular damage. In this article, we propose a complementary view of aging from the perspective of endogenous bioelectricity which has not yet been integrated into aging research. We propose a view of aging as a morphostasis defect, a loss of biophysical prepattern information, encoding anatomical setpoints used for dynamic tissue and organ homeostasis. We hypothesize that this is specifically driven by abrogation of the endogenous bioelectric signaling that normally harnesses individual cell behaviors toward the creation and upkeep of complex multicellular structures in vivo. Herein, we first describe bioelectricity as the physiological software of life, and then identify and discuss the links between bioelectricity and life extension strategies and age-related diseases. We develop a bridge between aging and regeneration via bioelectric signaling that suggests a research program for healthful longevity via morphoceuticals. Finally, we discuss the broader implications of the homologies between development, aging, cancer and regeneration and how morphoceuticals can be developed for aging.

Keywords:  Aging; Bioelectricity; Morphogenesis; Senescence

DOI:  https://doi.org/10.1016/j.arr.2024.102310
Int J Biol Sci. 2024 ;20(6): 2008-2026

Chk2 Modulates Bmi1-Deficiency-Induced Renal Aging and Fibrosis via Oxidative Stress, DNA Damage, and p53/TGFβ1-Induced Epithelial-Mesenchymal Transition.

Jinhong Lu, Weiwei Sun, Boyang Liu, Jinge Zhang, Rong Wang, David Goltzman, Dengshun Miao.

  Renal aging may lead to fibrosis and dysfunction, yet underlying mechanisms remain unclear. We explored whether deficiency of the Polycomb protein Bmi1 causes renal aging via DNA damage response (DDR) activation, inducing renal tubular epithelial cell (RTEC) senescence and epithelial-mesenchymal transition (EMT). Bmi1 knockout mice exhibited oxidative stress, DDR activation, RTEC senescence, senescence-associated secretory phenotype (SASP), and age-related fibrosis in kidneys. Bmi1 deficiency impaired renal structure and function, increasing serum creatinine/urea, reducing creatinine clearance, and decreasing cortical thickness and glomerular number. However, knockout of the serine-threonine kinase Chk2 alleviated these aging phenotypes. Transcriptomics identified transforming growth factor beta 1 (TGFβ1) upregulation in Bmi1-deficient RTECs, but TGFβ1 was downregulated upon Chk2 knockout. The tumor suppressor protein p53 transcriptionally activated TGFβ1, promoting EMT in RTECs. Bmi1 knockout or oxidative stress (induced with H2O2) increased TGFβ1 expression, and EMT in RTECs and was partly reversed by p53 inhibition. Together, Bmi1 deficiency causes oxidative stress and DDR-mediated RTEC senescence/SASP, thus activating p53 and TGFβ1 to induce EMT and age-related fibrosis. However, blocking DDR (via Chk2 knockout) or p53 ameliorates these changes. Our study reveals mechanisms whereby Bmi1 preserves renal structure and function during aging by suppressing DDR and p53/TGFβ1-mediated EMT. These pathways represent potential targets for detecting and attenuating age-related renal decline.

Keywords:  Bmi1; Chk2; TGFβ1; aging-related renal fibrosis; p53

DOI:  https://doi.org/10.7150/ijbs.93598
Physiol Plant. 2024 Mar-Apr;176(2):176(2): e14283

Plant-derived nanovesicles offer a promising avenue for anti-aging interventions.

Yiming Meng, Jing Sun, Tao Yu, Haozhe Piao.

Over the past few years, the study of plant-derived nanovesicles (PDNVs) has emerged as a hot topic of discussion and research in the scientific community. This remarkable interest stems from their potential role in facilitating intercellular communication and their unique ability to deliver biologically active components, including proteins, lipids, and miRNAs, to recipient cells. This fascinating ability to act as a molecular courier has opened up an entirely new dimension in our understanding of plant biology. The field of research focusing on the potential applications of PDNVs is still in its nascent stages. However, it has already started gaining traction due to the growing interest in its possible use in various branches of biotechnology and medicine. Their unique properties and versatile applications offer promising future research and development prospects in these fields. Despite the significant progress in our understanding, many unanswered questions and mysteries surround the mechanisms by which PDNVs function and their potential applications. There is a dire need for further extensive research to elucidate these mechanisms and explore the full potential of these fascinating vesicles. As the technology at our disposal advances and our understanding of PDNVs deepens, it is beyond doubt that PDNVs will continue to be a subject of intense research in anti-aging therapeutics. This comprehensive review is designed to delve into the fascinating and multifaceted world of PDNV-based research, particularly focusing on how these nanovesicles can be applied to anti-aging therapeutics.

DOI: https://doi.org/10.1111/ppl.14283
iScience. 2024 Apr 19. 27(4): 109642

Long-lived proteins and DNA as candidate predictive biomarkers for tissue associated diseases.

Xiaosong Liu, Bozidar Novak, Christian Namendorf, Barbara Steigenberger, Yaoyang Zhang, Christoph W Turck.

  Protein turnover is an important mechanism to maintain proteostasis. Long-lived proteins (LLPs) are vulnerable to lose their function due to time-accumulated damages. In this study we employed in vivo stable isotope labeling in mice from birth to postnatal day 89. Quantitative proteomics analysis of ten tissues and plasma identified 2113 LLPs, including widespread and tissue-specific ones. Interestingly, a significant percentage of LLPs was detected in plasma, implying a potential link to age-related cardiovascular diseases. LLPs identified in brains were related to neurodegenerative diseases. In addition, the relative quantification of DNA-derived deoxynucleosides from the same tissues provided information about cellular DNA renewal and showed good correlation with LLPs in the brain. The combined data reveal tissue-specific maps of mouse LLPs that may be involved in pathology due to a low renewal rate and an increased risk of damage. Tissue-derived peripheral LLPs hold promise as biomarkers for aging and age-related diseases.

Keywords:  Disease; Protein; Proteomics; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2024.109642
Biomed Pharmacother. 2024 Apr 13. pii: S0753-3322(24)00476-1. [Epub ahead of print]174 116592

Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight.

Lisa Dal Pozzo, Zhe Xu, Shan Lin, Jida Wang, Ying Wang, Ogbe Susan Enechojo, Joseph Kofi Abankwah, Yanfei Peng, Xiaoqian Chu, Huifang Zhou, Yuhong Bian.

  Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.

Keywords:  Epigenetics; Geroprotector; Senescence; Skin Aging; Traditional Chinese Medicine

DOI:  https://doi.org/10.1016/j.biopha.2024.116592
Aging (Albany NY). 2024 Apr 12. 16

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Stephen A Banse, E Grace Jackson, Christine A Sedore, Brian Onken, David Hall, Anna Coleman-Hulbert, Phu Huynh, Theo Garrett, Erik Johnson, Girish Harinath, Delaney Inman, Suzhen Guo, Mackenzie Morshead, Jian Xue, Ron Falkowski, Esteban Chen, Christopher Herrera, Allie J Kirsch, Viviana I Perez, Max Guo, Gordon J Lithgow, Monica Driscoll, Patrick C Phillips.

  Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Keywords:  aging; compound intervention; genetic diversity; healthspan

DOI:  https://doi.org/10.18632/aging.205743
Nat Commun. 2024 Apr 18. 15(1): 3336

LKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes.

Pengfei Lv, Xingzhuo Yang, Juan Du.

To understand aging impact on the circadian rhythm, we screened for factors influencing circadian changes during aging. Our findings reveal that LKRSDH mutation significantly reduces rhythmicity in aged flies. RNA-seq identifies a significant increase in insulin-like peptides (dilps) in LKRSDH mutants due to the combined effects of H3R17me2 and H3K27me3 on transcription. Genetic evidence suggests that LKRSDH regulates age-related circadian rhythm changes through art4 and dilps. ChIP-seq analyzes whole genome changes in H3R17me2 and H3K27me3 histone modifications in young and old flies with LKRSDH mutation and controls. The results reveal a correlation between H3R17me2 and H3K27me3, underscoring the role of LKRSDH in regulating gene expression and modification levels during aging. Overall, our study demonstrates that LKRSDH-dependent histone modifications at dilps sites contribute to age-related circadian rhythm changes. This data offers insights and a foundational reference for aging research by unveiling the relationship between LKRSDH and H3R17me2/H3K27me3 histone modifications in aging.

DOI: https://doi.org/10.1038/s41467-024-47740-4
Eur Heart J. 2024 Apr 16. pii: ehae206. [Epub ahead of print]

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

Yuebin Lv, Yue Zhang, Xinwei Li, Xiang Gao, Yongyong Ren, Luojia Deng, Lanjing Xu, Jinhui Zhou, Bing Wu, Yuan Wei, Xingyao Cui, Zinan Xu, Yanbo Guo, Yidan Qiu, Lihong Ye, Chen Chen, Jun Wang, Chenfeng Li, Yufei Luo, Zhaoxue Yin, Chen Mao, Qiong Yu, Hui Lu, Virginia Byers Kraus, Yi Zeng, Shilu Tong, Xiaoming Shi.

   BACKGROUND AND AIMS: Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China.
METHODS: A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality.
RESULTS: During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955-0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950-0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928-0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036-1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064-1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016-1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC.
CONCLUSIONS: Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Keywords:  Body mass index; Causal inference; Mendelian randomization; Mortality; Waist circumference

DOI:  https://doi.org/10.1093/eurheartj/ehae206