Aging-related Diseases Research Articles

Can salivary and skin microbiome become a biodetector for aging-associated diseases? Current insights and future perspectives.

Growth and aging are fundamental elements of human development. Aging is defined by a decrease in physiological activities and higher illness vulnerability. Affected by lifestyle, environmental, and hereditary elements, aging results in disorders including cardiovascular, musculoskeletal, and neurological diseases, which accounted for 16.1 million worldwide deaths in 2019. Stress-induced cellular senescence, caused by DNA damage, can reduce tissue regeneration and repair, promoting aging. The root cause of many age-related disorders is inflammation, encouraged by the senescence-associated secretory phenotype (SASP). Aging's metabolic changes and declining immune systems raise illness risk via promoting microbiome diversity. Stable, individual-specific skin and oral microbiomes are essential for both health and disease since dysbiosis is linked with periodontitis and eczema. Present from birth to death, the human microbiome, under the influence of diet and lifestyle, interacts symbiotically with the body. Poor dental health has been linked to Alzheimer's and Parkinson's diseases since oral microorganisms and systemic diseases have important interactions. Emphasizing the importance of microbiome health across the lifetime, this study reviews the understanding of the microbiome's role in aging-related diseases that can direct novel diagnosis and treatment approaches.

The potential of Andaliman (Zanthoxylum acanthopodium DC) fruit as an ethanol extract for neuroprotection in aged model rat.

Dementia is a common aging-related neurodegenerative disease in the elderly worldwide. Alterations in neurogenesis and angiogenesis factors have been linked to cognitive impairment in neurological disorders. However, synthetic drugs to improve memory disorders have uncomfortable side effects. The purpose of this study is to explore the neuroprotective potential of the fruit ethanol extract of andaliman (Zanthoxylum acanthopodium DC) [Andaliman fruit ethanol extract (AEE)] on brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and spatial memory in rat models of aging. This study had an experimental design with AEE. The 4 groups were treated as follows: N (normal), M (served as positive control), P1 (AEE 150 mg/kg bw), and P2 (AEE 300 mg/kg BW) for 8 weeks. Aged model rats (M, P1, and P2) were obtained by inducing D-galactose (150 mg/kg bw). BDNF and VEGF expression were determined by RT-PCR, and spatial memory was assessed using the test of the Moris Water Maze (MWM). The Kruskal-Wallis and Mann-Whitney tests were used to assess the statistical analysis. AEE had a tendency to increase BDNF in P2 compared to the normal group (1.98 versus 1). VEGF expression increased in P1 and P2 compared to the normal group (1.14 and 1.29 versus 1). AEE at a dose of 300 mg/kg bw significantly improved spatial memory (p = 0.026). For eight weeks, AEE at a dose of 300 mg/kg bw considerably increased the potential to enhance VEGF and BDNF expression as well as spatial memory.

Skeletal phenotypes and molecular mechanisms in aging mice.

Aging is an inevitable physiological process, often accompanied by age-related bone loss and subsequent bone-related diseases that pose serious health risks. Research on skeletal diseases caused by aging in humans is challenging due to lengthy study durations, difficulties in sampling, regional variability, and substantial investment. Consequently, mice are preferred for such studies due to their similar motor system structure and function to humans, ease of handling and care, low cost, and short generation time. In this review, we present a comprehensive overview of the characteristics, limitations, applicability, bone phenotypes, and treatment methods in naturally aging mice and prematurely aging mouse models (including SAMP6, POLG mutant, LMNA, SIRT6, ZMPSTE24, TFAM, ERCC1, WERNER, and KL/KL-deficient mice). We also summarize the molecular mechanisms of these aging mouse models, including cellular DNA damage response, senescence-related secretory phenotype, telomere shortening, oxidative stress, bone marrow mesenchymal stem cell (BMSC) abnormalities, and mitochondrial dysfunction. Overall, this review aims to enhance our understanding of the pathogenesis of aging-related bone diseases.

Curcumin improves atrial fibrillation susceptibility by regulating tsRNA expression in aging mouse atrium.

Age is an independent risk factor for atrial fibrillation (AF), and curcumin can delay aging related disease through reducing oxidative stress and inflammation. However, its target in aging-related AF remains unclear. Transfer RNA-derived small RNA (tsRNA) is a novel short non-coding RNA (sncRNA), and exerts a potential regulatory function in aging. This study was to explore the therapeutic targets of curcumin in atrium of aged mice by PANDORA-seq. Aged mice (18 month) were treated with curcumin (100 mg/kg). Rapid transjugular atrial pacing was performed to observe AF inducibility. SA-β-gal staining, reactive oxygen species (ROS) detection and qRT-PCR were used to assess the degree of aging and oxidative stress/inflammation levels. PANDORA-seq was performed to reveal the differentially expressed sncRNAs in the atrium of mice. The results showed that curcumin reduced the susceptibility AF of aged mice by improving aging-related atrial fibrosis. Compared to young mice (5 month) group, aged mice yielded 473 significantly altered tsRNA sequences, while 947 tsRNA sequences were significantly altered after treated with curcumin. Enrichment analysis revealed that the target genes were mainly related to DNA damage and protein modification. Compared with the 5 month group, the expression levels of mature-mt_tRNA-Val-TAC_CCA_end, mature-mt_tRNA-Glu-TTC_CCA_end, and mature-tRNA-Asp-GTC_CCA_end were up-regulated in the 18 month group, while the expression of mature-mt_tRNA-Thr-TGT_5_end was down-regulated. This trend was reversed in the 18 month + curcumin group. Increased cellular ROS levels, inflammation expression and senescence in aged mice atrium were improved by the down-regulation of mature-mt_tRNA-Val-TAC_CCA_end. In conclusion, our findings identified mature-mt_tRNA-Val-TAC_CCA_end participated in the mechanism of aging-related atrial fibrosis, providing new intervention target of aging-related AF.

The role and research progress of MDSC in immune aging-related diseases

The role and research progress of MDSC in immune aging-related diseases

The role and research progress of MDSC in immune aging-related diseases

The role and research progress of MDSC in immune aging-related diseases

Exploring mechanisms of insulin action and strategies to treat diabetes.

Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.

The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation

Ethnopharmacological relevanceThe Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited. Aim of the studyIn this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis. Materials and methodsBy RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-β-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence. ResultsWe reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence. ConclusionsTogether these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.

GLP1 Receptor Agonists-Effects beyond Obesity and Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits of GLP1RA may be indirect due to their effects on obesity and glucose metabolism. However, there is building evidence that GLP1RA may also act directly on multiple organs implicated in aging-related pathology. This review aims to compile the studies reporting the effects of GLP1RA on aging-related diseases and discuss potential underlying mechanisms.

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

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.

Ginseng promotes the function of intestinal stem cells through the Wnt/β-catenin signaling pathway in D-galactose-induced aging mice

BackgroundIntestinal stem cells (ISCs) are the reservoir source of various types of intestinal cells, and the decline of stem cell function in the gut may be a potential factor for aging-related disease. The present study aimed to explore the regulatory mechanisms of Panax ginseng C.A.Meyer (Araliaceae, Panax genus) that could restore gut aging by enhancing intestinal function and regulating ISCs in aging mice based on the Wnt/β-catenin signaling pathway. MethodsA total of 60 ICR male mice were randomly divided into control, model, metformin, and ginseng water decoction (GWD) 3.6, 1.8, and 0.9 g/kg groups. The aging model was induced by 1 % D-galactose (s.c. 0.1 mL/10 g) for 28 days. Moreover, GWD was given to aging mice intragastrically (i.g.) once a day for 28 successive days. The learning memory ability, pathological status, and function in the ileum tissue, the activity of digestive enzymes, and short-chain fatty acid (SCFA) content in the colon were evaluated, and the related mechanism was investigated. ResultsGinseng can decrease the escape latency time and increase the swimming speed and the number of crossing platforms in aging mice. Moreover, the pathology of ileum tissue improved, the length of the intestinal villi increased, and the width of the villi and the depth of the crypts decreased. The activities of trypsin, α-amylase, and lipase increased in duodenal content and intestinal mucosa. In the colon, the content of SCFA, such as acetic acid, propionic acid and butyric acid, increased, indicating that ginseng significantly improves intestinal function impairment. The mRNA expressions and protein levels of β-catenin, C-myc, GSK-3β, Lgr5, and Olfm4 were upregulated in the ginseng group. ConclusionsGinseng improves intestinal function and regulates the function of ISCs in order to protect intestinal health by activating the Wnt/β-catenin signaling pathway in aging mice.

Discovery of a 4-Hydroxy-3'-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent.

With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3'-trifluoromethoxy-substituted resveratrol derivative (4-6), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4-6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body's immunity in the spleen. Further D-gal-induced brain aging studies showed that 4-6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4-6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta-trifluoromethoxy substituted 4-6 deserved to be further investigated as an effective anti-aging candidate drug.

3-HK SUPPLEMENTATION INCREASES NICOTINATE PHOSPHORIBOSYLTRANSFERASE (NAPRT) EXPRESSION IN DROSOPHILA

Abstract The increasing prevalence of physical frailty and aging related diseases in older adults necessitates the development of novel biological strategies to slow age-related declines. In humans, tryptophan metabolism through the kynurenine pathway (KP), which produces the energy metabolite and cellular cofactor nicotinamide adenine dinucleotide (NAD+), has been linked to various aging-related diseases including metabolic syndrome, neurodegenerative diseases, and physical frailty. Elevated levels of KP metabolites, such as 3-hydroxykinurenine (3-HK), correlate negatively with lifespan and physical function. A profile of downstream KP metabolites in the serum of older adults showed that 3-HK was increased in frail compared to both non-frail and young subjects, and liver kynurenine/tryptophan ratio correlates negatively with maximum lifespan in twenty-six mammalian species. To comprehensively explore the effects of elevated cytotoxic KP metabolites, we fed DGRP_229 Drosophila males diet infused with 3-HK. We found that treatment with 3-HK reduced average lifespan by 17% (P< 0.0001) compared against control. To elucidate the biological mechanisms of 3-HK treatment, we performed qRT-PCR on 11 genes involved in tryptophan metabolism. We found that treatment with 3-HK significantly decreased the expression of nicotinate phosphoribosyltransferase (Naprt) (P=0.0022), which plays an important role in NAD+ biosynthesis and protects against oxidative stress. Our findings indicate that some of the detrimental effects observed after 3-HK supplementation may be mediated by changes in NAD+ biosynthesis and highlight the potential feasibility of using NAD+ supplementation as an intervention method.

TRANSCRIPTOMIC SIGNATURES FOR AGING AND EXTREME OLD AGE IDENTIFIED IN LONG LIFE FAMILY STUDY

Abstract Transcriptional studies of blood have previously identified changes in gene expression profiles associated with age. Centenarians, a rare population of individuals that reach 100 years of age, experience delays in aging-related diseases and mortality. Thus, the analysis of their blood transcriptome may help shed light on mechanisms contributing to healthy aging and extreme longevity, as well as enable the discovery of candidate molecular therapeutic targets. In this project, we analyzed RNAseq-based blood transcriptomic data and genetic data from 1,286 participants in the Long Life Family Study age ranged from 25 to 108. To identify transcripts with different abundances at different ages, we used linear mixed-effect models and included relevant covariates to control for genetic, socioeconomic, and technical confounders. We also estimated a genetic relationship matrix (GRM) from the genotype data to account for familial relatedness. We used the same models and covariates to compare transcripts’ abundance between the extreme old and younger participants to discover markers of extreme old age. Among the 11k RNA transcripts tested, we identified 5,249 aging markers (FDR ≤ 0.01) and 761 extreme old age markers (FDR ≤ 0.01). We successfully replicated our aging signature with previously published aging signature in another cohort with comparable Z-scores. Currently, further investigation is ongoing to distinguish markers that contribute to extreme longevity from markers that represent extreme old age. This study found large signatures of age and extreme old age and will serve as a valuable reference for future research to identify molecular mechanisms of healthy aging.

ESTIMATING THE EFFECTS OF A POTENTIAL VACCINE FOR CYTOMEGALOVIRUS ON DISABILITIES AMONG OLDER ADULTS IN THE US

Abstract Cytomegalovirus (CMV) infection has been identified as contributing to the development several aging-related diseases, such as disabilities. However, the development of CMV vaccines has been slow, particularly of those targeting older individuals. With few studies that have investigated the potential effects of a CMV vaccine on disabilities among older adults, we aim to study such effects on mobility disabilities by tasks. We use longitudinal data from the Health and Retirement Study (HRS) from 2016 to 2020 to quantify what proportion of disabilities could be prevented in the United States with a viable CMV vaccine. The analytic sample includes N=5,855 individuals aged 65 or above. Under the assumption that a hypothetical vaccine would shift CMV levels from seropositive to seronegative, we construct a binary indicator based on the continuous IgG antibody measure of serum CMV. Using a novel logistic regression-based approach that allows adjustment for continuous age, we estimate attributable fractions (AF) to seropositive CMV levels for five dichotomous outcomes about difficulty with activities of daily living (ADLs), including walking across a room, dressing, bathing, eating, getting in and out of bed, and using the toilet, and stratify the analyses by sex and race/ethnicity. The findings will implicate the potential impact of a vaccine for CMV on mobility disability in older adults, laying the groundwork for future studies to examine the impact of vaccines on disabilities at different time points with varying efficacy levels among the elderly.

HARNESSING COMPLEMENTARY RESEARCH SKILLS TO ADVANCE RESEARCH ON FINANCIAL DECISION MAKING

Abstract Financial decision making comprises a set of cognitive skills including problem-solving, critical thinking, and an understanding of key financial facts that help people make informed decisions about their money. Research indicates that financial decision making is one of the earliest areas of cognitive functioning to be affected by aging and by aging-related neurological disease. The Financial Decision Making Special Interest Group (SIG) has brought together several interdisciplinary researchers from social work and neuropsychology to advance our understanding of financial decision making trajectories in older adults, and how these trajectories impact their risk of harmful financial outcomes. Members bring different skills to the collaboration--cognitive assessment, working with clinical populations, and deep knowledge of the effects of poor decision making on financial security and risk of fraud and exploitation. In this presentation, SIG members will share how they overcame challenges to develop a collaborative research agenda, including building membership and identifying samples in which to pilot measures of financial decision making.

EARLY-LIFE EXPOSURE TO THE GREAT DEPRESSION AND THE PACE OF BIOLOGICAL AGING

Abstract The Developmental Origins of Health and Disease hypothesis proposes that insults to early-life development can result in increased risk for aging-related disease later in life. There is growing interest within gerontology in the potential role such early life exposures play in shaping processes of aging. However, causal research linking early-life exposures to processes of aging in later life is rare. Moreover, there are difficulties in distinguishing the impacts of exposures occurring at different stages of early life development. In this study, we build on a quasi-natural experiment design we developed that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposure in early life on aging outcomes in the US Health and Retirement Study (HRS) (2022 PNAS). Our design allows us to distinguish effects of exposure during different periods of early life development – in-utero, in the first year of life, and later in childhood. In the present study, we apply this framework specifically to study impacts of early-life exposure to the Great Depression on pace of aging in later life. We measure pace of aging using repeated-measures longitudinal functional test and biomarker data and, in parallel, a single-timepoint blood-DNA methylation assessment of the DunedinPACE epigenetic clock through the 2016 HRS assessment wave. We further examine whether impacts of the Great Depression on the pace of aging translate into differences in morbidity and mortality through 2020.

MULTIOMIC SYSTEMS ANALYSIS OF LIFESPAN-EXTENDING INTERVENTIONS IN MOUSE TISSUES

Abstract Aging is associated with dysregulation of molecular, cellular, and physiological processes. Nutritional and pharmacological interventions with different postulated modes of action have been shown to extend lifespan and delay aging-related diseases in model organisms, suggesting the existence of core cellular processes that mediate the effect on lifespan and healthspan. However, these underlying molecular processes remain largely uncharacterized. In this study, we analyzed multiomic tissue-derived data of lifespan-extending interventions in mice including metabolomics and proteomics from the NIA Longevity Consortium and previously reported transcriptomics. We applied three systems techniques, differential rank conservation (DIRAC) analysis, weighted gene co-expression network analysis (WGCNA), and mouse genome-scale metabolic model (GEM) reconstruction, to the mouse liver proteomic and transcriptomic datasets of lifespan-extending interventions (e.g., acarbose, 17α-estradiol, and rapamycin). We found that these interventions generally strengthen the rank conservation of biological processes and shift metabolic fluxes, with fatty acid metabolism emerging as a common process affected by multiple interventions. We then applied these approaches to an expanded experimental data with additional interventions (e.g., canagliflozin) and tissues (e.g., kidney, muscle, and plasma), confirming our results and further observing varied inter-omic and inter-tissue patterns exerted by lifespan-extending interventions. Our findings highlight the potential of integrative systems analysis to elucidate common and unique cellular and physiological changes relating to aging and lifespan-extending interventions, which have translational potential as preventive and prognostic measures to improve human health.

IN UTERO EXPOSURE TO THE DUTCH HUNGER WINTER AND THE PACE OF BIOLOGICAL AGING

Abstract Adults with histories of early-life adversity experience younger age-of-onset for aging-related disease and shorter lifespan, suggesting an accelerated pace of biological aging. To test this hypothesis, we analyzed data from an established natural experiment: in-utero exposure to famine conditions induced by a Nazi blockade of the Southern Netherlands in Winter 1944-5. We analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N=951). DHWFS enrolled survivors of in-utero famine exposure, matched controls born in the same hospitals as the survivors immediately prior to and following the famine period, and siblings of these individuals. Blood samples were collected when the famine survivors were aged 58. We analyzed blood DNA methylation data to measure the GrimAge and PhenoAge 2nd-generation epigenetic clocks and the DunedinPACE 3rd-generation clock. We tested if famine survivors were biologically older and aging faster as compared to controls. We found that famine survivors had faster DunedinPACE pace of aging, as compared with controls, but similar PhenoAge and GrimAge biological ages. In sex-stratified analyses, we found stronger effects of famine exposure in women as compared with men, including for the GrimAge and PhenoAge clocks; among women, famine exposure was associated with faster DunedinPACE and older GrimAge and PhenoAge, whereas in men effect-sizes were near zero. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Sibling-difference analyses reproduced size and direction of effect estimates. Findings provide natural-experiment evidence for long-term effects of in-utero famine exposure on the pace biological aging.

Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications.

It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by 'imbalanced adipokines' in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.