Accelerated biological aging six decades after prenatal famine exposure.

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N=951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944-5, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Exposure to the 1959-1961 Chinese famine and risk of non-communicable diseases in later life: A life course perspective.

Child undernutrition and later-life non-communicable diseases (NCDs) are major global health issues. Literature suggests that undernutrition/famine exposure in childhood has immediate and long-term adverse health consequences. However, many studies have theoretical and methodological limitations. To add to the literature and overcome some of these limitations, we adopted a life course perspective and used more robust methods. We investigated the association between exposure to the 1959-1961 Chinese famine and later-life NCDs and if this association depends on: life stage at exposure, famine severity, and sex. We conducted a secondary data analysis of a large-scale, nationally representative, longitudinal study-the China Health and Retirement Longitudinal Study (2011-2018, 11,094 participants). We measured famine exposure/severity using self-reported experience, life stage using age at exposure, and health using the number of NCDs. We performed Poisson growth curve models. We obtained three findings. First, compared with unexposed participants, those exposed before age 18 had a higher risk of later-life NCDs, particularly if exposed in-utero (IRR = 1.90, 95% CI [1.70, 2.12], p < .001) and in the "first 1,000 days" of life (IRR = 1.86, 95% CI [1.73, 2.00], p < .001; for 0-6 months group, IRR = 1.95, 95% CI [1.67, 2.29], p < .001). Second, the famine effects among participants moderately and severely exposed were similar (IRR = 1.18, 95% CI [1.09, 1.28], p < .001 and IRR = 1.24, 95% CI [1.17, 1.32], p < .001). Third, the famine effects did not differ between females and males (IRR = 0.98, 95% CI [0.90, 1.07], p = .703). In an individual's life course, in-utero and the "first 1,000 days" are a particularly sensitive time period with marked long-term implications for NCDs if undernutrition/famine is experienced in this period. However, this window remains open until young adulthood. This highlights the need to invest more in preventing and treating child/adolescent undernutrition to tackle later-life NCDs.

Evolution of the income-related gap in health with old age: evidence from 20 countries in European and Chinese panel datasets.

Some studies show that the protective effect of higher income on health weakens with old age (age-as-leveller pattern), whereas others show that it strengthens with old age (cumulative advantage/disadvantage pattern). Many existing studies are limited in that they use single-country and/or single-timepoint designs. To overcome these limitations and better understand how the income-health gradient evolves in older age, we used cross-national and longitudinal data of the Survey of Health, Ageing and Retirement in Europe (2004-2019, N = 73,407) and the China Health and Retirement Longitudinal Study (2011-2018, N = 10,067). We operationalised health using multimorbidity and three alternative indicators (functional disability, mobility disability, and memory). We performed Poisson growth curve modelling to capture the between-participant effects of age and the within-participant effects of aging. We obtained three consistent and robust findings for Europe (patterns were observed in most countries) and China. First, the protective effect of higher income on multimorbidity, functional disability, and mobility disability was weaker for older than for younger adults (between-participant age-as-leveller pattern). Second, only the protective effect of higher income on mobility disability weakened over the later life course (within-participant age-as-leveller pattern). Third, the protective effect of higher income on memory was stronger for older than for younger adults and strengthened over the later life course (between-participant and within-participant cumulative advantage/disadvantage pattern). Longitudinal data, growth curve modelling distinguishing the between-participant from within-participant effect, and adjustments for potential confounders based on the hypothesised causal structure enabled us to better navigate the landscape of causal inference. Findings suggest that the income-related gap in physical health but not in cognitive health narrows in old age for both Europe and China.

Multimorbidity among middle-aged and older persons in urban China: Prevalence, characteristics and health service utilization.

AIM: The knowledge on multimorbidity and its impact on healthcare systems is lacking in low- and middle-income countries. We aimed to estimate the prevalence of multimorbidity, and analyze the health service use of middle-aged and older persons with multimorbidity in urban China. METHODS: Study participants included 3737 urban residents aged ≥45 years from the China Health and Retirement Longitudinal Study 2011. A total of 16 pre-specified self-reported chronic conditions were used to measure multimorbidity, which was defined as having two or more conditions. Logistic regression was used to analyze the characteristics and health service use of persons with multimorbidity. Analyses were weighted to adjust for sampling design and non-response. RESULTS: Of the study population, 51.9% were men and 20.1% were aged >70 years. Hypertension (33.1%) was the most prevalent condition, followed by arthritis (25.4%), digestive disease (18.7%), dyslipidemia (18.3%) and heart disease (17.7%). The prevalence of multimorbidity was 45.5% (95% CI 41.4-49.7%). Multivariate analyses showed that the prevalence of multimorbidity was significantly higher in respondents who are older and socioeconomically disadvantaged than that in their counterparts. Multimorbid patients used 72.7% of outpatient services and 77.3% of inpatient services. After controlling for demographic, socioeconomic, health behavior and health insurance factors, condition counts still had a positive relationship with outpatient or inpatient service use. CONCLUSIONS: The burden of multimorbidity is high among the middle-aged and older urban Chinese population. Management of multimorbidity therefore deserves more attention from health policymakers, providers and educators of health professionals in China and in other low- and middle-income countries. Geriatr Gerontol Int 2018; 18: 1447-1452.

Effects of exendin-4 on the intrarenal renin-angiotensin system and interstitial fibrosis in unilateral ureteral obstruction mice: Exendin-4 and unilateral ureteral obstruction.

OBJECTIVE: The objective of this article is to investigate the renoprotecive effects of exendin-4 in a mouse model of unilateral ureteral obstruction (UUO) and explore the putative mechanisms. METHODS: Male Balbc mice underwent sham operation or UUO surgery, and then received intraperitoneal injection of vehicle or exendin-4, respectively. After 14 days, mice were sacrificed and the left kidneys were collected and analyzed by histology, immunohistochemistry, Western blot, quantitative real-time reverse transcription polymerase chain reaction, radioimmunoassay and enzyme-linked immunosorbent assay. RESULTS: As compared to the sham group, mice that underwent UUO surgery developed more severe tubular injury and interstitial fibrosis, as well as higher expression of fibronectin (FN), collagen-1 (Col-1) and α-smooth muscle actin (α-SMA). Also, we observed higher expression of angiotensin-converting enzyme (ACE) while lower expression of angiotensin-converting enzyme 2 (ACE2), higher levels of intrarenal angiotensin II (Ang II) while lower levels of intrarenal angiotensin-(1-7), and higher expression of transforming growth factor ß1 (TGF-ß1) and phosphorylation of Smad3 (p-Smad3) in the obstructed kidneys. Impressively, these pathologic changes were significantly attenuated in the mice group of UUO treated with exendin-4. CONCLUSION: Our present study indicates for the first time that exendin-4 exerts renoprotective effects in an experimental model of UUO, partly through regulating the balance of the intrarenal renin-angiotensin system and then inhibiting the Ang II-mediated TGF-ß1/Smad3 signaling pathway.

Induction of TNF-alpha by LPS in Schwann cell is regulated by MAPK activation signals.

Mitogen-activated protein kinases (MAPKs) are important mediators of cytokine expression and are critically involved in the immune response. The lipopolysaccharide (LPS) of gram-negative bacteria induces the expression of cytokines and proinflammatory genes via the toll-like receptor 4 (TLR4) signaling pathway in diverse cell types. In vivo, Schwann cells (SCs) at the site of injury may also produce tumor necrosis factor-- alpha (TNF-alpha). However, the precise mechanisms of TNF-alpha synthesis are still not clear. The purpose of the present study was to elucidate the underlying molecular mechanisms in the cultured SCs for its ability to activate the MAPKs and TNF-alpha gene, in response to LPS. Using enzyme-linked immunosorbent assay (ELISA), it was confirmed that treatment with LPS stimulated the synthesis of TNF-alpha in a concentration- and time-dependent manner. Intracellular location of TNF-alpha was detected under confocal microscope. Moreover, LPS activated extracellular signal-regulated kinase (ERK1/2), P38 and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and induced their phosphorylation. LPS-elicited SCs TNF-alpha production was also drastically suppressed by PD98059 (ERK inhibitor), SB202190 (P38 inhibitor), or SP600125 (SAPK/JNK inhibitor). Additionally, the expression of CD14 and TLR4 was examined by RT-PCR. It was demonstrated that the expression of CD14, TLR4 was crucial for the SCs responses to LPS. In conclusion, the results provide novel mechanisms for the response of SCs to LPS stimulation, through MAPKs signaling pathways.