There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here, we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4 + T-cells and CD14+ monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ layer compared with blood, demonstrates that the aDMR signature is a multitissue phenomenon. Moreover, we demonstrate that agingassociated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture.

The object of this work is to try to elucidate the role of genetic and environmental factors in the aetiology of diabetes by studying a series of identical twins.Concor&ince in identical (monozygotic) twins does not necessarily mean that a disease is genetic in origin. Twins usually live together in early life and thus share the same environment. Concordance could therefore be the result of genetic or environmental similarity. However, in later life most twins live apart and then concordance does suggest a genetic disease. Discordance, on the other hand, must indicate that a disease is due, at least in part, to nongenetic factors. We are therefore particularly interested in discordance in younger and concordance in older twins. Previous Twin StudiesThere have been five large studies of diabetic twins [1-5] but all have defects; none has categorised the twins as insulin dependent diabetics (IDDs) or noninsulin dependent diabetics (NIDDs) and in 0nly two were the unaffected twins examined by glucose tolerance.Then Berg [1] reported 47 identical twin pairs of whom 35 were over 43 years old. All of these were concordant for diabetes on history or glucose tolerance testing, but of the 12 younger twin pairs only 6 were concordant. White [2] found 16 of 33 pairs to be concordant but did not categorise them by age or type of diabetes. Gottlieb and Root [3] who, like White, worked at the Joslin Clinic but, we assume, were reporting on different patients, found seven out of 10 pairs in whom diabetes was diagnosed over the age of 40 were concordant, compared to only two out of 20 younger twins. Harvald and Hauge [4] ascertained twins from the Danish twin register. Of 47 "maturity-onset" pairs 26 were concordant, of 36 younger onset pairs only 12 were concordant but unaffected twins were not tested. Pollin et al [5] studied 53 identical twin pairs among US ex-service men aged 43 to 53 and found only three pairs were concordant but again unaffected twins were not tested.All but one of these studies have also reported concordance rates in non-identical twins. Then Berg [1] found nine out of 50 pairs of non-identical twins to be concordant, White [2] two out of 63, Gottlieb and Root [3] two out of 70 and Harvald and Hauge [4] 22 out of 158. The overall figure for concordance in nonidentical twin pairs in these four studies is 35 out of 341 (10%).In spite of the limitations of these studies three broad conclusions can be drawn. 1) Identical twins always show a higher concordance rate than non-identical twins irrespective of their age at diagnosis.2) Younger onset pairs of identical twins are often discordant for diabetes.3) Older onset pairs, on the other hand, are usually concordant for diabetes.Our own previous results [6] confirm these general conclusions. Of 96 pairs of identical twins 59 index twins became diabetic before the age of 40, 31 were concordant and 28 discordant; of the 37 pairs in which the index twin was diagnosed after the age of 40 all but three were concordant. Similar proportions were found as the study has...

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Adult non–insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes–susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.

OBJECTIVESpecific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes.RESEARCH DESIGN AND METHODSWe consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).RESULTSOf 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).CONCLUSIONSAdult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.