Alexander M. Vaiserman

Association between type 2 diabetes and prenatal exposure to the Ukraine famine of 1932–33: a retrospective cohort study

BACKGROUND The effect of fetal and early childhood living conditions on adult health has long been debated, but empirical assessment in human beings remains a challenge. We used data from during the man-made Ukrainian famine of 1932-33 to examine the association between restricted nutrition in early gestation and type 2 diabetes in offspring in later life. METHODS We included all patients with type 2 diabetes diagnosed at age 40 years or older in the Ukraine national diabetes register 2000-08, and used all individuals born between 1930 and 1938 from the 2001 Ukraine national census as the reference population. This study population includes individuals born before and after the famine period as controls, and those from regions that experienced extreme, severe, or no famine. We used prevalence odds ratios (ORs) as the measure of association between type 2 diabetes and early famine exposure, with stratification by region, date of birth, and sex for comparisons of diabetes prevalence in specific subgroups. FINDINGS Using these two datasets, we compared the odds of type 2 diabetes by date and region of birth in 43,150 patients with diabetes and 1,421,024 individuals born between 1930 and 1938. With adjustment for season of birth, the OR for developing type 2 diabetes was 1·47 (95% CI 1·37-1·58) in individuals born in the first half of 1934 in regions with extreme famine, 1·26 (1·14-1·39) in individuals born in regions with severe famine, and there was no increase (OR 1·00, 0·91-1·09) in individuals born in regions with no famine, compared with births in other time periods. Multivariable analyses confirmed these results. The associations between type 2 diabetes and famine around the time of birth were similar in men and women. INTERPRETATION These results show a dose-response relation between famine severity during prenatal development and odds of type 2 diabetes in later life. Our findings suggest that early gestation is a critical time window of development; therefore, further studies of biological mechanisms should include this period. FUNDING Ukraine State Diabetes Mellitus Program, US National Institutes of Health.

Effects of X-irradiation in early ontogenesis on the longevity and amount of the S1 nuclease-sensitive DNA sites in adult Drosophila melanogaster

The long-term consequences of the X-irradiationof Drosophila melanogaster fruit flyone-hour eggs with doses of 0.25, 0.50, 0.75,1, 2 and 4 Gy were investigated. Longevityhormesis was observed in males exposed to 0.5Gy and 0.75 Gy, but no longevity increase wasobserved in females. The electrophoreticanalysis has shown that the amount of the DNAsegments resulting from cleavage in S1nuclease-sensitive sites (<3 kb) reached39.2% of the total DNA from control males. DNAfrom the irradiated males had a smaller amountof such fragments (10–30% in differentexperimental groups). These findings indicatethat the longevity hormesis may be associatedwith irradiation-induced long-term structuraland/or functional DNA modifications.

Gut microbiota: A player in aging and a target for anti-aging intervention

Aging-associated alterations in composition, diversity and functional features of intestinal microbiota are well-described in the modern literature. They are suggested to be caused by an age-related decline in immune system functioning (immunosenescence) and a low-grade chronic inflammation (inflammaging), which accompany many aging-associated pathologies. The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health and aging by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of fat deposition and metabolism and prevention of insulin resistance. Recently, a high effectiveness and safety of novel therapeutic application such as fecal microbiota transplantation in the prevention and treatment of age-related pathological conditions including atherosclerosis, type 2 diabetes and Parkinsons disease has been demonstrated. In this review, recent research findings are summarized on the role of gut micribiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine.

Epigenetic drugs: a novel anti-aging strategy?

Aging is a natural phenomenon which is peculiar to all living organisms. However, it is believed by some scientists that senescence could be postponed or prevented by certain approaches. Some dietary ingredients and supplements have been suggested to have anti-aging and life-extending effects. Natural and synthetic dietary supplements including anti-oxidants, vitamins, and hormones are among the most popular products on the market, even without solid scientific evidence supporting their efficacy (Olshansky et al., 2002). Recently, a number of synthetic drugs used for various therapeutic applications have also been assumed to have anti-aging potential (Kapoor et al., 2009). In most cases, however, the high expectations for these drugs were not fulfilled. The effects of several substances, e.g., anti-oxidants, have been supported by data obtained in animal models, but when carefully controlled human trials have been conducted, questions about the efficacy and safety of these substances have emerged (Jerome-Morais et al., 2011). Excessive intake of anti-oxidants, vitamins, or hormones is known to destroy delicate control mechanisms of homeostatic balance, and it is not yet clear under which conditions, if any, they may have a long-term beneficial impact on life expectancy in humans (Cocheme and Murphy, 2010). Given this situation, it is necessary to increase the choice of chemical compounds which have the potential to positively affect longevity. In this Opinion, we present arguments that the development of specific drugs which target epigenetic pathways could be a highly promising anti-aging strategy.

Telomeric aging: mitotic clock or stress indicator?

Telomeres are regions of tandem arrays of TTAGGG repeats and associated proteins located at chromosomal ends that allow cells to distinguish chromosome ends from double-strand breaks and protect chromosomes from end-to-end fusion, recombination, and degradation (Houben et al., 2008). Telomeres are not linear structures, telomeric DNA is maintained in a loop structure due to many key proteins. This structure serves to protect the ends of chromosomes (Neidle and Parkinson, 2003). Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA (“end-replication problem”) (Muraki et al., 2012). Therefore, they assume to limit the number of cell cycles and act as a “mitotic clock” (Olovnikov, 1996). Shortened telomeres cause decreased proliferative potential, thus triggering senescence (Blackburn et al., 2006).

Cross-life stage and cross-generational effects of γ irradiations at the egg stage on Drosophila melanogaster life histories

The long-term effects of X-irradiation with 0.25, 0.5, 0.75 and 1 Gy of 1 h eggs on the fitness-related life history traits in adult Drosophila melanogaster fruit flies and their offspring were investigated. Following irradiation with 0.25, 0.5 and 0.75 Gy, both F0 and F1 flies have decreased adult body weight and increased locomotor (photo- and geotactic) activity, whereas metabolic rate measured as the rate of CO 2 production was unchanged or even increased, and female fecundity was slightly reduced compared to appropriate controls. In some cases, irradiation resulted in hormetic effects increased resistance to both starvation and heat shock stresses as well as life extension. An explanation of the beneficial long lasting effects induced by early irradiation is offered, which suggests that these effects are due to cross-life stage and cross-generational adaptive phenotypic plasticity.

Reciprocal cross differences in Drosophila melanogaster longevity: an evidence for non-genomic effects in heterosis phenomenon?

Reciprocal cross effects (i.e., differences between reciprocal hybrids that are developed by reversing the strains from which the dam and the sire are taken) are commonly used as a measure of sex-linkage or maternal effects. However, the papers reporting parental effects on life span of experimental animals are scarce. In order to investigate the potential of parent-of-origin effects for the longevity of hybrids, we determined the life spans of the inbred lines of Drosophila melanogaster [Oregon-R (OR), Canton-S (CS) and Uman (Um)] that differ significantly in longevity, as well as the life span of the progeny from the reciprocal crosses among them. The hybridization caused the increase in both flies’ mean and maximum life span mainly shifting the survival curves upward proportionally at all ages. This resulted in the reduction in the Gompertz intercept (frailty) whereas the Gompertz slope (the rate of aging) was predominantly unchanged. Better-parent heterosis was observed in hybrids between OR and Um inbred lines and the extent of heterosis was more pronounced in hybrids between CS and Um inbred lines if long-lived parent was used as the female parent, and short-lived parent was used as the male parent in the crossing scheme. Such discrepancy in life span between reciprocal crosses may indicate that non-chromosomal factors are significantly contributing to a heterotic response. Our data are in line with the previous reports suggesting the involvement of non-genomic factors, particularly epigenetic events attributed to hybridization, in the manifestation of heterosis.

Similar seasonality of birth in type 1 and type 2 diabetes patients: A sign for common etiology?

49[1] Vaiserman A, Carstensen B, Voitenko V, et al. Seasonality of 50birth in children and young adults (0–29 years) with type 1 51diabetes in Ukraine. Diabetologia 2007;50:32–5. 52[2] Wilkin TJ. Changing perspectives in diabetes: their impact 53on its classification. Diabetologia 2007;50:1587–92. 54[3] Chaparro RJ, Konigshofer Y, Beilhack GF, Shizuru JA, 55McDevitt HO, Chien Y. Nonobese diabetic mice express 56aspects of both type 1 and type 2 diabetes. Proc Natl Acad 57Sci USA 2006;103:12475–80. 58

Effect of X-irradiation at larval stage on adult lifespan in Drosophila melanogaster

The effects of X-ray irradiation at larval stage with doses of 1.2, 2.1, 4.2, 7.5 and 17.1 Gy on adult longevity and fecundity inDrosophila melanogaster fruit flies we restudied. A significant negative trend with increasing dose of irradiation was detected for the median lifespan in both sexes. In all experimental groups, both male and female mortality rates in irradiated flies were above control levels approximately for one month after emergence, and below control levels at older ages. The irradiation with 1.2 and 2.1 Gy resulted in 11.5% and 12.7% increase of male maximum lifespan, respectively. Irradiated females had in most cases a lower fecundity than control females. In all studied age groups, the decrease of fecundity was dose-related, and the negative effect of irradiation on fecundity was no longer observed in flies older than two weeks of age. Mean fecundity for the 4–25-day period of the irradiated females was shortened and dose-related [one-way ANOVA: F(5,414) = 10.56,P < 0.001], but significant differences from control were observed only for flies irradiated with doses of 4.2, 7.5 and 17.1 Gy. Mean fecundity for females irradiated with doses of 1.2 and 2.1 Gy did not differ from that of control females.

The role of the TOR pathway in mediating the link between nutrition and longevity

The target of rapamycin (TOR) pathway integrates signals from extracellular and intracellular agents, such as growth factors, nutrients, mediators of energy balance, oxygen availability and other environmental cues. It allows the regulation of multiple cellular processes including protein and lipid synthesis, ribosome biogenesis, autophagy and metabolic processes. Being conserved across different phyla, TOR regulates longevity of various organisms in response to dietary conditions. In this review we described the main components of the TOR pathway and its upstream effectors and downstream processes in relation to aging. The potential contribution of the TOR pathway in lifespan-extending effects of varied dietary interventions, and the anti-aging drugs rapamycin and metformin direct or indirect regulation of TOR activity in yeasts, worms, flies and mammals are also discussed.