Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945. RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.

Epigenetic enzymes: A role in aging and prospects for pharmacological targeting.

The development of interventions aimed at improving healthspan is one of the priority tasks for the academic and public health authorities. It is also the main objective of a novel branch in biogerontological research, geroscience. According to the geroscience concept, targeting aging is an effective way to combat age-related disorders. Since aging is an exceptionally complex process, system-oriented integrated approaches seem most appropriate for such an interventional strategy. Given the high plasticity and adaptability of the epigenome, epigenome-targeted interventions appear highly promising in geroscience research. Pharmaceuticals targeted at mechanisms involved in epigenetic control of gene activity are actively developed and implemented to prevent and treat various aging-related conditions such as cardiometabolic, neurodegenerative, inflammatory disorders, and cancer. In this review, we describe the roles of epigenetic mechanisms in aging; characterize enzymes contributing to the regulation of epigenetic processes; particularly focus on epigenetic drugs, such as inhibitors of DNA methyltransferases and histone deacetylases that may potentially affect aging-associated diseases and longevity; and discuss possible caveats associated with the use of epigenetic drugs.

The Use of Metformin to Increase the Human Healthspan.

Metformin is a safe, effective and useful drug for glucose management in patients with diabetes. However in recent years, more attention has been paid to the possibility of using metformin as an anti-aging drug. It was shown to significantly increase the lifespan in some model organisms and delay the onset of age-associated declines. The current review summarizes advances in clinical research on the potential role of metformin in the field of lifespan and healthspan extension. Growing amounts of evidence from clinical trials suggest that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, chronic inflammation and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain types of cancer. Moreover, metformin induces autophagy by activation of AMPK and can thus be potentially used to promote heathspan by hormesis-like mechanisms. Although long-term intake of metformin is associated with low risk of adverse events, well-designed clinical trials are still required to uncover the potential use of this drug as a geroprotector.

Additional Impact of Glucose Tolerance on Telomere Length in Persons With and Without Metabolic Syndrome in the Elderly Ukraine Population.

Rationale: Association between different components of metabolic syndrome and the rate of age-related telomere shortening was reported repeatedly, although some findings are inconsistent across studies, suggesting the need for further research on the topic. In the present study, we examined relationships between different components of metabolic syndrome (MetS); glucose tolerance reflected in 2-h post-load plasma glucose (2hPG) levels and age on the leukocyte telomere length (LTL) in Ukraine population. Methods: The study was conducted on the 115 adult individuals residing in the Kyiv region (Ukraine). Among them, 79 were diagnosed with MetS according to the International Diabetes Federation definition. LTL were determined by a qPCR-based method. Multivariate logistic regression (MLR) and artificial neural networks (ANN) modeling were used for the analysis of the results. ROC-analysis was also performed to compare the predictively values of this models. Results: MetS was associated with a high (OR = 3.0 CI 1.3-6.7; p = 0.01) risk of having shorter telomeres that remained significant after adjusting for age, gender and 2hPG levels. Fasting plasma glucose (FPG) levels and other MetS components did not affect the magnitude of the relationship and did not reveal the independent influence of these factors. The level of 2hPG in turn, demonstrated a significant relationship (OR = 1.3 CI 1.0-1.6 per 1 mmol/l; p = 0.04) with LTL regardless of the presence of MetS. The non-linearity of the interactions between age, gender and 2hPG level was revealed by neural network modeling (AUC = 0.76 CI 0.68-0.84). Conclusion: Our study found that impaired glucose tolerance, but not FPG levels, affected the association between LTL and MetS, which may be also indicative for pathophysiological differences in these hyperglycemia categories. 2hPG levels can provide an opportunity for a more accurate diagnostics of MetS and for evaluating the rate of aging in patients with MetS. Further research, however, is needed to verify this assumption.

Metformin as a geroprotector: experimental and clinical evidence.

Apart from being a safe, effective and globally affordable glucose-lowering agent for the treatment of diabetes, metformin has earned much credit in recent years as a potential anti-aging formula. It has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models. The current review summarizes advances in clinical research on the potential role of metformin in the field of geroprotection, highlighting findings from pre-clinical studies on known and putative mechanisms behind its beneficial properties. A growing body of evidence from clinical trials demonstrates that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain cancer types. Moreover, due to the ability of metformin to induce autophagy by activation of AMPK, it is regarded as a potential hormesis-inducing agent with healthspan-promoting and pro-longevity properties. Long-term intake of metformin is associated with low risk of adverse events; however, well-designed clinical trials are still warranted to enable potential use of this therapeutic agent as a geroprotector.

Implications of amino acid sensing and dietary protein to the aging process.

Every organism must adapt and respond appropriately to the source of nutrients available in its environment. Different mechanisms and pathways are involved in detecting the intracellular and extracellular levels of macronutrients including amino acids. Detection of amino acids in food sources is provided by taste cells expressing T1R1 and T1R3 type receptors. Additionally, cells of the intestine, pancreas or heart sense amino acids extracellularly. Neuronal and hormonal regulation integrates and coordinates the signals at the organismal level. Amino acid-sensitive mechanisms including GCN2 protein, mTOR and LYNUS machinery adjust cellular process according to the availability of specific amino acids. Triggering these mechanisms by genetic manipulations or by external manipulations with diets has a significant impact on lifespan. In model organisms, the restriction of protein or specific amino acids within the diet leads to lifespan-extending effects. However, the translation of results from model organisms to application in humans has to take into account lifestyle, psychology, social aspects and the possibility to choose what to eat and how it is cooked.

Insulin-Like Peptides Regulate Feeding Preference and Metabolism in Drosophila.

Fruit flies have eight identified Drosophila insulin-like peptides (DILPs) that are involved in the regulation of carbohydrate concentrations in hemolymph as well as in accumulation of storage metabolites. In the present study, we investigated diet-dependent roles of DILPs encoded by the genes dilp1-5, and dilp7 in the regulation of insect appetite, food choice, accumulation of triglycerides, glycogen, glucose, and trehalose in fruit fly bodies and carbohydrates in hemolymph. We have found that the wild type and the mutant lines demonstrate compensatory feeding for carbohydrates. However, mutants on dilp2,3, dilp3, dilp5, and dilp7 showed higher consumption of proteins on high yeast diets. To evaluate metabolic differences between studied lines on different diets we applied response surface methodology. High nutrient diets led to a moderate increase in concentration of glucose in hemolymph of the wild type flies. Mutations on dilp genes changed this pattern. We have revealed that the dilp2 mutation led to a drop in glycogen levels independently on diet, lack of dilp3 led to dramatic increase in circulating trehalose and glycogen levels, especially at low protein consumption. Lack of dilp5 led to decreased levels of glycogen and triglycerides on all diets, whereas knockout on dilp7 caused increase in glycogen levels and simultaneous decrease in triglyceride levels at low protein consumption. Fruit fly appetite was influenced by dilp3 and dilp7 genes. Our data contribute to the understanding of Drosophila as a model for further studies of metabolic diseases and may serve as a guide for uncovering the evolution of metabolic regulatory pathways.

Hyperglycemia attenuates the association between telomere length and age in Ukrainian population.

Diabetes-related conditions such as chronic hyperglycemia and related oxidative stress and inflammation were repeatedly associated with accelerated telomere shortening in epidemiological studies, although some findings are inconsistent. In present study, we aimed to assess the impact of disturbances in glucose metabolism on association between age and leukocyte telomere length (LTL) in the Ukrainian population. The study was conducted on the 119 adult subjects aged between 43 and 87 years residing in the Kyiv region, Ukraine. LTL was determined by a quantitative PCR-based method. LTL was negatively correlated with the measure of abdominal obesity such as waist-hip ratio, as well as with both fasting plasma glucose (FPG) and two-hour post-load glucose (2hPG) levels. Consistently with previous studies, a significant negative association between LTL and age was observed in individuals with normal (<5.6 mmol/L) FPG levels. Unexpectedly, however, no association was found in subjects with impaired glucose metabolism assessed by abnormal FPG or/and 2hPG levels. No association between LTL and age was observed in a logistic regression model; the association between LTL and age became significant after adjusting for FPG level. In the FPG-adjusted model, 1.6-time lower odds to have long telomere length were indicated for each 10 years increase in age. We hypothesize that the attenuation of association between LTL and age in hyperglycemic persons can likely be attributed to the interaction of multidirectional processes determining this relationship.

Birth weight predicts aging trajectory: A hypothesis.

Increasing evidence suggests that risk for age-related disease and longevity can be programmed early in life. In human populations, convincing evidence has been accumulated indicating that intrauterine growth restriction (IUGR) resulting in low birth weight (<2.5 kg) followed by postnatal catch-up growth is associated with various aspects of metabolic syndrome, type 2 diabetes and cardiovascular disease in adulthood. Fetal macrosomia (birth weight > 4.5 kg), by contrast, is associated with high risk of non-diabetic obesity and cancers in later life. Developmental modification of epigenetic patterns is considered to be a central mechanism in determining such developmentally programmed phenotypes. Growth hormone/insulin-like growth factor (GH/IGF) axis is likely a key driver of these processes. In this review, evidence is discussed that suggests that different aging trajectories can be realized depending on developmentally programmed life-course dynamics of IGF-1. In this hypothetical scenario, IUGR-induced deficit of IGF-1 causes "diabetic" aging trajectory associated with various metabolic disorders in adulthood, while fetal macrosomia-induced excessive levels of IGF-1 lead to "cancerous" aging trajectory. If the above reasoning is correct, then both low and high birth weights are predictors of short life expectancy, while the normal birth weight is a predictor of "normal" aging and maximum longevity.

Early-life adversity and long-term neurobehavioral outcomes: epigenome as a bridge?

Accumulating evidence suggests that adversities at critical periods in early life, both pre- and postnatal, can lead to neuroendocrine perturbations, including hypothalamic-pituitary-adrenal axis dysregulation and inflammation persisting up to adulthood. This process, commonly referred to as biological embedding, may cause abnormal cognitive and behavioral functioning, including impaired learning, memory, and depressive- and anxiety-like behaviors, as well as neuropsychiatric outcomes in later life. Currently, the regulation of gene activity by epigenetic mechanisms is suggested to be a key player in mediating the link between adverse early-life events and adult neurobehavioral outcomes. Role of particular genes, including those encoding glucocorticoid receptor, brain-derived neurotrophic factor, as well as arginine vasopressin and corticotropin-releasing factor, has been demonstrated in triggering early adversity-associated pathological conditions. This review is focused on the results from human studies highlighting the causal role of epigenetic mechanisms in mediating the link between the adversity during early development, from prenatal stages through infancy, and adult neuropsychiatric outcomes. The modulation of epigenetic pathways involved in biological embedding may provide promising direction toward novel therapeutic strategies against neurological and cognitive dysfunctions in adult life.

HDAC inhibitors: A new promising drug class in anti-aging research.

In the last years, epigenetic regulation of gene expression is regarded as an important factor involved in a broad spectrum of aging-associated processes including loss of physical activity, frailty and genomic instability, and in development of various pathological conditions such as atherosclerosis, type 2 diabetes, cancer, immune deficits and neurodegenerative diseases. Accordingly, inhibitors of the members of superfamilies of histone deacetylases (HDACs) have been proposed, among other drugs targeting epigenetic pathways, as a promising type of therapeutics that is able to combat aging and its manifestations. The main focus of this article is a review of the literature describing the healthspan-promoting and life-extending effects of inhibitors of HDAC activity in both animal and clinical studies.

Non-genomic transmission of longevity between generations: potential mechanisms and evidence across species.

Accumulating animal and human data indicate that environmental exposures experienced during sensitive developmental periods may strongly influence risk of adult disease. Moreover, the effects triggered by developmental environmental cues can be transgenerationally transmitted, potentially affecting offspring health outcomes. Increasing evidence suggests a central role of epigenetic mechanisms (heritable alterations in gene expression occurring without changes in underlying DNA sequence) in mediating these effects. This review summarizes the findings from animal models, including worms, insects, and rodents, and also from human studies, indicating that lifespan and longevity-associated characteristics can be transmitted across generations via non-genetic factors.

Early-Life Nutritional Programming of Type 2 Diabetes: Experimental and Quasi-Experimental Evidence.

Consistent evidence from both experimental and human studies suggest that inadequate nutrition in early life can contribute to risk of developing metabolic disorders including type 2 diabetes (T2D) in adult life. In human populations, most findings supporting a causative relationship between early-life malnutrition and subsequent risk of T2D were obtained from quasi-experimental studies ('natural experiments'). Prenatal and/or early postnatal exposures to famine were demonstrated to be associated with higher risk of T2D in many cohorts around the world. Recent studies have highlighted the importance of epigenetic regulation of gene expression as a possible major contributor to the link between the early-life famine exposure and T2D in adulthood. Findings from these studies suggest that prenatal exposure to the famine may result in induction of persistent epigenetic changes that have adaptive significance in postnatal development but can predispose to metabolic disorders including T2D at the late stages of life. In this review, quasi-experimental data on the developmental programming of T2D are summarized and recent research findings on changes in DNA methylation that mediate these effects are discussed.

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 Parkinson's 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.

Anti-aging pharmacology: Promises and pitfalls.

Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology.

Longevity-modulating effects of symbiosis: insights from Drosophila-Wolbachia interaction.

Microbial communities are known to significantly affect various fitness components and survival of their insect hosts, including Drosophila. The composition of symbiotic microbiota has been shown to change with the host's aging. It is unclear whether these changes are caused by the aging process or, vice versa, they affect the host's aging and longevity. Recent findings indicate that fitness and lifespan of Drosophila are affected by endosymbiotic bacteria Wolbachia. These effects, however, are inconsistent and have been reported both to extend and shorten longevity. The main molecular pathways underlying the lifespan-modulating effects of Wolbachia remain unclear, however insulin/insulin-like growth factor, immune deficiency, ecdysteroid synthesis and signaling and c-Jun N-terminal kinase pathways as well as heat shock protein synthesis and autophagy have been proposed to play a role. Here we revise the current evidence that elucidates the impact of Wolbachia endosymbionts on the aging processes in Drosophila.

Longevity-Promoting Pharmaceuticals: Is it a Time for Implementation?

Recent experimental studies demonstrate that medications targeting aging (antioxidants, calorie restriction mimetics, autophagy inductors, etc.) can substantially promote health and extend lifespan. Pharmacologically targeting aging appears to be more effective in preventing age-related pathology compared with treatments targeted to particular pathologies. The development of new antiaging drugs represents a great opportunity for the pharmaceutical and healthcare industries.

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.