Genome integrity as a potential index of longevity in Ashkenazi Centenarian's families.

The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls (p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.

Copy number variation as a tool for implementing pregnancy as an aging model.

Copy number variations (CNV) are a major contributor to genome variability and have been linked to aging and other degradable phenotypes such as pregnancy physiology. To demonstrate how pregnancy can be used as a model of aging, we used CNVs from pregnant mice. Candidate CNVs were selected by applying case-control analysis in human centenarians compared with control groups. These CNVs were aligned with the mouse genome and their copy variation was assessed using qRT-PCR in liver and blood tissue samples from pregnant mice throughout pregnancy (baseline; first, second, and third trimester; post-partum). Eight of the ten selected CNVs demonstrated a significant decline/increase trend throughout the pregnancy followed by opposite direction soon after delivery in the liver and blood of the mouse tissues. Furthermore, significant differential expression was detected among the candidate CNVs' close vicinity genes (APA2A, LSS, RBDHF1, PLAAT1, and SCL17A2), but not in the WSCD2 gene. Establishing a genetic link between longevity and pregnancy is a significant step toward implementing the pregnancy process as a model for aging. These results in pregnant mice highlight the mechanism and similarities between pregnancy and aging. Investigating the mechanisms that cause such rejuvenation after labor could change our aging treatment paradigm.

Epigenetics and Pregnancy: Conditional Snapshot or Rolling Event.

Epigenetics modification such as DNA methylation can affect maternal health during the gestation period. Furthermore, pregnancy can drive a range of physiological and molecular changes that have the potential to contribute to pathological conditions. Pregnancy-related risk factors include multiple environmental, behavioral, and hereditary factors that can impact maternal DNA methylation with long-lasting consequences. Identification of the epigenetic patterns linked to poor pregnancy outcomes is crucial since changes in DNA methylation patterns can have long-term effects. In this review, we provide an overview of the epigenetic changes that influence pregnancy-related molecular programming such as gestational diabetes, immune response, and pre-eclampsia, in an effort to close the gap in current understanding regarding interactions between the environment, the genetics of the fetus, and the pregnant woman.

Pregnancy as a model for aging.

The process of aging can be defined as the sum accumulation of damages and changes in metabolism during the life of an organism, due to both genetic predisposition and stochastic damage. During the gestational period and following parturition, similar damage can be seen due to the strenuous effect on the maternal body, exhibited on both the physiological and cellular level. In this review, we will focus on the similar physiological and cellular characteristics exhibited during pregnancy and aging, including induction of and response to oxidative stress, inflammation, and degradation of telomeres. We will evaluate any similar processes between aging and pregnancy by comparing common biomarkers, pathologies, and genetic and epigenetic effects, to establish the pregnant body as a model for aging. This review will approach the connection both in respect to current theories on aging as a byproduct of natural selection, and regarding unrelated biochemical similarities between the two, drawing on existing studies and models in humans and other species where relevant alike. Furthermore, we will show the response of the pregnant body to these changes, and through that illuminate unique areas of potential study to advance our knowledge of the maladies relating to aging and pregnancy, and an avenue for solutions.

The effects of environmental stressors on candidate aging associated genes.

BACKGROUND: Aging is defined as a biological and physical complex process that is characterized by the increase in susceptibility to diseases and eventually death. Aging may occur at different rates between and within species, especially or (it varies) among the long-lived ones. Here, we ask whether this diversity (e.g. aging phenotype) stems from genetic or environmental factors or as a combination between the two (epigenetics). Epigenetics play a central role in controlling changes in gene expression during aging. DNA methylation is the most abundant epigenetic modification among vertebrates and is essential to mammalian development. MATERIALS AND METHODS: In this study, we utilized the HELPtag assay to identify five candidate genes that were significantly hyper- or hypo-methylated across four different age groups in mice. The candidate genes were annotated using ensemble and their expression was further tested in vitro using the murine RAW 264.7 cell line to examine the effect of three environmental stressors (UV radiation, Hypoxia and fasting) on their expression. RNA was extracted at different time points followed by cDNA synthesis. Changes in gene expression were evaluated using qRT-PCR. RESULTS: We show that fasting and UV radiation reduced the viability of RAW264.7 cells. We also found a significant change in three candidate genes' expression levels during fasting (TOP2B, RNF13 and MRPL4). Furthermore, we found a significant change in the four candidate genes' expression levels following UVC treatment (TOP2B, RNF13, PKNOX1 and CREB5) and yet no changes were recorded in hypoxic conditions. CONCLUSION: Our results suggest that the model we used was a fitting model for the assessment of environmental stressors on candidate gene expression. In addition, we established a cellular response to the environment via changes in gene expression.