Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging

ABSTRACTCattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the chronological age of the oocyte donor. Both epigenetic clock studies and epigenome wide association studies revealed that blood and oocytes differ substantially with respect aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood, however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.

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Menstrual Changes Mark Reproductive Aging

Family Practice News ◽

10.1016/s0300-7073(12)70177-9 ◽

2012 ◽

Vol 42 (4) ◽

pp. 4

Author(s):

JENNIE SMITH

Keyword(s):

Reproductive Aging

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Faculty Opinions recommendation of TGF-β and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5789956.5771054 ◽

2010 ◽

Author(s):

Andy Golden

Keyword(s):

Insulin Signaling ◽

Reproductive Aging ◽

Quality Maintenance

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Kisspeptin level in the aging ovary is regulated by the sympathetic nervous system

Journal of Endocrinology ◽

10.1530/joe-16-0181 ◽

2017 ◽

Vol 232 (1) ◽

pp. 97-105 ◽

Cited By ~ 12

Author(s):

Daniela Fernandois ◽

Gonzalo Cruz ◽

Eun Kyung Na ◽

Hernán E Lara ◽

Alfonso H Paredes

Keyword(s):

Adrenergic Receptor ◽

Follicular Development ◽

Sympathetic Nerves ◽

Female Rats ◽

Reproductive Aging ◽

Beta Adrenergic Receptor ◽

Beta Adrenergic ◽

Primordial Follicles ◽

Follicular Cyst

Previous work has demonstrated that the increase in the activity of sympathetic nerves, which occurs during the subfertility period in female rats, causes an increase in follicular cyst development and impairs follicular development. In addition, the increase in ovarian sympathetic activity of aged rats correlates with an increased expression of kisspeptin (KISS1) in the ovary. This increase in KISS1 could participate in the decrease in follicular development that occurs during the subfertility period. We aimed to determine whether the blockade of ovarian sympathetic tone prevents the increase in KISS1 expression during reproductive aging and improves follicular development. We performed 2 experiments in rats: (1) an in vivo blockade of beta-adrenergic receptor with propranolol (5.0 mg/kg) and (2) an ovarian surgical denervation to modulate the sympathetic system at these ages. We measured Kisspeptin and follicle-stimulating hormone receptor (FSHR) mRNA and protein levels by qRT-PCR and western blot and counted primordial, primary and secondary follicles at 8, 10 and 12 months of age. The results showed that ovarian KISS1 decreased but FSHR increased after both propranolol administration and the surgical denervation in rats of 8, 10 and 12 months of age. An increase in FSHR was related to an increase in the number of smaller secondary follicles and a decreased number of primordial follicles at 8, 10 and 12 months of age. These results suggest that intraovarian KISS1 is regulated by sympathetic nerves via a beta-adrenergic receptor and participates locally in ovarian follicular development in reproductive aging.

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DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

Epigenetics & Chromatin ◽

10.1186/s13072-020-00379-z ◽

2021 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Jack Hearn ◽

Fiona Plenderleith ◽

Tom J. Little

Keyword(s):

Dna Methylation ◽

Caloric Restriction ◽

Daphnia Magna ◽

Single Gene ◽

Methylation Status ◽

Strain Differences ◽

Life History Trait ◽

Food Level ◽

Epigenetic Clock ◽

Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

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Nicotinamide Supplementation Improves Oocyte Quality and Offspring Development by Modulating Mitochondrial Function in an Aged Caenorhabditis elegans Model

Antioxidants ◽

10.3390/antiox10040519 ◽

2021 ◽

Vol 10 (4) ◽

pp. 519

Author(s):

Hyemin Min ◽

Mijin Lee ◽

Kyoung Sang Cho ◽

Hyunjung Jade Lim ◽

Yhong-Hee Shim

Keyword(s):

Caenorhabditis Elegans ◽

Mitochondrial Function ◽

Stress Responses ◽

Oocyte Quality ◽

Embryonic Lethality ◽

Reproductive Aging ◽

Control Female ◽

Offspring Development ◽

Developmental Growth ◽

Ros Accumulation

Aging is associated with a decline in the quality of biological functions. Among the aging processes, reproductive aging is a critical process because of its intergenerational effects. However, the mechanisms underlying reproductive aging remain largely unknown. Female reproductive aging is the primary reason for limited fertility in mammals. Therefore, we attempted to investigate a modulator that can control female reproductive aging using a Caenorhabditis elegans model. In the present study, we examined the role of nicotinamide (NAM) in oocyte quality and offspring development. The levels of reactive oxygen species (ROS) and oxidative stress responses in aged oocytes, embryonic lethality, and developmental growth of the offspring were examined with maternal NAM supplementation. Supplementation with NAM improved oocyte quality, decreased embryonic lethality, and promoted germ cell apoptosis. Furthermore, NAM supplementation in aged mothers reduced ROS accumulation and improved mitochondrial function in oocytes. Consequently, the developmental growth and motility of offspring were improved. These findings suggest that NAM supplementation improves the health of the offspring produced by aged mothers through improved mitochondrial function. Taken together, our results imply that NAM supplementation in the aged mother improves oocyte quality and protects offspring by modulating mitochondrial function.

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Ovarian Accumulation of Nanoemulsions: Impact of Mice Age and Particle Size

International Journal of Molecular Sciences ◽

10.3390/ijms22158283 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8283

Author(s):

Eike Folker Busmann ◽

Julia Kollan ◽

Karsten Mäder ◽

Henrike Lucas

Keyword(s):

Particle Size ◽

Ex Vivo ◽

Reticuloendothelial System ◽

Systematic Investigation ◽

Measured Signal ◽

Reproductive Aging ◽

Sex Steroid Hormone ◽

Adult Mice ◽

Radiant Efficiency

Nanotechnology in the field of drug delivery comes with great benefits due to the unique physicochemical properties of newly developed nanocarriers. However, they may come as well with severe toxicological side effects because of unwanted accumulation in organs outside of their targeted site of actions. Several studies showed an unintended accumulation of various nanocarriers in female sex organs, especially in the ovaries. Some led to inflammation, fibrosis, or decreasing follicle numbers. However, none of these studies investigated ovarian accumulation in context to both reproductive aging and particle size. Besides the influences of particle size, the biodistribution profile may be altered as well by reproductive aging because of reduced capacities of the reticuloendothelial system (RES), changes in sex steroid hormone levels as well as altering ovarian stromal blood flow. This systematic investigation of the biodistribution of intravenously (i.v) injected nanoemulsions revealed significant dependencies on the two parameters particle size and age starting from juvenile prepubescent to senescent mice. Using fluorescent in vivo and ex vivo imaging, prepubescent mice showed nearly no accumulation of nanoemulsion in their uteri and ovaries, but high accumulations in the organs of the RES liver and spleen independently of the particle size. In fertile adult mice, the accumulation increased significantly in the ovaries with an increased particle size of the nanoemulsions by nearly doubling the portion of the average radiant efficiency (PARE) to ~10% of the total measured signal of all excised organs. With reproductive aging and hence loss of fertility in senescent mice, the accumulation decreased again to moderate levels, again independently of the particle size. In conclusion, the ovarian accumulation of these nanocarriers depended on both the age plus the particle size during maturity.

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