NMN treatment reverses unique deep radiomic signature morphology of oocytes from aged mice

One of the earliest physiological consequences of advancing age is the loss of female reproductive potential. This is primarily due to oocyte quality and developmental competence, which is highly sensitive to biological age. We applied deep learning, swarm intelligence and discriminative analysis to images of mouse oocytes taken by common bright field microscopy and were successfully able to identify a highly informative deep radiomic signature (DRS) of oocyte age. This signature distinguished morphological changes in oocytes associated with maternal age with 92% accuracy (AUC~1), reflecting this decline in oocyte quality. We then employed the DRS to evaluate the impact of the treatment of reproductively aged mice with the NAD+ precursor nicotinamide mononucleotide (NMN). The DRS signature classified 60% of oocytes from NMN-treated aged mice as having a 'young' morphology, suggesting that NMN was able to rejuvenate the morphological changes identified by the DRS. These findings indicate that NMN therapy may be able to restore the quality of a sizable subset of oocytes affected by reproductive ageing, and that these oocytes will be able to be distinguished and selected by DRS.

Shared Genetics Between Age at Menopause, Early Menopause, POI and Other Traits

Reproductive ageing leading to menopause is characterized by depletion of follicles and its regulating mechanisms are only partly understood. Early age at menopause and premature ovarian insufficiency (POI) are associated with several other traits such as cardiovascular disease, dyslipidemia, osteoporosis and diabetes. In large cohorts of Northern European women hundreds of Single Nucleotide Polymorphisms (SNPs) have been identified to be associated with age at menopause. These SNPs are located in genes enriched for immune and mitochondrial function as well as DNA repair and maintenance processes. Genetic predisposition to earlier menopause might also increase the risk of other associated traits. Increased risk for cardiovascular disease in women has been associated with age at menopause lowering SNPs. Pleiotropy between early age at menopause and increased mortality from coronary artery disease has been observed, implicating that genetic variants affecting age at menopause also affect the risk for coronary deaths. This review will discuss the shared genetics of age at menopause with other traits. Mendelian Randomization studies implicate causal genetic association between age at menopause and age at menarche, breast cancer, ovarian cancer, BMD and type 2 diabetes. Although the shared biological pathways remain to be determined, mechanisms that regulate duration of estrogen exposure remain an important focus.

Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

There is substantial genetic variation for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Progress in high-throughput sequencing and genome-wide association studies (GWAS) have transformed our understanding of common genetic risk factors for complex traits and diseases influencing reproductive lifespan and fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. The observations also identify unique genetic risk factors specific to different reproductive diseases impacting on female fertility. Sequencing in patients with primary ovarian insufficiency (POI) have identified mutations in a large number of genes while GWAS have revealed shared genetic risk factors for POI and ovarian ageing. Studies on age at menopause implicate DNA damage/repair genes with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits.

ANTI-AGEING EFFECTS OF DIETARY BEE PRODUCTS AND CALORIE RESTRICTION ON SEMEN PRODUCTION AND OXIDATIVE DAMAGE IN OLDER BROILER BREEDER MALES

This study was conducted to investigate the effects of calorie restriction and dietary bee products (apilarnil plus royal jelly) supplementation on reproductive and oxidative responses and to determine the possibilities that these treatments may be used in retarding the reproductive ageing of broiler breeder males. At 52 weeks of age, broiler breeder males were assigned to four treatment groups. The control group was fed on restricted feed as recommended by the breeder company throughout the study; the ad libitum group was fed ad libitum for a four-week period; the bee products group was fed similar to the control group except that their diet was supplemented with apilarnil and royal jelly for a four-week period and in the last group calorie restriction (45 % of standard diet) was applied for a four-week period. After a four-week adaptation period, the experiment was continued for 18 weeks. The results obtained in the present study have demonstrated that the percentage of dead sperm was the most affected semen characteristic by reproductive ageing. Long-term moderate feed restriction could not prevent age-related declines in sperm production. Dietary bee products supplementation or calorie restriction for a fourweek period positively affected the semen characteristics, and these beneficial effects could be maintained to some extend up until 72 weeks of age. Calorie restriction enhanced antioxidant defence for the first four-week period; however, this beneficial effect could not be sustained until the end of the experiment.Key words: broiler breeder males; ageing; semen characteristics; oxidative stress; bee products; calorie restrictionVPLIV ČEBELJIH PRIDELKOV IN OMEJEVANJA KALORIJ NA PROIZVODNJO SEMENA IN OKSIDATIVNI STRES PRI STAREJŠIH SAMCIH PLEMENSKIH BROJLERJEVAbstrakt: Študija je bila izvedena z namenom raziskovanja učinkov omejevanja kalorij in dodajanja prehranskih čebeljih pridelkov (apilarnil in matični mleček) na reprodukcijske in oksidativne odzive ter ugotoviti možnosti uporabe prehranskih dodatkov za zaviranje reproduktivnega staranja samcev plemenskih brojlerjev. Pri starosti 52 tednov so bili samci plemenskih brojlerjev razporejeni v štiri skupine. Kontrolna skupina je bila ves čas študije krmljena z restrikcijsko krmo po priporočilih podjetja, ki se ukvarja z gojenjem plemenskih broilerjev; skupina ad libitum je bila štiri tedne hranjena ad libitum; skupina, pri kateri so bili dodani čebelji pridelki je bila krmljena podobno kot kontrolna skupina, le da je bila njihova prehrana štiri tedne dopolnjevana z apilarnilom in matičnim mlečkom, zadnja skupina pa je štiri tedne dobivala kalorično omejeno hrano (45 % običajne prehrane). Po štiritedenskem prilagoditvenem obdobju se je poskus nadaljeval še 18 tednov. Rezultati, pridobljeni v tej študiji, so pokazali, da je bila najbolj prizadeta značilnost staranja povišan odstotek mrtvih semenčic v ejakulatu. Dolgoročna zmerna omejitev krme ni preprečila starostnega zmanjšanja proizvodnje smenčic. Dodatek prehranskih čebeljih pridelkov ali omejevanje kalorij v obdobju štirih tednov je pozitivno vplival na značilnosti semena. Ti blagodejni učinki so se ohranili vse do starosti do 72 tednov. Omejitev kalorij je okrepila tudi antioksidativno obrambo v prvih štirih tednih raziskave; vendar pa se je ta ugodni učinek kasneje izgubil.Ključne besede:samci plemenskih brojlerjev; staranje; značilnosti semena; oksidativni stres; čebelji proizvodi; omejitev kalorij

Loss of the glucocorticoid receptor causes accelerated ovarian ageing in zebrafish

Reproductive decline in mid-adult females is an established phenotype of the ageing process. Stress and the rise in glucocorticoids (GCs) accelerate reproductive ageing, but little is known about the mechanisms involved. During stress, GCs activate the glucocorticoid receptor (GR), a ubiquitously expressed, ligand-bound transcription factor, to elicit physiological changes for restoring homeostasis. Here, we tested the hypothesis that GC-GR signalling is essential for accelerating reproductive ageing. To test this, we used a ubiquitous GR knockout (GRKO) zebrafish, which is inherently hypercortisolemic, to delineate the role of high cortisol and GR signalling on reproductive ageing. The loss of GR led to premature ovarian ageing, including high frequency of typical and atypical follicular atresia in vitellogenic oocytes, yolk liquefaction and large inflammatory infiltrates. The reduction in oocyte quality was also associated with a decline in ovarian tert expression in the adult GRKO fish compared to the early adult GRKO and adult wild-type zebrafish. Accelerated ovarian ageing also impacted the progeny, including lower breeding success, fecundity, egg fertilization rate and delayed somitogenesis and embryo survival in the adult GRKO fish. We adduce that GR signalling is essential for prolonging the reproductive lifespan and improving the egg quality and embryo viability in zebrafish.

Anti-Müllerian hormone levels and risk of type 2 diabetes in women

Aims/hypothesis Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is considered to be a marker of reproductive ageing. Although accelerated reproductive ageing has been associated with a higher risk of type 2 diabetes, research on the relationship between AMH and type 2 diabetes risk is scarce. Therefore, we aimed to investigate whether age-specific AMH levels and age-related AMH trajectories are associated with type 2 diabetes risk in women. Methods We measured AMH in repeated plasma samples from 3293 female participants (12,460 samples in total), aged 20–59 years at recruitment, from the Doetinchem Cohort Study, a longitudinal study with follow-up visits every 5 years. We calculated age-specific AMH tertiles at baseline to account for the strong AMH–age correlation. Cox proportional hazards models adjusted for confounders were used to assess the association between baseline age-specific AMH tertiles and incident type 2 diabetes. We applied linear mixed models to compare age-related AMH trajectories for women who developed type 2 diabetes with trajectories for women who did not develop diabetes. Results During a median follow-up of 20 years, 163 women developed type 2 diabetes. Lower baseline age-specific AMH levels were associated with a higher type 2 diabetes risk (HRT2vsT3 1.24 [95% CI 0.81, 1.92]; HRT1vsT3 1.62 [95% CI 1.06, 2.48]; ptrend = 0.02). These findings seem to be supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages in women who developed type 2 diabetes compared with women who did not. The trajectories also suggested that AMH levels declined at a slower rate in women who developed type 2 diabetes, although differences in trajectories were not statistically significant. Conclusions/interpretation We observed that lower age-specific AMH levels were associated with a higher risk of type 2 diabetes in women. Longitudinal analyses did not show clear evidence of differing AMH trajectories between women who developed type 2 diabetes compared with women who did not, possibly because these analyses were underpowered. Further research is needed to investigate whether AMH is part of the biological mechanism explaining the association between reproductive ageing and type 2 diabetes.