Epigenetic clocks of female reproductive system aging: Current application and future prospects

Table 1 Overview of key studies related to the female reproductive epigenetic clock

Clock	Tissue	Target population	Main findings	Ref.
Ovarian aging
Horvath clock	Leukocytes, cumulus cells	77 infertile women	Horvath clock accurately predicted age based on WBCs but not on cumulus cells. It was not associated with the response to ovarian stimulation	Morin et al[9]
Horvath clock	Leukocytes, cumulus cells	175 infertile women	Epigenetic age acceleration for WBCs samples was associated with a poor ovarian response in women < 38 years	Hanson et al[10]
Horvath, with 500 additional targeted intergenic loci	Leukocytes	39 infertile women	Epigenetic age acceleration was associated with a lower AMH and lower oocyte yield	Monseur et al[8]
Horvath clock, PhenoAge clock, Hannum clock, DunedinPoAm clock	Leukocytes	1000 spontaneous couples, 894 ART pregnant couples	DunedinPoAm epigenetic age acceleration was faster in ART mothers compared to non-ART mothers. Epigenetic age acceleration was not associated with intracytoplasmic sperm injection fathers	Lee et al[11]
Skin-Blood clock, PhenoAge clock	Leukocytes	107 infertile women	Both Skin-Blood and PhenoAge epigenetic age acceleration in WBCs not associated with young women with idiopathic early ovarian aging	Christensen et al[12]
Zbieć-Piekarska clock	Leukocytes	181 infertile women	Epigenetic age was lower in women with live birth	Li et al[13]
Horvath clock, Skin-Blood clock, Granulosa cell clock	Mural granulosa cells, leukocytes	119 infertile women	Leukocytes but not MGCs Horvath age predictor was associated with chronological age. Granulosa cell clock successfully predicted the age of both MGCs and leukocytes	Olsen et al[14]
Granulosa cell clock, Skin-Blood clock	Mural granulosa cells, leukocytes	119 infertile women	Both granulosa cell clock and Skin-Blood epigenetic age acceleration in MGCs and leukocytes were not associated with ovarian reserve	Olsen et al[15]
Horvath clock, Granulosa cell clock, PhenoAge clock, GrimAge clock	Follicular fluid	70 infertile women	GrimAge age acceleration was negatively associated with AMH levels, antral follicle count, the total number of retrieved oocytes, mature oocytes, and fertilized or two-pronuclear oocytes	Knight et al[16]
Horvath clock, Granulosa cell clock, GrimAge clock	Follicular fluid	61 infertile women	Horvath age acceleration of follicular fluid was associated with lower peak estradiol levels and decreased number of total and mature oocytes	Hood et al[17]
Uterine aging
Horvath clock	Endometrium, blood	9 infertile women	Significant correlation between chronological age and Horvath-biological age in endometrium	Olesen et al[18]
Horvath clock	Endometrium	26 women with endometriosis, 17 women without endometriosis	Horvath epigenetic age strongly correlates with chronological age in the endometrium. Horvath age deceleration in endometrial tissue from women with endometriosis	Leap et al[19]
Horvath clock, Hannum clock, GrimAge clock, PhenoAge clock	Myometrial, blood	27 women undergoing cesarean	Horvath, Hannum, and GrimAge epigenetic age were significant correlation with maternal chronological age, for both myometrium and blood samples	Erickson et al[20]

AMH: Anti-Müllerian hormone; ART: Assisted reproductive technology; MGCs: Mural granulosa cells; WBCs: White blood cells.