Table 1.

The physiological function and their age-related mechanisms of main stromal components in ovary aging

Physiological Functions	Age-Related Alterations	Mechanisms in Ovarian Aging
Theca-interstitial cells
Architectural support [29]  Paracrine [30, 31]  Androgen production [32]	Androgen production ↓ [33] Phasic sensitivity of LH ↓ [34] PPARα expression ↓, DHEA synthesis ↓ [35] LH receptor expression ↑ Actin-rich fibrotic cells ↑ [36, 37]	Steroidogenesis ↓ [33] Oocyte quality ↓, apoptosis ↑ [35] Ovulatory dysfunction [38] Stromal fibrosis ↑ [37] Secondary follicle development ↓ [37]
Immune cells
Monocyte/macrophage (Mφ)
Folliculogenesis: granulosa cell proliferation, vascular integrity [25]   Ovulation: pro-inflammation, matrix breakdown [39]   Luteal phase: vascularization, progesterone synthesis [40, 41]   Follicle atresia/luteolysis: scavenging debris/apoptotic cells [42]	Percentage of populations ↓: resident Mφ ↓, monocyte derived Mφ ↑ [43] Polarization from M1 to M2 [44] Phagocytotic function ↓ Iron/lipofuscin overload ↑ Multinucleated giant cells (MNGCs) ↑ [42, 45]	Granulosa proliferation ↓ [25]   Follicle growth ↓ [25] Steroidogenesis (E2, P4) ↓ [25, 41] Corpus luteal hemorrhage ↑ [25] Corpus luteum formation/lysis ↓ [41] Stromal waste/debris ↑ [46]
Other immune cells
Phagocytosis [47]   Antigen presentation [48]   Paracrine/autocrine [47]	CD4+ T cells ↑ NK cells ↑ CD8+ T cells ↓ [43] Plasma cells ↑ Naive CD4+ T cells ↑ [49]	Abnormal immunity [50, 51] Luteal regression [40] Autoimmune reaction [48]
Vasculature
Pericytes
Follicular vascularization [52]   Initiate luteal angiogenesis:   Endothelial cell migration   Capillary outgrowth   Vessel stablization [53]	Migration ↓ [54] Apoptosis ↑ Detachment ↑ Coverage ↓ [55] Differentiation to fibroblasts [56]	Altered angiogenesis [52] Vascular instability Luteal hemorrhage [53] Fibrosis [56]
Smooth muscular cells
Constituting arterioles and muscular venules [57]	Migration ↑ Proliferation ↑ Hypotrophy [57]	NA
Endothelial cells
Constituting blood/lymphatic vessels, secreting NO in response to hypoxia [58]   Interaction with perivascular cells [59]   Angiocrine [60]	Apoptosis ↑, Regeneration ↓, eNOS-NO ↓ [58] Senescence ↑ [61] Interaction with pericyte ↓ [62] Migration↓, proliferation ↓ [63] Suboptimal angiocrine [64]	Perifollicular angiogenesis ↓ [52] Postovulatory vascularization ↓ [59]
Blood vasculature
Supportive architecture   Delivering/removing nutrients and metabolites [65]	Stromal blood flow ↓ [66–68] Superficial cortex (> 30 yr): density ↑ [69] Deep cortical stroma (> 40 yr): abundance ↓ [69] Hyaline degeneration, sclerosis, and stenosis [67]	Primordial follicle activation ↑ Earliest follicle development ↑ [69] Terminal micro-vascularization [69]
Lymphatic vasculature
Extravascular fluids homeostasis   Hormone recruitment   Immune cell transport [65]	Capillary rarefaction; dilated; contractile ↓ Permeable ↑ [70]	Secondary follicle development ↓ [71] Follicular fluid accumulation [72]
Extra cellular matrix
Sequesteriation   Signaling [73, 74]   Biomechanics [75]	Collagen (type I and III) ↑ Hydroxyproline ↑ [76] Hyaluronan (HA) ↓ [77] Low molecular weight hyaluronan (LMW) ↑ [78]	Primordial follicle activation ↓ [75] Oocyte dormancy ↑ [27] Meiosis/maturation ↓ [77, 78] Ovulation ↓ [79] Granulosa cell proliferation ↓ Steroidogenesis ↓ [80]