Germline energetics, aging, and female infertility

Abstract

The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women.

Figure 1. Longevity pathways that promote health and survival

Current data indicate that environmental signals alter the pace of aging by modulating key metabolic sensors, such as SIRT1 and AMPK. These pathways interact with both mTOR and insulin/IGF-1 to control cell growth and energy intake. Obesity and aging reduce the ratios of NAD⁺/NADH and AMP/ATP, whereas DR has the opposite effect. Downstream, the actions of two transcriptional regulators, PGC-1α and FOXO, induce mitochondrial function and stress resistance, among other protective mechanisms. Together, this network coordinates cellular responses to stress, nutrient availability and metabolic demands, with mitochondria as key nexus points.

Figure 2. Proposed method of improving human IVF outcomes with AUGMENT

Reduced mitochondrial activity and bioenergetic potential contribute to aging-related impairments in female fertility, even with the use of assisted reproductive technologies such as IVF. Delivery of mitochondria derived from a patient’s own natural egg precursor cells (OSCs) into that same patient’s eggs during intracytoplasmic sperm injection raises the threshold level of mitochondria in that egg, providing sufficient energy to support successful fertilization and embryogenesis.

Figure 3. Identification and utility of female germ cell mitochondrial boosters

Culture of human OSCs, which are natural precursor cells for human oocytes, allows high-throughput screening of biological and pharmacological entities for their ability to increase various aspects of mitochondrial dynamics, including mtDNA content, mitochondrial membrane potential, and ATP-generating capacity. Positive hits can be further tested using a combination of in vitro and in vivo assays to assess if aging-related impairments in egg quality, embryonic developmental competence and fertility can be minimized.

Figure 4. Negative impact of maternal aging on ovulated egg quality and female fertility

Schematic depiction of how maternal aging-associated deficits in bioenergetic potential in oocytes compromises their ability to form fertilization-competent eggs. Insufficient energy in the eggs of older females leads to impaired meiotic spindle formation and maintenance, unequal segregation of genetic material at the completion of meiosis during fertilization, and aneuploid conceptions, which result in pre-implantation embryonic growth arrest, implantation failure, miscarriage and birth defects.