2023 GCRLE Grantees
The 2023 cohort of GCRLE Scholars encompasses 28 scientists spanning 4 continents pioneering the cutting edge of reproductive longevity research. Grantees were selected by an esteemed Scientific Advisory Council composed of leaders in the fields of Aging and Reproductive Biology.
2023 Junior Scholar Award Recipients
Miguel Angel Brieño- Enríquez, MD, PhD
University of Pittsburgh
Natural partial reprograming in the naked mole-rat ovary leads to ovarian rejuvenation and protracted fertility
Project Abstract
Lab website
Natural partial reprograming in the naked mole-rat ovary leads to ovarian rejuvenation and protracted fertility
Project Abstract
Natural partial reprograming in the naked mole-rat ovary
leads to ovarian rejuvenation and protracted fertility
Most mammals, including humans, are born with all the eggs they will ever have, which deplete over the course of their lifespan. Only one species of small rodent, the naked mole-rat (Heterocephalus glaber), among all mammals has the ability to produce new eggs throughout its long lifespan. Also unique to naked mole rats is that they live in colonies, like bees, and only one adult female, the queen, is reproductively active while the rest of the adult females are subordinate and infertile. When the queen is removed, any of these subordinate females can become queen and start producing eggs and offspring, even if they are quite old. How can an animal remain infertile for decades, yet develop such enormous fertility so quickly? My project will use these extraordinary traits of this creature and figure out how they rejuvenate eggs and keep ovaries healthy across all ages. Perhaps the same triggers that allow naked mole rats to become and remain fertile late into life could be applied to delaying the decline of human reproduction.
Most mammals, including humans, are born with all the eggs they will ever have, which deplete over the course of their lifespan. Only one species of small rodent, the naked mole-rat (Heterocephalus glaber), among all mammals has the ability to produce new eggs throughout its long lifespan. Also unique to naked mole rats is that they live in colonies, like bees, and only one adult female, the queen, is reproductively active while the rest of the adult females are subordinate and infertile. When the queen is removed, any of these subordinate females can become queen and start producing eggs and offspring, even if they are quite old. How can an animal remain infertile for decades, yet develop such enormous fertility so quickly? My project will use these extraordinary traits of this creature and figure out how they rejuvenate eggs and keep ovaries healthy across all ages. Perhaps the same triggers that allow naked mole rats to become and remain fertile late into life could be applied to delaying the decline of human reproduction.
Lab website
Longhua Guo, PhD
University of Michigan
Molecular and genetic drivers of female reproductive aging and rejuvenation
Project Abstract
Lab website
Molecular and genetic drivers of female reproductive aging and rejuvenation
Project Abstract
Molecular and genetic drivers of female reproductive aging
and rejuvenation
We study the planarian flatworm Schmidtea mediterranea that has amazed scientists with its extraordinary regenerative capabilities. These tiny creatures can rebuild their entire bodies from tiny fragments, and defy aging for far longer than such a simple animal should. Perplexingly, despite these powers, this species still experiences reproductive aging, becoming infertile not long after sexual maturity. I want to understand the reasons why these creatures undergo reproductive senescence even when they escape other features of aging. My past research developed multiple genetically diverse strains to serve this purpose: some exhibit early reproductive senescence within two months, while others remain fertile for up to 2 years. I will sequence these animals’ genomes, track their reproductive aging rates, and pinpoint the genes strongly associated with reproductive aging. Even more strangely, my preliminary evidence has found that older, reproductively senescent planarians regain their fertility after being cut into parts and regenerating. This finding suggests that S. mediterranea can reverse reproductive aging. Unraveling the mechanisms behind this could potentially point the way towards regenerating reproductive potential in humans.
We study the planarian flatworm Schmidtea mediterranea that has amazed scientists with its extraordinary regenerative capabilities. These tiny creatures can rebuild their entire bodies from tiny fragments, and defy aging for far longer than such a simple animal should. Perplexingly, despite these powers, this species still experiences reproductive aging, becoming infertile not long after sexual maturity. I want to understand the reasons why these creatures undergo reproductive senescence even when they escape other features of aging. My past research developed multiple genetically diverse strains to serve this purpose: some exhibit early reproductive senescence within two months, while others remain fertile for up to 2 years. I will sequence these animals’ genomes, track their reproductive aging rates, and pinpoint the genes strongly associated with reproductive aging. Even more strangely, my preliminary evidence has found that older, reproductively senescent planarians regain their fertility after being cut into parts and regenerating. This finding suggests that S. mediterranea can reverse reproductive aging. Unraveling the mechanisms behind this could potentially point the way towards regenerating reproductive potential in humans.
Lab website
Sarah Ocanas, PhD
Oklahoma Medical Research Foundation
Comparison of macrophage activational response to immunomodulatory and hormonal signaling in the female mouse brain and ovary with reproductive aging.
Project Abstract
Lab website
Comparison of macrophage activational response to immunomodulatory and hormonal signaling in the female mouse brain and ovary with reproductive aging.
Project Abstract
Comparison of macrophage activational response to
immunomodulatory and hormonal signaling in the female mouse brain and ovary with
reproductive aging.
Ovarian aging not only causes menopause and infertility, it is also associated with increased risk of many diseases, including some neurodegenerative diseases like Alzheimer’s Disease.When rodents undergo decreased estrogen levels due to ovariectomy or reproductive aging, it triggers the activation of microglia - the most common type of immune cell found in the brain. A state of chronic activation in these cells leads to increased inflammation, a factor that has been implicated in the onset of Alzheimer's in humans. Interestingly, microglia have recently also been discovered in the ovaries, where they perform vital functions. Echoing their counterparts in the brain, these ovarian microglia can become over-activated with age, contributing to inflammation, fibrosis, and the release of inflammatory signals into the bloodstream. Does a decline in estrogen contribute to ovarian microglia overactivation? My research will explore how brain and ovarian microglia respond similarly to these hormonal changes with aging. We will probe into whether estrogen receptor signaling is affected by aging and stress, and how these changes relate to microglia activation in both the brain and the ovary. The data generated in this project will be used to identify new therapeutics to delay ovarian inflammation, which could be useful in both delaying reproductive senescence and associated neurodegeneration.
Ovarian aging not only causes menopause and infertility, it is also associated with increased risk of many diseases, including some neurodegenerative diseases like Alzheimer’s Disease.When rodents undergo decreased estrogen levels due to ovariectomy or reproductive aging, it triggers the activation of microglia - the most common type of immune cell found in the brain. A state of chronic activation in these cells leads to increased inflammation, a factor that has been implicated in the onset of Alzheimer's in humans. Interestingly, microglia have recently also been discovered in the ovaries, where they perform vital functions. Echoing their counterparts in the brain, these ovarian microglia can become over-activated with age, contributing to inflammation, fibrosis, and the release of inflammatory signals into the bloodstream. Does a decline in estrogen contribute to ovarian microglia overactivation? My research will explore how brain and ovarian microglia respond similarly to these hormonal changes with aging. We will probe into whether estrogen receptor signaling is affected by aging and stress, and how these changes relate to microglia activation in both the brain and the ovary. The data generated in this project will be used to identify new therapeutics to delay ovarian inflammation, which could be useful in both delaying reproductive senescence and associated neurodegeneration.
Lab website
2023 Senior Scholar Award Recipients
Diana Laird, PhD
University of California, San Francisco
The aging of human follicles: a molecular portrait and 3D landscape
Project Abstract
Lab website
The aging of human follicles: a molecular portrait and 3D landscape
Project Abstract
Identifying Novel Drivers in Central Control of Female Reproduction
When the number of eggs left in the ovary, often referred to as the 'ovarian reserve,' dips below a certain threshold, menopause is triggered. Despite its importance, scientists still have a lot to learn about the ovarian reserve - we still don’t know most details of how and why eggs are lost at the rate they are. Learning more requires a far clearer picture of what is going on in the ovaries than we currently have. Harnessing the power of new cutting-edge technologies like single-cell sequencing and whole organ imaging, we will create a comprehensive cell atlas of aging ovaries in humans and mice across the lifespan. This project will create a 3D map of the ovaries for scientists to use at an unprecedented level of detail – a resource that promises to be instrumental for the reproductive longevity community. Using this data, I will also test the emerging hypothesis that the aging of oocytes is accelerated by the inflammation in the ovary brought about by menstrual cycling. Together these studies will enable the development of therapies to rejuvenate the ovary as well as identify characteristics of healthier oocytes. Because we still do not understand what makes a healthy egg, defining the impact of continuous ovulation on the ovarian reserve will potentially inform strategies for extending the lifespan of the ovary and boosting healthspan.
When the number of eggs left in the ovary, often referred to as the 'ovarian reserve,' dips below a certain threshold, menopause is triggered. Despite its importance, scientists still have a lot to learn about the ovarian reserve - we still don’t know most details of how and why eggs are lost at the rate they are. Learning more requires a far clearer picture of what is going on in the ovaries than we currently have. Harnessing the power of new cutting-edge technologies like single-cell sequencing and whole organ imaging, we will create a comprehensive cell atlas of aging ovaries in humans and mice across the lifespan. This project will create a 3D map of the ovaries for scientists to use at an unprecedented level of detail – a resource that promises to be instrumental for the reproductive longevity community. Using this data, I will also test the emerging hypothesis that the aging of oocytes is accelerated by the inflammation in the ovary brought about by menstrual cycling. Together these studies will enable the development of therapies to rejuvenate the ovary as well as identify characteristics of healthier oocytes. Because we still do not understand what makes a healthy egg, defining the impact of continuous ovulation on the ovarian reserve will potentially inform strategies for extending the lifespan of the ovary and boosting healthspan.
Lab website
Michael Stout, PhD
Oklahoma Medical Research Foundation
Unraveling how mTORC1 activity in stromal fibroblasts contributes to ovarian inflammation, cellular senescence, fibrosis, & follicular exhaustion
Project Abstract
Lab website
Unraveling how mTORC1 activity in stromal fibroblasts contributes to ovarian inflammation, cellular senescence, fibrosis, & follicular exhaustion
Project Abstract
Unraveling how mTORC1 activity in stromal fibroblasts
contributes to ovarian inflammation, cellular senescence, fibrosis, & follicular
exhaustion
Ovarian aging is characterized by the steady reduction in eggs, which leads to menopause and infertility. Imagine a world where the clock on ovarian aging could be paused, extending not just the period of fertility, but also delaying the onset of age-related diseases often linked with menopause. To realize this world, we first need to build a much greater understanding of the mechanisms underlying ovarian aging. Basic questions such as ‘Which ovarian cell types age most quickly?’ and ‘Do specific cell types play an outsized role in ovarian failure?’ are key, but remain unanswered. My project aims to better understand one of these cell types - ovarian fibroblasts, known to play a role in the fibrosis and inflammation that occurs with age in this tissue. One central regulator of growth in cells, the mammalian target of rapamycin complex 1 (mTORC1), impacts a diverse array of cellular processes and has been implicated in aging. However, the role of mTORC1 activity in ovarian fibroblasts and its potential to bring about ovarian decline remain undefined. We will alter mTORC1 activity exclusively within ovarian fibroblasts to decipher their specific effects on mechanisms of ovarian senescence, inflammation, and fibrogenesis. The long-term objective of this work is to devise pharmacological solutions that slow ovarian aging, with the hope that curbing ovarian aging may have a positive ripple effect on overall body aging.
Ovarian aging is characterized by the steady reduction in eggs, which leads to menopause and infertility. Imagine a world where the clock on ovarian aging could be paused, extending not just the period of fertility, but also delaying the onset of age-related diseases often linked with menopause. To realize this world, we first need to build a much greater understanding of the mechanisms underlying ovarian aging. Basic questions such as ‘Which ovarian cell types age most quickly?’ and ‘Do specific cell types play an outsized role in ovarian failure?’ are key, but remain unanswered. My project aims to better understand one of these cell types - ovarian fibroblasts, known to play a role in the fibrosis and inflammation that occurs with age in this tissue. One central regulator of growth in cells, the mammalian target of rapamycin complex 1 (mTORC1), impacts a diverse array of cellular processes and has been implicated in aging. However, the role of mTORC1 activity in ovarian fibroblasts and its potential to bring about ovarian decline remain undefined. We will alter mTORC1 activity exclusively within ovarian fibroblasts to decipher their specific effects on mechanisms of ovarian senescence, inflammation, and fibrogenesis. The long-term objective of this work is to devise pharmacological solutions that slow ovarian aging, with the hope that curbing ovarian aging may have a positive ripple effect on overall body aging.
Lab website
2023 Pilot Award Recipients
Elvan Böke, PhD
Centre for Genomic Regulation
Deciphering cell-intrinsic and cell-extrinsic mechanisms of oocyte ageing
Project Abstract
Lab website
Deciphering cell-intrinsic and cell-extrinsic mechanisms of oocyte ageing
Project Abstract
Deciphering cell-intrinsic and cell-extrinsic mechanisms of
oocyte ageing
All the eggs (oocytes) a person will ever have are created before birth. They remain dormant for decades before they are activated for fertilization. During puberty, a batch of these dormant oocytes are activated and experience a 64-fold increase in size within a year, transitioning into fertilizable eggs. Scientists don’t know whether the defects observed in older eggs develop during their long dormant period or during their rapid growth phase prior to fertilization. To answer this question, I will determine whether defects in eggs arise due to problems with the development of the eggs themselves, or the environment around them using a transplantation approach. I will transplant young ovaries into young and old hosts, enabling us to determine whether errors arising in eggs are due to aging in the eggs themselves or the tissue surrounding them. Understanding whether the aging-related defects seen in mature oocytes are already present in dormant oocytes or are mostly acquired during maturation could greatly impact the advice given to women hoping to extend fertility and inform the direction for therapeutic development in the future.
All the eggs (oocytes) a person will ever have are created before birth. They remain dormant for decades before they are activated for fertilization. During puberty, a batch of these dormant oocytes are activated and experience a 64-fold increase in size within a year, transitioning into fertilizable eggs. Scientists don’t know whether the defects observed in older eggs develop during their long dormant period or during their rapid growth phase prior to fertilization. To answer this question, I will determine whether defects in eggs arise due to problems with the development of the eggs themselves, or the environment around them using a transplantation approach. I will transplant young ovaries into young and old hosts, enabling us to determine whether errors arising in eggs are due to aging in the eggs themselves or the tissue surrounding them. Understanding whether the aging-related defects seen in mature oocytes are already present in dormant oocytes or are mostly acquired during maturation could greatly impact the advice given to women hoping to extend fertility and inform the direction for therapeutic development in the future.
Lab website
Iain Cheeseman, PhD
Whitehead Institute for Biomedical Research
Analyzing mRNA splicing as a source of reduced oocyte quality during female reproductive aging
Project Abstract
Lab website
Analyzing mRNA splicing as a source of reduced oocyte quality during female reproductive aging
Project Abstract
Analyzing mRNA splicing as a source of reduced oocyte
quality during female reproductive aging
Female gametes, termed oocytes, are amongst the rarest cells in the human body, but are responsible for transmitting all heritable information from mother to progeny. At birth, human females are endowed with finite numbers of oocytes, which are formed prenatally and then pause in an extended arrest state that can persist for decades. This requirement for oocytes to persist indefinitely in a paused state, while being poised to continue their division processes, is a central challenge for maintaining developmental competency during female reproductive aging. As humans are increasingly reproducing later in life, 1 in 8 couples face reproductive challenges. In mammalian oocytes, errors in the distribution of the genetic material that occur during oocyte maturation (termed meiosis) increase markedly with reproductive age. These errors are a leading cause of chromosome imbalances that result in reduced fertility, miscarriages, and developmental disorders. However, the basis for these increased errors and reduced oocyte quality during maternal age remains poorly understood. Our lab is investigating the changes to the cell division machinery that occur during female reproductive aging. For this proposed work, we will use mouse models to visualize the changes that occur in oocytes during reproductive aging and to test the consequences of specific perturbations to fertility and reproductive longevity. In particular, this work will investigate the changes that occur to the production of core proteins required for meiotic cell division during oocyte aging.
Female gametes, termed oocytes, are amongst the rarest cells in the human body, but are responsible for transmitting all heritable information from mother to progeny. At birth, human females are endowed with finite numbers of oocytes, which are formed prenatally and then pause in an extended arrest state that can persist for decades. This requirement for oocytes to persist indefinitely in a paused state, while being poised to continue their division processes, is a central challenge for maintaining developmental competency during female reproductive aging. As humans are increasingly reproducing later in life, 1 in 8 couples face reproductive challenges. In mammalian oocytes, errors in the distribution of the genetic material that occur during oocyte maturation (termed meiosis) increase markedly with reproductive age. These errors are a leading cause of chromosome imbalances that result in reduced fertility, miscarriages, and developmental disorders. However, the basis for these increased errors and reduced oocyte quality during maternal age remains poorly understood. Our lab is investigating the changes to the cell division machinery that occur during female reproductive aging. For this proposed work, we will use mouse models to visualize the changes that occur in oocytes during reproductive aging and to test the consequences of specific perturbations to fertility and reproductive longevity. In particular, this work will investigate the changes that occur to the production of core proteins required for meiotic cell division during oocyte aging.
Lab website
Hattie Chung, PhD
Broad Institute of MIT and Harvard
Profiling the spatiotemporal dynamics of cellular diversity during ovarian aging
Project Abstract
Profiling the spatiotemporal dynamics of cellular diversity during ovarian aging
Project Abstract
Profiling the spatiotemporal dynamics of cellular diversity
during ovarian aging
The ovary is an incredibly complex ecosystem, teeming with a diverse array of cell types interacting across various locations, all changing with time. The composition of these cell types, their gene activity, and their interactions shift throughout the menstrual cycle and aging, significantly impacting the process of ovulation. The process of ovulation requires a coordinated, dramatic remodeling of the entire ovary each cycle to release an egg. Ovulation must be meticulously choreographed to perform properly. It involves a dramatic remodeling of large swaths of the ovary each cycle to release an egg. This complex process requires precise communication patterns between numerous different cell types, all perfectly timed. This process breaks down with age, but we still don’t have a clear picture of exactly how this happens. To understand these changes across estrous cycles and aging, I will apply a new cutting-edge tool that offers us an unprecedented look into the activities of individual cells at a higher resolution than ever before, all within the intact tissue. Because ovaries are incredibly dynamic tissues with enormous heterogeneity and complex structure, precisely where an activity occurs can matter as much as the activity itself. Our novel technique will tell us where and how remodeling occurs in the ovaries with age and across the estrous/menstrual cycle, giving us invaluable information on how eggs are affected by these processes.
The ovary is an incredibly complex ecosystem, teeming with a diverse array of cell types interacting across various locations, all changing with time. The composition of these cell types, their gene activity, and their interactions shift throughout the menstrual cycle and aging, significantly impacting the process of ovulation. The process of ovulation requires a coordinated, dramatic remodeling of the entire ovary each cycle to release an egg. Ovulation must be meticulously choreographed to perform properly. It involves a dramatic remodeling of large swaths of the ovary each cycle to release an egg. This complex process requires precise communication patterns between numerous different cell types, all perfectly timed. This process breaks down with age, but we still don’t have a clear picture of exactly how this happens. To understand these changes across estrous cycles and aging, I will apply a new cutting-edge tool that offers us an unprecedented look into the activities of individual cells at a higher resolution than ever before, all within the intact tissue. Because ovaries are incredibly dynamic tissues with enormous heterogeneity and complex structure, precisely where an activity occurs can matter as much as the activity itself. Our novel technique will tell us where and how remodeling occurs in the ovaries with age and across the estrous/menstrual cycle, giving us invaluable information on how eggs are affected by these processes.
Aubrey Converse, PhD, Michele Pritchard, PhD
Northwestern University
Macrophage-derived multinucleated giant cells as drivers of aging in the mammalian ovary
Project Abstract
Macrophage-derived multinucleated giant cells as drivers of aging in the mammalian ovary
Project Abstract
Macrophage-derived multinucleated giant cells as drivers of
aging in the mammalian ovary
As mammals age, their ovaries undergo changes marked by shifts in immune cell populations and the inflammatory molecules they produce, resulting in chronic inflammation and its consequences; fibrosis. Our research has previously found that aging ovaries in many mammals contain a cell type called immune-derived multinucleated giant cells (MNGCs) that are absent in young ovaries. Their exact role within the aging ovary is unclear. Our study aims to define the function of the ovarian MNGC population and assess its impact on various ovarian compartments. We plan to trace the prevalence of these cells in a wide range of animal species and establish innovative methods to isolate and study them in the lab. We will identify the unique molecular markers of MNGCs, creating new options to track, isolate, and manipulate these cells. And in a research first, we will culture these primary ovarian MNGCs in our lab to probe their direct effects on the ovaries. This study will be the first to fully define the ovarian MNGC population, paving the way for future studies to determine why MNGCs form within the ovary and how they can be targeted therapeutically.
As mammals age, their ovaries undergo changes marked by shifts in immune cell populations and the inflammatory molecules they produce, resulting in chronic inflammation and its consequences; fibrosis. Our research has previously found that aging ovaries in many mammals contain a cell type called immune-derived multinucleated giant cells (MNGCs) that are absent in young ovaries. Their exact role within the aging ovary is unclear. Our study aims to define the function of the ovarian MNGC population and assess its impact on various ovarian compartments. We plan to trace the prevalence of these cells in a wide range of animal species and establish innovative methods to isolate and study them in the lab. We will identify the unique molecular markers of MNGCs, creating new options to track, isolate, and manipulate these cells. And in a research first, we will culture these primary ovarian MNGCs in our lab to probe their direct effects on the ovaries. This study will be the first to fully define the ovarian MNGC population, paving the way for future studies to determine why MNGCs form within the ovary and how they can be targeted therapeutically.
Francesca Duncan, PhD
Northwestern University
Shear wave elastography (SWE) in assessment of human ovarian stiffness and reproductive longevity
Project Abstract
Lab website
Shear wave elastography (SWE) in assessment of human ovarian stiffness and reproductive longevity
Project Abstract
Shear wave elastography (SWE) in assessment of human
ovarian stiffness and reproductive longevity
There is an urgent need to better understand the mechanisms that underlie ovarian aging. Our lab made the critical discovery that the ovarian environment in which eggs develop, known as the stroma, undergoes drastic age-related changes. As the ovary ages, it becomes inflamed and fibrotic due to the accumulation of fibrous tissue, much like the process of scarring. Fibrosis changes the properties of the aging ovary such that it is physically stiffer or tougher compared to younger ovaries. Increased stiffness can negatively impact ovarian function, compromising the ability of follicles to grow, develop, produce hormones, and even undergo ovulation. Rejuvenation of the ovary through therapies that reverse or prevent tissue stiffness, such as use of anti-fibrotic drugs, hold tremendous promise for extending reproductive longevity and improving healthspan for women. We will use shear wave elastography, a cost effective and non-invasive method that can be combined with routine gynecological ultrasound, to measure, monitor, and track human ovarian stiffness and determine its relationship to age. This technology will ultimately enable the broad use of ovarian stiffness as a novel clinical biomarker of reproductive longevity and will lay the foundation for translating our research into clinical trials to test therapeutic interventions that target ovarian stiffness.
There is an urgent need to better understand the mechanisms that underlie ovarian aging. Our lab made the critical discovery that the ovarian environment in which eggs develop, known as the stroma, undergoes drastic age-related changes. As the ovary ages, it becomes inflamed and fibrotic due to the accumulation of fibrous tissue, much like the process of scarring. Fibrosis changes the properties of the aging ovary such that it is physically stiffer or tougher compared to younger ovaries. Increased stiffness can negatively impact ovarian function, compromising the ability of follicles to grow, develop, produce hormones, and even undergo ovulation. Rejuvenation of the ovary through therapies that reverse or prevent tissue stiffness, such as use of anti-fibrotic drugs, hold tremendous promise for extending reproductive longevity and improving healthspan for women. We will use shear wave elastography, a cost effective and non-invasive method that can be combined with routine gynecological ultrasound, to measure, monitor, and track human ovarian stiffness and determine its relationship to age. This technology will ultimately enable the broad use of ovarian stiffness as a novel clinical biomarker of reproductive longevity and will lay the foundation for translating our research into clinical trials to test therapeutic interventions that target ovarian stiffness.
Lab website
Deena Emera, PhD
Buck Institute for Research on Aging
The genetic basis of reproductive longevity in exceptionally long-lived mammals
Project Abstract
The genetic basis of reproductive longevity in exceptionally long-lived mammals
Project Abstract
The genetic basis of reproductive longevity in exceptionally
long-lived mammals
Female mammals produce their lifetime’s supply of eggs during fetal development, which is depleted over life by ovulation and egg death. Females of most mammalian species, including the long-lived baleen whales, continue to reproduce throughout their lifespan. Yet human women are relatively unique in that they experience a rapid decline in egg quality and quantity starting in their mid-thirties, leading to menopause around the age of fifty. While many scientists are investigating the biological causes of accelerated reproductive aging in women, my project uses a unique and exciting approach to learn more = by looking to nature for answers.How have certain long-lived mammals avoided menopause and continued reproduction into old age? Baleen whales, elephants, and naked mole rats have cracked this biological puzzle, with female bowhead whales living and breeding even when they're over a hundred years old. I hypothesize that genetic mechanisms such as enhanced DNA repair, which we suspect also contributes to cancer resistance in these mammals, could be the key to their reproductive longevity. I will test this hypothesis by comparing the genomes and ovarian gene expression of species with and without extended reproductive lifespans to identify strategies already used in nature for reproductive longevity. In the future we may be able to mimic these strategies in humans with targeted interventions, with a profound impact on female fertility, overall health, and quality of life.
Female mammals produce their lifetime’s supply of eggs during fetal development, which is depleted over life by ovulation and egg death. Females of most mammalian species, including the long-lived baleen whales, continue to reproduce throughout their lifespan. Yet human women are relatively unique in that they experience a rapid decline in egg quality and quantity starting in their mid-thirties, leading to menopause around the age of fifty. While many scientists are investigating the biological causes of accelerated reproductive aging in women, my project uses a unique and exciting approach to learn more = by looking to nature for answers.How have certain long-lived mammals avoided menopause and continued reproduction into old age? Baleen whales, elephants, and naked mole rats have cracked this biological puzzle, with female bowhead whales living and breeding even when they're over a hundred years old. I hypothesize that genetic mechanisms such as enhanced DNA repair, which we suspect also contributes to cancer resistance in these mammals, could be the key to their reproductive longevity. I will test this hypothesis by comparing the genomes and ovarian gene expression of species with and without extended reproductive lifespans to identify strategies already used in nature for reproductive longevity. In the future we may be able to mimic these strategies in humans with targeted interventions, with a profound impact on female fertility, overall health, and quality of life.
Michael Garratt, PhD, Rebecca Campbell, PhD, and Greg Anderson, PhD
University of Otago
Uncoupling nutrition from reproduction to extend female fertility
Project Abstract
Lab website
Uncoupling nutrition from reproduction to extend female fertility
Project Abstract
Uncoupling nutrition from reproduction to extend female
fertility
Research has shown that we can double the reproductive lifespan of female rodents simply through dietary restriction during their early life. This period of limited diet during the weaning stage inhibits puberty, leading animals into a non-reproductive state until food becomes plentiful again. When these animals return to normal feeding, they restart normal reproduction and can continue to reproduce much later in life compared to their unrestricted counterparts. This discovery led us to predict that specific neurons in the brain control this process. Manipulating these could open the door to increased female reproductive longevity. In our project, we plan to switch off these neurons that control puberty onset during periods of low food intake. This unique approach will allow our animal subjects to stay fertile even when their diet is restricted, helping us probe whether the benefits of extended reproductive life are intrinsically tied to early-stage fertility loss or if these can be decoupled. This research could reveal a pathway to find interventions providing extended fertility independent of dietary restriction.
Research has shown that we can double the reproductive lifespan of female rodents simply through dietary restriction during their early life. This period of limited diet during the weaning stage inhibits puberty, leading animals into a non-reproductive state until food becomes plentiful again. When these animals return to normal feeding, they restart normal reproduction and can continue to reproduce much later in life compared to their unrestricted counterparts. This discovery led us to predict that specific neurons in the brain control this process. Manipulating these could open the door to increased female reproductive longevity. In our project, we plan to switch off these neurons that control puberty onset during periods of low food intake. This unique approach will allow our animal subjects to stay fertile even when their diet is restricted, helping us probe whether the benefits of extended reproductive life are intrinsically tied to early-stage fertility loss or if these can be decoupled. This research could reveal a pathway to find interventions providing extended fertility independent of dietary restriction.
Lab website
Arjumand Ghazi, PhD
University of Pittsburgh
Defining a Molecular Signature of Aging Induced by Gonadal Dysfunction
Project Abstract
Lab website
Defining a Molecular Signature of Aging Induced by Gonadal Dysfunction
Project Abstract
Defining a Molecular Signature of Aging Induced by Gonadal
Dysfunction
Our recent research, for the first time, has discovered that disrupting a vital part of the egg maturation process called meiosis can trigger a domino effect of senescence that extends beyond the egg and ultimately shortens the lifespan of the entire organism. Young worms incapable of undergoing meiosis display gene expression profiles akin to those in elderly animals. Cellular snapshots of these C. elegans meiosis mutants also bear a remarkable resemblance to aging human tissues. This suggests cross-species conservation, hinting that meiotic disability may trigger similar molecular changes across the animal kingdom. In this project, we will probe this connection deeper by identifying specific proteins involved in this process and defining their molecular ‘signature’, a marker that may eventually be used to measure aging in both worms and humans. Our lab will also engage in rigorous testing of drugs that could be potential remedies to these defects with the overarching goal of slowing down reproductive aging.
Our recent research, for the first time, has discovered that disrupting a vital part of the egg maturation process called meiosis can trigger a domino effect of senescence that extends beyond the egg and ultimately shortens the lifespan of the entire organism. Young worms incapable of undergoing meiosis display gene expression profiles akin to those in elderly animals. Cellular snapshots of these C. elegans meiosis mutants also bear a remarkable resemblance to aging human tissues. This suggests cross-species conservation, hinting that meiotic disability may trigger similar molecular changes across the animal kingdom. In this project, we will probe this connection deeper by identifying specific proteins involved in this process and defining their molecular ‘signature’, a marker that may eventually be used to measure aging in both worms and humans. Our lab will also engage in rigorous testing of drugs that could be potential remedies to these defects with the overarching goal of slowing down reproductive aging.
Lab website
Kathryn Grive, PhD
Women's and Infants Hospital of Rhode Island
Revealing the Role of Ubiquitin C-Terminal Hydrolase L1 and the Ovarian Proteasome Pathway in Female Reproductive Aging
Project Abstract
Lab website
Revealing the Role of Ubiquitin C-Terminal Hydrolase L1 and the Ovarian Proteasome Pathway in Female Reproductive Aging
Project Abstract
Revealing the Role of Ubiquitin C-Terminal Hydrolase L1 and
the Ovarian Proteasome Pathway in Female Reproductive Aging
Our previous work on a protein known as UCHL1 unearthed a vital role this protein plays in fertility in mice. With UCHL1 knocked out, these mice exhibited abnormal ovarian development, hormonal disruption, and a hindered ability to ovulate. While UCHL1's function in controlling protein abundance in cells is well-known, its role in the reproductive system remains unexplored. So far, we've faced limitations in understanding how UCHL1, a protein that manages the abundance and degradation of other proteins, may be linked to ovarian aging, because mice without the protein age prematurely and experience severe neurological effects by mid-life. To solve this problem and gain deeper insight into how UCHL1 and its associated pathways influence ovarian aging, we've created a mouse line that lacks UCHL1 expression only in developing eggs. We plan to test the reproductive longevity and fitness of these animals, evaluate their ovarian development and aging, assess their hormone function, and examine the molecular makeup of their oocytes. This will provide us with the most detailed picture of UCHL1's impact on ovarian health yet. Moreover, we will explore the relationship between UCHL1 levels in the blood and the age of the ovary in both healthy animals and those with premature reproductive decline. Our hope is that this research could unearth a novel biomarker for ovarian aging, providing us with a powerful tool for early detection and intervention.
Our previous work on a protein known as UCHL1 unearthed a vital role this protein plays in fertility in mice. With UCHL1 knocked out, these mice exhibited abnormal ovarian development, hormonal disruption, and a hindered ability to ovulate. While UCHL1's function in controlling protein abundance in cells is well-known, its role in the reproductive system remains unexplored. So far, we've faced limitations in understanding how UCHL1, a protein that manages the abundance and degradation of other proteins, may be linked to ovarian aging, because mice without the protein age prematurely and experience severe neurological effects by mid-life. To solve this problem and gain deeper insight into how UCHL1 and its associated pathways influence ovarian aging, we've created a mouse line that lacks UCHL1 expression only in developing eggs. We plan to test the reproductive longevity and fitness of these animals, evaluate their ovarian development and aging, assess their hormone function, and examine the molecular makeup of their oocytes. This will provide us with the most detailed picture of UCHL1's impact on ovarian health yet. Moreover, we will explore the relationship between UCHL1 levels in the blood and the age of the ovary in both healthy animals and those with premature reproductive decline. Our hope is that this research could unearth a novel biomarker for ovarian aging, providing us with a powerful tool for early detection and intervention.
Lab website
Zachary Knight, PhD
University of California, San Francisco
Effect of reproductive aging on the gut-brain axis
Project Abstract
Lab website
Effect of reproductive aging on the gut-brain axis
Project Abstract
Effect of reproductive aging on the gut-brain axis
The decline in estrogen after menopause is associated with weight gain. This is because estrogen is thought to inhibit feeding by modulating a key brainstem site for sensing nutritional signals. The underlying mechanisms of this process are unknown. Recently, we developed new tools that make it possible to dissect how estrogen controls food intake by manipulate the key estrogen- responsive cell types in the brain in awake mice. Using a mouse model that mimics menopause in rodents, our project aims to identify which cell types mediate the effects of estrogen on appetite, and further characterize how estrogen modulates these cells. This will provide a foundation for targeted approaches that reverse the effects of menopause on energy balance.
The decline in estrogen after menopause is associated with weight gain. This is because estrogen is thought to inhibit feeding by modulating a key brainstem site for sensing nutritional signals. The underlying mechanisms of this process are unknown. Recently, we developed new tools that make it possible to dissect how estrogen controls food intake by manipulate the key estrogen- responsive cell types in the brain in awake mice. Using a mouse model that mimics menopause in rodents, our project aims to identify which cell types mediate the effects of estrogen on appetite, and further characterize how estrogen modulates these cells. This will provide a foundation for targeted approaches that reverse the effects of menopause on energy balance.
Lab website
T Rajendra Kumar, PhD
University of Colorado
Re-routed FSH Secretion and Female Reproductive Longevity
Project Abstract
Lab website
Re-routed FSH Secretion and Female Reproductive Longevity
Project Abstract
Re-routed FSH Secretion and Female Reproductive Longevity
Hormone regulation is key in the reproductive lifespan of female mammals. In the human pituitary gland , cells called gonadotropes produce two hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Both these hormones are crucial for female reproduction as they support egg and hormone production. LH and FSH are very structurally similar but have very different functions and are released in very different manners, with FSH released continuously and LH in pulses. We have been experimenting with modifying FSH's release pattern in mice to mimic that of LH. This change has led to a significant increase in the number of viable eggs being produced and has extended the reproductive lifespan of these mice. In this project, I will investigate how this modified FSH release pattern impacts the ovaries at a molecular level. First, we will study the gene networks activated by this modified FSH release pattern. We will explore whether these networks differ from those triggered by the regular release of FSH, comparing both young and old mice. This exploration aims to identify potential gene networks unique to the modified FSH patterning that may play a role in promoting reproductive longevity. Second, we will examine components of cellular health in the ovaries of both young and old FSH-modified mice, including markers of cell death, survival, inflammation, oxidative damage, and fibrosis. Our goal is to determine whether the altered FSH release pattern does indeed create a healthier ovarian environment for a longer period. This research could lead to the identification of new gene networks in the ovaries that influence reproductive longevity, shedding light on possible interventions to extend fertility and overall female healthspan.
Hormone regulation is key in the reproductive lifespan of female mammals. In the human pituitary gland , cells called gonadotropes produce two hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Both these hormones are crucial for female reproduction as they support egg and hormone production. LH and FSH are very structurally similar but have very different functions and are released in very different manners, with FSH released continuously and LH in pulses. We have been experimenting with modifying FSH's release pattern in mice to mimic that of LH. This change has led to a significant increase in the number of viable eggs being produced and has extended the reproductive lifespan of these mice. In this project, I will investigate how this modified FSH release pattern impacts the ovaries at a molecular level. First, we will study the gene networks activated by this modified FSH release pattern. We will explore whether these networks differ from those triggered by the regular release of FSH, comparing both young and old mice. This exploration aims to identify potential gene networks unique to the modified FSH patterning that may play a role in promoting reproductive longevity. Second, we will examine components of cellular health in the ovaries of both young and old FSH-modified mice, including markers of cell death, survival, inflammation, oxidative damage, and fibrosis. Our goal is to determine whether the altered FSH release pattern does indeed create a healthier ovarian environment for a longer period. This research could lead to the identification of new gene networks in the ovaries that influence reproductive longevity, shedding light on possible interventions to extend fertility and overall female healthspan.
Lab website
Lena Pernas, PhD
University of California, Los Angeles
Identification of novel regulators of steroidogenesis
Project Abstract
Identification of novel regulators of steroidogenesis
Project Abstract
Identification of novel regulators of steroidogenesis
Mitochondria play a pivotal role in many aspects of our overall health, but one that is often overlooked is their part in the production of steroid hormones. Steroid hormones are vital for our health, and are involved in development of sexual characteristics and female fertility. One of these hormones, dehydroepiandrosterone (DHEA), serves as a precursor for estrogens - the primary female sex hormones. As we age, our bodies' production of both DHEA and estrogen decline, leading to a myriad of health issues and a notable decrease in female fertility. Scientists still don’t fully understand why these hormonal levels drop with age, and we completely lack any effective treatments to counteract this decline. A well-characterized observation about aging is that it is accompanied by a decline in mitochondrial function. Given the central role of mitochondria in steroid hormone production, this raises the question: Could age-related mitochondrial dysfunction be a driving force behind the decrease in DHEA and estrogen levels during reproductive aging? In this research, we're seeking to uncover the answers to this mystery. We aim to identify new factors that regulate the production of steroid hormones within mitochondria, and explore the potential link between age-related mitochondrial dysfunction and the reduced levels of DHEA and estrogen.
Mitochondria play a pivotal role in many aspects of our overall health, but one that is often overlooked is their part in the production of steroid hormones. Steroid hormones are vital for our health, and are involved in development of sexual characteristics and female fertility. One of these hormones, dehydroepiandrosterone (DHEA), serves as a precursor for estrogens - the primary female sex hormones. As we age, our bodies' production of both DHEA and estrogen decline, leading to a myriad of health issues and a notable decrease in female fertility. Scientists still don’t fully understand why these hormonal levels drop with age, and we completely lack any effective treatments to counteract this decline. A well-characterized observation about aging is that it is accompanied by a decline in mitochondrial function. Given the central role of mitochondria in steroid hormone production, this raises the question: Could age-related mitochondrial dysfunction be a driving force behind the decrease in DHEA and estrogen levels during reproductive aging? In this research, we're seeking to uncover the answers to this mystery. We aim to identify new factors that regulate the production of steroid hormones within mitochondria, and explore the potential link between age-related mitochondrial dysfunction and the reduced levels of DHEA and estrogen.
Augusto Schneider, PhD
Universidade Federal de Pelotas
BCAAs regulate ovarian aging in response to diet composition and exercise
Project Abstract
Lab website
BCAAs regulate ovarian aging in response to diet composition and exercise
Project Abstract
BCAAs regulate ovarian aging in response to diet
composition and exercise
Diet and lifestyle choices undeniably have a profound influence on our health, including our reproductive health. For example, we know that caloric restriction and regular exercise can help preserve eggs in women, thereby extending their fertility. Conversely, diets high in fat or protein have been linked to accelerated egg loss and the eventual onset of infertility and menopause. Our preliminary research suggests that the benefits of caloric restriction could be mimicked by restricting the intake of a specific type of protein, known as branched-chain amino acids (BCAAs). Scientists have also discovered that exercise appears to ramp up the body's breakdown of these BCAAs, a clue as to why exercise may protect from some aspects of reproductive aging. The understanding gained from this study could potentially redefine our understanding of reproductive health and fertility, particularly for women attempting to lose weight, athletes, or those leading an active lifestyle. We could provide practical dietary guidelines and exercise regimens that extend fertility while promoting overall health.
Diet and lifestyle choices undeniably have a profound influence on our health, including our reproductive health. For example, we know that caloric restriction and regular exercise can help preserve eggs in women, thereby extending their fertility. Conversely, diets high in fat or protein have been linked to accelerated egg loss and the eventual onset of infertility and menopause. Our preliminary research suggests that the benefits of caloric restriction could be mimicked by restricting the intake of a specific type of protein, known as branched-chain amino acids (BCAAs). Scientists have also discovered that exercise appears to ramp up the body's breakdown of these BCAAs, a clue as to why exercise may protect from some aspects of reproductive aging. The understanding gained from this study could potentially redefine our understanding of reproductive health and fertility, particularly for women attempting to lose weight, athletes, or those leading an active lifestyle. We could provide practical dietary guidelines and exercise regimens that extend fertility while promoting overall health.
Lab website
2023 Postdoctoral Scholar Award Recipients
Olga Bielska, PhD
Buck Institute for Research on Aging
Uncovering a new gene linking aging, mitochondria, and infertility
Project Abstract
Lab website
Uncovering a new gene linking aging, mitochondria, and infertility
Project Abstract
Uncovering a new gene linking aging, mitochondria, and infertility
Kickstarting new life takes a lot of energy. In order to fuel the beginning of embryonic development, eggs contain ten times more mitochondria than other cells. Yet, as time goes by, these mitochondria start to age and lose function, leading to defects in the eggs that have remained dormant in the body for decades. A How important are dysfunctional mitochondria to deteriorating egg quality as we age? In this project, I will focus on one crucial mitochondrial protein; in my previous work, I observed that as this protein's levels plummet with age in female reproductive organs, leading to infertility in mice. The resulting physiological consequences from this decline mirrors the changes we see in human aging and infertility. Some other interesting preliminary findings suggest that this protein isn't just influencing mitochondria, it could be orchestrating changes throughout the body, acting as a crucial 'node' in the hypothalamic–pituitary–gonadal (HPG) hormonal axis, which is a key player in reproductive health. We aim to examine this infertility phenotype comprehensively and explore the underlying mechanism using advanced methods. Our findings could pave the way for new therapies to extend female reproductive longevity and improve overall women's health.
Kickstarting new life takes a lot of energy. In order to fuel the beginning of embryonic development, eggs contain ten times more mitochondria than other cells. Yet, as time goes by, these mitochondria start to age and lose function, leading to defects in the eggs that have remained dormant in the body for decades. A How important are dysfunctional mitochondria to deteriorating egg quality as we age? In this project, I will focus on one crucial mitochondrial protein; in my previous work, I observed that as this protein's levels plummet with age in female reproductive organs, leading to infertility in mice. The resulting physiological consequences from this decline mirrors the changes we see in human aging and infertility. Some other interesting preliminary findings suggest that this protein isn't just influencing mitochondria, it could be orchestrating changes throughout the body, acting as a crucial 'node' in the hypothalamic–pituitary–gonadal (HPG) hormonal axis, which is a key player in reproductive health. We aim to examine this infertility phenotype comprehensively and explore the underlying mechanism using advanced methods. Our findings could pave the way for new therapies to extend female reproductive longevity and improve overall women's health.
Lab website
Hannes Campo, PhD
Northwestern University
Development of a vascularized microfluidic ovarian senescence model for senolytic drug screening.
Project Abstract
Lab website
Development of a vascularized microfluidic ovarian senescence model for senolytic drug screening.
Project Abstract
Development of a vascularized microfluidic ovarian
senescence model for senolytic drug screening.
With age, a cell type called senescent cells accumulate in tissue and accelerate the aging process. These are damaged cells that, instead of dying off, stick around and release inflammatory signals around them. Some researchers have recently shown that these cells can be specifically destroyed by drugs called senolytics, leading to an improvement in age-related disease. Our laboratory has recently identified the presence of these cells in the post-menopausal ovary, particularly in close proximity to blood vessels, where they have never been described before. Could these cells be drivers of reproductive aging? With the help of sophisticated cell culture models that closely mimic human physiology, including the incorporation of blood vessels and structural cells called endothelial cells, I aim to deepen our understanding of these senescent cells. We will test a common senolytic drug combination's effects on senescence in this model, with and without the endothelium present. Besides providing a better understanding of senescence in the ovaries, honing this advanced model may provide valuable data to help scientists in the future avoid common drug development challenges, like the inability for therapeutics to make it out of the bloodstream into tissue.
With age, a cell type called senescent cells accumulate in tissue and accelerate the aging process. These are damaged cells that, instead of dying off, stick around and release inflammatory signals around them. Some researchers have recently shown that these cells can be specifically destroyed by drugs called senolytics, leading to an improvement in age-related disease. Our laboratory has recently identified the presence of these cells in the post-menopausal ovary, particularly in close proximity to blood vessels, where they have never been described before. Could these cells be drivers of reproductive aging? With the help of sophisticated cell culture models that closely mimic human physiology, including the incorporation of blood vessels and structural cells called endothelial cells, I aim to deepen our understanding of these senescent cells. We will test a common senolytic drug combination's effects on senescence in this model, with and without the endothelium present. Besides providing a better understanding of senescence in the ovaries, honing this advanced model may provide valuable data to help scientists in the future avoid common drug development challenges, like the inability for therapeutics to make it out of the bloodstream into tissue.
Lab website
Haiyuan Mu, PhD
UC Berkeley
Regulation and functional roles of retrotransposon in ovarian aging
Project Abstract
Lab website
Regulation and functional roles of retrotransposon in ovarian aging
Project Abstract
Regulation and functional roles of retrotransposon in ovarian
aging
Genomic anomalies in eggs, which can result in infertility, often arise from DNA damage or degradation, especially in long-lived cells such as oocytes. One major source of such damage is retrotransposons, mobile stretches of DNA that can extract and reinsert themselves in different genome locations, where they can interrupt normal functions. In mammals, retrotransposons are usually repressed by the genome, but this silencing process can become faulty during aging. I study one group of retrotransposons, called the IAPE family. I have found in previous research that this group accounts for ~10% of mutations in laboratory mice. Activation of these retrotransposons could contribute to the aging of eggs through DNA damage. I aim to better characterize the contribution of retrotransposons in oocyte aging, opening the door to diagnostics for premature oocyte aging and new therapeutic targets.
Genomic anomalies in eggs, which can result in infertility, often arise from DNA damage or degradation, especially in long-lived cells such as oocytes. One major source of such damage is retrotransposons, mobile stretches of DNA that can extract and reinsert themselves in different genome locations, where they can interrupt normal functions. In mammals, retrotransposons are usually repressed by the genome, but this silencing process can become faulty during aging. I study one group of retrotransposons, called the IAPE family. I have found in previous research that this group accounts for ~10% of mutations in laboratory mice. Activation of these retrotransposons could contribute to the aging of eggs through DNA damage. I aim to better characterize the contribution of retrotransposons in oocyte aging, opening the door to diagnostics for premature oocyte aging and new therapeutic targets.
Lab website
Yasuhita Munakata, PhD
University of California, Davis
Chromatin regulatory mechanisms of ovarian reserve underlying disrupted gene expression in aged oocytes
Project Abstract
Lab website
Chromatin regulatory mechanisms of ovarian reserve underlying disrupted gene expression in aged oocytes
Project Abstract
Chromatin regulatory mechanisms of ovarian reserve underlying disrupted gene expression in aged oocytes
Much of the research into aging eggs is done in full-grown oocytes, yet eggs spend much of their life in a dormant state in the primordial follicle pool, in a state called non-growing oocytes (NGOs). This project aims to bridge the knowledge gap by examining whether the age-related decline in oocyte quality occurs during maturation after follicle activation, or if it is established in NGOs while they remain dormant. I hypothesize that the chromatin state—a regulatory 'code' governing gene expression—undergoes detrimental alterations with age in NGOs. To investigate this, I plan to examine chromatin across the entire genome, both before and after deletion of proteins responsible for chromatin state remodeling. These studies will be conducted in both young and aged mice, and we will observe the effects on the ovarian reserve. I suspect that this chromatin remodeling factor may help maintain the ovarian reserve, and that learning more about its role will help provide clues of how to extend reproductive longevity. This approach will determine if age-related declines in oocyte quality originate in NGOs, improving our understanding of ovarian reserve maintenance and offering the opportunity for innovative treatments to maintain the ovarian reserve.
Much of the research into aging eggs is done in full-grown oocytes, yet eggs spend much of their life in a dormant state in the primordial follicle pool, in a state called non-growing oocytes (NGOs). This project aims to bridge the knowledge gap by examining whether the age-related decline in oocyte quality occurs during maturation after follicle activation, or if it is established in NGOs while they remain dormant. I hypothesize that the chromatin state—a regulatory 'code' governing gene expression—undergoes detrimental alterations with age in NGOs. To investigate this, I plan to examine chromatin across the entire genome, both before and after deletion of proteins responsible for chromatin state remodeling. These studies will be conducted in both young and aged mice, and we will observe the effects on the ovarian reserve. I suspect that this chromatin remodeling factor may help maintain the ovarian reserve, and that learning more about its role will help provide clues of how to extend reproductive longevity. This approach will determine if age-related declines in oocyte quality originate in NGOs, improving our understanding of ovarian reserve maintenance and offering the opportunity for innovative treatments to maintain the ovarian reserve.
Lab website
Periklis Paganos, PhD
Marine Biological Laboratory
Gene regulatory networks controlling sea star reproductive longevity and aging
Project Abstract
Lab website
Gene regulatory networks controlling sea star reproductive longevity and aging
Project Abstract
Gene regulatory networks controlling sea star reproductive
longevity and aging
Sea stars are incredibly fertile creatures, able to produce hundreds of thousands of eggs over their 35+ year lifespan. Unlike humans, they don't seem to experience a decline in fertility as they age. What makes them so different? The secrets to such extreme fertility may lie in the genes expressed by the reproductive system of these creatures. To investigate this, I will use cutting-edge scientific tools that allow us to identify and characterize every single gene expressed within individual cells in the sea star. This will help us pinpoint the exact cell types and specific genes that give sea stars their remarkable fertility. By comparing what we find in sea stars with data from other organisms, we hope to identify the key differences and similarities between the 'ageless' fertility of the sea star and the 'aging' human ovary. This exploration could open up entirely new understandings of how and why human reproductive aging happens.
Sea stars are incredibly fertile creatures, able to produce hundreds of thousands of eggs over their 35+ year lifespan. Unlike humans, they don't seem to experience a decline in fertility as they age. What makes them so different? The secrets to such extreme fertility may lie in the genes expressed by the reproductive system of these creatures. To investigate this, I will use cutting-edge scientific tools that allow us to identify and characterize every single gene expressed within individual cells in the sea star. This will help us pinpoint the exact cell types and specific genes that give sea stars their remarkable fertility. By comparing what we find in sea stars with data from other organisms, we hope to identify the key differences and similarities between the 'ageless' fertility of the sea star and the 'aging' human ovary. This exploration could open up entirely new understandings of how and why human reproductive aging happens.
Lab website
Na-Young Rho, PhD
Yale University
Determining Molecular Pathways in Human Ovarian Aging
Project Abstract
Lab website
Determining Molecular Pathways in Human Ovarian Aging
Project Abstract
Determining Molecular Pathways in Human Ovarian Aging
Ovarian aging is closely tied to the efficiency of DNA repair. As the body ages, the capacity of a specific DNA repair pathway, known as the ATM pathway, declines in eggs, leading to an accumulation of DNA damage and accelerating cell death. This decline is particularly noticeable in women with certain genetic mutations, such as BRCA1, who often experience menopause earlier than usual. I hypothesize that this diminishing ATM pathway function, and subsequent DNA repair activity, may be a central cause for key aspects of ovarian aging. Using advanced sequencing techniques, I plan to investigate the role of the ATM pathway in this context. Upon establishing the pathway's involvement, I will disturb the ATM pathway’s function and assess the consequences on fertility, egg health, and ovarian reserve, comparing these to the effects observed during aging. These experiments will establish the role of DNA repair in ovarian aging, identify potential alternative pathways in the process, and ultimately reveal molecular targets to reverse, retard, or prevent ovarian aging.
Ovarian aging is closely tied to the efficiency of DNA repair. As the body ages, the capacity of a specific DNA repair pathway, known as the ATM pathway, declines in eggs, leading to an accumulation of DNA damage and accelerating cell death. This decline is particularly noticeable in women with certain genetic mutations, such as BRCA1, who often experience menopause earlier than usual. I hypothesize that this diminishing ATM pathway function, and subsequent DNA repair activity, may be a central cause for key aspects of ovarian aging. Using advanced sequencing techniques, I plan to investigate the role of the ATM pathway in this context. Upon establishing the pathway's involvement, I will disturb the ATM pathway’s function and assess the consequences on fertility, egg health, and ovarian reserve, comparing these to the effects observed during aging. These experiments will establish the role of DNA repair in ovarian aging, identify potential alternative pathways in the process, and ultimately reveal molecular targets to reverse, retard, or prevent ovarian aging.
Lab website
Laura Wester, PhD
Max Planck Institute for Biology of Ageing
Translating the translatome: How reproductive quiescence and activation are regulated by mRNA translation-based mechanisms in Caenorhabditis elegans
Project Abstract
Lab website
Translating the translatome: How reproductive quiescence and activation are regulated by mRNA translation-based mechanisms in Caenorhabditis elegans
Project Abstract
Translating the translatome: How reproductive quiescence
and activation are regulated by mRNA translation-based mechanisms in Caenorhabditis
elegans
Translation, the process of building proteins from mRNA, is critical for both egg dormancy and egg maturation. But scientists still don’t know the answers to crucial questions such as how the translation machinery is preserved during egg dormancy, and which proteins are the first to be synthesized upon activation. In this project, I will use the diapause life stage of the roundworm Caenorhabditis elegans (C. elegans) as a model for studying egg dormancy and reactivation. In response to adverse environmental conditions, like food scarcity, C. elegans enters a dormant state. This significantly slows its metabolism, halting reproduction and extending its overall lifespan. Once conditions improve, these roundworms "reactivate," resume reproduction, and live a normal lifespan. This is akin to the activation process in human eggs. My project’s focus will be on the processes of mRNA translation that underpin both maintaining dormancy and the ‘recovery’ from it, during activation. Our findings could then guide the development of interventions or treatments to mitigate or reverse the effects of aging on fertility, initially in C. elegans and eventually in humans.
Translation, the process of building proteins from mRNA, is critical for both egg dormancy and egg maturation. But scientists still don’t know the answers to crucial questions such as how the translation machinery is preserved during egg dormancy, and which proteins are the first to be synthesized upon activation. In this project, I will use the diapause life stage of the roundworm Caenorhabditis elegans (C. elegans) as a model for studying egg dormancy and reactivation. In response to adverse environmental conditions, like food scarcity, C. elegans enters a dormant state. This significantly slows its metabolism, halting reproduction and extending its overall lifespan. Once conditions improve, these roundworms "reactivate," resume reproduction, and live a normal lifespan. This is akin to the activation process in human eggs. My project’s focus will be on the processes of mRNA translation that underpin both maintaining dormancy and the ‘recovery’ from it, during activation. Our findings could then guide the development of interventions or treatments to mitigate or reverse the effects of aging on fertility, initially in C. elegans and eventually in humans.
Lab website
2020 GCRLE Grantees
Recipients of the 2020 GCRLE Scholar Awards comprise a global group who share our vision of advancing research to better understand the underlying causes of female reproductive aging. Grantees were selected by a Scientific Advisory Council composed of leaders in the fields of Aging and Reproductive Biology. Grantees range from early career scientists to established scholars in the field.
2020 Senior Scholar Award Recipients
Holly Ingraham, PhD
University of California, San Francisco
Identifying Novel Drivers in Central Control of Female Reproduction
Project Abstract
Lab website
Listen to Dr Ingraham discuss her research in OVA Hour | Episode 9
Listen to Dr Ingraham present her research in Making Reproductive Longevity a Reality | Episode 2
Identifying Novel Drivers in Central Control of Female Reproduction
Project Abstract
Identifying Novel Drivers in Central Control of Female Reproduction
In this GCRLE-funded project, our main goal is to uncover novel hormone-responsive brain regions that coordinate and maximize reproductive fitness in female mice. As a senior investigator who has worked for 25 years to define sex-dependent mechanisms in the brain and gonads, it is apparent that a major obstacle to new discoveries in reproductive health is the narrow focus and siloed nature of our research area. In stark contrast to the phenomenal progress made in the central control of other processes, such as feeding, concepts as to how the female brain exerts control over ovarian function and optimizes reproduction have fundamentally remained unchanged for the last four decades. Indeed, nearly all studies published to date in this research space have narrowly focused on just a few of the many thousands of neurons subtypes in our brains. With the recent realization that there is an amazing degree of neuronal diversity in the brain, and that neuronal outputs are often different between males and females, we wish to ask whether new, sex-specific neurocircuits exist that are critically important for reproductive physiology.
This new GCRLE initiative provides an unparalleled opportunity to break down traditional barriers and foster discovery-based research that might eventually translate into novel therapeutic strategies to improve reproductive health in women. Building upon our knowledge of estrogen-responsive nodes in brain regions, we aim to identify neurons and signals in the brain that remodel the molecular workings of the ovary to optimize reproduction. In this proposal, we will test the hypothesis that the brain is a key player for reproductive success by directly or indirectly controlling egg quality, ovarian reserve, hormone levels, ovulation, and mating behaviors. This basic information will be foundational for forming a mechanistic understanding of reproductive aging, and importantly, for generating novel treatments for infertility.
In this GCRLE-funded project, our main goal is to uncover novel hormone-responsive brain regions that coordinate and maximize reproductive fitness in female mice. As a senior investigator who has worked for 25 years to define sex-dependent mechanisms in the brain and gonads, it is apparent that a major obstacle to new discoveries in reproductive health is the narrow focus and siloed nature of our research area. In stark contrast to the phenomenal progress made in the central control of other processes, such as feeding, concepts as to how the female brain exerts control over ovarian function and optimizes reproduction have fundamentally remained unchanged for the last four decades. Indeed, nearly all studies published to date in this research space have narrowly focused on just a few of the many thousands of neurons subtypes in our brains. With the recent realization that there is an amazing degree of neuronal diversity in the brain, and that neuronal outputs are often different between males and females, we wish to ask whether new, sex-specific neurocircuits exist that are critically important for reproductive physiology.
This new GCRLE initiative provides an unparalleled opportunity to break down traditional barriers and foster discovery-based research that might eventually translate into novel therapeutic strategies to improve reproductive health in women. Building upon our knowledge of estrogen-responsive nodes in brain regions, we aim to identify neurons and signals in the brain that remodel the molecular workings of the ovary to optimize reproduction. In this proposal, we will test the hypothesis that the brain is a key player for reproductive success by directly or indirectly controlling egg quality, ovarian reserve, hormone levels, ovulation, and mating behaviors. This basic information will be foundational for forming a mechanistic understanding of reproductive aging, and importantly, for generating novel treatments for infertility.
Lab website
Listen to Dr Ingraham discuss her research in OVA Hour | Episode 9
Listen to Dr Ingraham present her research in Making Reproductive Longevity a Reality | Episode 2
Coleen Murphy, PhD
Princeton University
Defining a “Clock” for Female Reproductive Decline
Project Abstract
Lab website
Listen to Dr Murphy present her research in Making Reproductive Longevity a Reality | Episode 1
Defining a “Clock” for Female Reproductive Decline
Project Abstract
Defining a “Clock” for Female Reproductive Decline
Women begin to experience decreased fertility on average in the late 30s to mid-40s, preceding menopause by more than a decade; this decline in reproductive ability is marked by increased rates of infertility, miscarriages, and birth defects that arise from aneuploidies and generally decreased oocyte quality. The range of ages when such problems arise is quite broad (10-15 years), and varies highly from individual to individual. Currently it is not possible for a woman to know where she stands on this scale of age-related oocyte quality decline, as current measures of oocyte quality are both short-range and highly invasive. Here we propose the development of a non-invasive diagnostic that would predict age-related oocyte quality decline to identify changes that are reflected in aging of reproductive tissues, which will accelerate our ability to both study and treat reproductive aging.
The work proposed here will enable the analysis of underlying mechanisms that regulate reproductive aging, and provide women with information about their relative reproductive aging status; this will allow them to make more informed decisions about their reproductive lives, perhaps avoiding maternal age-related infertility, miscarriage, and birth defects. Additionally, a blood diagnostic will allow the development of drug treatments for maternal age-related decline. The ability to diagnose and eventually treat fertility problems early will lower maternal age-related birth defect rates and pregnancy complications.
Women begin to experience decreased fertility on average in the late 30s to mid-40s, preceding menopause by more than a decade; this decline in reproductive ability is marked by increased rates of infertility, miscarriages, and birth defects that arise from aneuploidies and generally decreased oocyte quality. The range of ages when such problems arise is quite broad (10-15 years), and varies highly from individual to individual. Currently it is not possible for a woman to know where she stands on this scale of age-related oocyte quality decline, as current measures of oocyte quality are both short-range and highly invasive. Here we propose the development of a non-invasive diagnostic that would predict age-related oocyte quality decline to identify changes that are reflected in aging of reproductive tissues, which will accelerate our ability to both study and treat reproductive aging.
The work proposed here will enable the analysis of underlying mechanisms that regulate reproductive aging, and provide women with information about their relative reproductive aging status; this will allow them to make more informed decisions about their reproductive lives, perhaps avoiding maternal age-related infertility, miscarriage, and birth defects. Additionally, a blood diagnostic will allow the development of drug treatments for maternal age-related decline. The ability to diagnose and eventually treat fertility problems early will lower maternal age-related birth defect rates and pregnancy complications.
Lab website
Listen to Dr Murphy present her research in Making Reproductive Longevity a Reality | Episode 1
Mary Zelinski, PhD
Oregon Health & Science University
Interventions for Ovarian Aging
Project Abstract
Lab website
Listen to Dr Zelinski present her research in Making Reproductive Longevity a Reality | Episode 9
Interventions for Ovarian Aging
Project Abstract
Interventions for Ovarian Aging
A woman’s capacity to produce eggs that are capable of being fertilized and carried to term in a healthy pregnancy is called ovarian reserve, and it diminishes with age. Immature eggs are stored inside the ovary in follicles, which have to be activated in order for a mature egg to be released each cycle. The number of women of advanced reproductive ages seeking to have a child has steadily increased; unfortunately, they have few follicles remaining in their ovaries from which to produce healthy eggs. Understanding the mechanisms that control the size of the ovarian reserve as well as the rate of follicle recruitment is paramount for preventing age-related reproductive decline.
Rapamycin is an approved drug that potently suppresses the immune system at high doses, and is approved for treating cancer and reducing the likelihood of rejection after organ transplantation. In rodent models lower doses of rapamycin can extend healthy lifespan as well as reproductive lifespan when administered to older animals. We will use a pre-clinical mammalian model of reproductive aging to test the hypothesis that chronic low dose rapamycin treatment beginning in mid-life may temporarily suppress follicle activation in older females, thereby allowing a greater pool of follicles from which healthy eggs can be obtained at advanced ages. If the rate of primordial follicle activation can be controlled, the potential to produce even a few high-quality eggs would significantly impact fertility in women of advanced reproductive age and improve overall health.
A woman’s capacity to produce eggs that are capable of being fertilized and carried to term in a healthy pregnancy is called ovarian reserve, and it diminishes with age. Immature eggs are stored inside the ovary in follicles, which have to be activated in order for a mature egg to be released each cycle. The number of women of advanced reproductive ages seeking to have a child has steadily increased; unfortunately, they have few follicles remaining in their ovaries from which to produce healthy eggs. Understanding the mechanisms that control the size of the ovarian reserve as well as the rate of follicle recruitment is paramount for preventing age-related reproductive decline.
Rapamycin is an approved drug that potently suppresses the immune system at high doses, and is approved for treating cancer and reducing the likelihood of rejection after organ transplantation. In rodent models lower doses of rapamycin can extend healthy lifespan as well as reproductive lifespan when administered to older animals. We will use a pre-clinical mammalian model of reproductive aging to test the hypothesis that chronic low dose rapamycin treatment beginning in mid-life may temporarily suppress follicle activation in older females, thereby allowing a greater pool of follicles from which healthy eggs can be obtained at advanced ages. If the rate of primordial follicle activation can be controlled, the potential to produce even a few high-quality eggs would significantly impact fertility in women of advanced reproductive age and improve overall health.
Lab website
Listen to Dr Zelinski present her research in Making Reproductive Longevity a Reality | Episode 9
2020 Junior Scholar Award Recipients
Bérénice Benayoun, PhD
University of Southern California
Establishing new age-relevant mouse models of menopause
Project Abstract
Lab website
Listen to Dr Benayoun present her research in Making Reproductive Longevity a Reality | Episode 4
Establishing new age-relevant mouse models of menopause
Project Abstract
Establishing new age-relevant mouse models of menopause
Menopause marks the shutdown of female sex-steroid hormones synthesis in humans and is often dismissed as the mere cessation of reproductive capacity. However, later age-at-menopause is a strong predictor for women’s health and longevity, with post-menopausal women being at much higher risk for many age-related diseases. With a mean menopause age of 51 years, women spend a large portion of their life in reproductive senescence. Although laboratory mice show decreased reproductive capacity with aging, they normally poorly recapitulate the process of menopause. Indeed, the most commonly used models of menopause in mice (such as ovariectomy) fail to recapitulate key aspects of human menopause. Further, the few studies that do investigate menopause usually use young animals, thus failing to model the menopausal state in an appropriately aged organism, when menopause would occur in humans.
We hypothesize that the development of complementary, age-relevant rodent models of menopause will help transform our understanding of female aging, and ultimately provide new therapeutic handles to improve women’s health. To address the current lack of well-characterized age-appropriate menopause models, we propose to characterize and compare the outcome of three independent potential models of menopause in rodents, all of which can be used to model menopause in middle-aged mice and with intact ovaries. First, we will characterize the dynamics of “menopause” onset in these animals and evaluate how the animals’ longer-term health is affected by ovarian failure at middle-age. Second, we will extensively characterize the cellular and molecular landscape of ovaries isolated from menopause and control animals using single cell RNA-sequencing. Molecular characterization and comparison across models will allow the identification of potential therapeutic targets. Successful completion of this project will lead to the characterization of novel, age-relevant rodent models of menopause, which will greatly facilitate the inclusion of the impact of menopause in basic studies of aging.
Menopause marks the shutdown of female sex-steroid hormones synthesis in humans and is often dismissed as the mere cessation of reproductive capacity. However, later age-at-menopause is a strong predictor for women’s health and longevity, with post-menopausal women being at much higher risk for many age-related diseases. With a mean menopause age of 51 years, women spend a large portion of their life in reproductive senescence. Although laboratory mice show decreased reproductive capacity with aging, they normally poorly recapitulate the process of menopause. Indeed, the most commonly used models of menopause in mice (such as ovariectomy) fail to recapitulate key aspects of human menopause. Further, the few studies that do investigate menopause usually use young animals, thus failing to model the menopausal state in an appropriately aged organism, when menopause would occur in humans.
We hypothesize that the development of complementary, age-relevant rodent models of menopause will help transform our understanding of female aging, and ultimately provide new therapeutic handles to improve women’s health. To address the current lack of well-characterized age-appropriate menopause models, we propose to characterize and compare the outcome of three independent potential models of menopause in rodents, all of which can be used to model menopause in middle-aged mice and with intact ovaries. First, we will characterize the dynamics of “menopause” onset in these animals and evaluate how the animals’ longer-term health is affected by ovarian failure at middle-age. Second, we will extensively characterize the cellular and molecular landscape of ovaries isolated from menopause and control animals using single cell RNA-sequencing. Molecular characterization and comparison across models will allow the identification of potential therapeutic targets. Successful completion of this project will lead to the characterization of novel, age-relevant rodent models of menopause, which will greatly facilitate the inclusion of the impact of menopause in basic studies of aging.
Lab website
Listen to Dr Benayoun present her research in Making Reproductive Longevity a Reality | Episode 4
Lynae Brayboy, MD
Charité – Universitätsmedizin, Berlin
Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte
Project Abstract
Lab website
Listen to Dr Brayboy present her research in Making Reproductive Longevity a Reality | Episode 7
Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte
Project Abstract
Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte
Infertility affects 186 million people worldwide, however the cause of one prevalent diagnosis of infertility-diminished ovarian reserve (DOR) (associated with decreased egg (oocyte) quantity and quality)-is unknown and often requires treatment with in vitro fertilization (IVF). One explanation is that egg dysfunction mediated by chronic metabolic stress and toxicity is caused by the loss of detoxification proteins known as multidrug resistance transporters (MDRs). My work seeks to understand how MDRs guard eggs from metabolic stress and toxicants which can lead to infertility and long-term health sequelae. Oocyte quality has been inextricably linked to mitochondrial function. My data show that MDR-1, expressed on both the oocyte and mitochondrial membranes is essential for mitochondrial health. I have additional data showing loss of MDR-1 function leads to poor quality oocytes. The long-term goal of this project is to understand the mechanism of MDR-1 function in oocyte mitochondria.
The overall objective is to test how MDR-1 loss leads to poor oocyte quality/embryo progression, abnormal mitochondrial physiology and DOR. We have a clinical need to understand the pathophysiology of DOR, perhaps the key lies in MDRs. This has led to my hypothesis that MDR-1 directs mitochondrial function and protects oocytes from metabolic stress. I will pursue the following project goals: 1) Investigate how MDR-1 dysfunction impacts oocyte quality and embryo progression The goal is to evaluate the effect of MDR-1 loss on egg quality, which involves two aspects: the capability of the egg to mature normally and provide healthy cellular infrastructure for embryo development. 2) Study how loss of MDR-1 leads to abnormal mitochondrial function in oocytes. Here I will test the contribution of MDR-1 loss on metabolic stress, mitochondrial activity and function in oocytes. 3) Examine how loss of MDR-1 contributes to DOR My aim is to understand the implication of MDR-1 loss on premature ovarian aging. Studying oocyte MDR-1 introduces a novel link between MDR-1 loss, mitochondrial dysfunction and poor oocyte quality leading to infertility. The overall impact will be insight into mechanisms of premature ovarian aging.
Infertility affects 186 million people worldwide, however the cause of one prevalent diagnosis of infertility-diminished ovarian reserve (DOR) (associated with decreased egg (oocyte) quantity and quality)-is unknown and often requires treatment with in vitro fertilization (IVF). One explanation is that egg dysfunction mediated by chronic metabolic stress and toxicity is caused by the loss of detoxification proteins known as multidrug resistance transporters (MDRs). My work seeks to understand how MDRs guard eggs from metabolic stress and toxicants which can lead to infertility and long-term health sequelae. Oocyte quality has been inextricably linked to mitochondrial function. My data show that MDR-1, expressed on both the oocyte and mitochondrial membranes is essential for mitochondrial health. I have additional data showing loss of MDR-1 function leads to poor quality oocytes. The long-term goal of this project is to understand the mechanism of MDR-1 function in oocyte mitochondria.
The overall objective is to test how MDR-1 loss leads to poor oocyte quality/embryo progression, abnormal mitochondrial physiology and DOR. We have a clinical need to understand the pathophysiology of DOR, perhaps the key lies in MDRs. This has led to my hypothesis that MDR-1 directs mitochondrial function and protects oocytes from metabolic stress. I will pursue the following project goals: 1) Investigate how MDR-1 dysfunction impacts oocyte quality and embryo progression The goal is to evaluate the effect of MDR-1 loss on egg quality, which involves two aspects: the capability of the egg to mature normally and provide healthy cellular infrastructure for embryo development. 2) Study how loss of MDR-1 leads to abnormal mitochondrial function in oocytes. Here I will test the contribution of MDR-1 loss on metabolic stress, mitochondrial activity and function in oocytes. 3) Examine how loss of MDR-1 contributes to DOR My aim is to understand the implication of MDR-1 loss on premature ovarian aging. Studying oocyte MDR-1 introduces a novel link between MDR-1 loss, mitochondrial dysfunction and poor oocyte quality leading to infertility. The overall impact will be insight into mechanisms of premature ovarian aging.
Lab website
Listen to Dr Brayboy present her research in Making Reproductive Longevity a Reality | Episode 7
Ingrid Fetter-Pruneda, PhD
Universidad Nacional Autónoma de México
The molecular and cellular basis of high fecundity in social insects
Project Abstract
Lab website
Listen to Dr Fetter-Pruneda present her research in Making Reproductive Longevity a Reality | Episode 4
The molecular and cellular basis of high fecundity in social insects
Project Abstract
The molecular and cellular basis of high fecundity in social insects
A common trade-off in animals is that an increase in fecundity is associated with a decrease in longevity. This is not the case in social insects such as ants, bees and wasps, where the reproductives (queens) simultaneously have very high fecundity and very long lifespans. The queens of some species of ants, for example, can live up to 30 years while continuously laying eggs. Non-reproductive individuals have much shorter lifespans, from weeks to months, even though they share the same genes.
How and why social insect queens can have such high fecundity and be so long-lived at the same time remains to be answered. My project aims to find genes involved in high fecundity and long healthspan in ants by analyzing differences in gene expression in ovaries and endocrine tissues of longer- and shorter-lived individuals within and between species. We will characterize the function of these genes in an experimentally amenable ant species and in fruit flies, in which there are many molecular tools available. This will allow us to test and manipulate predicted fecundity and reproductive aging pathways in ants and other organisms to identify genes and pathways that could be conserved across species, which may accelerate the development of strategies to increase fecundity and prevent or delay ovarian aging.
A common trade-off in animals is that an increase in fecundity is associated with a decrease in longevity. This is not the case in social insects such as ants, bees and wasps, where the reproductives (queens) simultaneously have very high fecundity and very long lifespans. The queens of some species of ants, for example, can live up to 30 years while continuously laying eggs. Non-reproductive individuals have much shorter lifespans, from weeks to months, even though they share the same genes.
How and why social insect queens can have such high fecundity and be so long-lived at the same time remains to be answered. My project aims to find genes involved in high fecundity and long healthspan in ants by analyzing differences in gene expression in ovaries and endocrine tissues of longer- and shorter-lived individuals within and between species. We will characterize the function of these genes in an experimentally amenable ant species and in fruit flies, in which there are many molecular tools available. This will allow us to test and manipulate predicted fecundity and reproductive aging pathways in ants and other organisms to identify genes and pathways that could be conserved across species, which may accelerate the development of strategies to increase fecundity and prevent or delay ovarian aging.
Lab website
Listen to Dr Fetter-Pruneda present her research in Making Reproductive Longevity a Reality | Episode 4
Amanda Kallen, MD
Yale University
Ovarian Senescence as a Novel Driver of Female Reproductive Aging
Project Abstract
Lab website
Listen to Dr Kallen present her research in Making Reproductive Longevity a Reality | Episode 5
Ovarian Senescence as a Novel Driver of Female Reproductive Aging
Project Abstract
Ovarian Senescence as a Novel Driver of Female Reproductive Aging
The health risks of female reproductive aging are severe and include changes in neuroendocrine hormones, declining bone health and osteoporosis, cardiovascular disease, and cognitive decline. Therefore, women approaching menopause represent a unique group that appears to be at increased risk for long-term health effects. Moreover, human chronological life span has extended dramatically over the last century, while the timing of menopause has remained relatively constant. Thus, women will spend a larger portion of their lives in the post-menopausal period, and the incidence of these comorbidities will increase. In order to address the role that female reproductive aging plays in overall population health and longevity, it is critical to define these molecular processes which underpin the normal physiology of ovarian aging and the decline of ovarian function.
Cellular senescence, a response to cellular insult involving cellular arrest, is a key hallmark of aging in non-reproductive tissues. The senescence biomarker p16, a cyclin-dependent kinase inhibitor which enforces growth arrest, impairs organ function in tissues including kidney and heart and shortens healthy lifespan in mice. Elimination of p16-expressing senescent cells in mice attenuates age-related deterioration of these organs and extends lifespan. p16 is expressed in oocytes of primordial and early primary follicles of 8 week mice, and in follicles at all stages of maturity, with varying expression levels. Moreover, in a mouse model of ovarian failure induced by repetitive superovulation, p16 increased in GCs with successive ouvlations, suggesting that recurrent ovulation may promote senescence and ovarian aging via a p16-mediated pathway
However, the contribution of senescent cells to the naturally aging ovary - specifically, whether a critical accumulation of senescent cells in the ovary is detrimental to ovarian function - is unknown. In studies in which p16-expressing cells were globally eliminated and mouse lifespan was increased, the presence of senescent cells in the reproductive tract and the effect of their clearance on ovarian aging and reproductive lifespan was not evaluated. Therefore, in this proposal, we will utilize a mouse model of ovarian senescence to define the role of senescent cells, and the effect of their clearance, in the aging ovary. Because the ovary contains a heterogeneous population of cell types that critically contribute to follicular survival and whose age-related transcriptomes have not been characterized, we will then utilize human ovarian tissue to characterize the expression of senescence markers in individual ovarian cell types and create a comprehensive cellular atlas of the transcriptome of the ovarian aging. We expect our proposed Aims to generate highly impactful findings with translational relevance to ovarian aging, thus improving the long-term health of over half of the population.
The health risks of female reproductive aging are severe and include changes in neuroendocrine hormones, declining bone health and osteoporosis, cardiovascular disease, and cognitive decline. Therefore, women approaching menopause represent a unique group that appears to be at increased risk for long-term health effects. Moreover, human chronological life span has extended dramatically over the last century, while the timing of menopause has remained relatively constant. Thus, women will spend a larger portion of their lives in the post-menopausal period, and the incidence of these comorbidities will increase. In order to address the role that female reproductive aging plays in overall population health and longevity, it is critical to define these molecular processes which underpin the normal physiology of ovarian aging and the decline of ovarian function.
Cellular senescence, a response to cellular insult involving cellular arrest, is a key hallmark of aging in non-reproductive tissues. The senescence biomarker p16, a cyclin-dependent kinase inhibitor which enforces growth arrest, impairs organ function in tissues including kidney and heart and shortens healthy lifespan in mice. Elimination of p16-expressing senescent cells in mice attenuates age-related deterioration of these organs and extends lifespan. p16 is expressed in oocytes of primordial and early primary follicles of 8 week mice, and in follicles at all stages of maturity, with varying expression levels. Moreover, in a mouse model of ovarian failure induced by repetitive superovulation, p16 increased in GCs with successive ouvlations, suggesting that recurrent ovulation may promote senescence and ovarian aging via a p16-mediated pathway
However, the contribution of senescent cells to the naturally aging ovary - specifically, whether a critical accumulation of senescent cells in the ovary is detrimental to ovarian function - is unknown. In studies in which p16-expressing cells were globally eliminated and mouse lifespan was increased, the presence of senescent cells in the reproductive tract and the effect of their clearance on ovarian aging and reproductive lifespan was not evaluated. Therefore, in this proposal, we will utilize a mouse model of ovarian senescence to define the role of senescent cells, and the effect of their clearance, in the aging ovary. Because the ovary contains a heterogeneous population of cell types that critically contribute to follicular survival and whose age-related transcriptomes have not been characterized, we will then utilize human ovarian tissue to characterize the expression of senescence markers in individual ovarian cell types and create a comprehensive cellular atlas of the transcriptome of the ovarian aging. We expect our proposed Aims to generate highly impactful findings with translational relevance to ovarian aging, thus improving the long-term health of over half of the population.
Lab website
Listen to Dr Kallen present her research in Making Reproductive Longevity a Reality | Episode 5
2020 Pilot Award Recipients
Ivana Celic, PhD
Tulane University
LINE1 Retrotransposons in Female Reproductive Aging
Project Abstract
Lab website
Listen to Dr Celic present her research in Making Reproductive Longevity a Reality | Episode 3
LINE1 Retrotransposons in Female Reproductive Aging
Project Abstract
LINE1 Retrotransposons in Female Reproductive Aging
Female reproductive life span is determined by the size of the oocyte pool and oocyte quality. In humans, female fertility starts to decline significantly in the 30s with more rapid loss after the age of 37, but still more than a decade earlier than the function of ovaries ceases and menopause starts. This age-related decline in fertility presents a significant burden on the female workforce, particularly in developing countries, where women often delay childbearing for career choices, only to face struggles with infertility later in life. Therefore, understanding molecular mechanisms affecting oocyte quality is essential for identifying potential therapeutic targets to treat infertility and extend female reproductive life span.
Genomic instability, mainly in the form of chromosomal segregation errors, is the major cause of age-related infertility. Long-lived cells like human oocytes are particularly susceptible to the cumulative effect of DNA damage. Mammalian genomes encode many copies of a potent endogenous mutagen called the LINE1 (L1) retrotransposon, that can cause genome instability and DNA damage. Because of its potentially deleterious effect on the stability of mammalian genomes, L1 expression and activity are tightly controlled and most tissues express undetectable levels of L1. One of the few cell types that express L1 under normal conditions are mammalian germ cells. The physiological role for L1 expression in germ cells is not well defined, but even in this cell type, L1 expression and activity must be tightly controlled. In the male germ line, loss of control of L1 expression leads to meiotic arrest and infertility. In female germ cells, increased expression of L1 correlates with increased oocyte death during fetal development. Although the amount of L1 expressed in aging ovaries has not been examined in detail, there is evidence that L1 expression levels are elevated in other organs of aged mice.
Given that the germ cell environment and the aging process are two cellular states that favor L1 expression, in this project, we will test the hypothesis that the aging process in ovaries allows expression of L1, leading to accumulation of DNA damage and contributing to genomic instability in aging oocytes.
Female reproductive life span is determined by the size of the oocyte pool and oocyte quality. In humans, female fertility starts to decline significantly in the 30s with more rapid loss after the age of 37, but still more than a decade earlier than the function of ovaries ceases and menopause starts. This age-related decline in fertility presents a significant burden on the female workforce, particularly in developing countries, where women often delay childbearing for career choices, only to face struggles with infertility later in life. Therefore, understanding molecular mechanisms affecting oocyte quality is essential for identifying potential therapeutic targets to treat infertility and extend female reproductive life span.
Genomic instability, mainly in the form of chromosomal segregation errors, is the major cause of age-related infertility. Long-lived cells like human oocytes are particularly susceptible to the cumulative effect of DNA damage. Mammalian genomes encode many copies of a potent endogenous mutagen called the LINE1 (L1) retrotransposon, that can cause genome instability and DNA damage. Because of its potentially deleterious effect on the stability of mammalian genomes, L1 expression and activity are tightly controlled and most tissues express undetectable levels of L1. One of the few cell types that express L1 under normal conditions are mammalian germ cells. The physiological role for L1 expression in germ cells is not well defined, but even in this cell type, L1 expression and activity must be tightly controlled. In the male germ line, loss of control of L1 expression leads to meiotic arrest and infertility. In female germ cells, increased expression of L1 correlates with increased oocyte death during fetal development. Although the amount of L1 expressed in aging ovaries has not been examined in detail, there is evidence that L1 expression levels are elevated in other organs of aged mice.
Given that the germ cell environment and the aging process are two cellular states that favor L1 expression, in this project, we will test the hypothesis that the aging process in ovaries allows expression of L1, leading to accumulation of DNA damage and contributing to genomic instability in aging oocytes.
Lab website
Listen to Dr Celic present her research in Making Reproductive Longevity a Reality | Episode 3
Iain Cheeseman, PhD
Whitehead Institute, MIT
Analyzing centromere rejuvenation during female reproductive aging
Project Abstract
Lab website
Listen to Dr Cheeseman present his research in Making Reproductive Longevity a Reality | Episode 6
Analyzing centromere rejuvenation during female reproductive aging
Project Abstract
Analyzing centromere rejuvenation during female reproductive aging
Female gametes, termed oocytes, are amongst the rarest cells in the human body, but are responsible for transmitting all heritable information from mother to progeny. At birth, human females are endowed with finite numbers of oocytes, which must exist in a paused state that can persist for decades into adulthood until they transformed into fertilization-competent eggs. This requirement for oocytes to persist indefinitely in a paused state, while being poised to re-enter and continue their division is a central challenge for maintaining developmental competency during female reproductive aging. Indeed, errors in oocyte cell division are a leading cause of the reduced fertility, miscarriages, and developmental disorders that increase markedly with reproductive age.
Our goal is to define the changes that occur to core cell division structures during female reproductive aging and to determine the basis for the molecular rejuvenation of these structures, with the ultimate goal of harnessing their rejuvenation to counteract the age-related changes in oocyte fidelity.
Female gametes, termed oocytes, are amongst the rarest cells in the human body, but are responsible for transmitting all heritable information from mother to progeny. At birth, human females are endowed with finite numbers of oocytes, which must exist in a paused state that can persist for decades into adulthood until they transformed into fertilization-competent eggs. This requirement for oocytes to persist indefinitely in a paused state, while being poised to re-enter and continue their division is a central challenge for maintaining developmental competency during female reproductive aging. Indeed, errors in oocyte cell division are a leading cause of the reduced fertility, miscarriages, and developmental disorders that increase markedly with reproductive age.
Our goal is to define the changes that occur to core cell division structures during female reproductive aging and to determine the basis for the molecular rejuvenation of these structures, with the ultimate goal of harnessing their rejuvenation to counteract the age-related changes in oocyte fidelity.
Lab website
Listen to Dr Cheeseman present his research in Making Reproductive Longevity a Reality | Episode 6
Marco Conti, MD
University of California, San Francisco
mRNA translation program and oocyte aging
Project Abstract
Lab website
Listen to Dr Conti present his research in Making Reproductive Longevity a Reality | Episode 8
mRNA translation program and oocyte aging
Project Abstract
mRNA translation program and oocyte aging
Women’s aging is associated with a decline in fertility that becomes evident already during the third decade of life. This decrease in fertility is becoming a major and urgent concern as women in developed countries are under socio-economic pressure to delay pregnancies. There is general consensus that the decline in fertility of aging women is caused by a decrease in both the number of eggs produced and their quality. Although egg number can be readily monitored in an ART clinic, reliable measurements of egg quality has remained elusive and is currently based mostly on subjective morphological criteria. Our laboratory is exploring and developing new means to quantify egg quality. Since the health of an egg is dependent on the accumulation of proteins necessary to support fertilization and prepare the egg for embryo development and pregnancy, we are investigating how gene expression required to produce proteins is regulated in the egg. Pursuing preliminary data that our lab has generated, we will test the hypothesis that protein production is disrupted with maternal aging. Using the mouse as an experimental model, we have devised new strategies to quantify gene expression in eggs and relate this function to egg quality. Taking advantage of these methods, we propose to generate a large cohort of aging mice as a source of eggs. We will use these mice to quantify gene expression and to define the molecular defects at the base of these age-related defects. The interpretation of the data generated and some measurements will rely on the support and will be done in coordination with scientists at the Buck Institute. Ultimately, we will be able to develop reliable biomarkers of egg quality that will pave the way to new strategies to prevent the decline in egg fitness associated with aging.
Women’s aging is associated with a decline in fertility that becomes evident already during the third decade of life. This decrease in fertility is becoming a major and urgent concern as women in developed countries are under socio-economic pressure to delay pregnancies. There is general consensus that the decline in fertility of aging women is caused by a decrease in both the number of eggs produced and their quality. Although egg number can be readily monitored in an ART clinic, reliable measurements of egg quality has remained elusive and is currently based mostly on subjective morphological criteria. Our laboratory is exploring and developing new means to quantify egg quality. Since the health of an egg is dependent on the accumulation of proteins necessary to support fertilization and prepare the egg for embryo development and pregnancy, we are investigating how gene expression required to produce proteins is regulated in the egg. Pursuing preliminary data that our lab has generated, we will test the hypothesis that protein production is disrupted with maternal aging. Using the mouse as an experimental model, we have devised new strategies to quantify gene expression in eggs and relate this function to egg quality. Taking advantage of these methods, we propose to generate a large cohort of aging mice as a source of eggs. We will use these mice to quantify gene expression and to define the molecular defects at the base of these age-related defects. The interpretation of the data generated and some measurements will rely on the support and will be done in coordination with scientists at the Buck Institute. Ultimately, we will be able to develop reliable biomarkers of egg quality that will pave the way to new strategies to prevent the decline in egg fitness associated with aging.
Lab website
Listen to Dr Conti present his research in Making Reproductive Longevity a Reality | Episode 8
Arjumand Ghazi, PhD
University of Pittsburgh
Genetic & Chemical Modulation of Splicing to Combat Reproductive Senescence
Project Abstract
Lab website
Listen to Dr Ghazi present her research in Making Reproductive Longevity a Reality | Episode 5
Genetic & Chemical Modulation of Splicing to Combat Reproductive Senescence
Project Abstract
Genetic & Chemical Modulation of Splicing to Combat Reproductive Senescence
The process of alternative splicing (AS) allows a cell to generate different types of RNA molecules from a single gene and underlies the staggering diversity of proteins seen in our cells. AS is widespread in all organisms and in humans up to 90% genes are predicted to undergo AS. Errors during splicing have been shown to lead to innumerable diseases including several cancers. Recently, defective AS has also been observed during aging in many species, including humans. Indeed, AS is emerging as a new hallmark of organismal aging. In many animals carrying mutant copies of splicing factors, proteins that bring about AS, defects have been observed within the germ cells i.e., cells that give rise to sperm and ova. Interestingly, genetic variants that change AS efficiency of genes in germ cells have been implicated in influencing the age of menopause in women.
However, the role of AS in reproductive aging has not been addressed systematically in any species. We propose to address this knowledge gap by investigating the mechanism by which a conserved splicing factor, TCER-1, retards reproductive senescence in the model organism C. elegans. Previously, we identified TCER-1 as a longevity-enhancing protein that is critical for reproductive health in C. elegans. Our recent, preliminary studies lead us to hypothesize that TCER-1 retards reproductive aging by regulating AS fidelity. We will test this hypothesis using a combination of genetic and molecular approaches, and investigate how TCER-1 prevents age-related reproductive decline. We will also explore chemicals that alter AS for their therapeutic prospects in delaying reproductive aging. The human counterpart of TCER-1, TCERG1, also regulates AS. Hence, these studies can potentially reveal knowledge of fundamental and clinical relevance to human reproductive longevity.
The process of alternative splicing (AS) allows a cell to generate different types of RNA molecules from a single gene and underlies the staggering diversity of proteins seen in our cells. AS is widespread in all organisms and in humans up to 90% genes are predicted to undergo AS. Errors during splicing have been shown to lead to innumerable diseases including several cancers. Recently, defective AS has also been observed during aging in many species, including humans. Indeed, AS is emerging as a new hallmark of organismal aging. In many animals carrying mutant copies of splicing factors, proteins that bring about AS, defects have been observed within the germ cells i.e., cells that give rise to sperm and ova. Interestingly, genetic variants that change AS efficiency of genes in germ cells have been implicated in influencing the age of menopause in women.
However, the role of AS in reproductive aging has not been addressed systematically in any species. We propose to address this knowledge gap by investigating the mechanism by which a conserved splicing factor, TCER-1, retards reproductive senescence in the model organism C. elegans. Previously, we identified TCER-1 as a longevity-enhancing protein that is critical for reproductive health in C. elegans. Our recent, preliminary studies lead us to hypothesize that TCER-1 retards reproductive aging by regulating AS fidelity. We will test this hypothesis using a combination of genetic and molecular approaches, and investigate how TCER-1 prevents age-related reproductive decline. We will also explore chemicals that alter AS for their therapeutic prospects in delaying reproductive aging. The human counterpart of TCER-1, TCERG1, also regulates AS. Hence, these studies can potentially reveal knowledge of fundamental and clinical relevance to human reproductive longevity.
Lab website
Listen to Dr Ghazi present her research in Making Reproductive Longevity a Reality | Episode 5
Polina Lishko, PhD
University of California, Berkeley
Endocannabinoid signaling in the mammalian ovary and reproductive longevity
Project Abstract
Lab website
Listen to Dr Lishko present her research in Making Reproductive Longevity a Reality | Episode 2
Endocannabinoid signaling in the mammalian ovary and reproductive longevity
Project Abstract
Endocannabinoid signaling in the mammalian ovary and reproductive longevity
The aging of the reproductive systems has broad implications on the well-being of the entire organism. Particularly, the onset of female reproductive aging contributes to the development of other age-associated dysfunctions, such as cardiovascular problems, osteoporosis, and muscular and neurological declines. These progressive deteriorations of physiological functions go hand in hand with the changes in bioactive lipid signaling, such as changes in the function of the endogenous cannabinoid system (ECS) and in the levels of circulating steroid hormones. Interestingly, it appears that the endocannabinoid and steroid systems are closely connected as sex steroid hormones have been found to regulate ECS. Recent research indicates that ECS is active in the ovaries, where it affects egg maturation. Several studies also indicate that the levels of endocannabinoids decrease during aging, while the activity of enzymes that break endocannabinoids down- increases. We recently characterized one of these enzymes, termed α/β hydrolase domain- containing protein 2 (ABHD2). Unlike any other enzymes in this family, ABHD2 brakes down endocannabinoids only when it is activated by steroid progesterone. Thus, due to its unusual functional properties as an unconventional progesterone receptor, ABHD2 links together two major signaling systems: endocannabinoids and sex steroids. Interestingly, ABHD2 is highly expressed in the ovarian stroma – the tissue with a well-established role in the ovarian aging. Our preliminary data indicate that the female Abhd2-deficient mice show delayed reproductive aging. Despite this aging phenotype, little is known about the role of ECS in the ovarian stroma and its contribution to age-related changes in the ovary.
Here, we propose to further investigate the role of ABHD2 in aging and elucidate the signaling pathways by which ABHD2 exerts its action, as well as determine the changes in bioactive lipid profiles that occur with age in the ovaries. The project will utilize transgenic mouse models, genome editing, state-of-the-art electrophysiology, imaging, and mass spectrometry approaches. Based on the exceptional evolutionary conservancy of ABHD2 we can successfully use the mouse as an animal model in our research. This proposal addresses two main questions of broad importance to the physiology of aging: 1) how endocannabinoid-steroid axis participates in ovarian aging, and 2) how this system could be modulated to address age-related disorders and extend the healthy lifespan. The outcome of this research may identify new molecular targets to develop successful methods to treat age-related disorders.
The aging of the reproductive systems has broad implications on the well-being of the entire organism. Particularly, the onset of female reproductive aging contributes to the development of other age-associated dysfunctions, such as cardiovascular problems, osteoporosis, and muscular and neurological declines. These progressive deteriorations of physiological functions go hand in hand with the changes in bioactive lipid signaling, such as changes in the function of the endogenous cannabinoid system (ECS) and in the levels of circulating steroid hormones. Interestingly, it appears that the endocannabinoid and steroid systems are closely connected as sex steroid hormones have been found to regulate ECS. Recent research indicates that ECS is active in the ovaries, where it affects egg maturation. Several studies also indicate that the levels of endocannabinoids decrease during aging, while the activity of enzymes that break endocannabinoids down- increases. We recently characterized one of these enzymes, termed α/β hydrolase domain- containing protein 2 (ABHD2). Unlike any other enzymes in this family, ABHD2 brakes down endocannabinoids only when it is activated by steroid progesterone. Thus, due to its unusual functional properties as an unconventional progesterone receptor, ABHD2 links together two major signaling systems: endocannabinoids and sex steroids. Interestingly, ABHD2 is highly expressed in the ovarian stroma – the tissue with a well-established role in the ovarian aging. Our preliminary data indicate that the female Abhd2-deficient mice show delayed reproductive aging. Despite this aging phenotype, little is known about the role of ECS in the ovarian stroma and its contribution to age-related changes in the ovary.
Here, we propose to further investigate the role of ABHD2 in aging and elucidate the signaling pathways by which ABHD2 exerts its action, as well as determine the changes in bioactive lipid profiles that occur with age in the ovaries. The project will utilize transgenic mouse models, genome editing, state-of-the-art electrophysiology, imaging, and mass spectrometry approaches. Based on the exceptional evolutionary conservancy of ABHD2 we can successfully use the mouse as an animal model in our research. This proposal addresses two main questions of broad importance to the physiology of aging: 1) how endocannabinoid-steroid axis participates in ovarian aging, and 2) how this system could be modulated to address age-related disorders and extend the healthy lifespan. The outcome of this research may identify new molecular targets to develop successful methods to treat age-related disorders.
Lab website
Listen to Dr Lishko present her research in Making Reproductive Longevity a Reality | Episode 2
Zita Santos, PhD, Carlos Ribeiro, PhD
Fundação D. Anna de Sommer Champalimaud e Dr. Carlos Montez Champalimaud
Metabolic reprogramming, dietary nutrients and food cravings in ovary aging
Project Abstract
Lab website
Listen to Dr Ribeiro and Dr Santos present their research in Making Reproductive Longevity a Reality | Episode 3 and Episode 8
Metabolic reprogramming, dietary nutrients and food cravings in ovary aging
Project Abstract
Metabolic reprogramming, dietary nutrients and food cravings in ovary aging
As women age, they experience a decline in fertility as well as an increased risk of miscarriage and birth defects. Senescence is generally associated with physiologic and metabolic alterations. We hypothesise that changes in the ovarian metabolic programs drive reproductive senescence and that this phenomenon can be reduced using targeted dietary interventions. Drosophila melanogaster, has emerged as an important model organism to study metabolism, aging, reproduction and feeding behavior. Drosophila females also undergo a decrease in egg production and egg viability with age. Moreover, we have shown that the metabolic status of the fly germline is critical for fertility. The female germline undergoes a carbohydrate metabolic reprograming required for viable egg production, a process which concomitantly induces a potent sugar appetite. We will use this model organism to explore the prominent metabolic changes that occur during ovarian senescence. We propose to use a combination of single cell RNA sequencing and metabolomics to pinpoint changes in the expression of genes encoding metabolic pathway enzymes and in the abundance of related metabolites in the aging ovarian tissue. In parallel we will characterize the cellular outcomes of ovarian senescence and monitor the feeding behaviour of these animals. This will allow us to devise dietary stratagies to reverse the identified alterations and increase reproduction in old female flies. We believe that this is a powerful path to identify potentially reversible mechanisms underlying reproductive senescence.
As women age, they experience a decline in fertility as well as an increased risk of miscarriage and birth defects. Senescence is generally associated with physiologic and metabolic alterations. We hypothesise that changes in the ovarian metabolic programs drive reproductive senescence and that this phenomenon can be reduced using targeted dietary interventions. Drosophila melanogaster, has emerged as an important model organism to study metabolism, aging, reproduction and feeding behavior. Drosophila females also undergo a decrease in egg production and egg viability with age. Moreover, we have shown that the metabolic status of the fly germline is critical for fertility. The female germline undergoes a carbohydrate metabolic reprograming required for viable egg production, a process which concomitantly induces a potent sugar appetite. We will use this model organism to explore the prominent metabolic changes that occur during ovarian senescence. We propose to use a combination of single cell RNA sequencing and metabolomics to pinpoint changes in the expression of genes encoding metabolic pathway enzymes and in the abundance of related metabolites in the aging ovarian tissue. In parallel we will characterize the cellular outcomes of ovarian senescence and monitor the feeding behaviour of these animals. This will allow us to devise dietary stratagies to reverse the identified alterations and increase reproduction in old female flies. We believe that this is a powerful path to identify potentially reversible mechanisms underlying reproductive senescence.
Lab website
Listen to Dr Ribeiro and Dr Santos present their research in Making Reproductive Longevity a Reality | Episode 3 and Episode 8
Yousin Suh, PhD
Columbia University
Genetic Control of Ovarian Aging in Humans
Project Abstract
Lab website
Genetic Control of Ovarian Aging in Humans
Project Abstract
Genetic Control of Ovarian Aging in Humans
Ovarian aging influences diverse health outcomes in women including lifespan, cardiovascular disease, metabolic syndromes, neurodegenerative disorders and various types of cancer. Yet, the mechanisms behind this broad implication remain elusive. Family and twin studies have demonstrated a strong relationship between genetics and age at menopause. Identification of the genetic factors contributing to age at menopause will provide mechanistic insights into the biological processes underlying ovarian aging.
The work proposed is aimed at uncovering the molecular mechanisms underlying ovarian aging, informed by genetic factors associated with age at menopause in humans. Genome-wide association studies (GWAS) have identified common variants robustly associated with human traits, including age at menopause, and such knowledge is transforming our understanding of human biology. There is increasing evidence that the majority (>90%) of common variants associated with human traits occur in non-coding regions and are enriched in cell type-specific transcriptional regulatory regions, especially within enhancers specific to disease-relevant cell types, suggesting that they contribute to genetic risk by altering gene expression. We hypothesize that genetic variants associated with age at menopause contribute to ovarian aging by altering tissue- and cell-specific transcriptional regulatory programs. We propose a systematic multidisciplinary approach to investigate how menopause risk variants exert their effects on transcription programs by exploiting contemporary computational and experimental technologies.
The objective of this proposal is: 1) To use computational methods to identify a set of candidate causal regulatory variants in enhancers and their target genes that contribute to genetic factors influencing age at menopause, and to create models that can predict candidate genes and pathways of relevance to ovarian aging (Aim 1); 2) To define the ovarian cell types that causal regulatory variants act on by generating cell type-specific regulatory profiles in the ovary during aging (Aim 2); and 3) To experimentally validate the top candidate causal variants and their target genes by assessing the functional impacts of causal regulatory variants on gene expression and gene regulatory networks by using granulosa cell (GC) models differentiated from human embryonic stem cells (hESCs) that are genetically engineered to carry causal enhancer variants, in order to ascertain the causality and biological significance (Aim 3). By defining the age-related factors that drive pathogenic programs of gene expression, thereby predisposing women to reproductive aging, our approach will allow the identification of new intervention targets to maintain reproductive health and healthspan in our aging female population.
Ovarian aging influences diverse health outcomes in women including lifespan, cardiovascular disease, metabolic syndromes, neurodegenerative disorders and various types of cancer. Yet, the mechanisms behind this broad implication remain elusive. Family and twin studies have demonstrated a strong relationship between genetics and age at menopause. Identification of the genetic factors contributing to age at menopause will provide mechanistic insights into the biological processes underlying ovarian aging.
The work proposed is aimed at uncovering the molecular mechanisms underlying ovarian aging, informed by genetic factors associated with age at menopause in humans. Genome-wide association studies (GWAS) have identified common variants robustly associated with human traits, including age at menopause, and such knowledge is transforming our understanding of human biology. There is increasing evidence that the majority (>90%) of common variants associated with human traits occur in non-coding regions and are enriched in cell type-specific transcriptional regulatory regions, especially within enhancers specific to disease-relevant cell types, suggesting that they contribute to genetic risk by altering gene expression. We hypothesize that genetic variants associated with age at menopause contribute to ovarian aging by altering tissue- and cell-specific transcriptional regulatory programs. We propose a systematic multidisciplinary approach to investigate how menopause risk variants exert their effects on transcription programs by exploiting contemporary computational and experimental technologies.
The objective of this proposal is: 1) To use computational methods to identify a set of candidate causal regulatory variants in enhancers and their target genes that contribute to genetic factors influencing age at menopause, and to create models that can predict candidate genes and pathways of relevance to ovarian aging (Aim 1); 2) To define the ovarian cell types that causal regulatory variants act on by generating cell type-specific regulatory profiles in the ovary during aging (Aim 2); and 3) To experimentally validate the top candidate causal variants and their target genes by assessing the functional impacts of causal regulatory variants on gene expression and gene regulatory networks by using granulosa cell (GC) models differentiated from human embryonic stem cells (hESCs) that are genetically engineered to carry causal enhancer variants, in order to ascertain the causality and biological significance (Aim 3). By defining the age-related factors that drive pathogenic programs of gene expression, thereby predisposing women to reproductive aging, our approach will allow the identification of new intervention targets to maintain reproductive health and healthspan in our aging female population.
Lab website
2020 Postdoctoral Scholar Award Recipients
Cristina Quesada Candela, PhD
Magee-Women's Research Institute and Foundation
University of Pittsburgh
Proteasomal Targets Driving Meiotic Failure During Reproductive Aging
Project Abstract
Lab website
University of Pittsburgh
Proteasomal Targets Driving Meiotic Failure During Reproductive Aging
Project Abstract
Proteasomal Targets Driving Meiotic Failure During Reproductive Aging
Reproductive aging is a major concern in our society as more women than ever postpone having children. Advance maternal age is associated with reduced fertility due to a dramatic decline of reproductive fitness beyond the mid-30s. The decline in oocyte quality is associated with defects that cause the wrong number of chromosomes to be partitioned into the developing eggs. Such errors lead to fetuses that have the incorrect number of chromosomes or are aneuploid, a major cause of pregnancy loss and developmental disabilities.
A growing body of evidence suggests that misfolded and damaged proteins accumulate with age and that proteasomal insufficiency itself drives the aging process. The proteasome is a multi-subunit complex that degrades proteins in a controlled and tightly regulated manner in the nucleus and cytoplasm of the cells. Data from our group and others have detected severe defects in chromosome segregation in mutants carrying a structurally compromised proteasome (Ahuja JS et al.,2017; Prasada Rao H.B.D et al., 2017). It has been shown that the proteasome is tethered to chromosomes during meiosis as part of an evolutionarily conserved mechanism for controlling protein dynamics at distinct chromosomal sites, like synaptonemal complex (SC) proteins. These studies suggest that altered stability of components of the SC, the chromosomes scaffold upon which it assembles, or its regulatory binding proteins are affected. For this reason, I am interested in identifying and characterizing proteasome targets relevant for homolog pairing and recombination that could drive meiotic failure in aged females.
Further knowledge of these proteasome targets would allow us to better understand the changes that occur during female reproductive aging and it will give us more tools to pursue reproductive longevity and equality.
Reproductive aging is a major concern in our society as more women than ever postpone having children. Advance maternal age is associated with reduced fertility due to a dramatic decline of reproductive fitness beyond the mid-30s. The decline in oocyte quality is associated with defects that cause the wrong number of chromosomes to be partitioned into the developing eggs. Such errors lead to fetuses that have the incorrect number of chromosomes or are aneuploid, a major cause of pregnancy loss and developmental disabilities.
A growing body of evidence suggests that misfolded and damaged proteins accumulate with age and that proteasomal insufficiency itself drives the aging process. The proteasome is a multi-subunit complex that degrades proteins in a controlled and tightly regulated manner in the nucleus and cytoplasm of the cells. Data from our group and others have detected severe defects in chromosome segregation in mutants carrying a structurally compromised proteasome (Ahuja JS et al.,2017; Prasada Rao H.B.D et al., 2017). It has been shown that the proteasome is tethered to chromosomes during meiosis as part of an evolutionarily conserved mechanism for controlling protein dynamics at distinct chromosomal sites, like synaptonemal complex (SC) proteins. These studies suggest that altered stability of components of the SC, the chromosomes scaffold upon which it assembles, or its regulatory binding proteins are affected. For this reason, I am interested in identifying and characterizing proteasome targets relevant for homolog pairing and recombination that could drive meiotic failure in aged females.
Further knowledge of these proteasome targets would allow us to better understand the changes that occur during female reproductive aging and it will give us more tools to pursue reproductive longevity and equality.
Lab website
Ana Milunovic Jevtic, PhD, DVM
University of California, Berkeley
The role of endocannabinoid hydrolase ABHD2 in the ovarian aging
Project Abstract
Lab website
The role of endocannabinoid hydrolase ABHD2 in the ovarian aging
Project Abstract
The role of endocannabinoid hydrolase ABHD2 in the ovarian aging
The aging of reproductive systems has broad implications on the homeostasis of an entire organism, as it contributes to the development of other age-associated dysfunctions, such as cardiovascular problems, decrease in bone density, and muscular and neurological decline. Steroid hormones estrogen and progesterone together with gonadotropins are the essential regulators of female reproductive cycle and egg formation. Progesterone signals through either nuclear or membrane receptors and is well known for its role in pregnancy.
We have recently characterized a novel progesterone receptor, termed α/β hydrolase domain–containing protein 2 (ABHD2), that is highly expressed in the ovarian stroma. Our preliminary results suggest ABHD2 plays an important role in the formation of mature and fertile eggs as Abhd2-deficient mice produce a significantly higher number of fertile eggs than wild-type mice, and overall display delayed reproductive aging. Unlike other progesterone receptors, ABHD2 is an enzyme that regulates the levels of endogenous cannabinoid 2-arachidonoylglycerol (2-AG). Recent studies indicate that 2-AG levels decrease in the aging tissues, while the activity of 2-AG degrading enzymes increases. Our goal is to explore ABHD2 as a potential candidate to regulate reproductive aging. Additionally, ABHD2 may represent a necessary link between steroid and endocannabinoid systems which emphasizes its role in the regulation of female fertility.
The aging of reproductive systems has broad implications on the homeostasis of an entire organism, as it contributes to the development of other age-associated dysfunctions, such as cardiovascular problems, decrease in bone density, and muscular and neurological decline. Steroid hormones estrogen and progesterone together with gonadotropins are the essential regulators of female reproductive cycle and egg formation. Progesterone signals through either nuclear or membrane receptors and is well known for its role in pregnancy.
We have recently characterized a novel progesterone receptor, termed α/β hydrolase domain–containing protein 2 (ABHD2), that is highly expressed in the ovarian stroma. Our preliminary results suggest ABHD2 plays an important role in the formation of mature and fertile eggs as Abhd2-deficient mice produce a significantly higher number of fertile eggs than wild-type mice, and overall display delayed reproductive aging. Unlike other progesterone receptors, ABHD2 is an enzyme that regulates the levels of endogenous cannabinoid 2-arachidonoylglycerol (2-AG). Recent studies indicate that 2-AG levels decrease in the aging tissues, while the activity of 2-AG degrading enzymes increases. Our goal is to explore ABHD2 as a potential candidate to regulate reproductive aging. Additionally, ABHD2 may represent a necessary link between steroid and endocannabinoid systems which emphasizes its role in the regulation of female fertility.
Lab website
Bikem Soygur, PhD
University of California, San Francisco
How duration of meiotic prophase affects development and aging of oocytes
Project Abstract
Lab website
Listen to Dr Gul Soygur Kaya present her research in Making Reproductive Longevity a Reality | Episode 6
How duration of meiotic prophase affects development and aging of oocytes
Project Abstract
How duration of meiotic prophase affects development and aging of oocytes
While life expectancy has increased remarkably, the age-related decline in female fertility remains a problem. As women age, the diminishing number of eggs and increased risk of having a child with an abnormal number of chromosomes (or aneuploidy, such as Down Syndrome) is compounded by social trends towards delaying childbirth. A major challenge to studying the egg is that critical events in its formation occur when a woman is still developing in her mother’s womb. The goal of this project is to use genetic engineering and imaging technologies in the laboratory mouse to connect the events in the early development of egg precursors to reproductive aging. A critical process in the formation of eggs during fetal life is the specialized cell division known as meiosis. Errors during the early stages of meiosis contribute to aneuploidy, but it remains unclear whether the increase in aneuploidy of eggs with maternal age results from pre-existing differences in eggs or accumulated damage over time. Although human egg development is asynchronous, it is not known whether the timing and length of meiosis has consequences for egg function and fertility. In mice, we discovered that the duration of early meiosis depends on the time of meiotic entrance, suggesting a connection between fetal development and the fidelity of meiosis.
Using tools we developed to mark cells in living mice, we will trace the fate of eggs from meiotic initiation in the fetus through aging, comparing fitness and metabolism between eggs with earlier and shorter meiosis and those with later and faster meiosis. This work will bridge the gap between fetal egg development and adult function, identifying molecular heterogeneity within the egg population associated with developmental differences could provide tools for predicting or augmenting egg quality during aging.
While life expectancy has increased remarkably, the age-related decline in female fertility remains a problem. As women age, the diminishing number of eggs and increased risk of having a child with an abnormal number of chromosomes (or aneuploidy, such as Down Syndrome) is compounded by social trends towards delaying childbirth. A major challenge to studying the egg is that critical events in its formation occur when a woman is still developing in her mother’s womb. The goal of this project is to use genetic engineering and imaging technologies in the laboratory mouse to connect the events in the early development of egg precursors to reproductive aging. A critical process in the formation of eggs during fetal life is the specialized cell division known as meiosis. Errors during the early stages of meiosis contribute to aneuploidy, but it remains unclear whether the increase in aneuploidy of eggs with maternal age results from pre-existing differences in eggs or accumulated damage over time. Although human egg development is asynchronous, it is not known whether the timing and length of meiosis has consequences for egg function and fertility. In mice, we discovered that the duration of early meiosis depends on the time of meiotic entrance, suggesting a connection between fetal development and the fidelity of meiosis.
Using tools we developed to mark cells in living mice, we will trace the fate of eggs from meiotic initiation in the fetus through aging, comparing fitness and metabolism between eggs with earlier and shorter meiosis and those with later and faster meiosis. This work will bridge the gap between fetal egg development and adult function, identifying molecular heterogeneity within the egg population associated with developmental differences could provide tools for predicting or augmenting egg quality during aging.
Lab website
Listen to Dr Gul Soygur Kaya present her research in Making Reproductive Longevity a Reality | Episode 6
Min Hoo Kim, PhD
University of Southern California
Elucidating causal effects of the microbiome on reproductive aging
Project Abstract
Lab website
Listen to Dr Kim present her research in Making Reproductive Longevity a Reality | Episode 7
Elucidating causal effects of the microbiome on reproductive aging
Project Abstract
Elucidating causal effects of the microbiome on reproductive aging
Menopause is a key event in female aging that has significant impact on the overall well-being of the individual. Despite current understanding on the negative impacts of menopause, the underlying molecular mechanism and key factors that contribute to menopause progression are not fully understood. Cumulative studies have suggested a close functional relationship between the gut microbiome and ovarian function. The adult human gut microbiome is believed to be composed of approximately 10 to 100 trillion micro-organisms. With its numbers exceeding that of human cells by more than 10-folds, the microbiome is believed to have a more prominent effect on the host than previously perceived. For example, the human gut microbiome was shown to metabolize estrogen substrates, regulating the concentration of circulating estrogen in the bloodstream. Additionally, a study showed that transplantation of microbial species extracted from Polycystic Ovary Syndrome patients to mice induces significant ovarian dysfunction in the recipient mice. Although a bidirectional relationship between the microbiome and female reproductive function has been considered, a direct causal role has never been established.
The proposed study aims to elucidate the causal functions of the gut microbiome in ovarian aging. In order to characterize the effects of the microbiome on ovarian aging, microbial species from reproductively senescent intact females and from a mouse model of menopause (including pre-, peri- and post-“menopausal” states) will be collected. The collected microbial extracts will be transferred to young female mice with established regular estrus cycling. Changes in ovarian function, including serum hormone levels and histology, and to the microbiome, including metagenomics, will be regularly monitored and analyzed. Using the state-of-the-art microbiome analysis pipelines, specific metabolic pathways that participate in ovarian aging will be identified and characterized. The identification of molecular pathways underlying microbiome-driven female reproductive aging will not only contribute to our understanding of ovarian aging, but also has a great potential to drive novel therapeutic developments.
Menopause is a key event in female aging that has significant impact on the overall well-being of the individual. Despite current understanding on the negative impacts of menopause, the underlying molecular mechanism and key factors that contribute to menopause progression are not fully understood. Cumulative studies have suggested a close functional relationship between the gut microbiome and ovarian function. The adult human gut microbiome is believed to be composed of approximately 10 to 100 trillion micro-organisms. With its numbers exceeding that of human cells by more than 10-folds, the microbiome is believed to have a more prominent effect on the host than previously perceived. For example, the human gut microbiome was shown to metabolize estrogen substrates, regulating the concentration of circulating estrogen in the bloodstream. Additionally, a study showed that transplantation of microbial species extracted from Polycystic Ovary Syndrome patients to mice induces significant ovarian dysfunction in the recipient mice. Although a bidirectional relationship between the microbiome and female reproductive function has been considered, a direct causal role has never been established.
The proposed study aims to elucidate the causal functions of the gut microbiome in ovarian aging. In order to characterize the effects of the microbiome on ovarian aging, microbial species from reproductively senescent intact females and from a mouse model of menopause (including pre-, peri- and post-“menopausal” states) will be collected. The collected microbial extracts will be transferred to young female mice with established regular estrus cycling. Changes in ovarian function, including serum hormone levels and histology, and to the microbiome, including metagenomics, will be regularly monitored and analyzed. Using the state-of-the-art microbiome analysis pipelines, specific metabolic pathways that participate in ovarian aging will be identified and characterized. The identification of molecular pathways underlying microbiome-driven female reproductive aging will not only contribute to our understanding of ovarian aging, but also has a great potential to drive novel therapeutic developments.
Lab website
Listen to Dr Kim present her research in Making Reproductive Longevity a Reality | Episode 7
Seungsoo Kim, PhD
Columbia University
Integrative bioinformatic analysis of human ovarian aging and healthspan
Project Abstract
Lab website
Integrative bioinformatic analysis of human ovarian aging and healthspan
Project Abstract
Integrative bioinformatic analysis of human ovarian aging and healthspan
The age at menopause has impacts on a broad range of health outcomes such as coronary heart disease, heart failure, type 2 diabetes, respiratory disease mortality, body mass index, bone mineral density, bone fracture, and various cancers. Multiple epidemiological studies reported that the late onset of menopause is significantly correlated with longer life expectancy. However, the biological mechanisms underlying the genetic contributions to female reproductive aging and age at menopause are still unknown. In this study, we hypothesize that genetic factors impacting age at menopause also influence risk for many age-related diseases, as well as longevity. By uncovering the shared genetic architectures between age at menopause and age-related diseases, we hope to identify common genes and pathways, revealing the genetic drivers underlying female reproductive aging. The main goals of this project are 1) to uncover phenotypic associations between age at menopause and longevity, healthspan, and age-related diseases, and 2) to determine the shared genetic architecture between these traits, identifying the underlying genes and pathways.
To achieve these goals, we propose to utilize population-scale trait and genetic data from the 500,000 participants of the UK Biobank, applying robust statistical approaches such as mixed linear models, polygenic risk scores, linkage disequilibrium score regression, and Mendelian randomization, to complete the following aims: In Aim 1, we will test for phenotypic associations between age at menopause and longevity, age-related diseases and healthspan. In Aim 2, we will determine the shared genetic structures of female reproductive aging, lifespan, healthspan, and age-related disease, and identify the underlying genes and pathways. By uncovering the shared genetic architecture between a major proxy for female reproductive aging, age at menopause, and complex traits such as age-related disease, we will be able to identify genetic drivers of female reproductive aging.
The age at menopause has impacts on a broad range of health outcomes such as coronary heart disease, heart failure, type 2 diabetes, respiratory disease mortality, body mass index, bone mineral density, bone fracture, and various cancers. Multiple epidemiological studies reported that the late onset of menopause is significantly correlated with longer life expectancy. However, the biological mechanisms underlying the genetic contributions to female reproductive aging and age at menopause are still unknown. In this study, we hypothesize that genetic factors impacting age at menopause also influence risk for many age-related diseases, as well as longevity. By uncovering the shared genetic architectures between age at menopause and age-related diseases, we hope to identify common genes and pathways, revealing the genetic drivers underlying female reproductive aging. The main goals of this project are 1) to uncover phenotypic associations between age at menopause and longevity, healthspan, and age-related diseases, and 2) to determine the shared genetic architecture between these traits, identifying the underlying genes and pathways.
To achieve these goals, we propose to utilize population-scale trait and genetic data from the 500,000 participants of the UK Biobank, applying robust statistical approaches such as mixed linear models, polygenic risk scores, linkage disequilibrium score regression, and Mendelian randomization, to complete the following aims: In Aim 1, we will test for phenotypic associations between age at menopause and longevity, age-related diseases and healthspan. In Aim 2, we will determine the shared genetic structures of female reproductive aging, lifespan, healthspan, and age-related disease, and identify the underlying genes and pathways. By uncovering the shared genetic architecture between a major proxy for female reproductive aging, age at menopause, and complex traits such as age-related disease, we will be able to identify genetic drivers of female reproductive aging.
Lab website
Olfat Malak, PhD
Buck Institute for Research on Aging
Role of sympathetic transmission in the regulation of ovarian aging
Project Abstract
Lab website
Role of sympathetic transmission in the regulation of ovarian aging
Project Abstract
Role of sympathetic transmission in the regulation of ovarian aging
It is well appreciated that after the age of 30, women experience a lower chance of pregnancy accompanied by a sharp decline in egg quality. However, we know little about the mechanisms responsible for this age-dependent decline. Our proposal will address this unmet need by studying the role of neuronal innervation of the ovaries in the regulation of egg quality and ovarian longevity in aging mice. Ovaries and their vasculature are richly innervated by autonomic sympathetic neurons, and mounting evidence over the past decade in women and animal models suggests that aging is accompanied by an increase in sympathetic activity.
In addition, accumulating evidence in animal models indicates that metabolic conditions such as diabetes and high fat diet-induced obesity can compromise ovarian function and egg quality while increasing sympathetic drive. It is, therefore, conceivable, that interventions that could reduce sympathetic drive in old mice could have beneficial effects on the ovarian function and longevity. Despite these studies, the functional link between sympathetic activity and ovarian function is poorly understood, and we lack a mechanistic understanding of how this functional link is affected by aging or under chronic metabolic conditions. I propose to develop a model for studying the role of sympathetic transmission in the regulation of ovarian function. I hypothesize that genetic and/or pharmacological reduction in sympathetic transmission in old mice, or high fat diet- induced obese mice, can improve ovarian function and oocyte quality.
This proposal combines a genetic approach with imaging, electrophysiology and biochemistry in mice to investigate the consequence of genetic and/or pharmacological manipulation of sympathetic input in ovarian health and oocyte quality. Our proposed experiments will provide important insights into ovarian biology and will establish a novel paradigm for testing pharmacological and genetic interventions aimed at countering ovarian decline as a result of aging.
It is well appreciated that after the age of 30, women experience a lower chance of pregnancy accompanied by a sharp decline in egg quality. However, we know little about the mechanisms responsible for this age-dependent decline. Our proposal will address this unmet need by studying the role of neuronal innervation of the ovaries in the regulation of egg quality and ovarian longevity in aging mice. Ovaries and their vasculature are richly innervated by autonomic sympathetic neurons, and mounting evidence over the past decade in women and animal models suggests that aging is accompanied by an increase in sympathetic activity.
In addition, accumulating evidence in animal models indicates that metabolic conditions such as diabetes and high fat diet-induced obesity can compromise ovarian function and egg quality while increasing sympathetic drive. It is, therefore, conceivable, that interventions that could reduce sympathetic drive in old mice could have beneficial effects on the ovarian function and longevity. Despite these studies, the functional link between sympathetic activity and ovarian function is poorly understood, and we lack a mechanistic understanding of how this functional link is affected by aging or under chronic metabolic conditions. I propose to develop a model for studying the role of sympathetic transmission in the regulation of ovarian function. I hypothesize that genetic and/or pharmacological reduction in sympathetic transmission in old mice, or high fat diet- induced obese mice, can improve ovarian function and oocyte quality.
This proposal combines a genetic approach with imaging, electrophysiology and biochemistry in mice to investigate the consequence of genetic and/or pharmacological manipulation of sympathetic input in ovarian health and oocyte quality. Our proposed experiments will provide important insights into ovarian biology and will establish a novel paradigm for testing pharmacological and genetic interventions aimed at countering ovarian decline as a result of aging.
Lab website
Farners Amargant i Riera, PhD
Northwestern University
Targeting fibrosis and inflammation to extend reproductive longevity
Project Abstract
Lab website
Listen to Dr Amargant present her research in Making Reproductive Longevity a Reality | Episode 9
Targeting fibrosis and inflammation to extend reproductive longevity
Project Abstract
Targeting fibrosis and inflammation to extend reproductive longevity
Female reproductive aging refers to the loss of reproductive function that starts when women reach their mid-thirties and ends at menopause, resulting in infertility and hormonal perturbations. Medical advances have resulted in increased life expectancy; however, menopause still occurs at around age 50. After menopause, estrogen levels decrease, affecting the function of the reproductive system as well as downstream organs, such as the bones, the heart and the brain. The development of new approaches to delay reproductive aging will enhance reproductive longevity and delay general adverse health outcomes of aging. We recently discovered that the ovarian microenvironment or stroma in which oocytes develop changes with age. Specifically, collagen I/III accumulates, resulting in fibrosis. Concurrently, a pro-inflammatory milieu develops with a significant increase in pro-inflammatory cytokine production, including interleukin-6. These changes in the milieu likely influences oocyte quality.
Here we will test the hypothesis that targeting stromal fibrosis and inflammation can extend reproductive longevity, maintain endocrine function, and improve overall health outcomes. To test this hypothesis, we will establish a preclinical pipeline using mice to test whether anti-fibrotic and anti-inflammatory drugs can delay reproductive aging phenotypes. Beginning at 7 months, when fibrosis is first observed in the ovarian stroma, we will transplant an osmotic pump to continuously deliver a broad spectrum anti-fibrotic drug, an anti-inflammatory drug, or the combination of both directly to the ovary. The treatment will be performed for a total of 6-weeks, and mice in each experimental cohort will be analyzed at 0-, 2- and 4-months post-treatment to evaluate ovarian fibrosis and inflammation, reproductive longevity by analyzing the ovarian reserve, and bone mass density as a read out of overall health. This work has translational potential because fibrosis and inflammation are hallmarks of the aging ovarian microenvironment also in humans. Furthermore, it will establish a pre-clinical model to screen drugs which enhance reproductive longevity and overall health, which could be used in the future to test new therapeutic approaches.
Female reproductive aging refers to the loss of reproductive function that starts when women reach their mid-thirties and ends at menopause, resulting in infertility and hormonal perturbations. Medical advances have resulted in increased life expectancy; however, menopause still occurs at around age 50. After menopause, estrogen levels decrease, affecting the function of the reproductive system as well as downstream organs, such as the bones, the heart and the brain. The development of new approaches to delay reproductive aging will enhance reproductive longevity and delay general adverse health outcomes of aging. We recently discovered that the ovarian microenvironment or stroma in which oocytes develop changes with age. Specifically, collagen I/III accumulates, resulting in fibrosis. Concurrently, a pro-inflammatory milieu develops with a significant increase in pro-inflammatory cytokine production, including interleukin-6. These changes in the milieu likely influences oocyte quality.
Here we will test the hypothesis that targeting stromal fibrosis and inflammation can extend reproductive longevity, maintain endocrine function, and improve overall health outcomes. To test this hypothesis, we will establish a preclinical pipeline using mice to test whether anti-fibrotic and anti-inflammatory drugs can delay reproductive aging phenotypes. Beginning at 7 months, when fibrosis is first observed in the ovarian stroma, we will transplant an osmotic pump to continuously deliver a broad spectrum anti-fibrotic drug, an anti-inflammatory drug, or the combination of both directly to the ovary. The treatment will be performed for a total of 6-weeks, and mice in each experimental cohort will be analyzed at 0-, 2- and 4-months post-treatment to evaluate ovarian fibrosis and inflammation, reproductive longevity by analyzing the ovarian reserve, and bone mass density as a read out of overall health. This work has translational potential because fibrosis and inflammation are hallmarks of the aging ovarian microenvironment also in humans. Furthermore, it will establish a pre-clinical model to screen drugs which enhance reproductive longevity and overall health, which could be used in the future to test new therapeutic approaches.
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Listen to Dr Amargant present her research in Making Reproductive Longevity a Reality | Episode 9
Zijing Zhang, PhD
University of Arkansas for Medical Sciences
The impact of ovarian macrophage population on mouse ovarian aging
Project Abstract
Lab website
The impact of ovarian macrophage population on mouse ovarian aging
Project Abstract
The impact of ovarian macrophage population on mouse ovarian aging
For women, the ovary is a very important organ which produce not only eggs, but also hormones that regulate bodily functions. However, the ovary is quite “short-lived”, as its function starts to deteriorate early in life. This natural decline in ovarian functions, or ovarian aging, is a main cause behind the reduction of women’s fertility around the age of 35 and the loss of fertility at menopause around the age of 51. The ovary goes through a lot of changes over the course of aging. Previous studies in mice and human found marked signs of inflammation in ovaries from the old individuals, which point to altered immune cell activities in the ovary as the individual age. In line with these findings, our recent study revealed fundamental changes in several properties of the macrophages in the old ovaries. Macrophages are a major type of immune cells with a diverse of functions and behaviors in different settings. They are known to “swallow up” foreign bodies and cell debris, and produce many chemical signals that help coordinate other cells to protect the host and amend the damaged tissues. These functions not only serve to fight infections, but are also important for keeping normal tissues intact and healthy.
The proposed study aims to investigate how the changes in macrophage properties in the old ovaries affect the functions of the ovary. Using the mouse model, I will first examine how gene expression and chemical production differ between macrophages from the young and the old ovaries. Then I will test how the altered macrophage activities influence the growth, survival and hormone production capability of the ovarian follicles (egg with its supporting cells in the ovary). The proposed study represents a novel direction in the research on ovarian aging. Clarifying the role of macrophages in ovarian aging will inform the development of new treatment strategies that mitigate the effect of ovarian aging.
For women, the ovary is a very important organ which produce not only eggs, but also hormones that regulate bodily functions. However, the ovary is quite “short-lived”, as its function starts to deteriorate early in life. This natural decline in ovarian functions, or ovarian aging, is a main cause behind the reduction of women’s fertility around the age of 35 and the loss of fertility at menopause around the age of 51. The ovary goes through a lot of changes over the course of aging. Previous studies in mice and human found marked signs of inflammation in ovaries from the old individuals, which point to altered immune cell activities in the ovary as the individual age. In line with these findings, our recent study revealed fundamental changes in several properties of the macrophages in the old ovaries. Macrophages are a major type of immune cells with a diverse of functions and behaviors in different settings. They are known to “swallow up” foreign bodies and cell debris, and produce many chemical signals that help coordinate other cells to protect the host and amend the damaged tissues. These functions not only serve to fight infections, but are also important for keeping normal tissues intact and healthy.
The proposed study aims to investigate how the changes in macrophage properties in the old ovaries affect the functions of the ovary. Using the mouse model, I will first examine how gene expression and chemical production differ between macrophages from the young and the old ovaries. Then I will test how the altered macrophage activities influence the growth, survival and hormone production capability of the ovarian follicles (egg with its supporting cells in the ovary). The proposed study represents a novel direction in the research on ovarian aging. Clarifying the role of macrophages in ovarian aging will inform the development of new treatment strategies that mitigate the effect of ovarian aging.
Lab website