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.
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
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
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.
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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.
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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
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