As we age, there is a decline in Mitochondrial function that parallels the declining rate of fertility in women of advanced maternal age (AMA), women roughly over 35 years old. Infertility due to age is more often caused by decreased egg quality and dysfunctional Mitochondria rather than womb environment, according to everywhere and everyone 🙂

I will be doing an IVF retrieval sometime towards the end of this year, and I have already started gathering my arsenal of Mitochondria boosters! Be sure to subscribe so you do not miss the line up I’ve got coming your way! I would advice every women trying to conceive over 40 to follow suite.

Before going any further, I would like to announce two things. The first is that I have made a facebook group to connect with my blog and podcast. It will be just like the other groups you find out there, except NTW leans more towards research and discussion and peoples personal journeys. I like to connect with people and hear about their situation. If you are alone out there and need a private place to go, we got you! No one will know you have joined. Your friends will never find out, etc etc (thumbs up). I will post links in the facebook group to my blog posts and Wednesday Write-ups! (You like that!… Cute, huh!?). I hope to see some friendly and new fake profile faces, lol! 😉 (A quick side-note, subscribing lets me know you are out there <3 I am very much trying to serve you better quality content than you can find elsewhere regarding fertility over forty. Better understanding, better human connection, better vibe, better info and hopefully better outcome!)

The second thing I’d like to mention is that I will be using the term “late 30s” and “over 35” a lot more from now on. I think a lot of women around the age of 35 start having the issues we discuss as over 40 women, and all women of AMA need to feel welcome here and know that this information serves them well, too! My Podcast, on the other hand, will remain 40+ (give or take a year).

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*Each mitochondrion is a power box that turns fats and sugars into ATP energy*

What Are Mitochondria and What Do They Do?

Recall that primordial follicles are formed inside the ovaries while the female is a fetus growing in the womb. At birth, a female has all of the oocytes that she will ever have, sleeping dormant until their hopeful recruitment later during a menstrual cycle. The Mitochondria that live inside of oocytes, creating all that life energy, replicated from the original Mitochondria found inside the primordial follicles, thus making them as susceptible to age-induced damage as everything else in the body (Wilding, download below).

Mitochondria are known as the cell’s power station. They create the energy (ATP) needed for the cell to do all the things that cells need to do to live, grow, be healthy and even die and be disposed of properly. We need Mitochondria like nobody’s business, and we need them to function properly so our cells perform as they should.

MITOCHONDRIAL DNA (mtDNA)

Most of us remember that the nucleus of a cell contains its genetic material, or nuclear DNA (nDNA). Well, Mitochondria are very special in that they have their very own DNA known as Mitochondrial DNA (mtDNA). It is inherited exclusively from the mother! This is an extremely huge deal in the world of biology. For trying to conceive over 35 purposes, it matters a whole hell of a lot!

To help you better understand mtDNA, take a look at the image below. You can see that the nucleus of the cell contains the DNA. You can also see the potato bug-looking Mitos (trust me, you’ll get tired of saying it too!) swimming all around inside the cytoplasm, outside the nucleus, just making all that energy! Now, if you zoom in and take a closer look inside the Mitos themselves, you will see they have their own DNA and it was inherited from the host’s mother 😊 In other words:

“You Got Yo Mitos from Yo Mama!“

Mitochondrial Function in Reproduction

Mitochondrial Function in Folliculogenesis

Oocyte production and growth takes an incredible amount of ATP energy. Midcycle, a mature oocyte is exposed to high levels of LH. It is at this time of great LH exposure that the energy needs of the egg are at their highest (Chappel). It is also during this time that one of the most intricate and energy intensive activities takes place inside the oocyte: the assembly and disassembly of microtubules.

Metaphase alignment of the chromosomes

The metaphase alignment of the chromosomes depends on the assembly and disassembly of microtubules, or said differently, the proper positioning and segregation of chromosomes (Chappel). This process is like an intricate dance among DNA bits… it’s beautiful really, and it needs to go off without a hitch!

*It needs to go off without a hitch, progress without a hitch and end without a hitch!*

“Metaphase is the third phase of mitosis, the process that separates duplicated genetic material carried in the nucleus of a parent cell into two identical daughter cells. During metaphase, the cell's chromosomes align themselves in the middle of the cell through a type of cellular "tug of war." The chromosomes, which have been replicated and remain joined at a central point called the centromere, are called sister chromatids… the kinetochore microtubules [extended from poles on either end of the centromere] pull the sister chromatids back and forth until they align along the equator of the cell, called the equatorial plane.” Scitable, by Nature

If you read that little description above, you can see that the process of properly positioning and segregating chromosomes is mind-blowing, astonishing… absolutely necessary for life! Let’s not forget what I said two paragraphs ago: this process so vital to life is dependent on the assembly and disassembly of microtubules. What I want you to walk away knowing is this:

When we reach a certain age… whether it be 32, 35 or 40, our mtDNA reaches that age as well (oocytes also). The egg’s ability to produce adequate spindle microtubules decreases. What is the consequence? A marked increase of aneuploidy, or an abnormal number of chromosomes instead of the proper amount.
Chappel

Mitochondrial Function IN Sperm

The mature oocyte might contain the highest number of mitochondria of any cell type, but mitochondrial activity is just as important in male fertility (Barbagallo). Mitochondria produce the ATP energy needed for spermatogenesis and fertilization to take place, as well as act as the primary support for sperm motility (Barbagallo, Pang).

In addition to giving the sperm enough energy to move themselves forward to meet the egg, there is a whole mess of stuff mito does inside those swimmers. For instance, mitochondria are essential in regulating several vital sperm functions through ATP production. They regulate “spermatogonial stem cell differentiation, testicular somatic cell development, testosterone production in the testes, luminal acidification and sperm DNA condensation in the epididymis as well as ROS homeostasis for sperm capacitation and acrosome reaction in the female reproductive tract” (Chapel).

“Several reports indicate that motility and fertility of human sperm is closely correlated with mitochondrial function and these organelles have been indicated as biomarkers of sperm quality in several species”
Gualtieri

When Mito become dysfunctional (unruly teenagers!) in spermatozoa, male factor infertility is likely the result. If your significant other is in their wiser years, they likely need some mitochondrial assistance.

Mitochondrial Function in Embryogenesis

After fertilization and until implantation begins, about 6 days past ovulation, the embryo’s energy needs are fulfilled solely by the mitochondria that were present at ovulation. If you are 43 years old, your oocytes and your energy making mitos are 43 as well. There are things we can do, though, so make sure to subscribe to this blog so you get a new article link delivered to your inbox every Wednesday (sometime before 4pm, lol)!

Embryonic mitochondrial replication does not begin until after the blastocyst hatches. Even then, it is specific to the “outer” cells called the trophectodermal cells which will create the placenta. The inner cell mass, which will become the embryo, prevent mtDNA replication until the proper signals for replicating cells has been given.
St. John

The guise of the healthy-looking embryo

After implantation begins, the embryo will have a renewed source of energy; however, the future human must make it through all the possible health checkpoints up to that point on what gas is left in the tank! There is no new mitochondria created at this point because early stage cells cannot replicate to increase the amount of mitochondria. Unfortunately, many super-attractive embryos are lacking enough energy to carry them the distance.

Think of the Hollywood movie stars whom look, literally, like a million bucks but they are just rotting away in a cesspool of self-loathing and dire unhappiness. Great graded embryos look wonderful on the outside, but not all of them have the energy to implant properly. The little blastocyst will surely try by using both anaerobic (no oxygen required) and aerobic (requires oxygen and therefore free radical production). However, anaerobic respiration is not as efficient, and it cannot provide all the energy needed for the embryo to develop (Chappel).

Anaerobic respiration (no oxygen required) can produce “short term energy” when there are deficiencies in the supply of aerobic respiration and ATP energy, but this energy does not last long (Wingling, download below). Therefore, Mitochondrial function needs to be operating at full capacity in the oocyte way before implantation to help the zygote go the distance! In fact, your egg needs good-functioning mitos from the moment it is selected from the primordial pool each cycle. Basically, if you do not have enough ATP energy, your embryo will not develop normally, or at all.

If an embryo looks and behaves great, has zero odd-shaped cells and zero fragmentation, chances are good that it might develop into a healthy human baby. However, it could be a burst of short term energy keeping the early embryo dividing properly until day 5 or 6, and then shortly after that it will run out of steam.

Age Negatively Impacts Mitochondrial Function

We now know that Mitochondria literally keep the power on in our cells. They are the primary source, the back up generators, the candles in your drawer! Imagine your eggs at 25 years old beaming like Clark Griswald’s house on Christmas Eve! Never a dull moment, literally. They were shining so bright – from a constant influx of Mito Energy – that you had to wear shades!

^ You’re Welcome 😉

Imagine your oocytes now, at 40 years old, give or take a few years. It’s like our follicles are trying to grow in the middle of a never-ending windstorm. I mean that wind is just whipping the power box around like a windsock! The lights are flickering every few minutes, power is cutting out, it’s a little chilly here and there, the internet is spotty… everyone is complaining! My God, the poor follicles can’t get a steady stream of ATP to…. well, yeah.. to save their lives.

An Increased Risk For Aneuploidy

As a woman ages, fertilization becomes susceptible to abnormal chromosomes at an alarming rate, moreso than during egg maturation (Chappel). If spindle formation and fertilization weren’t dicey enough, the embryo needs a great deal more energy for cell division after fertilization, as we’ve learned.

Mutations specific to mtDNA

Most nuclear DNA, the genetic material inside the nucleus of the cell, and their mutations and deletions, are inherited from each parent. Humans get one copy from their mother and one from their father. Recall that mtDNA are unique because they are inherited only from the mother and they are found outside the nucleus swimming in cytoplasm. Unfortunately, the hundreds of currently classified diseases related to mutations of mtDNA come from the mother as well.

How Do mtDNA Mutations Occur?

An oocyte contains many mitochondria, some are normal and others are mutant. No one egg cell has all normal mitochondria; that is just not how life operates. It is the balance between normal and mutant mitos that determines the fate of the cell’s health. If an egg cell has more mutant mitochondria than healthy ones, the child that develops would likely have mitochondrial disease. If a child is conceived from a “healthy” egg with mostly normal mitochondria, the resulting child would probably not develop disease (Muscular Dystrophy Association).

Can you imagine how few mitochondria are left in each cell when an embryo has divided into 100 cells! In fact, there are very few mitochondria found inside a hatched blastocyst, and it’s theorized that the most homoplasmic mtDNA are the ones that get transferred to offspring.

Some of us aren’t good with numbers so let’s talk it out. Imagine you had a magic orange, and the amazing thing about this orange is that each individual slice inside can turn into a whole, full-grown orange!

The momma orange has about 80 mitochondria inside of her juicy self! This means that if there are 8 slices of orange inside, each slice has about 10 mitochondria from which to develop into a full-grown piece of fruit (one could have 8 mitos, one might have 12, you get the picture)! When you think about a little slice having to turn into a whole orange in hardly any time at all, it doesn’t seem possible! There are just a few mitos that remain in each slice (each embryonic cell), how can they have enough energy to turn into a full-fledged orange (human baby!)?

It definitely is outstanding! We can surmise that if the mama orange is healthy and in the prime of her life – she was gently picked and put right in the crisper – then her eight slices shouldn’t have any trouble turning into new oranges! However, leave that orange out on the counter for a few days and you know what will happen… she be startin’ to get mushy…. Those eight Mitos? Yikes… I don’t even want to know! If you leave her out to age a bit, her peel will get crunchy and turn green!

Cell division in embryogenesis is very similar to the orange example, except there are a ton of little mitos in our oocytes, thank goodness! I know the orange doesn’t divide, but it might help some people see that after each time the egg divides, the number of mitochondria that were present get divided in half. If there were 1 million in the oocyte, then there are now 500,000 in each new cell. Again divided, each cell would now have 250,000 mitos. No more mitochondria are created so each division leaves the energy capability of the new cell only half of what it just was (half the mitos in a whole cell of it’s own to keep energized!).

The eggs in us older gals have a great number of mitochondria mutations, deletions and variations that impair function. Even if you are a marathon runner, or eat a healthy diet and get plenty of exercise and rest, your mitochondria are as old as they are old. There is no getting around the fact that:

The increased frequency of age-related damage, along with less mitochondrial activity in general, can result too little energy being produced for an embryo to continue developing properly. This is a leading cause of pregnancy failure in women of advanced maternal age.
Chappel

Gonadotropins Increase Mitochondrial Dysfunction

Controlled ovarian hyperstimulation is one of the most common forms of artificial reproductive technology (ART). It increases the probability of success in patients with advanced maternal age (AMA), diminished ovarian reserve (DOR)/low AMH, repeat pregnancy loss (RPL), repeat implantation failure (RIF). Unfortunately, the medicine used in these protocols have been shown to decrease the quality of oocytes because gonadotropins may further impair mitochondrial function within the egg (Chappel).

Mitochondrial DNA Mutations

Most nuclear DNA, the genetic material inside the nucleus of the cell, and their mutations and deletions are inherited from each parent. Humans receive one copy from their mother and one from their father. Recall that mtDNA are unique because they are inherited only from the mother and they are found outside the nucleus. Unfortunately, the hundreds of currently classified diseases related to mutations of mtDNA come from the mother as well.

How do mtDNA Mutations Occur?

An oocyte contains many mitochondria, some are normal and others are mutant. No one egg cell has all normal mitochondria, that isn’t how life operates. It is the balance between normal and mutant mitos that determines the fate of the cell’s health. If an egg cell has more mutant mitochondria than healthy ones, the child that develops would likely have mitochondrial disease. If a child is conceived from a “healthy” egg with mostly normal mitochondria, the resulting child would probably not develop disease (Muscular Dystrophy Association).

*The severity of a mitochondrial disease in a child depends on the percentage of abnormal (mutant) mitochondria in the egg cell that formed them.*

Oxidative stress cAUSES MITOCHONDRIAL DAMAGE

Dysfunction and dis-ease within the oocyte is part of the aging process. Oxidative stress is a leading cause of mitochondrial dysfunction in the eggs of wiser woman (35+). A higher oxidative stress load means more mutations and deletions in mtDNA and nuclear DNA. More mutations and deletions are associated with poor egg quality and embryonic development. In addition, they lead to suboptimal implantation and placentation rates (Chappel).

free Radical Formation In Spermatazoa

Free Radicals can be formed by sperm’s mitochondria if either the electron transport or the formation of adducts is disrupted (Park). Free Radicals cause sperm to lose their mitochondrial membrane potential (MMP), as well as cause lipid peroxidation and impair sperm motility (Park). They sound down right awful, whatever those are!

free Radical Formation In Oocyte

Mitochondria produce the ATP energy required by cells to grow and thrive by converting glucose into pyruvate. The metabolic process of turning glucose into ATP energy results in a lot of pesky, unwanted ROS (Free Radicals). As we learned last week, all metabolic processes create Free Radicals as a bi-product. Also, when there is an over-production of Free Radicals, oxidative stress can occur.

As we age, our mitochondria are exposed to increasing levels of Free Radicals. We also know that oxidative stress causes cellular damage (Melatonin to the Rescue!). Yes, oxidative stress can cause mutations and deletions of mtDNA. Furthermore, oxidative stress causes lesions in the ATP synthase gene, perhaps leading to ovarian insufficiency and loss of ovarian function (Chappel). I know, it’s an enormous bummer, but increasing age equates to increasing oxidative stress and less ATP energy.

Free radicals decrease mitochondrial function and cause mutations in mtDNA, thus likely limiting energy production. “As a result, the cell has a decreased capacity to support all cellular events, especially normal chromosomal segregation during cell division.”
Chappel

Mitochondria-and-human-preimplantation-embryo-development Download

Remember how our ATP is trying to light up our house in a windstorm, our old power box is knocking around up on our pole… well you can keep patching up that box over and over and re-hanging it on your telephone pole for only a matter of time before that box is just too old and gnarly to work good anymore. The wind, a euphemism for age, eventually beats down our energy box, our Mitochondria.

There are several cellular events that happen after fertilization that require vast amounts of ATP energy. For instance, the “polymerization of microtubules, cell cycle regulation, segregation of chromosomes, and membrane biosynthesis” all need enough energy to be completed properly (Chappel). At the pronuclear stage, inappropriate mitochondrial activity has been linked to early embryogenesis failure and demise (Chappel).

Unfortunately, the development of the pre-implantation embryo, little bean from fertilization to about 6 days past ovulation, is directly impacted by the health of the existing mitochondria and how well they function. Let’s face it, we need help in this department, and help I will be <3

Are you trying to conceive over 35? Are you trying to conceive in your forties, like I am? You will want to stay tuned for Mitochondria May! Two posts coming that will give you a steep advantage to succeed by increasing Mitochondrial function <3

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Thank you for being here,

<3 BK

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