Mitochondrial Point Mutations Contribute to Female Reproductive Aging, and NAD+ Upregulation Attenuates These Consequences in Mice

Today's open access paper discusses the impact of mitochondrial DNA damage on female reproductive capabilities. Mitochondria are the power plants of the cell, a herd of hundreds of organelles responsible for packaging the chemical energy store molecule ATP, used to power cellular processes. They are additionally deeply integrated into many core cellular processes. Mitochondria are the evolved descendants of ancient symbiotic bacteria: they carry their own small genome, the mitochondrial DNA, and replicate like bacteria. Unfortunately this mitochondrial DNA is more vulnerable and less proficiently repaired than the nuclear DNA in the cell nucleus, and it accumulates mutational damage. Most is washed out by cell turnover in the body, but this damage nonetheless adds up over a lifetime.

Some rare forms of mitochondrial DNA mutation, such as large deletions, can give rise to dysfunctional mitochondria that overtake their cells. The cell itself becomes dysfunction, exporting damaging reactive molecules into the surrounding tissue. This happens infrequently, but is sufficiently problematic when it does occur for it to contribute to aging. Other forms of mitochondrial mutation, such as point mutations, can also be a problem via a more subtle degradation of mitochondrial function. Mutator mice that accumulate this form of damage much more rapidly than their peers exhibit accelerated age-related degeneration, however. This is driven by the progressively greater dysfunction of mitochondria throughout the body.

Researchers here note that the dysfunction of mitochondria produced by point mutations in mutator mice causes a disruption in NAD metabolism. NAD in aging and mitochondrial function has been a topic of growing interest for some years now. NAD levels decline with age, but the cycling of NADH to NAD+ and back again is a central portion of the processes by which mitochondria produce ATP. There are a variety of ways in which NAD levels can be increased, primarily compounds vitamin B3 and related compounds: niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth. It is unclear than any of these produce better results than exercise programs when it comes to increasing NAD+ levels, but they can be convenient tools for animal studies. That is the case here, where nicotinamide mononucleotide is used to reverse some of the imbalance in mitochondrial function caused by point mutations, and thus restore some lost ovarian function.

On the whole, it seems surprising that stochastic mitochondrial DNA point mutations could be responsible for meaningful age-related degeneration in humans (the sizeable loss of fertility) by age 40, given that a 40 year old human is still in fairly good physical shape, looking at mortality and disease risk across the board. Why just this ovarian loss of function and not a much larger general decline, if there are point mutations degrading mitochondrial function everywhere? It may be the case that critical ovarian tissue is especially sensitive to this particular mechanism of aging, but more research is needed on that topic.

Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox

Aging is one of the key factors in both male fertility and female fertility. Indeed, female fertility normally peaks at age 24 and diminishes after 30, with pregnancy occurring rarely after 50. Mitochondrial malfunction has been hypothesized to play important roles in age- and environment-induced infertility. For instance, mitochondrial DNA (mtDNA) deletions were reported to accumulate in human ovarian aging. However, the links among aging, mtDNA mutations, and infertility remain not fully understood.

mtDNA-mutator (PolgAMut/Mut) mice are widely used as an experimental model to study the roles of mtDNA mutations in aging process. The PolgAMut/Mut mice harbor a mutation in the nuclear DNA-encoded mitochondrial polymerase PolgA, leading to the inactivation of its proofreading function. As compared to wild-type (WT) mice, the PolgAMut/Mut mice exhibited a ~10-fold higher mtDNA mutation frequency, eventually leading to a progressive decline in the function of mtDNA-encoded respiratory complexes. PolgAMut/Mut mice were reported to show a reduced life span that is limited to 13-15 months. Consistently, aging-associated disorders occurred approximately 6-8 months after the birth of the PolgAMut/Mut mice.

In the present study, we first determined how mtDNA mutations in human female oocytes changed with age. We analyzed oocyte quality of young (≤30 years old) and elder (≥38 years old) female patients and show the elder group had lower blastocyst formation rate and more mtDNA point mutations in oocytes. Using the PolgAMut/Mut mouse model, we demonstrate mtDNA mutations decrease the fertility of females, but not males, via reducing ovarian primordial and mature follicles. We further show that accumulation of mtDNA mutations decreases female fertility by reducing oocyte's NADH/NAD+ ratio and that nicotinamide mononucleotide (NMN) is remarkably capable of ameliorating infertility in female PolgAMut/Mut mice.

Comments

Pure off topic. It seems that UBX is scandal ridden and in top of it was based on questionable science. https://forbetterscience.com/2020/09/21/jan-van-deursens-senolytics-from-bench-to-failed-clinical-trial/amp/ . Damn, this will damage the whole field of Senolytics and and even anti-aging.

While my hopes in UBX weren't that high I was expecting just smaller results.

Let's hope OISIN will come with something usable soon, or the whole field can see the money doing up for the next few years

Posted by: Cuberat at September 21st, 2020 10:45 PM

@cuberat
If you look close enough more often than not these 'mice model' trials/studies that fail to translate to humans don't fail because of inherently different biologies but because of shoddy science and fraudulent publications.
I recommend on forbetterscience:
Never-ageing Anti-aging to cure COVID-19 (NAD+)
David Sabatini TORmented by steaming turds (mTOR)
Dark Satanic Papermills

I didn't link the articles because it triggers the censorship algo.

Posted by: Jones at September 22nd, 2020 2:18 AM

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