HIF-1 alpha can be stabilized by ROS originating from complex III of the ETC as part of retrograde response ( Bell et al., 2007).
Pharmacological stabilization ofHIF-1 alpha in PGC- 1 a / b knockout myotubes reduced expression of mitochondrially encoded genes ...
Stabilized HIF-1 alpha appears to do the damage, stopping the mitochondria from making messenger RNA and hence proteins needed for proper energy production. This
can happen from oxidative stress. So controlling oxidative stress inside the cell and especially mitochondria is critical. Its implied that stabilization means damaged and so not able to function, but I am still unclear on this. What they seem to be showing though is that something other than oxidative stress might be a major factor.
A gene called c-Myc is a big part of the process, and helps HIF-1 alpha to induce mitochondrial mRNA activation.
SIRT1 works by some kind of activation of HIF-1alpha, and this depends on c-Myc. This whole process appears to depend on NAD+, which is one of the activating factors for SIRT1.
All of this appears to work because a substance called AMPK acts as a switch, increasing mitochondrial mRNA production, though I am not sure I am interpreting this right.
Treatment of 22-month-old mice for 1 week with NMN, a precursor to NAD+ that increases NAD+ levels in vivo ( Yoshino et al., 2011), reversed the decline in VHL and accumulation of HIF-1 alpha (Figures 7 E and 7F); reduced lactate levels; and increased ATP, COX activity, and mitochondrially encoded OXPHOS transcripts (Figures 7 G–7I and S6 D).
So anything that boosts NAD+ might be good, including metabolic precursors that get turned into NAD+.
Strikingly, treatment of old mice with NMN reversed all of these biochemical aspects of aging and switched gastrocnemius muscle to a more oxidative fiber type (Figures S6 E–S6H).
In mice, under artificial conditions, the process is reversible.
In summary:
NAD+ -> SIRT1 -> HIF-1 alpha -> higher AMPK (still unsure about this) -> increased mitochondrial mRNA -> more assembled oxidative phosphorylation complexes -> higher capacity for using oxygen and fuel to make energy.
Figure N on p1635 is their diagramatic summary.
Abbreviations/Acronyms/Key terms
CR = Calorie Restriction
NMN = Nicotinamide Mononucleotide
I wonder what would happen if resveratrol and NADH were taken together? What if this were accompanied by a high protein diet and occasional fasts? They indicate a high fat diet would be bad though.
Background Reading
http://en.wikipedia.org/wiki/Sirtuin_1
http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide
On NMN:
http://www.cell.com/cell-metabolism/abstract/S1550-4131(11)00346-9?script=true This paper also confirms a high fat diet in
humans causes an issue here.
NMN might be available as coenzymated vitamin B3, I am looking into this. However B3 (particularly as niacinamide) alone may be all that is needed. Alcohols can seriously deplete B3 however, which might be an additional reason why we cannot tolerate alcohol. NADH may have a simialar effect, though I would perhaps be inclined to look at combining B3 and NADH, and so utilize two different paths to NAD. NAD can also be bought as a supplment, iHerb sells it though it is currently out of stock.
But here is the downside to using nicotinamide or regular B3:
http://www.sciencedaily.com/releases/2009/12/091222105449.htm
Niacin can be dangerous if you are diabetic, and due to possible hypoxia in ME this might apply to most of us.. But see this:
http://news.wustl.edu/news/Pages/4169.aspx
In diabetic patients, blood sugar levels are elevated, a condition known as hyperglycemia; in addition, tissues damaged by diabetes often have low levels of oxygen, or hypoxia. Williamson and his coauthors used in vitro studies of rat retinas to show that both of these conditions decrease the ratio of NAD to NADH in different ways. Hyperglycemia does it by increasing the rate of transformation of NAD to NADH. Hypoxia makes it difficult for cells to turn NADH back to NAD.
In both conditions the increased NADH is recycled back to NAD by processes that produce free radicals, chemically reactive compounds that can damage tissue. Williamson and his coauthors propose that long-term use of these processes causes the damage seen in diabetes.
[
My bolding]
Does this mean we need to be sure we get NAD and not NADH? Possibly.
All is not lost however.
http://www.nutrimedlogic.com/r-alpha-lipoic-acid-diabetes.html
(Caveat: this is a press release by a commercial company.)
R-Alpha Lipoic Acid is capable of entering the cells via the vitamin transport channel and, once inside, it has been suggested that each molecule of R-Alpha Lipoic Acid is capable of accepting one hydrogen for NADH (the H stands for hydrogen). When NADH loses its H (hydrogen) it becomes NAD and as the levels of NAD goes up, so does the metabolism of glucose (sugar)..
So taking niacinamide, NADH and R-Alpha Lipoic acid in combination might work, but getting the ratios and doses right could be a serious problem.