cron-web.org

[A1CR]

[posted on behalf of CRON4healthyfuture; 2006-02-15]
Finkel and Balaban: p66shc longevity gene regulates mitochondrial metabolism......

This is an interesting manuscript that just showed up at the Journal of Biological Chemistry.

If you delete the p66shc gene in mice, the mice live about 30% longer.

They found the p66shc gene promotes mitochondrial function. When you delete the p66shc gene, the mitochondria stop working as well. As a result, the cell shifts from oxidative metabolism to glycolytic metabolism. Less "oxidative burden" is associated with this shift.

What is particularly interesting is that fasting "messes around" with mitochondria, too. If slightly dysfunctional mitochondria are key to longevity, then there may be a lot of different interventions may can dance around this effect.

There are lot of interesting points that intersect with other research fronts.......

Like, increased lactate (metformin side effect, lactic acidosis......)

and increased NADH........(Sir2 regulation?)

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http://www.jbc.org/cgi/content/abstract/M511626200v1

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"In particular, despite similar cytochrome content, under basal conditions, the oxygen consumption of spontaneously immortalized p66shc -/- mouse embryonic fibroblasts were lower than similarly maintained wild type cells. Differences in oxygen consumption were particularly evident under chemically uncoupled conditions demonstrating that p66shc -/- cells have a reduction in both their resting and maximal oxidative capacity. We further demonstrate that reconstitution of p66shc expression in p66shc-/- cells increases oxygen consumption. The observed defect in oxidative capacity seen in p66shc -/- cells is partially offset by augmented levels of aerobic glycolysis. This metabolic switch is manifested by p66shc -/- cells exhibiting an increase in lactate production and a stricter requirement for extracellular glucose in order to maintain intracellular ATP levels. In addition, using an in vivo NADH photobleaching technique, we demonstrate that mitochondrial NADH metabolism is red
uced in
p66shc-/- cells. These results demonstrate that p66shc regulates mitochondrial oxidative capacity and suggest that p66shc may extend lifespan by repartitioning metabolic energy conversion away from oxidative and towards glycolytic pathways. "

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http://tinyurl.com/ayhyz

"Compared with fed rats, fasted animals showed increased
serum non-esterified fatty acid (NEFA) levels [30], and
decreased muscle carbohydrate supply, which was compensated
by enhanced fatty acid oxidation [31, 32].
Therefore, one can suggest that, during fasting, fatty
acids are the principal fuels oxidised by SS mitochondria,
which, being localised beneath the sarcolemmal membrane,
experience a higher NEFA amount than IMF mitochondria.
In fact, NEFA concentration then dilutes in the
sarcoplasm. In SS mitochondria, the higher NEFA availability
associated with the increased palmitate-induced
uncoupling may contribute to lower efficiency. Superoxide
production from the electron transport chain has been
reported to be high during fatty acid oxidation in isolated
muscle mitochondria [33]. In addition, ROS production is
more pronounced if ATP demand is lower in the presence
of a great availability of energy substrates [34, 35]. As for
ATP demand, SS mitochondria supply ATP to energy-requiring
reactions, such as protein synthesis and ATPase
pumps that are lowered during fasting [36, 37], while
IMF mitochondria produce ATP for contractile elements
[1, 4] that are not influenced by fasting [38]. It follows
that SS mitochondria during fasting could produce a large
amount of ROS. On the other hand, we found in SS mitochondria
from fasted rats a reduction in oxidative damage
as indicated by determination of the basal/total aconitase
activity ratio. Since no increase in SOD specific activity
was found in the fed-fasting transition, the above reduction
could be due to enhanced palmitate-induced uncoupling
found in SS mitochondria from fasted rats, which is
one way to mitigate ROS damage [12]."

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http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15175015

"Injection of dexamethasone for 5 days resulted in an increase in the fraction of the proton cycle of phosphorylating liver mitochondria, which was associated with a decrease in the efficiency of the mitochondrial oxidative phosphorylation process in liver."

[A1CR]

Another CRONie wondered:

>>If so then retinyl palmitate (full name)
>>might be good for cronies

CRON4healthyfuture replied:

I would not advise emphasizing this compound unless you want to have
a "bone-crackin'" good time.

I think there are some Senators that would throw you in the brig for trying
to foist this compound on the unsuspecting masses.

However, perhaps "caloric restriction physiology" is "different". I don't
see a large body of evidence indicating that, however.

[A1CR]

Another CRONie noted:

> Do the comments in the article suggest that more
> palmitate might induce more uncoupling of
> mitochondria? If so then retinyl palmitate (full name)
> might be good for cronies as uncoupling has been shown
> in numerous other posts to our group to be of benefit.

MR responds:

First, as CRON4healthyfuture indicates, getting more than a very moderate amount
(~2000 IU total from diet & supplements) of preformed vitamin A
(retinol/retinyl esters) is a really bad idea from the perspective of
maintaining functional bones.

Second, the amount of palmitic ester in a dose of retinol is too small
to have any pharmacological effect systemically on your mt; there are
orders of magnitude more in a tablespoon of olive oil (let alone of
lard, tallow, cocoa butter and palm oil).

Third, the cardiac risk of increasing dietary palmitate clearly makes
the proposed experiment a bad tradeoff even if successful.

Fourth, one absolutely key experiment (feed animals palmitate to see if
it increases mt uncoupling via a route that actually reduces mtROS)
hasn't been done; this study is related to increased delivery of fatty
acids, including palmitate, to the mt because of the increased use of
FFA for fuel during fasting, not on increasing DIETARY palmitate. Basing
one's diet on biochemical speculation is a bad idea.

And fifth, the OTHER absolutely key experiment (increasing uncoupling
via the routes that appear to reduce mtROS and seeing if it actually
increases healthy lifespan) Also hasn't been done (tho' there is
significant evidence to suggest it, unlike the whole palmitate
scenario), hasn't been done; again, basing one's diet on biochemical
speculation is a bad idea.

-MR