Tom Prolla (UW) - Gene Expression in CR
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Death rate is exponential with time because many systems fail in parallel as
one gets older.
Free radical (ROS) theory is still most popular theory of aging.
Talked about mutations that create smaller animals in general tend to lead
to longer lifespan. Often related to growth hormones, and particularly IGF-1
(and insulin).
Went over Okinawan data suggesting CR works in people.
Does gene expression profiling to look for biomarkers of aging using gene
chip micrarrays. Thousands of markers on a single chip. Each gene marker
lights up when that gene is being expressed to a high degree in the cell
that is being sampled.
In typical aging, stress response genes go up, inflammatory response go up,
and a host of other things change (in mice). CR prevents most (80%) of these
changes.
They then did the same thing in the NIA monkeys at University of Wisconsin
(UW).
Sampled leg muscles of muscles.
Inflammation genes upregulated in normal aging in monkeys.
Gene markers of oxidative stress go up in aging.
Energy metabolism genes get downregulated - mitochondria not working as well
with aging.
Surprisingly, CR *also* lowers genes involved in energy metabolism - like in
AL monkeys.
The cause of this surprise is likely to be reducing in thyroid hormone.
In other words, energy metabolism downregulated in AL animals because the
mitochondria are messed up, and not creating the proteins. In CR, energy
metabolism is reduced due to lower thyroid hormones, and therefore less
energy utilization.
Gene expression differences between CR and AL middle age monkey's weren't
apparent, perhaps because middle age is too early - the two populations may
be "crossing over" in their gene expression.
Latest gene study in the heart. CR does a lot of good things in gene
expression in the heart of rodents.
COQ10 and Alpha Lipoic Acid compared with CR in terms of survival. The
antioxidants didn't help lifespan, Only CR did.
*Lots* of gene in the heart change in activity as a result of CR in rodents.
CR results in reduction of heart hypertrophy (which normally happens w/
age), and downregulation of genes involved in this process.
Heart genes involved in carbohydrate and fatty acid metabolism in the heart
changed a lot in CR animals - expression more similar to young animals.
Saw reduced apoptosis gene expression in heart - suggesting less cell
damage, and thus less programmed cell death.
CR started at middle age reduced age related changes in the heart by about
20% - matches changes in longevity of these mice. CoQ10 and ALA didn't help
prevent age related changes, and may have actually hurt a bit.
PGC-1 is gene that is induced by hypothermia. It is a regulatory gene. It
regulates expression of other genes that regulate mitochondrial activity.
PGC-1 expression goes up with CR.
"CR changes the expression of so many genes, it may be hard to find a mimic
that duplicates the effects of CR. This is supported by the failure of
antioxidants to create
Michael Rae - Questioned the significance of gene changes - e.g.
testosterone goes down w/ age, but that doesn't mean reversing testosterone
decline would be a good thing. The reduction in testosterone (and gene
expressions) may be a protective response. Inflammation fighting gene
expression changes may be necessary.
Prolla things some supplements may have positive impact on average lifespan,
or on particular systems (e.g. brain aging), but doesn't think any will be
as effective as CR.
p53 knockout mice don't do much apoptosis, and are dying earlier from
cancer.
Question: What about CR + supplements? Can such a combination be beneficial?
Prolla said it hasn't been tried, since no supplements tested so far have
been disappointing - so why try adding them on top of CR.
Michael Rae things the only beneficial compound in coffee is the caffeine -
for helping prevent Parkinson's disease.
