[nagdu] Fw: Healthy Aging in a Pill To extend life span

[Ed Meskys]

I am forwarding this for a paragraph about 1/3 of the way diown in this 
article. Research is being done which might extend the working life of dogs, 
which would be great news! Ed Meskys

Subject: Healthy Aging in a Pill To extend life span


Healthy Aging in a Pill To extend life span
scientists envision a drug that mimics the benefits of a near-starvation 
diet
By Laura Beil June 4th, 2011; Vol.179 #12
(p. 22) Animals live long and prosper when eating from a menu that puts them
just
this side of starvation.
So far, experiments with yeast, worms, flies, spiders, fish and rodents all 
have
shown the antiaging power of severely restricting calories. And research in
rhesus
monkeys suggests similar benefits in primates: One study found that monkeys
eating
30 percent less than their cage mates appeared to be protected from 
age-related
diseases
and had lower mortality 15 to 20 years later. At this moment, human 
volunteers
at
three different U.S. sites have given up 25 percent of normal daily calories 
to
test
whether the less-food, longer-life phenomenon applies to people as well.
Yet even if the human experiment confirms that it's possible to diet your 
way to
a 120-year life span, a society accustomed to supersizing probably isn't 
going
to
replace an order of fries with a stick of celery. So scientists are looking 
for
shortcuts
that people could use to achieve the antiaging windfall of calorie 
restriction
without
actually having to do it a way to eat your cake and survive it, too.
A drug that postpones aging could also have profound health benefits, since 
most
common diseases (such as cancer, heart disease and dementia) accompany old 
age.
That's
what's driving us, says Donald Ingram, head of the nutritional neuroscience 
and
aging
laboratory at Pennington Biomedical Research Center in Baton Rouge, La. We 
would
like to see some kind of a product that would promote healthy aging.
So far, scientists have singled out a handful of synthetic and natural 
compounds
that appear to trigger the same biochemical mechanisms that kick in when 
cells
are
partially starved of nutrients, part of a coping mechanism that protects 
against
stress. Some, such as resveratrol (a substance found in red grapes and 
wine),
have
already reached an almost pop-star status because of their antiaging 
potential.
Others
are lower profile but similarly promising. It's still too soon to know 
whether
any
of the compounds will work at all, much less work safely.
Interestingly, the race to put time in a bottle has not been deterred by the
fact
that the mechanism of growing old is still largely a mystery. So too is the 
way
that
a drastic drop in calories pushes the slow-motion button.
I've been in the field 15 years now, and it's amazing how theories come and 
go
very
quickly. There isn't a central agreed theory about what aging is at the 
moment.
But
I think in the next decade we'll know, says David Gems, a biologist at the
Institute
of Healthy Aging at University College London. When it comes to caloric
restriction,
the thing you have to understand is that we don't really know how it works. 
Much
of the research is housed at universities and government research labs, but 
a
small
antiaging biotech industry (populated largely by current and former 
academics)
has
also sprung up.
When food is scarce
Many leaps into the antiaging market seek to mimic biochemical reactions 
that
occur
naturally in cells when eating slows way down. While the script remains
incomplete,
research has uncovered some key molecular players such as the family of 
enzymes
known
as sirtuins, which are the target of resveratrol. When food intake plummets,
emergency
alarms go off inside a cell. There are energy sensors somewhere that turn on
some
genes and turn off other genes, says George Roth, formerly at the National
Institute
on Aging and now the CEO at GeroScience, a Maryland-based biotech firm 
trying to
develop an antiaging drug. This genetic fire drill appears to protect 
tissues
from
normal wear and tear. To scientists, each gene switched off or on offers a
possible
antiaging bull's-eye.
A lot of compounds have come down the pike, says Ingram, who helped found
GeroScience.
Some approaches have already lost favor, such as the idea of 
short-circuiting
aging
solely through antioxidants, chemicals that neutralize damaging molecules 
called
free radicals. Many were built around the antioxidant hypothesis, and just 
have
gone
nowhere.
The antioxidant approach probably didn't pay off because it was too simple 
an
answer
for a complex problem. The body ages for many reasons, and more than one are
tied
to calorie intake. During times of plenty, the body doesn't seem to protect
itself
as much from the harmful by-products shed during the business of daily 
living.
When
food is scarce, protection matters most.
Overeating probably also fuels disease in indirect ways, by inciting
inflammation
or raising insulin levels, which in turn helps stoke energy-hungry tumors.
Ingram
and Roth wrote in the February-March Experimental Gerontology that any 
antiaging
drug must have a global impact on chemical reactions in the body, just as
calorie
restriction does. Our perspective has always been that aging operates on
multiple
mechanisms, Ingram says.
The GeroScience research focuses on the processing of glucose, the body's 
source
of energy. Of special interest is mannoheptulose, a compound which occurs
naturally
in avocados, though Roth says it degrades quickly once the fruit ripens.
Mannoheptulose
partially turns off hexokinase, an enzyme that ignites a series of chemical
reactions,
known as the glycolytic pathway, when glucose enters a cell. Starving a cell 
of
hexokinase
is like sending a chemical memo that less energy is coming in. At a meeting 
in
2009,
Roth reported unpublished data showing that mice fed mannoheptulose lived 
about
30
percent longer on average than normal mice, even though the groups consumed 
the
same
number of calories.
Products based on mannoheptulose may be years away from use in man, but 
maybe
not
in man's best friend. Roth and colleagues reported at the 2010 Experimental
Biology
meeting that mannoheptulose appears to be biologically active in dogs. The 
team
won't
discuss further details because GeroScience has now joined with Procter &
Gamble's
pet food division to explore commercial use.
An antiaging dog food wouldn't just allow people to keep their canine 
companions
longer. Since dogs have shorter life spans than people, an antiaging effect
would
be evident sooner in dogs. We think that a compound like mannoheptulose or a
glycolytic
inhibitor is going to be superior to any of the products that are out there,
because
of the fact that it does work somewhat similarly to true caloric 
restriction,
Ingram
says.
But mannoheptulose isn't the only natural substance that appears to mimic a
state
of calorie restriction. The most headline-grabbing compound of the bunch has
been
the sirtuin-targeting resveratrol.
Celebrity compounds under fire
In cells, sirtuins have a day job of stripping acetyl groups (small 
carbon-rich
chemical
bunches) from proteins. Most important, the enzymes are particularly busy 
during
times of mild stress, such as when calorie intake drops. Somehow, for 
reasons
that
are still being worked out, cells awash in sirtuins are more protected from
damage.
When we are obese, the body gets lazy and turns those protections off, says
David
Sinclair, who studies aging at Harvard Medical School in Boston. A decade of
research
has suggested that sirtuins may help shield the body from a number of
afflictions,
including diabetes, stroke and even neurodegenerative diseases such as
Alzheimer's
and Parkinson's.
Sirtuins' path to stardom began in 2003 with a report in Nature , in which
Sinclair
and his colleagues announced that resveratrol could artificially stimulate
sirtuins.
Thus began the quest to develop an artificial, more potent incarnation of
resveratrol.
In 2004, Sinclair helped form the company Sirtris with this goal. (The
pharmaceutical
giant Glaxo-SmithKline bought Sirtris in 2008 for $720 million.) Although 
seven
different
forms of sirtuins exist in humans, most antiaging research has zeroed in on 
one
called
SIRT1.
The role of sirtuins in aging is still highly debated, so much so that in 
August
of last year Science featured a pointed letter volley over whether it was
justified
to omit sirtuins from a review of the biology of aging published a few 
months
earlier.
The problem is that resveratrol and the sirtuins haven't convincingly shown 
that
they can lengthen life, as opposed to simply protecting against diseases 
that
shorten
life prematurely. The distinction may sound trivial, but in antiaging 
research,
the
two concepts are very different.
Adding to resveratrol's woes is the fact that some scientists have raised 
doubts
about whether the results seen in studies of resveratrol and its 
experimental
cousins
are valid. For example, in 2010 in the Journal of Biological Chemistry ,
researchers
from Pfizer Global Research and Development described experiments 
questioning
whether
the effect was a testing artifact or resveratrol and three other Sirtris
compounds
actually activated SIRT1. Our present data are significant for the field as 
we
provided
strong evidence that neither the Sirtris series nor resveratrol are direct 
SIRT1
activators, the team wrote.
Sinclair points to a follow-up study published in the same journal in 
October
2010
from Sirtris scientists that reached the exact opposite conclusion. So at
Sirtris,
the research continues undaunted. Last December, the company abandoned a 
study
of
one SIRT1 activator called SRT501, but testing of other activators is 
continuing
in human trials. SRT501 was being tested in patients with multiple myeloma, 
some
of whom developed kidney problems.
Targeting cell growth
Less controversial, but toting its own baggage, is the drug rapamycin. It 
has
the
advantage of already being on the market and having an almost undisputed 
record
of
lengthening life span in animals. The drug has long been prescribed to
transplant
patients because it helps guard against rejection. It has also been 
investigated
in cancer treatment because it has the capacity to starve tumors of 
nutrients
and
indeed, transplant patients taking rapamycin appear to have a lower cancer 
risk.
Rapamycin inhibits a series of reactions in a cell that begins with a 
protein
called
(in a practical bit of nomenclature) target of rapamycin, or TOR. The TOR
chemical
pathway is one of life's fundamental processes; it exists in some form from
yeast
to mammals, where it is designated mTOR, and helps regulate cell growth, the
production
of ribosomes (cellular protein factories) and protein turnover. mTOR, in 
turn,
activates
a protein called S6K1.
In 2009, a team led by British researchers reported in Science that mice 
with
mutations
that left them without any functional S6K1 lived longer. Just as 
significant,
genes
in the mice were switched off and on in patterns consistent with calorie
restriction.
A study in Nature in 2009 reported that rapamycin could extend life span in
mice,
even when the drug was given during older age. Last year, writing in Cell
Metabolism
, European researchers reported that rapamycin also extends the life span of
flies,
while another report in the American Journal of Pathology described an 
extension
of life span in cancer-prone mice.
As far as rapamycin goes, it works, says Luigi Fontana, a physician and 
calorie
restriction
researcher at Washington University in St. Louis. By giving rapamycin, you 
are
telling
the cells that there is not enough energy. But rapamycin has its drawbacks. 
Most
notably, the drug is given to transplant patients because it suppresses the
immune
system. This hasn't been an issue in mice because the animals are housed in
pathogen-free
environments. Human beings are not living in pathogen-free facilities, 
Fontana
says.
I would never take rapamycin.
The immune system concerns will probably keep the drug, at least in its 
current
form,
off the antiaging market. It will not be prescribed to healthy people 
because it
is labeled as an immuno-suppressant, says Mikhail Blagosklonny, a scientist
studying
cell stress biology at the Roswell Park Cancer Institute in Buffalo, N.Y. 
This
is
enough to make people scared. Blagosklonny (who has helped form a company,
Tartis-Aging,
to develop rapamycin as an antiaging drug) believes that in the smaller 
doses
that
would be given to healthy people, rapamycin would not dampen the immune 
system.
Writing
last year in Cell Cycle , he even went so far as to say that taken together 
with
its ability to suppress cellular aging and to increase life span, this may 
call
to
re-label rapamycin from immuno-suppressant to aging-suppressant
(gerosuppressant).
If that doesn't happen, the body's biology offers plenty of other targets 
for
drugs.
Acting on the body's system of glucose detection and insulin production, the
diabetes
drug metformin has also been an attractive antiaging candidate. And in the
future,
scientists may be able to capitalize on the signals from mitochondria (a 
cell's
energy
factories) that affect life span independently of calorie restriction. In
January,
researchers from the Salk Institute for Biological Sciences and the Scripps
Research
Institute, both in La Jolla, Calif., announced in Cell that they had 
pinpointed
a
chemical distress signal put out by mitochondria that lengthened the life 
span
of
worms. In the experiment, the signal was produced only in the intestine and
nerve
cells, yet affected the entire organism.
Should any new compound reach commercial development, scientists acknowledge
that
the resulting antiaging drug would still face hurdles to reach the aging 
public.
A drug that might be taken in otherwise healthy people, perhaps for years, 
would
need to demonstrate it was safe beyond doubt.
Calorie restriction exists at the twilight between health enhancement and
outright
starvation, so a compound would have to be precisely calibrated. If the body
gets
too strong a signal that energy is low, organs may fail. Scientists have 
known
since
a study in 1950 that people who reduce calories by 50 percent can experience
depression,
apathy, slower movement and other detrimental effects.
It's also clear that tinkering with the aging mechanism might have 
unexpected
side
effects. Ingram and colleagues identified one promising glycolytic inhibitor
more
than a decade ago, while he was still at the National Institute on Aging. 
Called
2-deoxyglucose, it fared well in early tests but was later found in animal
studies
to be toxic to the heart and to increase mortality.
So for now, people are left to protect their aging bodies the old-fashioned 
way,
by exercising enough and not eating too much. In the battle against aging, 
it
remains
to be seen whether the future will offer a bigger menu.
View larger image
Averages and outliers Jeanne Calment of France was 122 when she died in 
1997,
making
her the longest-lived person known. That a small percentage of people live
beyond
110 raises the possibility of extending average human life span and 
motivates
scientists'
search for antiaging drugs. For 2009, global average life span was 68. But
substantial
differences exist: The map shows average life expectancies for people born
between
2005 and 2010, broken down by country.
Credit: Geoatlas/graphi-ogre, adapted by Janel Kiley ; Source:Guinness World
Records;
WHO World Health Statistics; UN World Population Prospects: The 2006 
Revision
Drastically reducing daily calorie intake has successfully slowed aging in 
many
organisms.
Now scientists are finding out whether drugs and genetic tweaks that mimic 
this
dietary
restriction have similar life spanextending potential.
Organism On caloric restriction Using drugs or genetic modifications Yeast 
Lives
three times as long as normal.
Inhibiting the TOR nutrient-sensing pathway by deleting TOR and related 
genes
produces
a several-fold increase in life span.
Fruit fly Lives two times as long as normal.
Reducing activity of the insulin/insulin-like growth factor signaling (IIS)
pathway
through genetic deletions extends life. So does using rapamycin, a drug that
acts
via the TOR pathway.
Mouse Lives 30 to 50 percent as long as normal.
Mutations that reduce activity of the IIS pathway or the TOR pathway, called
mTOR
in mammals, increase life span. So do rapamycin and the diabetes drug 
metformin.
Mannoheptulose, which slows metabolism of glucose, may extend life by 30
percent.
Monkey Less age-related disease and lowered age-related mortality after 1520
years.
No published results of experimental drugs. Human
Long-term study of 25 percent reduction in calories is ongoing.
Not yet determined. Some researchers have hopes for rapamycin and
mannoheptulose,
among others. Studies of resveratrol and SIRT1 activators, which both 
stimulate
sirtuins,
and metformin are ongoing.