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As
the field of anti-aging research has matured, scientists
and companies have ceased to look for a Ponce de Leon-type
fountain of youth, turning instead to treatments for
age-related diseases. What they found may be an unending
fountain of cash.
The
new generation of anti-aging targets aim to slow or treat
cellular damage and senescence. And while that description
might sound a bit abstract, the list of diseases that fall
under the rubric are some of the biggest markets around,
including cancer, diabetes, obesity, and HIV/AIDS.
Telomeres
and HIV/AIDS
“The
segue from organismal aging to cellular aging is exactly
the pathway that the people who started Geron took,”
says Thomas Okarma, CEO of the company since 1999. “The
founder of Geron, Mike West, was interested in expanding
the human lifespan. That was the thesis around which Geron
was founded.
“That
was not very molecular, and for various reasons, including
my own personal ones, is not something I am too interested
in supporting. So the company quickly morphed into
cellular aging, which is relevant to disease in a number
of ways. That cellular senescence story quickly focused on
the telomere/telomerase story.”
Scientists
know that the specialized caps at the ends of the
chromosomes, called telomeres, shrink with age and their
loss induces cell death. Although few cells in the adult
body express the telomerase enzyme needed to lengthen the
telomeres, Geron’s researchers have found that some stem
cell populations in the skin, gut, and bone marrow can
transiently express low levels of telomerase. Such bursts
of activity give the cells the extra telomere reserve they
need to regenerate tissues in response to stress.
However,
even the transient telomerase activity is inadequate to
cope with chronic stress. “The crystal example of this
turns out to be in AIDS,” says Okarma. “The reason HIV
subjects progress from HIV positivity to frank diseases is
one thing: It is the telomeric attrition in the CD8+
anti-HIV cells that have been proliferating, in many cases
for years, in response to HIV proliferation. But the
immune system isn’t really designed for chronic viral
infections. So there is not enough telomerase in the
immune system to keep those cells from senescing.”
Without them the patients lose their primary defense
mechanism and progress to AIDS.
In
collaboration with the Biotechnology Research Corporation
of Hong Kong, Geron formed TA Therapeutics Limited (TAT)
to identify and develop telomerase activators. When they
incubate senescing CD8+ anti-HIV lymphocytes
with their lead compound, TAT002, the telomerase enzyme is
turned on, the cells recover, and once again repress HIV
proliferation. TAT002 is currently in preclinical testing
in animals. The company hopes to file an initial IND
during the 4th quarter of this year.
If
the compound makes it into clinical trials, the first test
will be to see if it can delay disease progression in HIV
patients who have started to lose immune function. But if
that works, the company has even bigger plans for the
agent: “The list of diseases we uncovered with telomere
loss is huge,” says Okarma. “It includes the AIDS
example, immunosenescence in general, ulcers in the skin,
atherosclerosis, osteoporosis, cirrhosis, osteoarthritis,
neurodegenerative diseases, responses to cardiac
infarction and stroke.
“We
are not trying to extend the lifespan, we are trying to
extend the health-span,” he says.
Resveratrol and SIRT1
Sirtris
is also using anti-aging research to tackle chronic
diseases, such as diabetes and obesity. Resveratrol, a
compound found in red wine, extends the lifespan of fruit
flies, C. elegans, and yeast via activation of the SIRT1
gene. Internet supplement companies sell resveratrol, but
the agent’s activity in mammals was unknown until last
fall when Sirtris Pharmaceuticals reported that
resveratrol protects mice from the ill effects of obesity.
Mice fed a high calorie diet still gained weight but they
had better insulin sensitivity, which suggests that the
compound might protect against diabetes.
The
news got even better a few weeks later when French
scientists reported, in collaboration with the company,
that that the compound works through the SIRT1 pathway in
mammals, just as it does in the other model systems. In
those tests resveratrol improved mitochondrial functioning
and aerobic capacity in the animals
Sirtris
is currently testing their small molecule SRT501 in phase
1b trials in diabetic patients. SRT501 activates SIRT1 and
improves mitochondrial functioning.
David
Sinclair, one of the founders of Sirtris and a professor
at Harvard Medical School declined to comment about the
work because the company has an upcoming IPO. If the drug
improves human metabolism in the presence of excess
calories the way it did the mice, those stocks could end
up being worth quite a lot.
IGF-1R
and cancer
In addition to resveratrol and SIRT1, research in model systems has implicated the insulin-like growth factor 1 receptor (IGF-1R) in aging. Down regulation of a C. elegans protein called daf-2 doubles the animals’ lifespan and slows aging-associated tissue damage. Because IGF-1R is the mammalian ortholog of the DAF-2 receptor, shutting down its activity could enhance lifespan or at least slow tissue aging.
Those
data alone might make it an interesting target for
companies concerned with aging, but the real focus thus
far is to use IGF-1R inhibitors as anti-cancer agents.
Several companies have antibodies that block the receptor
function in clinical trials, including Pfizer and ImClone
Systems.
OSI
Pharmaceuticals recently filed an IND for their small
molecule inhibitor of IGF-1R. Once approved the company
plans to launch phase I trials in solid tumor patients to
determine safety and pharmacokinetic data. If all goes as
planned, the company expects to test the drug in
combination with standard chemotherapies in colorectal
cancer and with Tarceva in non-small cell lung cancer.
“We
haven’t really thought outside of oncology yet, but that
would be a business decision if it were to come to the
fore,” says Neil Gibson, OSI’s chief scientific
officer. However, he doesn’t rule out partnering with
other companies to look for indications outside of cancer,
including aging research.
Mitochondria
and longer life
Of
course, not all companies or researchers are accepting the
view that lifespan itself cannot be prolonged. “I think
our life expectancy got longer by about 25 years or so
between 1900 and 2000,” says Bruce Ames, the founder and
director of Juvenon, as well as a professor at the
University of California in Berkeley. “And this next
century it is going to get even longer, so people will be
routinely living to 100 or more.”
Juvenon
sells a supplement designed to improve mitochondrial
functioning, so the organelles release fewer reactive
oxygen species (ROS) that damage chromosomes and cellular
proteins. “The mitochondria do decay with age,” he
says. “I don’t want to say it is the whole cause, but
I think it is going to be one major factor. Our research
is all aimed at tuning up the mitochondria and seeing what
causes the decay, how do you intervene.”
Sales
of the supplements – which do not have to go through FDA
approval – from the company website alone brought in $5
million last year, and is headed towards $10 in 2007, says
Nathan Hamilton, CEO of Juvenon. He estimates that if the
product hits retail shelves, it would be worth $100
million annually.
“This
is the perfect type of consumer product for baby
boomers,” says Hamilton, who wants to expand the
supplements into a branded line of consumer items,
including drinks and cosmeceuticals.
So
just how big does Ames think the market is for Juvenon and
similar products? “If it is really proves out, everybody
in the world who wants to live longer.”
That’s
a lot of buyers.
Copyright
2007, Cambridge Healthtech Institute. All Rights Reserved.
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