ENDOCRINE PATHWAY – Route to Youthful Longevity?

In the never-ending search for the fountain of youth,
human growth hormone has become the latest celebrity
health craze. The effectiveness and safety of using
growth hormone (GH) supplements to stave off aging,
however, remain controversial in the medical community.
In another approach to figuring out the path to longevity,
scientists are now aiming their anti-aging therapies
at hormones and other compounds that genetic studies
suggest play a key role in the aging process. The new
anti-aging focus is due to mounting evidence that mutations
in genes affecting an endocrine signaling pathway,
called the somatotropic axis, play a major role in determining
not only lifespan but also in delaying the onset
of debilitating illnesses that come with aging.

“Changing single genes within these pathways can
extend lifespan dramatically,” Cynthia Kenyon, Ph.D.,
at the University of California, San Francisco, wrote in a
2005 article in Cell. Kenyon’s studies on worms in 1993
showed that mutations in a single gene not only doubled
the animals’ lifespans, but the mutant worms were also
more mobile and exhibited fewer signs of physical deterioration
than those without the mutations. “Some of these
long-lived mutants are breathtaking; in human terms, they
look like forty-year-olds when they are actually eighty or
even older,” she wrote.

The discovery that a change in just one or two genes
could change lifespan was significant, said Joseph Baur,
Ph.D., of the University of Pennsylvania, who also studies
aging. “Most people thought there were thousands
of different things going wrong during aging and you
would never be able to change enough of them to make
a difference.”

The mutations occurred in genes that in humans determine
the activity of insulin, growth hormone (GH), or
insulin-like growth factor one (IGF-I), a trinity of compounds
that work together to enable animals to grow and
reproduce when food is sufficient. These compounds trigger
growth in stature in immature animals and influence the
growth of girth in adults when food is abundant. A lack
of food or stress reduces their actions, but in doing so
triggers a number of health-promoting mechanisms. “If
you reduce food intake, you turn down insulin-GH-IGF-I
activity,” explained Andrzej Bartke, Ph.D., an expert on
aging at Southern Illinois University.

Recently, researchers have linked changes in this growthpromoting
pathway to long life in humans. Studies in 2008
and 2011 found that people with impaired IGF-I activity
were more likely to live 100 years or more. In contrast, mice
with mutations that increased their GH or IGF-I activity
die young, as do people with acromegaly due to excessive
secretions of GH and IGF-I.

Not only does a lack of GH or IGF-I activity seem to promote
longevity, it also appears to delay aging. Many long-lived
animals with GH or IGF-I receptor mutations never develop a
number of age-related diseases, including cancer and heart
disease, “suggesting the possibility of forestalling multiple
diseases all at once by targeting aging itself,” Kenyon said.

Some evidence suggests that this might be the case in
humans as well. Laron dwarfs in Ecuador and other populations
that are unresponsive to growth hormones seem to
have remarkable protection from developing cancer and
diabetes. The Laron community, however, is not immune
to cardiovascular disease, researchers have noted, and the
findings on the effects of reduced GH or IGf-l signaling on
heart function remain inconclusive.

In contrast to Laron dwarfs, acromegalics have increased
growth hormone activity and an increased risk of diabetes,
heart disease, and cancer. Studies in both mice and humans
link elevated IGF-I levels with heightened risk for developing
a number of different types of cancers.

Insulin, GH, or IGF-I activity in the brain might also
play a role in fostering age-related brain disorders, such
as Alzheimer’s disease. When researchers suppressed insulin
activity only in brain cells, mice lived longer. Genetic
reduction of IGF-I activity also slowed the deterioration
of cognitive faculties and the death of brain cells or their
connections in mice with Alzheimer’s disease.

“Aging may be a common denominator for most diseases,”
said Bartke. “The data from long-lived people
suggest that whatever is extending their lives is also
protecting them from disease. These folks don’t seem to
experience serious chronic disease until the very end of
their lives—until the age of 95 or so they are in very good
shape. This teaches us that you can postpone age-related
health problems.”

How could one signaling pathway affect so many facets
of aging and disease? Numerous researchers are currently
seeking answers to this question, and results from studies
done in the last few years suggest several interacting mechanisms,
including increased stress protection, suppressed
inflammation, enhanced insulin sensitivity, reduced protein
clumping, and greater cleanup of protein trash within cells.

“If you reduce insulin or IGF-I action you get a lot of
bang for your buck because you activate all these beneficial
pathways,” Kenyon noted.

Several studies find that reduced GH or IGF-I activity
triggers the production of antioxidant enzymes that protects
cells from damage by free radicals and other reactive oxygen
compounds. Studies in worms and mice also reveal that suppression
of insulin, GH, or IGF-I activity appears to protect
neurons from the clumping of the beta amyloid protein that
is the hallmark of Alzheimer’s disease. Worm studies find
such suppression increases production of chaperone proteins
that help other proteins fold properly or escort misfolded
proteins to cellular garbage cans, thereby perhaps preventing
the harmful buildup of amyloid plaques in the brain.

There’s also evidence that deficient GH action in mice
favorably alters the distribution and function of fat tissue.
Although this deficiency boosts the amount of fat tissue in
mice, that fat tissue is less likely to be deposited in the abdomen
and promote insulin resistance, inflammation, and other
ills linked to abdominal obesity and the metabolic syndrome
in people. GH deficiency also boosts the amount of adiponectin,
a hormone secreted by fat cells that promotes insulin
sensitivity and has anti-inflammatory and anti-atherogenic
actions that increase longevity in both mice and humans.

Calorie Restriction Extends Life

The findings on the effects of growth hormone and IGF-I on aging may help explain why extreme calorie restriction extends life. When an animal is stressed by a lack of food or other factors, it suppresses energy-consuming growth and reproduction in favor of biochemistry that promotes repair and survival.

“What really matters from an evolutionary standpoint is leaving offspring and not how long you live,” Bartke explained. “Growth hormone fits into that concept because it makes you grow and reach sexual maturation and leave offspring.” For humans, who stop growing in stature relatively early in life but tend to still grow in girth due to an ever present abundance of food, growth hormone and IGF-I action, even at normal levels, may be harmful to health and longevity.

This conclusion is striking given our current obesity epidemic, Bartke and Kenyon pointed out. “People are overeating for their energy expenditure and becoming overweight,” said Bartke. “We’re doing something that is very wrong in terms of health and longevity and the current generation may be the first generation in recent history that won’t live longer than their parents.”

“I believe that we need to get rid of much of the sugar that’s in our diets and exercise more,” Kenyon added. The whole focus is on fat, but sugar is what triggers insulin activity and prevents the body from using its stored fat reserves. If you can maintain a lower insulin state, you can do wonders.”

This is already apparent in people who stick rigidly to extremely low-calorie diets with the hopes of forestalling aging. Studies on these individuals reveal they have very low insulin and blood glucose levels, impressive blood lipid profiles, and the blood pressures of people half their age. “They certainly look like they are not likely to get most of the things that kill people, but it remains to be seen whether they will live longer,” Bartke said.

Although inducing major stress or severely restricting food intake are not likely to be successful therapies in our culture, the recent findings on GH, IGF-I, and aging suggest that medications may be developed to adjust the amount of these compounds, or others downstream, so that the age of 60 may one day be the new 30. Studies in mice show it is possible to extend life with the drug rapamycin, even when the drug regimen isn’t started until the mice are middle-aged.

“Perturbing the Pathway”

But there could potentially be tradeoffs in tampering with Mother Nature. Although rapamycin causes mice to live longer healthier lives, for example, it is an immune suppressant that might have unacceptable side effects. And although low levels of IGF-I are tied to a lower risk of cancer, they are also linked to greater risk of developing type 2 diabetes, osteoporosis, and poor cognitive function.

It might be possible to “cause some modest reduction in GH and IGF-I activity that is within the physiological range and won’t be life threatening, but will keep insulin levels and sensitivity youthful,” Bartke suggested.

“You can imagine getting in there and perturbing the pathway in a way that doesn’t create unfavorable side effects,” said Kenyon. “I think that’s feasible because after all, small-breed dogs are small because they have low IGF-I levels, and they also live longer than large dogs and are very healthy.”

Another approach to lengthening the “youthspan” might be to induce a minor stress by administering a small amount of a toxin or some other substance, that might cause the body to roll out the protective responses triggered by reducing insulin-GH and IGF-I activity, Kenyon added. She is currently testing such an approach on human cells. She said she looks forward to the day when “people can take a drug that makes them naturally more resilient and able to live longer and resist disease.”

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