Insulin's effect upon the SKN-1 gene and aging

Human Aging, Position Paper
Longevity of adults has changed little
Senior runners postponed disability 8.7 years
Estrogen with progesterone lengthens women lives
Testosterone and vascular functions in aging
estrogen and longevity
Free radicals part of aging process
FAD AGING CURES EXPOSED, by leading scientists
genes that slow aging
Genes and aging
Insulin's effect upon the SKN-1 gene and aging
Telemores, sexual size dimorphism and gender gap in life expectancy
SKIN AGING: causes & treatments
Carbohydrates and aging and age related diseases
Arthritis reduced with vigorous physical activity
Why Women Live Longer than Men

Aging is mainly the result of oxidative damage, which slowly alters the functioning of all process.  While some of this effect is environmental, oxidative damage results from the production of energy through the Kreb’s cycle and other synthesis


Insulin’s effect upon the SKN-1 gene and aging


It has been known for at least 2 decades that the serum levels of glucose increase with age and the  insulin biochemical pathways deteriorates with age.  A decline in beta cells contributes to the increased development of IGT and type 2 diabetes, and their progressive nature.  Moreover, reactive oxygen plays a substantial role in the aging process, and glucose metabolism plays a key role in this process.  The article below is included because it sheds light on why some people age slowly—jk.


Insulin Has Previously Unknown Effect That Has Role In Aging And Lifespan

Mar. 20, 2008) — Researchers at the Joslin Diabetes Center have shown that insulin has a previously unknown effect that plays a role in aging and lifespan, a finding that could ultimately provide a mechanism for gene manipulations that could help people live longer and healthier lives.

The paper, published in the March 21st issue of Cell, reports that insulin inhibits a master gene regulator protein known as SKN-1, and that increased SKN-1 activity increases lifespan. SKN-1 controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress -- damage caused by elevated levels of free radicals (byproducts of metabolism) -- and various environmental toxins. The new finding was demonstrated in experiments on the digestive system of C. elegans,* a microscopic worm often used as a model organism.

"We've found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper. "This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize."

The idea down the line is that fine-tuning the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, he said. The work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

But, today's finding may be most important for what it teaches about aging in general, he said.

"The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues," said Blackwell. "The implications go far beyond diabetes."

It has been known since the 1990s that insulin inhibits a gene regulator protein known as FOXO, important in diabetes metabolism, tumor suppression and stem cell maintenance. FOXO controls a number of genes, including many involved in stress resistance. Studies in C. elegans showed that reduced insulin signaling boosted activity of a FOXO protein known as DAF-16, leading to greater stress resistance and longer life.

The new work places SKN-1 alongside FOXO as a second master gene regulator that is inhibited by insulin signaling and adds to the body of knowledge about insulin and its effects on gene pathways, stress resistance and aging. According to the paper, insulin's effect on SKN-1 occurs independently of its effect on DAF-16.

"You can manipulate the expression of SKN-1 and the worms live longer," said Blackwell, an Associate Professor of Pathology at Harvard Medical School and faculty member at the Harvard Stem Cell Institute.

The experiments will have to be repeated in mammals, where insulin and insulin-like growth factor-1 have a complex array of effects in different tissues. But, according to Blackwell, other findings in the C. elegans model have generally turned out to be applicable to mice and humans.

Blackwell's lab at Joslin is focusing on mechanisms of free radical resistance and aging, and on gene regulation mechanisms in C. elegans stem cells with the idea of using this knowledge towards reprogramming human stem cells into insulin-producing cells.

The research was funded by the National Institutes of Health and The Iacocca Foundation, the Fonds der Chemischen Industrie, BMBF NGFN2, Qualitaetsoffensive BW and Deutsche Forschungsgemeinschaft CRC746 and EC Network of Excellence Lifespan, as well as an NRSA, an NIH training grant, KRF and MOST/KOSEF.

Other researchers involved in the paper were Jennifer M.A. Tullet, Joseph Baker and Riva P. Oliveira of Joslin; Jae Hyung An of Joslin and Yonsei University in Korea; Ji Yun Hwang of Yonsei University; and Shi Liu, Ralf Baumeister and Maren Hertweck of the University of Freiburg.


*C. Elegans is a tiny flat worm, whose gnome was among the first mapped, and with whom we share many similar genes—thus justifying it role in research.


At bio.com http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?cid=22100011


09/26/06 -- Scientists in the Linus Pauling Institute at Oregon State University have discovered a new technique to let them watch, visualize and precisely measure a key oxidant in animal cells, an important breakthrough that could dramatically speed research on everything from Lou Gehrig's Disease to heart disease, hypertension, diabetes and aging.


The findings are being published online this week in Proceedings of the National Academy of Sciences, a professional journal. They could open the door to major advances on some of the world's most significant degenerative diseases, researchers say.

The OSU scientists, in collaboration with Molecular Probes-Invitrogen of Eugene, Ore., found a chemical process to directly see and visualize "superoxide" in actual cells. This oxidant, which was first discovered 80 years ago, plays a key role in both normal biological processes and - when it accumulates to excess - the destruction or death of cells and various disease processes.

"In the past, our techniques for measuring or understanding superoxide were like blindly hitting a box with a hammer and waiting for a reaction," said Joseph Beckman, a professor of biochemistry and director of the OSU Environmental Health Sciences Center. "Now we can really see and measure, in real time, what's going on in a cell as we perform various experiments."

In research on amyotrophic lateral sclerosis, or Lou Gehrig's Disease, which is one of his lab's areas of emphasis, Beckman said they have used the new technique to learn as much in the past three months about the basic cell processes as they did in the previous 15 years. Hundreds of experiments can now rapidly be done that previously would have taken much longer or been impossible.

"This will enable labs all over the world to significantly speed up their work on the basic causes and processes of many diseases, including ALS, arthritis, diabetes, Parkinson's disease, Alzheimer's disease, heart disease and others," Beckman said. "And it should be especially useful in studying aging, particularly the theory that one cause of aging is mitochondrial decay."

The process of oxidation in the body, researchers say, is one that's fundamental to life but also prone to problems. Oxygen in the cells can be reduced to a molecule called superoxide, which is part of normal immune system processes and may also have other functions - it was first named by OSU alumnus Linus Pauling in 1934.

"Oxygen is actually one of the more toxic molecules in the environment," Beckman said. "Breathing 100 percent pure oxygen will destroy your lungs in about three days because it increases the formation of superoxide."

Superoxide is efficiently removed by an enzyme, superoxide dismutase. Antioxidants in food, such as vitamin C and E, are also part of this process.  [Studies of these vitamins and their effect upon superoxide, however, have failed to show an effect upon aging—jk.] And in healthy animals, including humans, this delicate balancing act can work well and cause few problems. But sometimes the process breaks down and excess levels of superoxide begin to accumulate and lead to a wide variety of degenerative diseases.

Prior to this, there was no direct and accurate way to measure superoxide or its origin from the two places that produce it, the cell's cytosol or mitochondria. Now there is.

With the new system developed at OSU, researchers can use a fluorescent microscope, a fairly standard laboratory tool, to actually see levels of superoxide and observe changes as experiments are performed with living cells.

"If we poison the mitochondria, using something like the pesticides that have been implicated in Parkinson's disease, we can actually see superoxide levels begin to rapidly rise," Beckman said. "You get a similar reaction if a growth factor is added that's implicated in the development of Lou Gehrig's Disease."

The data available from this new technology, Beckman said, are so profound that for some time many in the science community didn't believe it was possible.

"This will become a critical tool in learning how superoxide works in a cell," he said. "I've been studying this for more than 10 years and never thought we would have such a clear and accurate picture of what's going on inside a living cell."

In their research on ALS, for instance, OSU scientists have used the new system to actually see cells eating themselves alive and dying from excess superoxide production. A new compound is in phase one clinical trials that appears to inhibit this process and may ultimately provide a therapy for the disease.

Oxidative stress resulting from mitochondrial dysfunction has already been implicated in neurodegeneration, aging, diabetes and cancer, the researchers said in their report. The new findings could rapidly speed research in all of those fields, they said.

Source: Oregon State University


This articles ties the pieces together.  High levels of blood glucose has been know of decades to be associated with aging and coronary disease.  This article describe the varied effects of the failure to regulate the level of glucose due to insulin resistance. Obesity is the most significant cause of insulin resistance.  




By Brenda Goodman Mon Aug 29, 2007, 5:33 PM ET

Diabetes drugs have made a big difference to George Marincin and Kristin Chapman. For a few weeks last year, Marincin, 77, from Tacoma, Wash., took artificial insulin, the hormone that's deficient in diabetics. And every day Chapman downs doses of Glucophage, a drug that helps the 38-year-old from Atlanta to better control the hormone.



But neither Marincin nor Chapman has diabetes.


What Marincin does have is Alzheimer's disease. He took insulin to test the idea that low levels might be linked to memory problems. "I did wonder how insulin could help George because he's not diabetic," says his wife, Mabel. "But it has. It's wonderful." Her husband has regained his sense of humor and can even complete simple tasks again like making a cup of tea, she says. Last month his doctors reported in the Archives of Neurology that other patients also seemed to benefit.


Chapman was just as surprised that adjusting insulin levels could help her. She has polycystic ovary syndrome, which causes infertility and dramatically raises her risk for heart disease. But her problem wasn't too little insulin but too much, which prevents ovulation. After seven years of struggling to conceive, she started taking Glucophage and was pregnant in a month. "It's mind boggling, isn't it?" she says. Now the happy mother of two kids, she'll stay on the drug for the rest of her life to keep her high insulin in check.


Insulin problems--too much or too little--go far, far beyond diabetes. The condition is called insulin resistance and, in addition to the ailments dogging Chapman and Marincin, doctors are now discovering it is linked to heart attacks, strokes, and several kinds of cancer and may affect 1 in 3 American adults. These findings have alarmed many specialists. "Insulin resistance is very common, and it's associated with the biggest killers," says endocrinologist Ronald Kahn, director of the Joslin Diabetes Center at Harvard University. "If we don't start paying attention to this now, we're all going to be paying a huge price for this condition." Physician David Katz, director of the Prevention Research Center at Yale Medical School, adds that "we're just beginning to understand that insulin throws a lot of big switches in the body. Is insulin the master control of all disease? I don't know, but it's certainly a candidate for that role."


Insulin's main job is to escort sugar out of the blood and into muscle and fat cells. But sometimes those cells resist letting it in. So the pancreas, which makes insulin, tries to crank out even more. If it can't, blood sugar climbs to dangerous levels and the result is Type II diabetes. More often, however, the pancreas does make more insulin. The extra hormone may restore blood sugar to normal, but it overwhelms the rest of the body. That spells trouble, because insulin is more than just a sugar ferry. It tells the kidneys, for example, to hold on to salt. And more salt means hypertension. It tells cancer cells to grow, and that can mean a tumor.


Fortunately, doctors are starting to devise new ways to treat insulin resistance--which is sometimes called "metabolic syndrome" --with drugs and lifestyle changes. They are still working out all the connections, but already they have a list of some of the leading insulin-related illnesses:



Insulin stimulates cell growth, and unfortunately cancer cells have six to 10 times the number of insulin receptors--molecules that grab on to the hormone--as do normal cells. So if extra hormone hits a pre-existing cancer cell, it makes a bad thing much, much worse. "For cancer, insulin is like pouring gasoline on a fire," says Edward Giovannucci, who studies the epidemiology of colon cancer at the Harvard School of Public Health.


Colon, breast, endometrial, pancreatic, and prostate cancers seem especially responsive. "We think breast cancer cells may have very special kinds of receptors, fetal insulin receptors, that are ultrasensitive to insulin," says Pamela Goodwin, director of the Marvelle Koffler Breast Center at Mount Sinai Hospital in Toronto. Insulin may also influence estrogen, another hormone that can trigger tumor growth. "So if you turn on one hormone, you turn on the other," Goodwin says. She is currently testing Glucophage to see if it can lower insulin levels in breast cancer survivors and plans to see if this affects cancer recurrence.


Cardiovascular Disease

High levels of insulin in the blood damage the lining of arteries, increase bad blood fats such as triglycerides and LDL cholesterol, and clump blood cells together so they are more likely to block up vessels. These observations prompted Gerald Reaven, the Stanford endocrinologist who first described insulin resistance in the 1980s, to finger the condition for heart attacks, strokes, and cases of high blood pressure.  Other research has come to back him up. A major study by Finnish researchers in the journal Circulation followed almost 1,000 men for 22 years and found insulin levels alone were the most powerful predictors of heart attack risk, especially in younger men. They were more powerful than obesity levels and physical inactivity, for example. Men with the highest insulin levels had more than three times the heart attack risk of those with the lowest. [Obese people are much more likely to have high insulin levels—jk]


The concept does have its critics. Last week in the journal Diabetes Care , Richard Kahn, chief scientific and medical officer for the American Diabetes Association, wrote an article questioning whether the idea of insulin resistance is truly useful, particularly when it comes to diagnosing and helping heart patients. Just calling something by a new name, he argues, doesn't change the recommended therapies. "I don't see the value . . . especially when the treatments are the same," says Kahn. He points out that if patients have high cholesterol, they're going to get cholesterol-lowering drugs and advice on diet and exercise, whether or not insulin resistance is the root cause.


But other experts see value in understanding insulin's role in the clustering of cardiovascular risk factors, particularly if it points the way toward new treatments. It's already doing that for stroke, for it's here that one new treatment is being tested. This spring the

National Institutes of Health began a study at more than 60 research sites to see if the drug Actos, an insulin sensitizer, can reduce stroke recurrence in certain patients.


Ovary Disease

According to the American Association of Clinical Endocrinologists, polycystic ovary syndrome affects 1 in 10 women and is the leading cause of infertility in the United States. High levels of insulin trigger excess production of other hormones by the ovaries, disrupting regular egg growth and menstrual cycles and preventing pregnancy. Some of these overproduced hormones, or androgens, can also cause male-pattern hair growth on the face and some other unpleasant appearance changes. Basically, says Mark Perloe, an Atlanta endocrinologist and polycystic ovary syndrome specialist, "insulin is driving the ovary crazy."


Doctors now treat this ovary syndrome with insulin-sensitizing medications like those taken by Chapman, and also recommend weight loss, which lowers insulin levels. Treatment is important even beyond fertility problems, because untreated women with the polycystic syndrome have more than seven times the risk of heart disease and three times the risk of diabetes of women without it.



Cells in the brain's memory and learning centers have a lot of insulin receptors. A quick spike in insulin improves memory and performance; take insulin away, and brain function begins to decline. But paradoxically, more insulin in the blood--insulin resistance--means less in the brain. One leading theory: Insulin's corrosive effects on blood vessel linings gums up tiny portals in the vessels that supply the brain, making it harder for the hormone to bring in sugar. Ultimately, this starves brain cells, suggests researcher Suzanne Craft of Veterans Administration Puget Sound Health Care System. That could set the stage for some cases of Alzheimer's, Parkinson's, and Huntington's diseases. Insulin also seems to clear away some beta-amyloid, a substance long implicated in Alzheimer's damage, so less of it could cause problems.


There are, of course, many theories about Alzheimer's, and this is far from the final word. But whatever the reason for the disease, there is preliminary evidence that getting insulin to the brains of Alzheimer's patients improves symptoms. In Craft's recent study, a small group of Alzheimer's patients, including Marincin, inhaled insulin. (Inhalation provides more of the hormone to the brain.) Compared with a group that only inhaled saline solution, these patients better recalled stories and lists. It's not known, however, how long these improvements last. Craft is now testing the insulin sensitizer Avandia in people with Alzheimer's to see if it might slow down the disease.


The tests of all these drugs may sound good, but they are far from the only treatment--or the best--for insulin resistance. There's a lot of hope to be found around the dinner table. Most people with resistance can actually undo it by losing as little as 5 to 20 pounds. The best eating plans, say experts, offer lots of soluble fiber, the kind found in berries and beans and whole oats, which seems to indirectly diminish resistance, as well as lean proteins like fish. Saturated fats may cause insulin to spike, so look for foods with healthy fats like nuts and avocados. But enjoy them in moderation.


Weight loss is important because all the risks for all the diseases associated with insulin resistance are multiplied by obesity. That spare tire many of us carry around the middle packs the liver in fat, and the liver responds by tossing high levels of free fatty acids into the blood. These fats seem to block insulin from docking with its receptors on cells, increasing the risk of starting the resistance syndrome.

Regular exercise also helps muscles better use insulin, so in addition to her medication, Kristin Chapman works out four times a week. She also gets her heart checked every year, and has started getting regular mammograms early, at age 35. If insulin does indeed turn on many diseases, she plans on doing her best not to throw the switch.