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Scientists have identified a number of genes that seem to have some effect on an animals longevity. Mostly they have been found in small, short-lived creatures whose longevity is easily studied, such as mice, fruit flies, or roundworms (C. elegans), though they frequently have analogues in humans. See here for an earlier discussion.

Of course, any gene which is important for inhibiting cancer, such as the well-known p53, will tend to improve longevity, for obvious reasons. But surprisingly, there are some longevity genes which dont have such an obvious relation to cancer, and may lengthen expected life span even when cancer is present.

Longevity genes fight cancer at its source

Over the years, biologists have discovered a handful of genes in roundworms, mice and flies that bestow a dramatic increase in lifespan on the organism that carries it – sometimes up to twice their normal life expectancy.

These genes are involved in diverse biochemical pathways including those for growth hormones, insulin, food intake and caloric restriction. But it is thought that they are all have a role in how the body responds to stress.

Julie Pinkston at the University of California in San Francisco, US, and colleagues, wondered if these longevity genes had something else in common: the power to fight cancer – a notoriously age-related disease.

Pinkston manipulated a C. elegans gene to make the worm more susceptible to cancer, and she also introduced a mutated version of the daf-2 insulin-like receptor gene, known to be longevity-enhancing. Worms with both mutations, even though they developed tumors, still lived twice as long as unmutated worms. Apparently the mutated daf-2 was doing something in addition to preventing tumors from forming.

The something else seems to be related to apoptosis:

Daf-2 seemed to protect against the lethal cancer by stimulating apoptosis – programmed cell death – which tumour cells usually avoid, the researchers say.

Its understandable that a gene which stimulates apoptosis helps fight cancer. The question is whether stimulating apoptosis also has harmful side effects. Apparently not so much in this case, if longevity is doubled anyhow.

But theres more to it than that:

One hallmark of cancerous growth is a rapid acceleration of cell division. Daf-2 also decreased the number of cell divisions in the roundworms by 50% compared to what was expected for those with the gld-1 gene, Pinkston says.

Other longevity-releated gene mutations are known in C. elegans, and when these mutations were present, the longevity effect also occurred:

The team then used the same process to test three other known longevity genes in turn against the life-shortening gld-1 gene. These three double-mutant worms also lived longer than normal roundworms. Each of the three genes (eat-2, isp-1 and clk-1) suppressed cell division, even though they did not appear to increase apoptosis.

Again, it would seem that suppressing cell division with these mutations is a net benefit for longevity, despite the need for some cell division outside of tumors. Perhaps they simply cause an animals life cycle to proceed at a slower pace.

But roundworms are rather simple animals. One wonders how such an effect would play out in a human...

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Other references:

Longevity genes fight back at cancer - subscription required

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Tags: cancer, longevity, lifespan, medicine, aging

Adiponectin is a hormone that is made exclusively in adipose (fat) tissue and secreted into the blood stream. It modulates a number of metabolic processes, such as glucose regulation and production of energy from fatty acids.

We had a long note on adiponectin last September (here), which has turned out to be very popular. That article summarized a number of research results concerning adiponectin that have appeared in the last few years. Undoubtedly, much of the interest in adiponectin is a result of its relevance to such things as weight control, diabetes, inflammation, cardiovascular disease, and kidney disease.

Some research that was reported in April had more to say about the relation to kidney disease:

Fat-cell Hormone Linked To Kidney Disease (4/22/08)

Reduced levels of a hormone produced by fat cells and linked to the development of insulin resistance may also be related to a higher risk of kidney disease, according to a study led by researchers at the University of California, San Diego School of Medicine and Thomas Jefferson University. ...

The new findings show that the hormone, adiponectin, produced by fat cells, circulates in the blood and acts to both suppress inflammation -- known to be a contributor to diabetes and cardiovascular disease -- and to reduce protein in the urine.

"A deficiency in adiponectin could be the major reason why obese patients develop the initial signs of kidney disease," said principal investigator Kumar Sharma.

The research showed that adiponectin promotes proper function of kidney cells called podocytes:

A network of fine capillaries in the kidney acts as a filter to prevent proteins in the blood from being secreted into the urine. This filter is made up of three components, one of which -- the podocyte cell -- serves to regulate albuminuria.

"We discovered that the hormone adiponectin, produced by fat cells, is directly linked to the healthy function of podocytes," said Sharma.

While thats interesting, its not clear that this activity has much to do with adiponectins effect on metabolism through favoring the use of fats as a source of energy instead of glucose. This may be a case where an important hormone really does have unrelated effects on different physiological systems.

Earlier research on adiponectin suggested that it served as a signal of low levels of available food calories, and hence caused the body to favor metabolism of stored fat as an energy source. This could well be related to the known effects of calorie restriction on longevity. Indeed, some research from last November suggested that longevity is promoted because metabolism of fat generates a lower level of reactive oxygen species than does metabolism of glucose:

Fat Hormone May Contribute To Longevity (11/21/07)

Using a mouse model of longevity, Terry Combs and colleagues report that changes in metabolism can indeed increase longevity. They demonstrated that long-lived Snell dwarf mice burn less glucose and more fatty acids during periods of fasting, and as a result produce fewer free radicals.

The key to this switch may be adiponectin, a hormone produced by fat cells that helps lower glucose production and stimulates cells to use fat for energy instead. The researchers found that Snell mice had three times as much adiponectin in their blood as control mice; Snell mice also had fewer triglycerides in their cells, indicative of higher fat metabolism.

The benefit of burning fats instead of glucose for energy is that it produces fewer oxygen radicals which can damage cells and exacerbate the effects of aging. Confirming this, Combs and colleagues found far less free radical damage.

Given that reactive oxygen species are also linked to increased inflammatory response and DNA damage, and that both of these effects are linked to cancer, its not too surprising to find that variations in the gene for adiponectin may affect cancer risk:

Gene Variations May Predict Risk Of Breast Cancer In Women (5/2/08)

According to a recent study, led by Virginia Kaklamani, MD, an oncologist at Northwestern Memorial Hospital and assistant professor of medicine, Northwestern University Feinberg School of Medicine, variations of the adiponectin gene, which regulates a number of metabolic processes, may increase a woman’s risk of developing breast cancer. ...

Dr. Kaklamani’s research, which is published in the May 1 issue of Cancer Research, suggests some women are born with different characteristics in the adiponectin gene which can alter its function and increase the risk of breast cancer. This finding, coupled with previous studies that have found a correlation between low levels of adiponectin in the body and cancer risk, suggest adiponectin may be the third gene linked to breast cancer among women with no previous family history of breast cancer. If confirmed through additional studies, adiponectin could be used along with TGF-beta and CHEK2, genes that have already been linked to breast cancer, to create a genetic testing model that will allow clinicians to more accurately predict breast cancer risk.

Further reading:

Happy fat: Calorie restriction modulates adipocyte gene expression – 7/17/07 blog article that discusses research relating calorie restriction to adiponectin

Adipogenic signaling in rat white adipose tissue: Modulation by aging and calorie restriction – abstract of the research discussed in the preceding item.

Tags: adiponectin, longevity, cancer, reactive oxygen species