It’s long been known that if you reduce a creature’s caloric intake to 30 or 40% of normal, it tends to live a healthier life that’s about 30% longer than average. In fact, severe calorie restriction is the only life extension technique that’s been proven to work.

But since such severe dieting as a treatment doesn’t work well with humans, scientists have been trying to determine what actually goes on when an organism is on a restricted diet.

According to this article in Scientific American:

Understanding the mechanisms by which calorie restriction works and developing medicines that reproduce its health benefits have been tantalizing goals for decades…. The phenomenon was long attributed to a simple slowing down of metabolism–cells’ production of energy from fuel molecules–and therefore reduction of its toxic by-products in response to less food.

But this view now appears to be incorrect. Calorie restriction does not slow metabolism in mammals, and in yeast and worms, metabolism is both sped up and altered by the diet. [Article authors David A. Sinclair and Lenny Guarente] believe, therefore, that calorie restriction is a biological stressor like natural food scarcity that induces a defensive response to boost the organism’s chances of survival. In mammals, its effects include changes in cellular defenses, repair, energy production and activation of programmed cell death known as apoptosis. We were eager to know what part Sir2 [a gene they’ve found extends the lifespan of yeast cells by 30%] might play in such changes, so we looked first at its role during calorie restriction in simple organisms.

What they learned is that by reducing caloric intake, life extension does occur, but only if the SIR2 gene is present:

Moreover, a fly that overproduces Sir2 has an increased life span that cannot be further extended by resveratrol or calorie restriction. The simplest interpretation is that calorie restriction and resveratrol [a compound that can activate Sir2] each prolong the lives of fruit flies by activating Sir2.

Once they had a handle on what keeps yeast cells and flies alive longer, scientists located a similar gene in mammals called the SIRT1:

Increased Sirt1 in mice and rats, for example, allows some of the animals’ cells to survive in the face of stress that would normally trigger their programmed suicide. Sirt1 does this by regulating the activity of several other key cellular proteins, such as p53, FoxO and Ku70, that are involved either in setting a threshold for apoptosis or in prompting cell repair. Sirt1 thus enhances cellular repair mechanisms while buying time for them to work.

Over the course of a lifetime, cell loss from apoptosis [programmed cell death] may be an important factor in aging, particularly in nonrenewable tissues such as the heart and brain, and slowing cell death may be one way Sirtuins promote health and longevity. A striking example of Sirt1’s ability to foster survival in mammalian cells can be seen in the Wallerian mutant strain of mouse. In these mice, a single gene is duplicated, and the mutation renders their neurons highly resistant to stress, which protects them against stroke, chemotherapy-induced toxicity and neurodegenerative diseases.
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In a more recent study by Christian Néri of the French National Institute of Health and Medical Research, resveratrol and another STAC, fisetin, were shown to prevent nerve cells from dying in two different animal models (worm and mouse) of human Huntington’s disease. In both cases, the protection by STACs required Sirtuin gene activity.

So researchers know that the SIRT genes (Sirtuins) protect cells during calorie restriction, and they think that the increase of NAD levels in the liver during fasting are what activate the Sirt1 gene.

Among the proteins Sirt1 acts on is an important regulator of gene transcription called PGC-1, which then causes changes in the cell’s glucose metabolism. Thus, Sirt1 was found to act both as a sensor of nutrient availability and a regulator of the liver’s response.

Similar data have given rise to the idea that Sirt1 is a central metabolic regulator in liver, muscle and fat cells because it senses dietary variations via changes in the NAD/NADH ratio within cells and then exerts far-reaching effects on the pattern of gene transcription in those tissues.

The authors are currently running tests in their labs to determine whether the SIRT1 gene improves health and increases the life span of mice. Unfortunately, they don’t expect to have conclusive results for at least 20 years.

Nevertheless, those of us already alive could live to see medications that modulate the activity of Sirtuin enzymes employed to treat specific conditions such as Alzheimer’s, cancer, diabetes and heart disease. In fact, several such drugs have begun clinical trials for treatment of diabetes, herpes and neurodegenerative diseases.

Read the whole article.

Tags: longevity | life extension | science | news | blog | weblog

It seems that breakthroughs in life-extension are being announced on a daily basis! Just last week, I posted one entry on the Klotho gene and its potential for extending our lives 20 to 30 years, and another one on the drug CX717 that may make sleep optional, tacking on 30 more. Today, The Times Online has a story that:

Scientists have created a “miracle mouse” that can regenerate amputated limbs or badly damaged organs, making it able to recover from injuries that would kill or permanently disable normal animals.

The experimental animal is unique among mammals in its ability to regrow its heart, toes, joints and tail.

The researchers have also found that when cells from the test mouse are injected into ordinary mice, they too acquire the ability to regenerate.

The discoveries raise the prospect that humans could one day be given the ability to regenerate lost or damaged organs, opening up a new era in medicine.

Read more!

From Forbes.com:

It’s your routine visit to the doctor in 2020. There’s the blood pressure check, the standard vision tests, and, oh yes, your anti-aging shot.

Such a possibility – an injection of a hormone to extend life – has come a little closer to reality with the release of a new report that found that a hormone made by a gene called Klotho suppresses aging in mice.

It’s a long way from here to there, said Dr. Makoto Kuro-o, lead author of the paper on the mouse study that appears Thursday in the online edition of the journal Science. But humans do have an almost identical version of the Klotho gene that is carried by mice, and “some studies show that variations of the Klotho gene are associated with extended life in humans,” Kuro-o said.

Read the whole article.

[Edit] National Geographic News also has an article on the Klotho gene.