The Longevity Gene SIRT1 – CR, Fasting and Aging Diseases

We have already talked about CR and longevity…now we are going to bring up what scientists are calling the “longevity” gene otherwise known as SIRT1. The main story quoted below comes from an article called “Unlocking the Secrets of Longevity Genes” in the Scientific American Feb 06 (all thanks to Thomas for sending me the issue). You can also read that article online here. (good read, more technical) Here’s some of the main highlights:

At one time, scientists believed aging to be not just deterioration but an active continuation of an organism’s genetically programmed development. This idea has been discredited, and conventional wisdom now holds that aging really is just wearing out over time because the body’s normal maintenance and repair mechanisms simply wane.

Evolutionary natural selection, the logic goes, has no reason to keep them working once an organism has passed its reproductive age. Yet we and other researchers have found that a family of genes involved in an organism’s ability to withstand a stressful environment, such as excessive heat or scarcity of food or water, have the power to keep its natural defense and repair activities going strong regardless of age.

By optimizing the body’s functioning for survival, these genes maximize the individual’s chances of getting through the crisis. And if they remain activated long enough, they can also dramatically enhance the organism’s health and extend its life span. In essence, they represent the opposite of aging genes–longevity genes.

So by under going types of stress, the body is able to respond and activate genes that are responsible for cellular repair and protection. So our aging model is essentially dictated by the cellular health (as it should be…since we are made up of trillions of cells in our bones, tissues, organs). Once our cells are damaged for whatever reason, they need to be repaired with healthy materials or they will continue along their destructive path (which can be cancer, disease or death).

Restricting an animal’s calorie intake is the most famous intervention known to extend life span. Discovered more than 70 years ago, it is still the only one absolutely proven to work. Most diseases, including cancer, diabetes and even neurodegenerative illnesses, are forestalled. The organism seems to be supercharged for survival.

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. We 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.

So this is pretty powerful stuff. Survival mechanisms turned on by Calorie Restriction/Fasting (a natural evolutionary stress) turn on a primal response that increase a cells defense (against toxins, free radicals or other destructive elements), can increase cellular repair (and therefore the health of wherever the cells are located….as if you repair cells in the heart, the heart gets stronger) and positively effect energy production which could lead to improved performance. Not only that but it also has the potential to stall progressive damage at the cellular level as seen in degenerative diseases such as cancer, diabetes and neuro-based illnesses.

The mammalian version of the yeast SIR2 gene is known as SIRT1 (“SIR2 homolog 1″). Several of these proteins targeted by Sirt1 have been identified and are known to control critical processes, including apoptosis, cell defenses and metabolism.

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 thus enhances cellular repair mechanisms while buying time for them to work.

Over the course of a lifetime, cell loss from apoptosis (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.

Recent research by Pere Puigserver of the Johns Hopkins University School of Medicine and his colleagues has shown that NAD levels rise in liver cells under fasting conditions, prompting increased Sirt1 activity.

Through CR/short term fasting conditions we send signals that could in fact slow down apoptosis/cell death. This is a breakthrough when it comes to anti-aging, as obviously the longer keep our cells and organs functioning properly, then the longer we are able to live. But have the cells in your brain, heart, lungs start to die off and cause disease through organ disfunction/decline…then you are accelerating your aging (which really is just a fancy way of saying getting closer to death).

By reducing fat stores, calorie restriction may establish a pattern of hormone signals that communicates “scarcity,” which activates cell defenses. Indeed, Sirt1 activity is increased in fat cells after food limitation, causing fat stores to move from the cells into the bloodstream for conversion to energy in other tissues. This effect on fat and the signals it sends would, in turn, set the pace of aging in the entire organism and make Sirt1 a key regulator of the longevity conferred by calorie restriction in mammals.

Another reason that losing weight and keeping it off is important to longevity and health. With a low bodyfat and CR/Fasting, you signal famine with little fat stores for backup…therefore increasing cell defenses for the upcoming stress of famine (more SIRT1 activity).

Another critical process modified by Sirt1 is inflammation, which is involved in a number of disorders, including cancer, arthritis, asthma, heart disease and neurodegeneration. Recent work by Martin W. Mayo and his colleagues at the University of Virginia has shown that Sirt1 inhibits NF-B, a protein complex that promotes the inflammatory response.

Sirt1 controls inflammation which is a factor in many diseases and aging. We have already seen the CR had positive effects on inflammation in this study (found in the resources section): Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderative asthma

The Sirt1-activating compound resveratrol has the same effect.

Also you may have heard of the health benefits of red wine, and now the latest supplement to hit the market called resveratrol. We can now see the pathway in which it can have in reducing inflammation, degenerative diseases and anti-aging through activating more Sirt1 activity. Could this stuff be for real? We look more into that in Part II.

As we wrap up Part I and all the info above, here are some additional interesting studies on Sirt1 including:

  • Sirt1 protects the heart from aging and stress: “In particular, we review our recent findings obtained from transgenic mice with cardiac-specific over expression of Sirt1, which demonstrated delayed aging and protection against oxidative stress in the heart. We propose that activation of known longevity mechanisms in the heart may represent a novel cardioprotection strategy against aging and certain types of cardiac stress, such as oxidative stress.”
  • A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy: “We demonstrate a role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. In particular, transient increased expression of Sirt1 is sufficient to stimulate basal rates of autophagy.” Ok many of you may be asking, “What the heck is autophagy”? Good question….but essentially it is the process in which the cell breaks down itself (especially damaged parts) and repairs. This is key when we talk about preventing (and even reversing already damaged cells) degenerative diseases (we will get more into this in Part II soon, see below).

photo above from physiologyonline.physiology.org

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