NAD+, The Sirtuin Activator That Governs Aging

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NAD+, The Sirtuin Activator That Governs Aging

In your body, NMN is converted into a related compound called nicotinamide adenine dinucleotide (NAD), which is found in every cell of living organisms and is essential for life.

NAD+ is crucial in fueling the seven different genes in our body that govern aging. These genes are called sirutins and are referred to as SIRT1-7. NAD+ is the sirtuin activator.

The sirtuins are a family of proteins involved in regulating cellular processes including the aging and death of cells and their resistance to stress. Unfortunately, as we age and our NAD+ levels decline, so do our sirutins.

Sirtuins are indispensable for DNA repair, controlling inflammation and antioxidative defense which makes them good anti-senescence/anti-aging targets.

The vital importance of NMN in activating all of the seven sirtuins is a key explanation of the wide-ranging activity of this supplement.

The sirtuins do not simply increase the numbers of mitochondria within the cell; they stimulate the death and destruction of damaged mitochondria and improve intercellular communication. They almost seem to act as a kind of team of proteins, restoring cellular functions to a much higher level of youthful effectiveness.

Calorie restriction (CR) is so far the only effective way to extend lifespan without genetic or pharmacological intervention. The effects of calorie restriction are manifested by physiological and behavioral changes, such as reduced body fat, decreased level of growth factors, glucose and triglycerides.

The level of almost all sirtuins, except SIRT4, increases as an effect of calorie restriction Therefore, it’s believed that sirtuins help mediate beneficial effects elicited by such a diet.

Let’s examine what each of the seven sirutins do to assist in health and longevity, as described in a study by Dr. Grabowska et al entitled, “Sirtuins, a promising target in slowing down the aging process.” [1]

Sirtuin 1 Repairs DNA and Arteries

SIRT1 is the best studied in the sirtuins family of seven.

Scientists think that the declining NAD+ availability as we age decreases SIRT1 in the liver, while simultaneously increasing DNA damage. Age-dependent decrease in the level of SIRT1 is seen also in the arteries, suggesting its involvement in the aging of the cardiovascular system.

As the level of SIRT1 diminishes, cells become more prone to apoptosis (a form of programmed cell death), researchers believe that declining SIRT1 is one of the mechanisms responsible for sustaining the balance between DNA repair, apoptosis and senescence. (Senescent cells occur when normal cells cease to divide, becoming zombie-like, neither alive or dead, but disrupting normal, healthy signaling between normal cells.)

SIRT1 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Cell survival, longevity, physical activity/increase in CR Cellular senescence, oxidative stress, inflammation, neurodegeneration, cardiovascular diseases, adiposity, insulin resistance, liver steatosis

Sirtuin 2 Can Reduce Body Fat and Oxidative Stress

SIRT2 has been implicated in regulating adipose (fat) tissue development and function. There is less SIRT2 in the fat tissue of obese people and more of it in the white fat tissue and kidneys of mice subjected to calorie restriction. The implication here is that SIRT2 expression is involved in reducing body fat.

The other prominent role SIRT2 has is that it can serve as a cellular senescence marker, given that it’s prominent in senescent (zombie) cells, but not in cells that entered apoptosis (dead cells). However, scientists don’t believe that SIRT2 is a factor in causing senescence, but may be an effect of the changes occurring in cells during senescence.

SIRT2 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Longevity/increase in CR

Oxidative stress, neurodegeneration (the progressive loss of structure or function of neurons, including death of neurons)

Sirtuin 3 is Thought to Influence Longevity

SIRT3 is the only sirtuin that current evidence indicates can influence longevity in humans.

A certain polymorphism (a genetic variation) in the SIRT3 gene can be found more often in long-lived people. People with less of it are less likely to survive to an old age.

Mice lacking SIRT3 are characterized by decreased oxygen consumption and a simultaneous increase in the production of reactive oxygen species (ROS, commonly referred to as “free radicals”), as well as higher oxidative stress in muscle.

SIRT3 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Longevity, metabolic health, glucose homeostasis/increase in CR Oxidative stress, neurodegeneration, cardiac hypertrophy (the abnormal enlargement, or thickening, of the heart muscle), adiposity (being severely overweight or obese), liver steatosis (fatty liver disease)

Sirtuin 4 Can Repress Tumors and Help with Autophagy

SIRT4 may act as an oncogene (a gene that can transform a cell into a tumor cell) and tumor suppressor gene, which may be dependent on the affected tissue types and specific tumor environment.

SIRT4 shows enhanced potential as an antitumor therapeutic when used with glucose metabolism inhibitors. More research is expected investigating the use of SIRT4 in combination with chemotherapy drugs, on the glucose metabolism and its effects on autophagy (the condition whereby the cells start to recycle damaged and garbage parts (defects) into basic elements thereby allowing the cells to remodel themselves). [2]

SIRT4 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Currently Unknown Fatty acid oxidation

Sirtuin 5 Helps Reduce Fatty Acids in the Liver and Oxidative Stress

SIRT5 can help eliminate of oxidative stress-promoting ammonium, as well as mitigate a buildup of fatty acids in the liver.

SIRT5 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Increase in CR Oxidative stress, fatty acid oxidation

Sirtuin 6 Regulates Blood Sugar and Decreases Insulin Resistance

The first evidence that sirtuins can be involved in regulation of mammalian aging came from mice lacking SIRT6. It appears that among sirtuins, SIRT6 depletion exhibits the most severe phenotype (observable physical characteristics), as it seems to be indispensable for reaching a normal lifespan.

Three weeks after birth such mice exhibit symptoms of degeneration and premature aging, such as a sudden decrease in subcutaneous fat, lordokyphosis (swayback spine), colitis (inflammatory bowel disease), severe lymphopenia (too few white blood cells), and osteopenia (thinning bones), which all together result in death in about the fourth week of life.
SIRT6 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Longevity, glucose homeostasis/increase in CR Cardiac hypertrophy, adiposity, liver steatosis, inflammation, insulin resistance

Sirtuin 7 Benefits the Heart

SIRT7 has been shown to have beneficial functions in the heart. SIRT7-deficient mice develop heart hypertrophy (enlarging) and inflammatory cardio-myopathy. SIRT7 appears to regulate heart cell death and damage and has been shown to block stress-induced cardiac hypertrophy by impinging upon ROS (free radical) generation. [3]

SIRT7 Aging and Age-related Diseases
Increase or Involvement in CR Decrease
Increase in CR Cardiac hypertrophy (the abnormal enlargement, or thickening, of the heart muscle)
Show references
  1. Wioleta Grabowska, et al: Sirtuins, a promising target in slowing down the aging process.
  2. Guoyu Huang, et al: Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer.
  3. Thaddeus T. Schug et al: Surprising sirtuin crosstalk in the heart.
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