eNews November 02, 2010

Branched chain amino acid (BCAA) supplements make mice live longer

The search for the fountain of youth has yielded yet another life-extending possibility – branched chain amino acids (BCAAs). A group of Italian scientists led by Dr. Enzo Nisoli at Milan University School of Medicine, Milan, Italy, has reported that a diet supplemented daily with an amino acid mixture enriched with BCAAs makes mice live longer (D'Antona et al. 2010). Similar mixtures may improve human health.

BCAAs

There are three BCAAs – isoleucine, leucine, and valine – so-called because they have branched carbon side chains off their main amino acid trunk. Combined, BCAAs make up approximately one third of the amino acids in a person's skeletal muscle. They are used in many areas of human health, including as nutritional supplements by athletes and as treatments for burns, neurological disorders, AIDS, cancer and late-stage kidney failure. Long-term dietary supplements with a specific mixture of BCAAs have been shown to extend life span in yeast and to mitigate age-related disorders in animals, including humans.

Enriched BCAA mixture extends mouse life span

Dr. Nisoli and his team reproduced an enriched BCAA mixture (BCAAem) shown to be effective in patients affected by sarcopenia or heart failure and placed it in the drinking water of male B6129SF2 hybrid mice – F2 hybrids between C57BL/6J (B6J, 000664) and 129S1/SvImJ (002448) mice. They found that the BCAAem supplement increases the median life span of these mice by 12% over untreated controls (869 vs. 774 days).

BCAAem fosters mitochondrial biogenesis

Research had shown that increased mitochondrial activity may be at least partly responsible for extending the life span of yeast, roundworms, fruit flies and some mammals – perhaps by reducing the production of disease-causing reactive oxygen species (ROS). Therefore, Nisoli and his team investigated the relationship between the BCAAem and mitochondrial biogenesis. They found that, whether in cultured cardiomyocytes or the cardiac and skeletal muscles of live B6129SF2 mice, the BCAAem not only promotes mitochondrial biogenesis but boosts the expression of a host of other potentially life span-extending factors, including proteins in the ROS defense system and SIRT1, the mouse equivalent of the yeast longevity gene SIR2. The effects of the BCAAem are even greater if the mice exercised.

BCAAem improves muscle form and function

Muscle efficiency gradually decreases with age. However, Nisoli's team found that the BCAAem restores the fiber cross-sectional area of vastus, gastrocnemius, and tibialis muscles of B6129SF2 mice, improves their endurance, whether they are sedentary or exercised, and improves their motor coordination, particularly if they are exercised.

Endothelial nitric oxide synthase mediates BCAAem benefits

Because Dr. Nisoli and others had found that endothelial nitric oxide synthase (eNOS, also called Nos3) is associated with the life span-extending effects of calorie restriction, mitochondrial biogenesis, and SIRT1 expression, he and his team investigated the relationship between the BCAAem and eNOS. They found that cardiomyocytes cultured with the BCAAem exhibit increased eNOS expression and activation. However, if eNOS expression is blocked in these cells, they become insensitive to the BCAAem and produce fewer markers of mitochondrial biogenesis and ROS defense. The BCAAem also induces mammalian target of rapamycin (mTOR) activity (another marker of increased cellular oxidative capacity and mitochondrial gene expression) in cultured cardiomyocytes. In contrast, the BCAAem has no effect on mTOR activity if the eNOS expression in these cells is blocked. Nor does it induce mTOR activity in eNOS-deficient (eNOS-/-; B6.129P2-Nos3tm1Unc/J (002684) mice, even if they are exercised.

Dr. Nisoli's team also demonstrated that the BCAAem does not increase either the median life span or mitochondrial biogenesis and function, strengthen the ROS defense system, increase the expression of SIRT1 and other life-extending factors or improve muscle function and form of eNOS-/- mice, even if they are exercised.

BCAAem reduces oxidative stress

A major cause of aging is increased oxidative damage caused by ROS. Nisoli and his team found that the mitochondria of BCAAem-treated B6.129S2 mice release less hydrogen peroxide (H2O2) and produce fewer ROS than do those of untreated mice. Also, the skeletal muscles of BCAAem-treated mice exhibit lower levels of lipid peroxidation (an indirect index of ROS levels) than do those of untreated mice.

In summary, Dr. Nisoli and his team found that an enriched mixture of BCAAs extends the life spans of mice. The BCAAem mixture they used is likely beneficial because it boosts mitochondrial biogenesis and reduces oxidative stress in cardiac and skeletal muscles via eNOS-mediated mechanisms. Their results suggest that similar BCAAems would mitigate age-related disorders and lengthen life span in humans.

Reference

D'Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, Caliaro F, Corsetti G, Bottinelli R, Carruba MO, Valerio A, Nisoli E. 2010. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab 12:362-72.