Alternate-day Fasting – a better alternative

By Victor

For humans who wish to live long lives, alternative-day fasting may be a better approach than following a restricted calorie diet.  The approach avoids premature induction of frailty most likely by periodically inhibiting myogenesis which encourages replenishment of progenitor satellite cell pools.  The argument for this proposition is presented here.  For background, see my earlier post Mechanisms and Effects of Dietary Restriction.

The body uses metabolic sensors to monitor and regulate anabolic and catabolic processes in response to various factors such as energy demands, nutrient availability, etc.  In most cells throughout the body cellular energy depends upon the availability of the critical cellular energy molecule, ATP.  When levels of ATP drop in response to increased energy demands from exercise, decreased nutrient availability from dietary restriction, or other factors the ratio of AMP to ATP increases, signaling the activation of AMPK (AMP-activated protein kinase), frequently referred to as “the master metabolic sensor”.  AMPK then switches on catabolic pathways which generate ATP, such as lipid and glucose oxidation; AMPK also switches off catabolic processes including synthesis of lipids, glucose, and proteins. 

AMPK activation produces very important changes in transcriptional activity by phosphorylating critical transcription factors.  (Kinases, like AMPK, work by a process called phosphorylation, see Kinase Inhbition for a more detailed explanation.)  AMPK can also be activated itself by direct phosphorylation, as well as certain signaling molecules, including adipokines, such as leptin.(ref)  For an earlier discussion of AMPK by Dr. Giuliano, please see AMPK and longevity

Sirt1 is one of seven human orthologs of the yeast silent information regulator 2 (sir2).  Sirt1 is a deacetylase which removes acetyl groups from other proteins including histones, various transcription factors, etc.  Sirt1 has been thought to be a molecular link between the dietary restriction and longevity.  Although recently this has been called into question, see the November 2011 publication An unSIRTain role in longevity.  Like AMPK, sirt1 is activated by nutrient restriction and exercise.  It also appears to be activated by AMPK through several mechanisms.  Directly, by AMPK-induced phorphorylation, and indirectly by AMPK phosophorylation of FoxO transcription factors (ref), and by AMPK-induced alterations in levels of NAD+, which is an essential coenzyme for sirt1 activity (ref).

Both AMPK and sirt1 have many of the same down-stream molecular targets.  Although specific effects vary depending upon tissue type, usually their effects are complementary, and very often interdependent (ref).  One example of divergent effects is the secretion of insulin by pancreatic beta cells.  Sirt1 increases insulin release, while AMPK actually inhibits it (ref,ref).  This, interestingly, explains why the anti-diabetic drug, metformin, paradoxically lowers plasma insulin levels.(ref)  Although this insulin-lowering effect is often erroneously explained as the result of increased peripheral insulin uptake, it is actually a direct result of the fact that metformin is an AMPK activator.(ref)  AMPK increases muscle glucose uptake, but it does so by directly activating the transportor, GLUT4 completely independent of insulin.(ref).  The is the same mechanism by which another AMPK activator, AICAR, increases muscle energy uptake.(ref). 

Sirt1 also activates GLUT4.  In fact, a recent transgenic mouse study demonstrates that sirt1 is necessary for AMPK to activate GLUT4, further demonstrating their frequent interdependence.(ref)  Together these results explain the mechanism of the observed improved insulin sensitivity, despite decreased insulin levels, that accompany caloric restriction.

Since AMPK and sirt1 both increase nutrient uptake in muscle tissue, it would be logical to conclude that activators of these compounds would increase muscle growth.  The ability of both AICAR and metformin to increase muscle glucose uptake has been confirmed in a recent animal study.(ref)  Of particular interest is the fact that this effect appears to be limited to muscle tissue; fortunately, for example, they do not increase uptake of glucose into liver tissue.

Sirt1 prevents myoblast differentiation.

Muscular growth is dependent upon the activation and differentiation of quiescent muscle satellite cells, a process known as “myogenesis”.  AMPK and sirt1 have been shown to inhibit this process, see:  Glucose Restriction Inhibits Skeletal Myoblast Differentiation by Activating SIRT1 through AMPK-Mediated Regulation of Nampt. 

This was found to be the case in glucose restriction and under normal caloric  conditions with the use of AMPK activators including AICAR and metformin.

“AICAR promoted AMPK and ACC phosphorylation in normocaloric (NC) conditions (Figure 1F), and cells exposed to AICAR in NC conditions failed to appropriately differentiate (Figures 1G and 1H). In addition to AICAR, two other AMPK activators—the furancarboxylic acid derivative D942 (Kosaka et al., 2005) and the hypoglycemic drug metformin (Zhou et al., 2001) —also inhibited cell differentiation in a dose-dependent manner (Fig. S1E, and F).

These results are consistent with the concept of AMPK sirt1 acting as metabolic switches which turn off anabolic processes when activated either by dietary restriction or by the use of synthetic activators such as AICAR, metformin including putative activators of sirt1, like resveratrol.  In this case, sirt1 appears to play the key role by deacetylating MyoD, a transcription factor essential for satellite cell activation which is necessary for both muscle growth (ref) and repair (ref).  In the experimental model, activation of AMPK failed to prevent myogenesis, when sirt1 was inhibited.

A problem with calorie restriction diets

Such catabolic effects have been commonly reported by practitioners of calorie restriction.  One such longevity enthusiast, Michael Young, who was featured on a recent BBC program, after consuming a reduced calorie diet for several years, found that he was suffering from premature frailty at the age of 42.  He was six feet tall, but only weighed 58k (about 138 lbs), and had underdeveloped bones.  See the video War against ageing.  This is one compelling reason that caloric restriction may not be advisable in humans.  Even under normal dietary conditions, most elderly eventually suffer from sarcopenia to some degree, along with accompanying risks and increased morbidity/mortality.  For many, age-related frailty can be as debilitating as cognitive decline, greatly restricting mobility, independence of living, and quality of life.

AMPK and Sirt1 Activity without Muscle Catabolism

Is there any way to have the benefits of caloric restriction without its unwanted catabolic effects?  Evidence suggests the answer is Yes, using a strategy known as “intermittent fasting.”  In particular, alternate day fasting (ADF) has been shown, in both animal and human studies, to reproduce the many of the same beneficial results as continuous caloric restriction, even though overall caloric intake need not be reduced.  ADF improves lipid and glucose metabolism, reduces inflammation, improves cardiovasucular, renal, and hepatic function.(ref)  It also improves the adikpokine secretion profile, as well as body fat distribution patterns.(ref)  ADF has been shown to increase longevity in both animal (ref, ref) and humans.(ref)  ADF has also been shown to prevent neurological aging, in part  by increasing expression of brain-derived neurotrophic factor (BDNF)(ref), and by dramatically increasing neuronal autophagy.(ref)

For review articles, see:

Alternate-day fasting and chronic disease prevention

Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals

ADF Improves Muscle Function

In contrast to caloric restriction, a recent study found that ADF was able to improve mobilization of nutrients during exercise, and increase lipid utilization, preventing muscle damage and oxidative stress even following strenuous exercise.  Muscle mass was not decreased, and physical strength and endurance were both increased by ADF.  See Muscle Physiology Changes Induced by Every Other Day Feeding and Endurance Exercise in Mice.  These results may reflect the beneficial effects of periodically inhibiting myogenesis, in order to allow for replenishment of progenitor satellite cell pools.  In this respect, it is interesting to note that sirt1-knockout mice have very small, underdeveloped muscles.  Both AMPK and sirt1 activity decrease with age, and could contribute to the age-related loss of satellite cell pools, ultimately leading to sarcopenia and frailty.(ref, ref)

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