Published On: Tue, Jan 1st, 2013

Age-Reversal, Calorie/Food Restriction and Longevity…

120 years old lady looking like 25.(It could be!)

120 years old lady looking like 25.(It could be!)

Age-Reversal, Calorie/Food Restriction and Longevity…

by Dr Bob Berger, MS, MVSc, PhD

The Basics

Some of the theories about age-reversal, caloric restriction and increased longevity create paradoxes. For example, there has been considerable debate during recent years over the effects of Calorie Restriction (CR) on Resting Metabolic Rate (RMR)the amount of energy required to allow our bodies to properly function [metabolically] when we are in a state of rest.

Investigators have shown that when CR is enforced, total RMR declines. With extended CR, as the body mass and food consumption also change, it is still unclear whether the metabolism at the tissue level declines, is unchanged, or even increases [Speakman, JR and Mitchell, SE (2011) Caloric Restriction. Mol. Aspects Med., 32, 159].

As RMR decreases, body temperature also drops, and there is a profound metabolic shift from carbohydrate (sugar) use in favor of lipid (fat) use for energy purposes (ibid). Then we must consider the Basal Metabolic Rate (BMR)-the minimum amount of energy required to allow our bodies to properly functioni.e., the minimum amount of metabolic energy that allows us to simply survive-to run our heart, lungs, organs; to just get by.

As BMR increases, body temperature universally increases. When body temperature increases, metabolism increases and energy is essentially “wasted”-here fat metabolism kicks in again because we need the high energy source which fat provides in order to burn a lot of calories rapidly. When we switch over to this increased fat burning, this mimics what happens to us when we are on CR.

So there is the paradox; if we restrict calories, we still have to survive, and in order to do so, we must go into a lower thermogenic state so we don’t burn ourselves up-almost like a “cryogenetic” extension and survival. Conversely, when we restrict caloric intake, (and still have to survive), our bodies turn to the next (after sugar) and highest energy source for energy-this is fat. But when fatty acids are released, β-oxidation takes over as a main energy source provider, and ketone bodies are utilized at a rapid rate-which occurs when CR is enforced or in starvation states, and our body core temperature riseswe would call this an elevated thermogenic state.

So how can this be, and how can two opposite thermogenic states occur simultaneously? But they do….it is just done in a balanced and modulated way. If not, then by the body increase in thermogenesis, this would tend to age us faster and burn us up-look at what long-term cocaine addicts and “Meth” users look like! We see 30 year olds who appear to look 20-25 years older than their chronological ages.

Our bodies, if provided the right tools in the way of nutrients, foods, supplements , lifestyle, positive thinking, exercise, environment, bio-feedback, genetics, and many other factors that help coordinate these tools in unison, are capable of achieving a “physical-type” of age-reversal and improved longevity. What was told to our ancestors years ago (that aging is inevitable, it’s the same for all folks, and you can’t change it), is now only a myth….we do have the ability to change what was once “written in stone!!!!

The Mitochondria

Keeping this cellular organelle healthy and functioning properly is the major key to longevity success. This “Powerhouse of the Cell” basically runs things and controls energy cycling in and out of our cells and tissues. The key to the proper energy chains and ATP (energy) production occurs in the mitochondrial compartment-thus, we really want to center our focus of age-reversal and longevity here.

In a study from the Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University[Hagen, TM and Moreau, R (2002) Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or Lipoic acid. Ann. NY Acad. Sci., 959, 491], it was pointed out that the aging and decay of the mitochondria may be the principle underlying cause of the aging process. The OSU investigators proposed to show how both acetyl-L-carnitine (ALCAR) and (R)-alpha-Lipoic acid (ALA) may improve myocardial (heart muscle) bioenergetics and lower the increased oxidative stress associated with aging. These two naturally occurring compounds are of vital importance for not only heart muscle energetics, but for the proper functioning of all cells in the body for ATP energy production and output. (ALCAR (and L-carnitine itself), is responsible for shuttling fatty acids through the mitochondrial membrane and into the mitochondrial matrix for fat oxidation (energy). ALA is a coenzyme required for the function of the mitochondrial energy chain and ATP production, metabolic rate control, as well as for protection against oxidative damage.)

The OSU investigators pointed out that earlier studies have shown that the feeding of older rats with ALCAR reverses their age-related decline in carnitine levels and improves mitochondrial β-oxidation in various tissues, including the heart and muscle tissue, but it does not appear to reverse the age-related decline in cardiac antioxidant status. So it appears that feeding and/or supplementation of ALCAR may not substantially alter indices of oxidative stress. Conversely, ALA does appear to increase low molecular weight antioxidant status and decrease age-associated oxidative insult. Thus, if ALCAR and ALA are given together in supplemental form, this might be an effective regimen for maintaining myocardial health and longevity.

Any time that there is a reduction of actual food intake or the stimulation and/or up-regulation of a metabolic process that mimics CR, we have seen this to have a positive effect on the health and the longevity (i.e., life-span), of a human and/or one of a variation of animal subjects. Sometimes, even the mild stress of exercise alone, the output of specific neurochemicals, or even that of hormonal release can mimic the effects of CR. At other times, combining exercise and CR together can show significant results on longevity in a positive way. So there are a lot of combinations that are possible that may enable us to reach the goal of improving health, changing body composition, increasing chances of increased longevity, etc….and the majority of these processes both directly as well as indirectly involve the improvement of mitochondrial health and function.

Novel Activation

Slowing down the age-related degeneration of the body would greatly improve the quality of life for all people and animals…no doubt. Age-related breakdown (the “disease” of aging), is inevitable-what we want to do is to delay it if possible, while at the same time insure that we just don’t “look” more vital but are still capable of doing the things (both physically and mentally), that we look like we should be able to do; if one is 60 years old, but looks 40, he or she should have the ability to perform physically and mentally as a 40 year oldor what’s the point of just looking younger?!

Getting face lifts, doing Botox, getting different body implants, hiding lost curves under “corset-type” clothing, wearing black all the time, using anti-wrinkle creams, etc., etc., etc., are all just fine-but we really want to backup these superficial/artificial measures with reality. This is true anti-aging!

From the Institute for Diabetes, Obesity, and Metabolism, Department of Physiology, University of Pennsylvania School of Medicine, investigators showed that a novel activator of SIRT1, the gene responsible for encoding the enzyme Sirtuin-1 (NAD-dependent deacetylase Sirtuin-1), which deacetylates proteins that contribute to the regulation of cell activity, is capable of producing the same physiological changes that occur in the body as when subjects undergo calorie restriction [Agarwal, B. and Baur, J.A. (2011) Resveratrol and life extension. Ann. NY Acad. Sci., 1215, 138].

As previously stated, it is already well-known (and well-accepted), that the slowing of age-related degeneration would greatly improve the quality of human life. Even in rats, calorie restriction is shown to extend lifespan by 50% (ibid). The question remains this; is an extended lifespan equal to the improvement in quality of life?

In the Penn study, the investigators stated that SIRT1 is proposed to mediate key aspects of CR and that the polyphenol, Resveratrol, activates SIRT1 in vitro and produces changes that resemble CR in vivo, including improvements in insulin sensitivity, endurance, and in the overall survival in obese mice. However, the investigators also stated that Resveratrol has other targets that could contribute to its health benefits. The bottom line is that the over-expression of SIRT1 or treatment with a novel activator (in this case, Resveratrol), has been shown to be sufficient to improve metabolism which supports the concept that Resveratrol could act through the same or similar pathways.

An important point to note from the Penn study is that these beneficial changes were shown in obese mice only, and unlike direct calorie restriction, Resveratrol has not been shown to extend the lifespan in lean mice. This requires more data and further testing on why this may be so.

An equally important point to note here is that because we are evaluating rodents and not humans, the anti-aging and longevity evaluations is “physical-data” derived, are not subjective, and the analysis of all data is all scientifically sound through chemical, physical, and purely observational testing. Because of this reasoning, there is no subjective (“how do you feel?”), psychological, or placebo effect to be taken into account. This makes the study (and others like it), more viable. (The CR and Resveratrol-fed mice had an extended lifespan that was 50% longer than controls-these are objective facts!)

Although many of us have been taught that speeding up metabolism was a good thing-and if it is balanced along with other metabolic and catalytic states, it actually is; burning sugars and fats is good and we certainly don’t want to store too much of either. But we also must be cognizant of the fact that when one burns up fuel (Kcal) too fast, we are also producing an excess of free radicals and oxidants that could overload our innate abilities to remove these potential “would-be toxins” from the body. Free radicals and oxidants will attack the cellular membranes of our most vital tissues and organs and these can (and will) lead to ultimate damage and possible disease. This is clearly not what we mean by proper anti-aging and longevity…these processes will actually age us faster!!!!

Two studies out of Harvard University emphasize as well as reinforce the true concept of proper CR and energy activation. From Harvard Medical School and Brigham and Woman’s Hospital[Hu, Y. and Liu, J., et al. (2011) The controversial links among calorie restriction, SIRT1 and Resveratrol. Free Radic. Biol. Med., 51, 250], investigators state that it has been widely known that the slow metabolism induced by calorie restriction can extend the life span of model organisms, and that the accumulated evidence suggests that SIRT1 may be actively involved in CR-induced signaling pathways. Thus as an activator of SIRT1, Resveratrol can partially mimic the physiological effects of CR. This concept is fairly well established up to this point.

In another study, this one from the Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School[Price, N.L. and Gomes, A.P., et al. (2012) SIRT1is required for AMPK activation and the beneficial effects of Resveratrol on mitochondrial function. Cell Metab., 15, 675], investigators presented data which showed that Resveratrol (which activates the SIRT1 gene), and because SIRT1 expression is needed for the activation of AMPK (AMP Protein Kinase, the master regulator of cellular energy), the SIRT1 activator not only mimics CR effects on the body, but appears to play a vital role in the increase of cellular energy itself.

In the Harvard study, mice that were treated with moderate doses of Resveratrol exhibited increased mitochondrial biogenesis/function, AMPK activation and increased skeletal muscle concentrations of NAD (+). This group of Mice were paired against a group of SIRT1-Null mice (known as SIRT1 knockout mice), who were also given Resveratrol, but where the SIRT1-gene is genetically altered in these mice to be absent-in what is called “whole-body deletion” (of the SIRT1). When the “knockout” group was treated with the same doses of Resveratrol as the non-altered (normal) group, none of the “energetic-factor” benefits that the non-altered group exhibited were displayed in the “Knockout” group. It was shown that there is a clear chemical-genetic connection between the SIRT1-gene and Resveratrol [Denu, J.M. (2012) Fortifying the link between SIRT1, Resveratrol, and Mitochondrial function. Cell Metab., 15, 566]. Asdoses of Resveratrol showed no improvements in the mitochondrial function in the animals lacking SIRT1, this provides evidence that SIRT1 is required for Resveratrol to stimulate mitochondrial biogenesis as well as for the energetics which are vital for oxidative muscle fiber function [ibid

Sirtuin Targets

Knowing that CR has the potential to extend lifespan as well as to produce metabolic profiles which are desirable for overcoming serious metabolic diseases and conditions, it is paramount to understand how to target these diseases for future therapies; one of these diseases is Type 2 Diabetes.

In a review out of China [Jiang, WJ (2008) Sirtuins: novel targets for metabolic disease in drug development. Biochem. Biophys. Res. Commun., 373, 341], scientists summarized some of the important aspects of recent research advances which support the possibility of using Resveratrol as a virtual Sirtuin activator in the pharmaceutical industry, and as a potential “drug” itself in the treatment for diabetes. (Labeling Resveratrol as a “drug” is stretching things, no doubt, but it does suggest that even the pharmaceutical industry realizes that not acknowledging the vast potential of “integrative compounds”(such as Resveratrol), could and most likely will eventually leave them out in the cold.)

In the review, Jiang and associates reiterate that SIRT1, (an NAD (+)-dependent deacetylase), is a principle downstream pathway modulator of CR. In this way, SIRT1 produces beneficial effects on glucose regulation as well as on insulin sensitivity. A scientific observation emphasized in the review was that Resveratrol not only mimics the effects of calorie restriction in lower organisms but also does so in mice fed a high-fat diet where it ameliorates insulin resistance…this is extremely valuable data!

The activation/modulation of SIRT1 (in this case, by Resveratrol), leads to the enhanced activity of specific proteins, such as Peroxisome proliferation-activated receptor gamma coactivator -1 alpha (PGC-1 alpha), which is a member of a family of transcription coactivators that plays a vital role in the regulation of cellular energy metabolism. PGC-1 alpha stimulates mitochondrial biogenesis and promotes muscle tissue/fiber remodeling…clearly of integral importance and focus in anti-aging and longevity.




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