Dietary and Nutritional Manipulation of the Nuclear Transcription Factors Peroxisome Proliferator-Activated Receptor and Sterol Regulatory Element-Binding Proteins As a Tool for Reversing the Primary Diseases of Premature Death and Delaying Aging

Introduction

Our continuous search for new substances to become the next magic pill has revealed undeniable signaling programmed into our DNA that can not only halt, but in some cases reverse, the primary etiologies that lead to aging and premature death. However, much of our tinkering has presented unexpected outcomes, false summits, and new puzzles to be solved. To safely and effectively tap into this programing, we must consider how it evolved to work. This can be achieved by looking at the symphony of signaling that occurs through the tight regulation of nuclear transcription factors.

Nuclear transcription factors (NTFs) and their response elements act as the primary interface between our DNA and our external environment. The nutrients we eat, the temperatures we experience, and our behaviors all ultimately funnel down to this interface of phenotypic expression. They activate when conditions are ripe to signal in a particular way. They can be manipulated from the inside via sirtuins or from the ever-changing environment of the intracellular space. A closer examination of these conditions, their heterodimeric partners, their agonists, and their antagonists, grants us profound insights into how their signaling evolved and how we can effectively influence NTFs through diet, nutrition, and pharmaceuticals to take advantage of the powers that we already know exist within us.

There is an ongoing dance between the two primary NTFs that are involved in gene regulation of and by fatty acids. Peroxisome proliferator-activated receptors (PPARs) play an essential role in metabolic adaptation to fasting by inducing the genes for mitochondrial and peroxisomal fatty acid (FA) oxidation as well as those for ketogenesis in mitochondria. ¹ Sterol regulatory element-binding proteins (SREBPs) are “global regulators of lipid synthesis,” ² including fatty acids, triglycerides, and cholesterol synthesis and expression of the low-density lipoprotein (LDL) receptor. ³

The advent of food cultivation and cooking that began 10,000 years ago has led us to one grand culmination of overexpression of SREBPs that has manifested as a phenotype of disease and premature death that we now see in the developed world. SREBPs are the NTFs of sugar and carbohydrates. They are an ancient NTF and are “conserved from fungi to humans.” ⁴ “Chronic activation of SREBPs from over-nutrition is associated with the various obesity related problems,” ² including fatty liver, ⁵ insulin resistance, ⁶ and atherosclerosis. ⁷

PPARs are the NTFs of fat and fasting. Their role is to activate genes that signal use of FAs as an energy source. PPARs are one of the youngest NTFs and are observed exclusively in the metazoan kingdom. It has been suggested that the emergence of the PPARs was a key factor in the metazoan's evolutionary success. In humans, PPARs have allowed us to survive times of famine and have enabled migration to latitudes where resources were only seasonally abundant. With regard to human health and longevity, hundreds of studies have demonstrated that activation of the various PPAR isotypes shows incredible promise for arresting and reversing the primary disease etiologies that have become the leading causes of premature aging and death.

PPARs and the Diseases of Aging

Methods and Caveats of PPAR Activation

Over the past 20 years multiple drugs have been developed and approved that activate the various PPAR isotypes. Though helpful, they were not as effective as hoped and came with several side effects. Why would substances with such promise leave us still fumbling to overcome the etiologies that prevent us from achieving longevity escape velocity? There is likely nothing wrong with the drugs. The problems likely resulted from mixed signaling perpetuated by combining these drugs with an un-substantiated and severely warped perception of a “healthy” diet. In the presence of small amounts of carbohydrates and thus insulin, SREBPs are activated and PPAR activity quickly wanes. In this scenario, introducing potent PPAR agonists generates signals that are contradictory to the evolution of the signaling itself.

In differentiated cells, the agonists, antagonists, and obligate heterodimers dictate a scenario in which PPARs and SREBPs are diametrically opposed. Ultimately, it seems the most effective way to activate the PPAR signaling is through diet.

Agonists for PPARs include ketone bodies, arachadonic acid, ²⁰ dietary polyunsaturated fatty acids (PUFA) except for linoleic acid, docosahexaenoic acid (DHA), ²¹ curcumin, ²² polyphenols in pomegranate, ⁹ resveratrol, ²³ alpha-lipoic acid, ²⁴ the Chinese herbs astragalus membranaceus and Pueraria thomsonii, ²⁵ glitazones, ²⁶ liver fatty acid-binding protein (L-FABP), which is produced in the liver upon introduction to lipids, ²⁷ and isohumulones from hops. ²⁸ “Interestingly, combining hop acids and selective agonists for PPARα or PPARγ resulted in additive inhibition of nuclear factor-κB (NF-κB) activity after T treatment.” ²⁹ PPAR is antagonized by metabolism. ³⁰ Despite this, PPAR agonists can reverse fatty liver disease in the face of continued ethanol consumption. It turns out that statins, which were developed to target SREBP1c, raise levels of FABPs. ³¹ It may turn out that the benefits observed from statins are actually from an indirect up-regulation of PPARs.

Introducing an agonist for PPAR does not mean that its full effects will be realized. Without dietary intervention, agonists for SREBPs, which include glucose and insulin, ² will antagonize the activation of PPARs. There are two primary reasons for this. First, competition between PPARs and SREBPs for their shared obligate heterodimeric partners, the RXR receptor and VDR receptor. ³²

Second, the “rate-limiting” effects of fibroblast growth factor 21 (FGF21) are exerted on the activity of PPARs and SREBPs. FGF21 is induced by HMGCS2 activity or by the ketone body, acetoacetate, ³³ both of which are produced during fasting or upon glucose deprivation. FGF21 represses the transcription of sterol regulatory element binding protein 1c (SREBP1c). ³⁴ It produces many of the same benefits that we observe with activation of PPARs ^35,36 and is optimized by the same physiologic conditions, suggesting that the observed benefits from FGF21 may be a result of up-regulation of PPARs and down-regulation of SREBPs. Interestingly, SREBP1 activity significantly attenuates the promoter activity of FGF21, ³² suggesting that when ligands for SREBPs are introduced, PPAR activity will wane, ultimately driving the entire process toward lipogenesis.

Another dilemma posed by artificially activating PPARs is that the conversion of excess glucose into triglycerides by activation of SREBPs will be stifled. This may slow the development of lipid-associated diseases like atherosclerosis but would likely result in an increase of advanced glycosylated end products (AGEs). Using these agonists must be done under dietary conditions that mimic the signaling for these pathways. Otherwise we risk passing the root of the problem on to other systems.

The evidence ultimately suggests that the most effective way to safely manipulate SREBPs and PPARs is to mimic the physiologic conditions in which they evolved. For PPARs this can be achieved with a ketogenic diet (KD). In this state, it does not matter if an agonist is present because PPAR will be strongly driven simply by virtue of the conditions necessary to produce ketosis. Very few studies have been done on the KD. However, we need look no further than populations who adapted to it for their own survival. Cultures like the Inuit and Mongolians still exist on a ketogenic diet for several months of the year. For over 30 years, it has been used for extended periods of time and with minimal side effects to reduce the frequency and severity in sufferers of epileptic seizures. It may turn out that the seizures improve from reduced inflammation through activation of PPAR. One study has demonstrated that a ketogenic diet reduced hippocampal tumor necrosis factor-α (TNF-α) levels and NF-κB translocation into the nucleus 2 hr after kainic acid (KA) treatment. ³⁷ Another study demonstrated that “mice eating KD failed to gain weight despite the high caloric density of the diet. Compared with mice fed standard chow, mice fed KD transiently lost weight and then stabilized at a lower weight than chow-fed animals in a pattern that was the same as that seen calorie-restricted mice. KD fed mice had a unique metabolic and physiological profile, exhibiting increased energy expenditure and very low respiratory quotient. Insulin levels were extremely low compared with both animals fed chow and animals fed high-fat diet. Furthermore, despite the consumption of saturated fat, serum lipids did not increase.” ³⁸

The activity of sirtuin1 (SIRT1) received attention for several years because of its correlation with caloric restriction and life extension in lower phyla. As a result, resveratrol, a known agonist for SIRT1 ²³ became the interim magic pill for those hoping to achieve longevity escape velocity. We know that SIRT1 is activated upon fasting and down-regulates both SREBPs and PPARs. ³⁹ However there is an exception. Expression of SIRT1 induces the expression of PPARα targets. ⁴⁰ PPARα is highly expressed in organ tissue. This underlying mechanism would preserve organ function in the face of food deprivation. Once again, we must ask ourselves what the effects are of artificially down-regulating signaling in the presence of normal caloric intake.

Ketones and the Kidneys

If the body is operating using glucose, the liver receives the burden and over time sustains damage and creates inflammatory chemicals that affect the entire body. If the body is operating using ketones, the kidneys receive the burden. Despite this, activation of SREBPs from diet-induced obesity or from insulin resistance activates oxidative stress, pro-inflammatory cytokines, and pro-fibrotic growth factors in the kidneys, suggesting that a burden of ketones may still be more desirable than sugar and carbohydrates. In addition, vitamin D supplementation further reduces damage to kidneys when challenged by overexpression of SREBPs. ⁴¹

In our quest to achieve longevity escape velocity, the KD is a powerful tool that mimics our physiologic evolution and can be used for up-regulating PPARs, down-regulating SREBPs, and ultimately postponing, and in some cases reversing, many of the leading causes of premature death and aging.